MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Terapie, podpůrné vlivy

5-HT receptor agonists and antagonists

  • Several of them have been shown to have anti-inflammatory activity (Tullis et al., 2015; Flanagan and Nichols, 2018; Flanagan et al., 2019a,b; Yu et al., 2021).

Acyclovir

  • Does not effectively treat stromal disease and iritis
  • Acyclovir, when given early, does not prevent stromal disease
  • Steroids reliably make symptoms of stromal disease resolve early
    • Symptoms disappeared and vision improved more rapidly
      • Although the final outcomes in terms of visual acuity and recurrences after treatment was discontinued were similar, whether the patients received steroids or not
  • Combination of steroids and antiviral eye drops does not result in increased complications, risks, or recurrences
  • no increases in recurrences were observed in patients followed for 6 months after steroids were discontinued
  • Acyclovir clearly reduced the recurrence rate
    • Reduction was only approximately 40%
  • Even with systemic acyclovir treatment, more than half of the patients with ocular herpes had recurrences
    • Leads to continued morbidity and blindness
  • Acyclovir was relatively effective in inhibiting viral multiplication on the surface of the cornea
  • Had little effect in inhibiting viral reactivation in the trigeminal ganglion
    • Even when given before heat stress was applied (Gebhardt BM, unpublished data, 2001)
  • iovs.arvojournals.org/article.aspx?articleid=2123004


Caffeic acid

  • Antiviral activity against herpes simplex virus (DNA virus) and polio virus (RNA virus)
  • Progeny virus yield was markedly decreased in the presence of caffeic acid
  • Suppression of MMP2 and MMP-9 (collagen IV metalloproteases)
  • Secondary metabolism of vegetables including
    • Olives,
    • Coffee beans,
    • Fruits,
    • Potatoes,
    • Carrots
    • Propolis
  • www.spandidos-publications.com/10.3892/ijmm.2014.1859

Cox-2 inhibitory

Curcumin

  • curcumin, a polyphenol extracted from the plant Curcuma longa, has demonstrated antiviral properties against a variety of viruses.

In vitro Vero cells

  • Treated Herpes simplex virus-1 (HSV-1) + (HSV-2)
  • After establishing the maximum non-cytotoxic concentrations of curcumin on Vero cells, HSV-1 and HSV-2 virions were treated with varying concentrations of curcumin.
  • Treating HSV-1 and HSV-2 viruses with curcumin, at a concentration of 30 uM
    • Reduces the production of infectious HSV-1 and HSV-2 virions in cultured Vero cells by interfering with the adsorption process
  • Potential of curcumin to be used as a therapeutic agent to reduce the transmission of HSV-1 and HSV-2.
  • www.scirp.org/journal/paperinformation.aspx?paperid=65445

EZH2 modulators

Curcumin, triptolide, ursolic acid, sulforaphane, davidiin, tanshindiols, gambogic acid, berberine and Alcea rosea

  • Inhibition of histone H3K4, H3K27 and H3K36 trimethylation
  • Down-regulation of matrix metalloproteinase expression
  • Competitive binding to the S-adenosylmethionine binding site of EZH2
  • Modulation of tumor-suppressive microRNAs
    • Demonstrated to mediate the EZH2-inhibitory activity of the mentioned natural products
  • Review summarizes the pathways that are regulated by various natural products
    • Resulting in the suppression of EZH2
  • Provides a plausible molecular mechanism for the putative anti-cancer effects of these compounds
  • pubmed.ncbi.nlm.nih.gov/28323035/

Triptolide

  • Diterpenoid triepoxide
  • Principal bioactive ingredient of extracts from Chinese Herb Tripterygium wilfordii Hook F (TWHF)
  • Triptolide treatment decreased the level of trimethylated H3K27
    • Effect was paralleled by the reduced mRNA and protein expression of EZH2
  • Led to cell cycle arrested in G2/M phase, induction of caspase-dependent apoptosis
    • Apoptosis and growth suppression in multiple myeloma cells
  • Dose and time-dependent
  • drmajeed.com/pdf/articles/2017/Mar/2017_Naturally_occurring_anti-cancer_agents_targeting_EZH2.pdf

Ursolic acid (UA)

Sulforaphane [SFN;1-isothiocyanato-4-(methylsulfinyl) butane]

  • Abundant bioactive isothiocyanate found in broccoli and broccoli sprouts

Resveratrol (3,5,40-trihydroxystilbene)

  • Red grape,
  • Red wine,
  • Other plant species

Davidiin

  • Polygonum capitatum is an Asian medicinal plant
  • Phytochemical extracted from P. capitatum
  • Directly downregulates EZH2 protein
  • Enhances proteasome-dependent degradation of EZH2

Tanshindiols

  • Root of Salvia miltiorrhiza (Danshen)
  • Tanshinones are the major class of active components present in S. miltiorrhiza roots
  • Tanshindiols B and C were reported to inhibit EZH2 methyltransferase activity
    • With IC50 values of 0.52 mM and 0.55 mM,

Gambogic acid and methyl jasmonate

  • Extracted from the resin secreted from the Garcinia hanburyi tree in Southeast Asia

Alcea rosea (AR)

  • Ornamental plant belonging to Malvaceae.
  • Known as Holyhock and is widely grown in gardens in the Southern Europe and Asia
  • Antiinflammatory, anti-bacterial and analgesic effects

Echinacea spp.

Small, randomized, placebo-controlled crossover clinical trial

  • no statistically significant differences between Echinacea extract of 800 mg twice per day for 6 months and placebo controls in treating recurrent genital herpes (Basch et al. 2005)
  • www.ncbi.nlm.nih.gov/books/NBK92761/

Epigallocatechin-3- gallate (EGCG)

  • Most abundant polyphenol derived from green tea (Camellia sinensis),
  • Lipophilic derivatives of EGCG have shown increased stability as well as increased antiviral efficacy
  • EGCG stearate (EGCG-S), a derivative of EGCG esterified at the 4’ position with stearic acid
    • Able to inhibit HSV-1 infection in cell culture
    • By interrupting viral attachment to cell membrane receptors
  • Antiviral effect was found to occur in a dose-dependent manner,
    • With 85.87 ± 0.07% inhibition exerted by 100 uM EGCG-S
    • 29.51 ± 0.13% inhibition by 75 uM
  • Treatment with
    • 75 uM EGCG-S resulted in 43.4 ± 0.2% inhibition
    • 100 uM resulted in 97.89 ± 0.11% inhibition
      • Virtually complete inhibition of HSV-1 binding
  • digitalcommons.montclair.edu/cgi/viewcontent.cgi?article=1220&context=etd

Glutamin

  • Activated T cells require increased glutamine

Mice infected with HSV-1 and guinea pigs infected with HSV-2

  • P.o. glutamine supplement or no treatment.
  • Mice treated with glutamine were less likely to experience recurrent HSV-1 activation
    • Compared with mice that received no supplementation
  • Similar results in the guinea pig models of HSV-2.
  • Multiple genes inducible by interferon gamma had a higher response, according to the study
    • Created by virus-specific T cells in infected nerve tissue
  • Glutamine increased the level of several IFN-gamma—inducible genes
    • Cxcl9, which is critical for controlling genital HSV-2
      • By mobilizing virus-specific cytotoxic T cells to the nervous system and vagina in mice
  • Glutamine
    • May reduce HSV reactivation by increasing T cell response
  • www.pharmacytimes.com/view/amino-acid-found-to-suppress-herpes-in-animals
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC5490748/
  • Glutamin byl zkoumán v různých zvláštních situacích
    • Snížit morbiditu u kriticky nemocných pacientů (snížit nozokomiálních infekcí)
    • Podstupující chemoterapii nebo podstupující transplantace kostní dřeně (snížení závažnosti stomatitida, snížení výskytu infekcí, zkrácení hospitalizace) a u pacientů s syndrom krátkého střeva (klesající požadavek na parenterální výživu)

Glutamine and Leucine




Hypericum cordifolium - Marmhendo

Hypericum hookerianum Hypericum

Hypericum mysorense Hypericum

Hypericum uralum - Urali phul

Melissa officinalis essential oil

  • Phytochemically examined by GC-MS analysis
  • Monoterpenaldehydes citral a, citral b and citronellal
  • Antiviral effect of lemon balm oil, the essential oil of Melissa officinalis, on herpes simplex virus was examined
  • Inhibitory activity against herpes simplex virus type 1 (HSV-1)and herpes simplex virus type 2 (HSV-2) was tested in vitro on monkey kidney cells
  • 50% inhibitory concentration (IC50) of balm oil for herpes simplex virus plaque formation was determined at high dilutions of 0.0004% and 0.00008% for HSV-1 and HSV-2
  • At noncytotoxic concentrations of the oil,plaque formation was significantly reduced by 98.8% for HSV-1 and 97.2% for HSV-2
  • Higher concentrations of lemon balm oil abolished viral infectivity nearly completely
  • Both herpesviruses were significantly inhibited by pretreatment with balm oil prior to infection of cells.
  • Melissa oil affected the virus before adsorption
    • But not after penetration into the host cell
  • Lemon balm oil is capable of exerting a direct antiviral effect on herpesviruses
  • Lipophilic nature of lemon balm essential oil, which enables it to penetrate the skin
    • High selectivity index,
    • Melissa officinalis oil might be suitable for topical treatment of herpetic infections.
  • pubmed.ncbi.nlm.nih.gov/18693101/

Lemon balm (Melissa officinalis)

  • Lemon-scented member of the mint family
  • Essential oil can be steam-distilled from the cut leaves.
  • Topical uses include treatment of herpes simplex and minor wounds.

Randomized, double-blind trial of 116 patients with herpes simplex lesions

  • 96% reported complete clearing of lesions at day 8
    • After using 1% balm extract cream five times a day (Wobling and Leonhardt 1994)

Trial where balm extract was placed on lesions within 72 hours of the onset of symptoms

  • Size of the lesions and healing time were found to be statistically better in the group
  • Tannin and polyphenols appear to be responsible for the antiviral effect (Peirce, Fargis, and Scordato 1999)
  • Very safe to use both topically and orally (McGuffin et al. 1997; Peirce, Fargis, and Scordato 1999).
  • www.ncbi.nlm.nih.gov/books/NBK92761/

Omeprazole + acyklovir

  • Improve the anti-cancer effects of the nucleoside analogue 5-fluorouracil
  • Did not affect the antiviral effects of ribavirin in non-toxic concentrations up to 80 µg/mL
  • Increased acyclovir-mediated effects on herpes simplex virus 1 and 2 (HSV-1 and -2) replication
    • In a dose-dependent manner
  • Omeprazole reduced HSV-1 and -2 titers
    • But not HSV-induced formation of cytopathogenic effects (CPE) at concentrations ?40 ug/mL.
  • Increased acyclovir activity at lower concentrations that did not directly interfere with HSV replication.

HSV-1

  • Omeprazole 80 ug/mL caused decrease of the acyclovir concentrations that reduced HSV-1-induced CPE formation by 50% (IC50)
    • 10.8-fold (Vero cells)
    • 47.7-fold (HaCaT cells)
  • Omeprazole 80 µg/mL reduced the HSV-1 titer in the presence of acyclovir 1 ug/mL by
    • 1.6 × 105-fold (HaCaT cells)
  • www.frontiersin.org/articles/10.3389/fmicb.2019.02790/full

HSV-2

  • The proton pump inhibitors pantoprazole, rabeprazole, lansoprazole, and dexlansoprazole
    • Increased the antiviral effects of acyclovir in a similar fashion as omeprazole
  • Candidates for antiviral therapies in combination with acyclovir
    • Particular for topical preparations for the treatment of immunocompromised individuals who are more likely to suffer from severe complications
  • www.frontiersin.org/articles/10.3389/fmicb.2019.02790/full

Peppermint oil

  • The essential oil of Mentha piperita
  • Inhibitory activity against herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2)
  • 50% inhibitory concentration (IC50) of peppermint oil for herpes simplex virus plaque formation was determined at 0.002% and 0.0008% for HSV-1 and HSV-2
  • Peppermint oil exhibited high levels of virucidal activity against HSV-1 and HSV-2 in viral suspension tests
  • Noncytotoxic concentrations of the oil, plaque formation was significantly reduced by 82% and 92% for HSV-1 and HSV-2
  • Higher concentrations of peppermint oil reduced viral titers of both herpesviruses by more than 90%
  • Time-dependent activity could be demonstrated
  • After 3 h of incubation of herpes simplex virus with peppermint oil an antiviral activity of about 99% could be demonstrated
  • Herpesviruses were significantly inhibited when herpes simplex virus was pretreated with the essential oil prior to adsorption
    • But not after penetration into the host cell
  • Peppermint oil is also active against an acyclovir resistant strain of HSV-1 (HSV-1-ACV(res)), plaque formation was significantly reduced by 99%
  • Peppermint oil might be suitable for topical therapeutic use as virucidal agent in recurrent herpes infection.
  • pubmed.ncbi.nlm.nih.gov/13678235/

Sweet marjoram

Peppermint

Propolis

TPH-1/2 inhibitors

  • Or intracellular uptake via SSRIs suppressed efficient HSV-1 replication.

Trifluridine


Acyclovir and its pro-drug valacyclovir

  • Guanosine analogue
  • Treatment of disease caused by herpes simplex virus 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV) (Zarrouk et al., 2017)
  • Acyclovir is activated by the viral thymidine kinase
    • Then di- and tri-phosphorylated by cellular kinases
  • Active tri-phosphorylated forms of acyclovir and then specifically interferes with the viral DNA polymerase and causes chain termination (Piret and Boivin, 2016; Chen et al., 2017; Zarrouk et al., 2017).
  • www.frontiersin.org/articles/10.3389/fmicb.2019.02790/full

Acyclovir

Cidofovir

Famciclovir (prodrug of penciclovir)

Fomivirsen

Foscarnet

  • Active against EBV, KSHV, human herpesvirus 6, acyclovir-resistant (and acyclovir-susceptible) HSV and VZV, and ganciclovir-resistant (and ganciclovir-susceptible) CMV
  • Some anti-HIV activity
  • IV or intravitreal injection: Efficacy similar to that of ganciclovir for treating and delaying progression of CMV retinitis
  • Renal toxicity in up to one third of patients if foscarnet is given without adequate hydration, electrolyte imbalances
  • www.msdmanuals.com/professional/multimedia/table/drugs-used-to-treat-herpesvirus-infections

Ganciclovir

  • In vitro activity against all herpesviruses, including CMV, but HSV strains that are resistant to acyclovir also cross-resistant to ganciclovir
  • Typically drug of choice for CMV
  • Used in HIV patients with CMV retinitis
  • IV form: Most common
  • Intravitreal injection: For CMV retinitis
  • Oral: Only 6 to 9% bioavailable; requires 12 capsules/day for a standard dose (1 g tid), limiting its usefulness
  • Primarily, bone marrow suppression, particularly neutropenia, which sometimes requires treatment*
  • www.msdmanuals.com/professional/multimedia/table/drugs-used-to-treat-herpesvirus-infections

Idoxuridine

Letermovir

Penciclovir

Trifluridine (trifluorothymidine)

Valacyclovir (prodrug of acyclovir)

  • Antiviral spectrum similar to that of acyclovir
  • Oral: 3–5 times more bioavailable than acyclovir
  • Similar to those of acyclovir
  • TTP/HUS in some patients with advanced HIV and in transplant recipients who received valacyclovir in higher doses than currently recommended
    • Valacyclovir should be used with caution in patients with advanced HIV and in transplant recipients.
  • www.msdmanuals.com/professional/multimedia/table/drugs-used-to-treat-herpesvirus-infections

Valganciclovir (prodrug of ganciclovir)

Vidarabine (adenine arabinoside, ara-A)

  • For HSV infections
  • IV form not used anymore because of neurotoxicity
  • Ophthalmic preparations: Effective for acute keratoconjunctivitis and recurrent superficial keratitis caused by HSV-1 and HSV-2
  • Superficial punctate keratitis with tearing, irritation, pain, and photophobia
  • * Severe neutropenia (< 500 neutrophils/mcL) may require one of the following:
  • Bone marrow stimulation with granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor
  • Discontinuation of ganciclovir
  • Reduction of the dose
  • www.msdmanuals.com/professional/multimedia/table/drugs-used-to-treat-herpesvirus-infections

B12 a k.listová

Patients in the acute phase of the disease

Baicalein

  • Inhibits HSV-1 replication in vitro
  • Baicalein was estimated in Vero and HaCat cells by CCK-8 assay after 72 h incubation.
  • Baicalein showed no obvious cytotoxicity in cells at concentrations lower than 200 µmol/L.
  • Vero and HaCat cells were pre-incubated with different concentrations of baicalein for 24 h, and then infected with HSV-1.
  • After infection, the cells were treated with baicalein or acyclovir for another 24 h.
  • Both baicalein and acyclovir exhibited dose-dependent antiviral activities against HSV-1 F strain.
  • Baicalein presented a lower antiviral efficacy against HSV-1 F strain
    • But showed superiority towards acyclovir-resistant strain (HSV-1/Blue) in both Vero cells and HaCat cells
  • www.sciencedirect.com/science/article/pii/S2211383520306171

In vitro

Ocular inoculation mice model

  • Baicalein markedly reduced in vivo HSV-1/F replication,
  • Receded inflammatory storm
  • Attenuated histological changes in the cornea.
  • Reduce the mortality of mice
  • europepmc.org/article/med/33354504

Viral loads both in nose and trigeminal ganglia

Ex vivo HSV-1-EGFP infection model in isolated murine epidermal sheets

  • Inhibiting IkappaB kinase beta (IKK-beta) phosphorylation
  • Inactivation of virions
  • May be useful especially acyclovir-resistant strain
  • europepmc.org/article/med/33354504

Achyranthes aspera - Devil’s horsewhip

Achyrocline flaccida  

Achyrocline satureioides  

Adiantum latifolium

Aglaia odorata - Chinese perfume plant

Agrimonia pilosa - Hairy agrimony

Aloe vera- Aloe Asphodelaceae

Aloysia gratissima - Whitebrush

Alpinia officinarum - Lesser galangal

Alternanthera sessilis - Sessile joyweed

Ampelozizyphus amazonicus  

Anacardium occidentale - Cashew

Anemone obtusiloba - Ratanjot - Rikabe

Anemopaegma setilobum

Annona muricata- Soursop

Antrodia camphorata  

Arachis hypogaea - Peanut

Araucaria angustifolia - Brazilian pine

  • Araucariaceae
  • Leaf Dichloromethane Ethyl acetate n-Butanol In vitro Vero cells  
  • Ethyl acetate and n-butanol extracts demonstrated similar antiviral activity against one HSV-1 strain.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Andrighetti-Frohner et al., 200541

Arctium lappa - Greater burdock

Ardisia squamulosa - Tagpo

Arisaema tortuosum - Whipcord cobra lily

  • Araceae
  • Leaf Ethanol n-Hexane Chloroform Ethyl acetate n-Butanol In vitro Vero cells
  •   Chloroform extract showed strong antiviral activity against HSV-2 and moderate activity against HSV-1.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Ritta et al., 202044

Aristotelia chilensis - Maqui Chilean Wineberry

Arrabidaea craterophora

Arrabidaea formosa  

  • Bignoniaceae
  • Leaf Stem Fruit Ethanol In vitro Vero cells  
  • Leaf and stem ethanolic extracts demonstrated moderate antiviral activity against HSV-1
  • The fruit ethanolic extract had minimal antiviral activity.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Brandao et al., 201037

Arrabidaea pulchra  

Arrabidaea sceptrum  

Artemisia douglasiana - California mugwort

Atractylis macrophylla  

Auriporia aureus  

Avicenna marina - Gray/white mangrove

Azadirachta indica - Neem tree

Baccharis anomala  

Baccharis erioclada

Baccharis genistelloides - Carqueja

Baccharis megapotamica  

Baccharis rubricaulis - Rubby

Baccharis trinervis  

Baccharis uncinella  

Barleria lupulina - Hophead

  • Acanthaceae
  • Leaf Twig Methanol In vitro Vero cells  
  • Extract demonstrated antiviral activity against HSV-2 standard strain and clinical isolates, but activity was much weaker than acyclovir.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Yoosook et al., 199953

Bauhinia candicans  

Bauhinia thonningii - Kalgo

Kudi and Myint, 199935

Bauhinia variegata - Orchid tree - Mountain ebony

Blumea chinensis - Katarai

Blumea lacera - Lettuce-leaf blumea

Boletus edulis - Porcini mushroom

Boswellia ameero

Boswellia elongata  

Boussingaultia gracilis  

Brainia insignis  

Buxus hildebrandtii - Box wood

Byrsonima verbascifolia  

Caesalpinia pulcherrima - Peacock flower

  • Fabaceae
  • Flower Stem and leaf Fruit and seed Water In vitro BCC-1/KMC cells  
  • Flower extract showed moderate antiviral activity against HSV-1 and HSV-2.
  • The other extracts showed weaker antiviral activity to both viruses.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Chiang et al., 200357

Caesalpinia sappan - Sappanwood

Cajanus cajan - Pigeon pea

Calotropis gigantea - Giant milkweed

Camelia sinensis - Green tea

Campomanesia eugenioides - Gabiroba

Capparis sinaica - Egyptian caper

Carissa edulis - Egyptian carissa

Cassia socotrana

Cassia stipulaceae  

Ceanothus Coeruleus - California lilac

Cecropia glaziovii  

Cedrus libani - Cedar of Lebanon

Centella asiatica - Gotu kola

Centipeda minima - Hachhyun - Hachhi mran

Ceramium rubrum - Red hornweed

Cerbera odollam - Suicide tree

Chenopodium ambrosioides - Wormseed

Chironia krebsii - Kreb’s chironia Gentianaceae

Chondracanthus acicularis  

  • Gigartinaceae
  • Whole plant Dichloromethane and methanol In vitro Vero cells  
  • Extract demonstrated strong antiviral activity against acyclovir-resistant HSV-2, but not against acyclovir-resistant HSV-1.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Soares et al., 201269

Chrysactinia mexicana - Damianita daisy

Cissus hamaderohensis  

Cissus subaphylla  

Citrus hystrix - Combava

  • Rutaceae
  • Leaf Methanol In vitro Vero cells  
  • Extract demonstrated antiviral activity against HSV-1.
-journals.sagepub.com/doi/10.1177/2515690X20978394 Fortin et al., 200270

Clematis cirrhosa - Freckles Clematis

  • Ranunculaceae
  • Acetone Methanol In vitro Vero cells  
  • Acetonic extract demonstrated antiviral activity against HSV-1 and HSV-2. Jaeger Greer et al., 201246
-journals.sagepub.com/doi/10.1177/2515690X20978394

Clematis drummondii - Old man’s beard - Texas virgin’s bower - Barba de chivato

Clinacanthus nutans  

  • Acanthaceae
  • Whole plant Methanol In vitro Vero cells  
  • Extract only demonstrated antiviral activity against HSV-2 standard strain and clinical isolates at its highest non-cytotoxic dose.
-journals.sagepub.com/doi/10.1177/2515690X20978394 Yoosook et al., 199953
  • Leaf n-Hexane Dichloromethane Methanol In vitro Vero cells  
  • All extracts demonstrated antiviral activity against HSV-1 and HSV-2.
  • The n-hexane extract was most potent against HSV-1,
  • Methanolic extract was most potent against HSV-2.
-journals.sagepub.com/doi/10.1177/2515690X20978394 Kunsorn et al., 201371

Clinacanthus siamensis  

  • Acanthaceae Leaf
  • N-Hexane Dichloromethane Methanol In vitro Vero cells  
  • All extracts demonstrated antiviral activity against HSV-1 and HSV-2.
  • The methanolic extract was most potent against HSV-1,
  • N-hexane extract was most potent against HSV-2.
-journals.sagepub.com/doi/10.1177/2515690X20978394 Kunsorn et al., 201371

Codium decorticatum  

  • Codiaceae
  • Whole plant Dichloromethane and methanol In vitro Vero cells
  •   Extract demonstrated strong antiviral activity against acyclovir-resistant HSV-1, but not against acyclovir-resistant HSV-2.
-journals.sagepub.com/doi/10.1177/2515690X20978394 Soares et al., 201269

Combretum micranthum - Kinkeliba

  • Combretaceae
  • Leaf Methanol In vitro Vero cells  
  • The NaOH autoxidized methanolic extract demonstrated antiviral activity against HSV-1 and HSV-2, but was more effective against HSV-1.
-journals.sagepub.com/doi/10.1177/2515690X20978394 Ferrea et al., 199372

Commiphora parvifolia  

Copaifera reticulata

  • Copaiba Fabaceae
  • Leaf Hydroethanol In vitro Vero cells
  •   Extract demonstrated antiviral and virucidal activity against HSV-2, particularly by preventing viral adsorption.
-journals.sagepub.com/doi/10.1177/2515690X20978394 Churqui et al., 201773
  • Leaf Hydroethanol In vivo   C57bl/6 mice
  • Extract prevented HSV-2 infection when administered with the virus.
-journals.sagepub.com/doi/10.1177/2515690X20978394 Churqui et al., 201773

Corallodiscus lanuginosus - Kumkum

  • Gesneriaceae
  • Whole plant Methanol In vitro Vero cells  
  • Extract demonstrated partial HSV-1 inhibition.
-journals.sagepub.com/doi/10.1177/2515690X20978394 Taylor et al., 199636

Cordia americana - Guajuvira

  • Boraginaceae
  • Bark Leaf Water Hydroalcohol In vitro Vero cells  
  • All extracts except the water bark extract demonstrated antiviral activity against HSV-1.
  • The 70% hydroalcoholic bark extract and the 50% hydroalcoholic leaf extract were most potent.
-journals.sagepub.com/doi/10.1177/2515690X20978394 Moura-costa et al., 201260

Cordia salicifolia Cha de bugre - Raintree

Cornus canadensis - Creeping dogwood

Costus speciosus - Crepe ginger

Crossostephium chinense - Chinese wormwood

Croton lechleri - Dragon’s blood

Cryptostegia grandiflora - Palai

Cuphea carthagenensis - Colombian waxweed

  • Lythraceae
  • Aerial parts Dichloromethane Ethyl acetate n-Butanol In vitro Vero cells  
  • All extracts demonstrated antiviral activity against one HSV-1 strain, but the ethyl acetate extract was most potent.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Andrighetti-Frohner et al., 200541

Cyperus rotundus - Purple nutsedge

Cystoseira myrica  

Dichrostachys glomerata - Dundu

Dorstenia socotrana

Dracaena cinnabari -Socotra dragon tree - Dragon blood tree

Drimys winteri - Winter’s Bark - Canelo

Drynaria fortunei  

Dunaliella salina  

  • Dunaliellaceae
  • Whole plant Hexane Ethanol Water In vitro Vero cells  
  • All extracts demonstrated antiviral activity against HSV-1, but the aqueous extract was more potent. Extracts were more effective with treatment prior to infection.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Santoyo et al., 201278

Duroia hirsuta  

Echinacea atrorubens - Topeka purple coneflower

Echinacea laevigata- Smooth cone flower

  • Asteraceae
  • Root Ethanol n-Hexane Ethyl acetate In vitro Vero cells  
  • The n-hexane and ethyl acetate fractions demonstrated slightly stronger antiviral activity against HSV-1.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Binns et al., 200279

Echinacea pallida - Pale purple coneflower

  • Asteraceae
  • Root Ethanol n-Hexane Ethyl acetate In vitro Vero cells  
  • Ethanolic extract and n-hexane fraction demonstrated antiviral activity against HSV-1, but the ethanolic extract was most potent.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Binns et al., 200279
  • Aerial parts Hydroethanol Pressed juice with ethanol In vitro Vero cells  
  • All extracts demonstrated antiviral activity against HSV-1 and HSV-2, but the pressed juice was most potent.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Schneider et al., 200980

Echinacea purpurea - Purple coneflower

  • Asteraceae
  • Root Ethanol n-Hexane Ethyl acetate In vitro Vero cells  
  • Ethanolic extract and n-hexane fraction demonstrated antiviral activity against HSV-1, but the n-hexane fraction was most potent.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Binns et al., 200279

Echium amoenum - Red feather

Ecklonia stolonifera

Elaeocarpus grandiflorus - Fairy petticoat - Lily of the valley tree

Eleusine indica - Indian goosegrass

Elytranthe globosa - Benalu

Elytranthe maingayi - Benalu

Elytranthe tubaeflora - Benalu

Elytropus chilensis - Quilmay - Poroto del campo

Ephedra alata - Alanda

Epimedium koreanum  

Equisetum giganteum - Giant horsetail

Erica multiflora- Mediterranean heath

Eriobotrya japonica - Japanese plum

Erythrina speciosa - Coral tree

2 Erythroxylum laurifolium - Bois de rongue

Eschweilera rufifolia

Eucalyptus globulus - Eucalyptus

Eugenia caryophyllus *Aka Syzygium aromaticum - Clove

Eugenia michelii- Surinam cherry

Eupatorium arnottianum  -

Eupatorium articulatum

Eupatorium catarium

Eupatorium patens

Euphorbia cestrifolia  

  • Euphorbiaceae
  • Leaf Stem Petroleum ether Dichloromethane Ethanol In vitro Vero cells HEp-2 cells  
  • Ethanolic stem extract and dichloromethane leaf extract demonstrated moderate antiviral activity against HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Betancur-Galvis et al., 200289

Euphorbia cotinifolia

  •   Euphorbiaceae
  • Leaf Stem Leaf/Stem Petroleum ether Dichloromethane Ethanol Hydromethanol In vitro Vero cells HEp-2 cells  
  • Hydromethanolic leaf/stem extract demonstrated strong antiviral activity and the ethanolic stem and dichloromethane leaf extracts demonstrated moderate activity against HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Betancur-Galvis et al., 200289

Euphorbia hirta - Garden spurge

Euphorbia spinidens

Euphorbia tirucalli

  •   Euphorbiaceae
  • Stem Leaf/Stem Petroleum ether Dichloromethane Ethanol Hydromethanol In vitro Vero cells HEp-2 cells  
  • Hydromethanolic leaf/stem extract demonstrated strong antiviral activity and the ethanolic stem extract demonstrated moderate antiviral activity against HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Betancur-Galvis et al., 200289

Euphorbia thymifolia

Eurycoma longifolia - Malaysian ginseng - Pasak bumi - Tongkat Ali

Ficus benjamina - Weeping ficus

  • Moraceae
  • Stem Methanol In vivo  
  • BALB/c mice Extract delayed the appearance of local vesicles and limited further development to mild zosteriform lesions, but did not reduce survival time or mortality.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Nawawi et al., 199992

Euryops arabicus  

Exacum affine - Persian violet

Fagonia luntii  

Ficus benjamina - Weeping fig

  • Moraceae
  • Leaf Fruit Stem Ethanol In vitro Vero cells  
  • Leaf extract demonstrated strong antiviral activity against HSV-1 and HSV-2 and was synergistic with acyclovir.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Yarmolinsky et al., 200993

Ficus carica - Common fig

  • Moraceae
  • Latex Hexane Ethyl acetate Methanol Chloroform Hexane-ethyl acetate In vitro Vero cells
  • Hexane and hexane-ethyl acetate extracts elicited antiviral activity against HSV-1, preventing viral penetration, adsorption, and intracellular replication.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Lazreg Aref et al., 201194

Ficus religiosa - Sacred fig - Bodhi tree - Bo tree

Filicium decipiens - Fern tree

Fomes fomentarius - Hoof fungus

Frankenia pulverulenta - Sea heath

  • Frankeniaceae
  • Stem bark Methanol In vivo   BALB/c mice
  • Extract delayed the appearance of local vesicles, but did not limit further development to mild zosteriform lesions, reduce survival time, or reduce mortality.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Nawawi et al., 199992

Frankenia pulverulenta - European sea-heath

Freycinetia malaccensis - Climbing pandanus

Gallesia gorazema - Pau-d’alho

Garcinia griffithii - Kandis Gajah

Garcinia mangostana - Mangosteen

Geranium sanguineum - Bloody geranium

  • Geraniaceae
  • Leaf Methanol In vivo  
  • BALB/c mice Extract delayed the appearance of local vesicles, but did not limit further development to mild zosteriform lesions, reduce survival time, or reduce mortality.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Nawawi et al., 199992

Geranium sanguineum - Bloody cranesbill

  • Geraniaceae
  • Aerial root parts Overground parts Ethanol Methanol Hydroethanol In vitro Vero cells E6SM cells
  •   All extracts showed antiviral activity against HSV-1, but the hydroethanolic extract was the strongest. The hydroethanolic extract also inhibited HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Serkedjieva and Ivancheva, 199997

Geum japonicum - Asian herb bennet

Glechon marifolia

Glechon spathulata  

Glycyrrhiza glabra - Licorice

Gnaphalium chilense  

Graptopetalum paraguayense Sedum weinbergii - Mother-of-pearl-plant - Ghost plant

  • Crassulaceae
  • Leaf Hydromethanol In vitro Vero cells  
  • Extract demonstrated antiviral activity against both wild-type and acyclovir-resistant strains of HSV-1 and HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Zaharieva et al., 2019102

Haematococcus pluvialis

  •   Haematococcaceae
  • Whole plant Hexane Ethanol Water In vitro Vero cells  
  • All extracts demonstrated antiviral activity against HSV-1, but the ethanolic extract was more potent. Extracts were more effective with treatment prior to infection.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Santoyo et al., 201278

Hamelia patens - Firebush

Harpullia arborea - Tulipwood tree


Hedyotis auricularia  

Heisteria acuminata  

Helichrysum aureonitens - Golden everlasting

Hemidesmus indicus - Indian sarsaparilla

Hura crepitans - Sandbox tree

Houttuynia cordata - Chameleon plant

Hymenoclea salsola - Aka Ambrosia salsola - Cheesebush - Winged ragweed

Hypericum cordifolium - Marmhendo

Hypericum hookerianum Hypericum

Hypericum mysorense Hypericum

Hypericum uralum - Urali phul

Hypnea spinella  

  • Cystocloniacae Whole plant Dichloromethane and methanol In vitro Vero cells  
  • Extract demonstrated strong antiviral activity against acyclovir-resistant HSV-1, but not against acyclovir-resistant HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Soares et al., 201269

Ilex brevicuspis - Holly

Ilex paraguariensis - Yerba mate

  • Aquifoliaceae
  • Leaf Water In vitro Vero cells  
  • Extract demonstrated antiviral activity against 2 HSV-1 strains.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Muller et al., 2007108
  • Leaf Hydroethanol Butanol Water
  • Ethyl acetate In vitro Vero cells GMK AH1  
  • Hydroethanolic extracts and all fractions demonstrated antiviral activity against HSV-1 and HSV-2, but effects were more potent against HSV-2. Most potent activity was demonstrated by the ethyl acetate fraction by preventing viral attachment and penetration.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Luckemeyer et al., 2012109

Ilex theezans - Holly

Illinita  

Indigofera heterantha - Himalayan indigo

Inonotus obliquus - Chaga mushroom

Iryanthera megistophylla  

Ixeris chinensis  

Jatropha unicostata - Sibru

Juglans australis - Nogal

  • Juglandaceae
  • Methanol Infusion In vitro Vero cells  
  • Infusion demonstrated antiviral activity against both HSV-1 and HSV-2, while the methanolic extract demonstrated activity against only HSV-1.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Ruffa et al., 200485

Juglans mandshurica - Manchurian walnut

Juglans mollis  

Kalanchoe farinacea  

Kalanchoe pinnata - Aka Bryophyllum pinnatum - Miracle leaf - Cathedral bells

Lafoensia pacari  

Lantana camara - Common lantana - Shrub verbena

Lantana grisebachii  

Laurencia dendroidea  

  • Rhodomelaceae
  • Whole plant Dichloromethane and methanol In vitro Vero cells  
  • Extract demonstrated strong antiviral activity against acyclovir-resistant HSV-1, but not against acyclovir-resistant HSV-2, and exhibited some cytotoxicity.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Soares et al., 201269

Leea indica - Bandicoot berry

Lepechinia floribunda  

Licania tomentosa  

  • Chrysobalanaceae
  • Seed Glycerol In vitro HEp-2 cells  
  • Extract demonstrated antiviral activity against acyclovir-resistant HSV-1, particularly with cellular pretreatment or after viral attachment.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Miranda et al., 2002114

Lilium candidum - Madonna lily

  • Liliaceae
  • Leaf Petal Bulb Ethanol In vitro Vero cells  
  • Leaf extract demonstrated strong antiviral activity against HSV-1 and HSV-2 and was synergistic with acyclovir.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Yarmolinsky et al., 200993

Limonium brasiliense - Kuntze

Lippia alba - Bushy lippia

  • Verbenaceae Leaf
  • Dichloromethane Ethyl acetate n-Butanol In vitro Vero cells  
  • N-Butanol extract demonstrated antiviral activity against acyclovir-resistant HSV-1.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Andrighetti-Frohner et al., 200541

Lithospermum officinale- European stoneseed

Lithraea molleoides  

Lobelia chinensis - Chinese lobelia

Lobophora variegata  

  • Dictyotaceae
  • Whole plant Dichloromethane and methanol In vitro Vero cells  
  • Extract demonstrated strong antiviral activity against acyclovir-resistant HSV-1, but not against acyclovir-resistant HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Soares et al., 201269

Lomatophyllum macrum - Mazambron marron

Luehea paniculatum  

Luma apiculata Temu - Chilean myrtle

Macaranga pustulata - Malato - Kala

Macrocystidia cucumis

Madura cochinchinensis  

Maesa macrophylla - Bhogati

Margyricarpus pinnatus - Pearl Berry

Maytenus ilicifolia - Espinheira santa

Melia toosendan  

Melaleuca armillaris - Bracelet honey myrtle

Melaleuca ericifolia - Swamp paperbark

Melaleuca leucadendron - Weeping paperbark

Melastoma malabathricum - Daun halendong - Mua e bong - Sendudok

Melia dubia - Malaivanbu

Melissa officinalis - Lemon balm

Mentha arvensis - Field mint

Mentha piperita - Peppermint Lamiaceae

Mentha suaveolens - Apple mint - Pineapple mint - Woolly mint

  • Lamiaceae
  • Leaf Essential oil In vitro Vero cells  
  • Extract demonstrated antiviral activity against HSV-1, particularly by inhibiting intracellular viral metabolism, and showed synergistic effects with acyclovir.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Civitelli et al., 2014128

Mitragyna inermis  

Moringa oleifera - Drumstick tree

Moringa peregrina - Ben tree

Myrteola nummularia - Cranberry-myrtle

Nauclea latifolia - African Peach

Nelumbo nucifera - Indian lotus - Sacred lotus

Nephelium lappaceum - Rambutan

Obetia ficifolia - Bois d’ortie

  • Urticaceae
  • Pericarp Methanol In vivo
  •   BALB/c mice Extract delayed the appearance of local vesicles and limited further development to mild zosteriform lesions, reduced survival time, and reduced mortality.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Nawawi et al., 199992

Ocimum basilicum - Basil

  • Lamiaceae
  • Leaf Water Ethanol In vitro BCC-1/KMC cells  
  • Water extract had potent antiviral activity against HSV-1 and HSV-2.
  • Ethanolic extract had potent activity against HSV-1. Water extract elicited greater effects than the ethanolic extract.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Chiang et al., 2005131

Ocimum gratissimum - Clove basil

Ophirrhiza nicobarica  

Opuntia streptacantha - Prickly pear

Orthosiphon aristatus - Cat’s whiskers

Paeonia suffruticosa - Moutan peony

Passiflora edulis - Passion flower

Pedilanthus tithymaloides - Devil’s-backbone

Peganum harmala - Wild rue

  • Nitrariaceae
  • Leaf Stem Seed Flower Hexane, dichloromethane, ethyl acetate, methanol, and ethanol In vitro Vero cells  
  • Seed extract demonstrated antiviral and virucidal activity against HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Benzekri et al., 2017135

Pelargonium sidoides - South African geranium

Penicillus capitatus  

  • Udoteaceae
  • Whole plant Dichloromethane and methanol In vitro Vero cells  
  • Extract demonstrated strong antiviral activity against both acyclovir-resistant HSV-1 and acyclovir-resistant HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Soares et al., 201269

Persea americana - Avocado

Petunia nyctaginiflora  

Phellodendron amurense - Amur cork tree - Huang Bai

Phoradendron crassifolium  

Phyllanthus amarus - Carry me seed

Phyllanthus niruri - Gale of the wind

Phyllanthus orbicularis - Wedge leaf flower

  • Euphorbiaceae
  • Stem and leaves Water In vitro Human foreskin fibroblasts  
  • Extract demonstrated antiviral activity against HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 del Barrio et al., 2000139
  • Stem and leaves Diethyl ether Chloroform Butanol Ethanol Acetic acid-water In vitro Human foreskin fibroblasts Vero cells  
  • Butanolic and acetic acid extracts demonstrated significant antiviral activity against 2 strains of HSV-1 in both cell types, particularly in the early stages of viral infection.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Fernandez Romero et al., 2003140

Phyllanthus urinaria - Chamber bitter

  • Euphorbiaceae
  • Whole plant Acetone Benzene Chloroform Ethanol Ethyl acetate n-Hexane Methanol In vitro Vero cells  
  • Acetone, ethanolic, and methanolic extracts demonstrated moderate antiviral activity against HSV-1 and significant activity against HSV-2, specifically when added to cells just after viral infection.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Yang et al., 2005141
  • Whole plant Water In vitro Vero cells  
  • Extract inhibited replication of HSV-1 and HSV-2 to similar degrees.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Tan et al., 2013138

Phyllanthus watsonii  

Piper aduncum Cordoncillo - Yanggona - Yaqona

Pistacia vera - Pistachio

  • Pistaciaceae
  • Seed Kernel Leaf Stem Branch Shell skins n-Hexane In vitro Vero cells  
  • Kernel, shell skin, and seed extracts demonstrated the strongest antiviral activity against HSV (type not specified).
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Ozcelik et al., 2005142

Pithecellobium clypearia  

Plantago asiatica - Chinese plantain

Plantago major - Greater Plantain

Pleurotus ostreatus - Oyster mushroom

Polygala tenufolia - Common polygala seed

Polygala virgata - Purple broom

Polygonum cuspidatum - Japanese knotweed

Polygonum minus - Knotweed

Polygonum punctatum - Dotted smartweed

Polysiphonia denudata  

  • Rhodomelaceae
  • Whole plant Water In vitro Vero cells E6SM cells  
  • Extract demonstrated antiviral activity against HSV-2 and different strains of HSV-1, particularly when added at adsorption or post-infection.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Serkedjieva et al., 2000145

Pongamia pinnata - Pongam tree

Princepia utilis

Protium serratum

Prunella vulgaris - Prunella

Psidium incanum

Psidium luridum  

Psilostrophe cooperi - Whitestem paper flower

Psychotria serpens - Creeping psychotria

Pulicaria stephanocarpa  

Punica granatum - Pomegranate

Punica protopunica - Pomegranate tree - Socotran pomegranate

Quercus brantii - Brant’s oak Fagaceae

  • Fruit Ethyl alcohol In vitro BHK cells  
  • Extract demonstrated antiviral activity against HSV-1, particularly when present during and after adsorption.
  • Karimi et al., 2017148

Rheum officinale - Chinese rhubarb

Rheum palmatum - Chinese rhubarb

Rhododendron ferrugineum - Snow rose - Alpen rose

Rhus aromatica - Fragrant sumac

Rhus javanica Sumac

Ribes nigrum - Blackcurrant

Ricinus communis - Castor oil plant

Rinorea anguifera  

Rosmarinus officinalis - Rosemary

Rubus eubatus - Blackberry

  • Rosaceae
  • Berry Ethanol In vitro OKF6 cells  
  • Extract demonstrated antiviral and virucidal activity against HSV-1, particularly by preventing viral adsorption and replication.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Danaher et al., 2011152

Rubus imperialis  

Salvia ballotiflora - Shrubby blue sage

Salvia officinalis - Sage

Salvia texana - Texas sage

Sambucus nigra - Elderberry

Sargassum cymosum  

  • Sargassaceae
  • Whole plant Dichloromethane and methanol In vitro Vero cells  
  • Extract demonstrated strong antiviral activity against acyclovir-resistant HSV-1, but not against acyclovir-resistant HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Soares et al., 201269

Sargassum ringgoldianum  

  • Sargassaceae
  • Whole plant Methanol In vitro Vero cells  
  • Extract demonstrated complete plaque inhibition against 3 HSV-1 strains, but demonstrated strong cytotoxicity to cells.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Park et al., 200581

Sargassum thunbergii  

Sasa senanensis - Senan bamboo

Satureja boliviana  

Schima wallichi - Needlewood tree Theaceae

Schinus molle - Brazilian peppertree

Schinus terebinthifolia - Aroeira

Sebastiania brasiliensis  

Sebastiania klotzschiana  

Securidaca longepedunculata - Violet tree

Senecio ambavilla - Ambaville

Senecio scandens

Serissa japonica - Snow rose

Sesbania punicea - Scarlet wisteria - Brazilian rattlebox

Sibbaldia micropetala - Bhui pasari jhar

Sloanea guianensis  

Smilax gracilis  

Solanum americanum - American black nightshade

Solanum paniculatum  

Sophora flavescens - Shrubby sophora

Spatholobus suberectus  

Spirogyra spp. -Water silk - Mermaid’s tresses - Blanket weed

Stephania cepharantha

Sterculia setigera Kukkugi

Stizophyllum perforatum

Strychnos pseudoquina - Quina

Stypopodium zonale  

  • Dictyotaceae
  • Whole plant Dichloromethane and methanol In vitro Vero cells  
  • Extract demonstrated strong antiviral activity against both acyclovir-resistant HSV-1 and acyclovir-resistant HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Soares et al., 201269

Swertia chirata - Chirata

Symphonia globulifera - Chewstick

Symphyocladia latiuscula  

  • Rhodomelaceae
  • Whole plant Methanol Hexane Dichloromethane Ethyl acetate Butanol Water In vitro Vero cells  
  • Methanolic extract demonstrated strong plaque inhibition against 2 HSV-1 strains. Dichloromethanic fraction exhibited the strongest antiviral activity.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Park et al., 200581
  • Whole plant Methanol In vitro   BALB/c mice
  • Extract significantly delayed the development and progression of HSV-1 lesions, increased survival time, decreased viral yields in skin, but had no effect on mortality rate.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Park et al., 200581

Syzygium aromaticum - Clove

Tamarix nilotica - Nile Tamarisk

Tanacetum parthenium - Feverfew

Tanacetum vulgare - Common tansy

  • Asteraceae
  • Aerial parts Water Ethyl acetate In vitro Vero cells  
  • Both extracts demonstrated mild antiviral activity against HSV-1.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Onozato et al., 2009163
  • Aerial parts Rhizome Methanol Petroleum ether Chloroform Ethyl acetate Butanol Water In vitro Vero cells  
  • Petroleum ether and ethyl acetate fractions of aerial parts and the methanolic rhizome extract demonstrated strong antiviral activity against HSV-1 and HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Alvarez et al., 2011164

Terminalia arjuna Arjuna - Arjun tree

Terminalia chebula  

Tessaria absinthioides  

Tetraclinis articulata - Sictus tree - Arar tree

Tillandsia aeranthos  

Tillandsia usneoides - Spanish moss

  • Aerial parts Dichloromethane Ethyl acetate n-Butanol In vitro Vero cells  
  • All extracts demonstrated antiviral activity against 2 HSV-1 strains, but the ethyl acetate extract was most potent.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Andrighetti-Frohner et al., 200541

Tithonia diversifolia - Mexican sunflower - Tree marigold

Thymus capitatus - Headed savory

  • Lamiaceae
  • Aerial parts Water Ethanol Essential oil In vitro Vero cells  
  • All 3 extracts showed antiviral activity against HSV-1 and HSV-2.
  • The strongest antiviral activity was seen with the ethanolic extract against HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Toujani et al., 2018166

Thymus vulgaris - Thyme

Toona sureni - Surian

  • Meliaceae
  • Leaf Water Methanol In vitro Vero cells  
  • Methanolic extract demonstrated complete HSV-1 inhibition, but also demonstrated cytotoxicity to cells.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Nawawi et al., 199992
  • Leaf Methanol In vivo   BALB/c mice
  • Extract delayed the appearance of local vesicles, but did not limit further development to mild zosteriform lesions, reduce survival time, or reduce mortality from HSV-1 infection.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Nawawi et al., 199992

Trametes versicolor - Turkey tail

Trichilia catigua - Catuaba

Trichilia glabra  

Trichocalyx obovatus  

Trixis divaricata  

Ulva fasciata  

  • Ulvaceae
  • Whole plant Dichloromethane and methanol In vitro Vero cells  
  • Extract demonstrated strong antiviral activity against acyclovir-resistant HSV-1, but not against acyclovir-resistant HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Soares et al., 201269

Ulva pertusa - Sea lettuce

Unicaria tomentosa    

Usnea complanta - Marappasi

Vachellia nilotica - Gum arabic tree - Thorn mimosa

  • Fabaceae
  • Bark Chloroform Methanol Water In vitro Vero cells  
  • All extracts demonstrated strong antiviral activity against HSV-2, and the methanolic extract additionally demonstrated activity against acyclovir-resistant HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Donalisio et al., 2018169

Ventilago denticulata - Drumstick tree

Veronica persica - Persian speedwell - Bird’s eye speedwell

  • Plantaginaceae
  • Aerial parts Ethanol Methanol In vitro Vero cells  
  • Ethanolic extract demonstrated moderate antiviral activity against HSV-1 and HSV-2, and the 80% methanolic fraction demonstrated strong activity against both viruses.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Sharifi-rad et al., 2018170

Viola yedoensis  

Virola multinervia

Vismia macrophylla - Kunth

Vitex polygama  

  • Lamiaceae
  • Fruit Leaf Ethyl acetate In vitro HEp-2 cells  
  • Both fruit and leaf extracts demonstrated antiviral activity against acyclovir-resistant HSV-1. Fruit extract had a stronger virucidal effect while the leaf extract was more potent post-infection.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Goncalves et al., 2001172

Wilbrandia ebracteata - Taiuia

Withania adunensis  

Woodfordia floribunda - Fire flame bush

Zanthoxylum rhoifolium - Prickly ash

Zataria multiflora - Shirazi thyme

Zeyheria tuberculosa  

Zygophyllum album  

Zygophyllum quatarense  

Hypericum perforatum + Sambucus nigra + Saponaria officinalis St. John’s Wort + Elderberry + Sweet William Hypericaceae + Adoxaceae + Caryophyllaceae Flower

Aconitum carmichaelii + Glycyrrhiza glabra + Zingiberis siccatum Shigyaku-to + Si Ni Tang

  • Ranunculaceae Fabaceae Zingiberaceae
  • Tuber Root Rhizome Saline In vivo   BALB/c mice
  • Herbal combination showed the greatest antiviral activity against HSV-1 at 20mg/kg, increasing survival rate.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Ikemoto et al., 1994175

Aconitum carmichaelii + Atractyloidis lanceae + Cinnamomum verum + Glycyrrhiza glabra + Kanzo-bushi-to + Gan Cao Fu Zhi Tang

  • Ranunculaceae Asteraceae Lauraceae Fabaceae
  • Tuber Rhizome Cortex Root Water In vivo   Thermally-injured BALB/c mice
  • Herbal combination improved susceptibility to and mortality from HSV-1 infection.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Matsuo et al., 1994176

Cinnamomi cassia + Ephedra sinica + Glycyrrhizae uralensis + Paeoniae lactiflora + Pueraria pseudo-hirsuta + Zingiberis officinale + Zizyphi jujuba + Kakkon-to + Ge Gan Tang

  • Lauraceae Ephedraceae Fabaceae Paeoniaceae Fabaceae Zingiberaceae Rhamnaceae
  • Cortex Herba Radix Radix Radix Rhizoma Fructus Water In vivo   BALB/c mice
  • Herbal combination decreased mortality, size, and severity of lesions when given prior to HSV-1 infection. Only noted difference when given during HSV-1 infection was a smaller size of lesions.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Nagasaka et al., 1995177

Artemisia capillaries + Gardenia jasminoids + Rheum officinale + Yin Chen Hao Tang

  • Rubiaceae Polygonaceae
  • Seed Fruit Rhizome Water In vitro Vero cells HEp-2 cells  
  • Herbal combination demonstrated antiviral activity against both HSV-1 and HSV-2, but effects were more potent against HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Cheng et al., 2008178

Alisma plantago-aquatica + Akebia quinata + Angelica sinensis + Bupleurum chinense + Gardenia jasminoides + Gentiana scabra + Glycyrrhiza uralensis + Plantago asiatica + Rehmannia glutinosa + Scutellaria baicalensis + Long Dan Xie Gan Tang

  • Alismataceae Lardizabalaceae Umbelliferae Umbelliferae Rubiaceae Gentianaceae Leguminosae Plantaginaceae Scrophulariaceae Labiatae
  • Tuber Fruit Root Root Fruit Root and rhizome Root and rhizome Seed Tuber Root Water In vitro Vero cells  
  • Herbal combination demonstrated antiviral activity against both HSV-1 and HSV-2, but effects were more potent against HSV-1.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Cheng et al., 2008179

Acacia catechu + Lagerstroemia speciosa + Phyllanthus emblica + Terminalia chebula Catechu + Crepe-myrtle + Indian gooseberry + Myrobalan

  • Fabaceae Lythraceae Phyllanthaceae Combretaceae
  • Heart wood Leaf Fruit Ethanol In vitro Vero cells Vk2/E6E7 cells  
  • Herbal combination demonstrated antiviral activity against HSV-2 in Vero cells and did not decrease viability or integrity nor increase mutagenic behavior or inflammatory cytokines in Vk2/E6E7 cells.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Mishra et al., 2018180

Melissa officinalis - Lemon balm

  • Lamiaceae

115 subjects with HSV lesions of skin or transitional mucosa

116 subjects with HSV lesions of skin or transitional mucosa

  • Leaf Cream In vivo  
  • Cream significantly reduced symptoms and HSV lesion swelling compared to placebo.
  • Subjects’ and physicians’ assessments of healing were significantly greater for the cream compared to placebo.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Wolbling et al., 1994182

66 subjects with at least 4 episodes of herpes labialis per year

Hypericum perforatum - St. John’s Wort Hypericaceae

149 subjects with HSV-1 or HSV-2 lesions

Coicis semen + Elfuinga applanata + Ganoderma lucidum + Terminalia chebulae + Trapa natans + Wisteria floribunda + Coix seed + Reishi + Black myrobalan + Water chestnut + Japanese wisteria

5 subjects with recurrent herpes labialis Herbal combination reduced the healing time of herpes lesions compared to previous outbreaks when no treatment was used. Pain associated with outbreaks was also reduced in one patient.

Coicis lachryma-jobi + Elfuinga applanata + Ganoderma lucidum + Terminalia chebulae + Trapa natans + Wisteria floribunda + Job’s tears + Reishi + Black myrobalan + Water chestnut + Japanese wisteria + Ganodermataceae +

28 subjects with either chronic herpes labialis or genitalis

Rheum officinale + Rheum palmatum + Salvia officinalis Chinese rhubarb + Chinese rhubarb + Sage

145 subjects with recurrent herpes labialis

  • The sage, sage-rhubarb, and acyclovir creams had similar mean time to healing and crust formation of HSV lesions.
  • Subjects who used the sage-rhubarb cream reported less pain compared to the sage cream subjects.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Saller et al., 2001187

Combretum micranthum

  • The antiviral activity of 4 methanolic extracts of tested against HSV-1 (strain F) and HSV-2 (strain G)
  • 72 Dried leaves were used to prepare the extracts using 4 different solvents:
    • Regular methanol,
    • Aqueous methanol,
    • Aqueous methanol with addition of HCl and NaOH, and NaOH autoxidized methanol.
  • Only the NaOH autoxidized methanolic extract showed anti-HSV activity.
  • Authors believe this is due to inactive precursors in the plant being transformed to active compounds by alkaline catalysis.
  • The extract was more effective when cells were treated at the same time of viral infection (EC50 was 8 µg/ml and 19 µg/ml for HSV-1 and HSV-2, respectively) compared to treatment after 1 hour of viral adsorption (EC50 was 150 µg/ml and 227 µg/ml for HSV-1 and HSV-2, respectively).
  • C. micranthum is potentially more effective against HSV-1 than HSV-2.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Ferrea et al.

Africké rostliny

  • Against HSV-1 (Mclntyre strain)
  • Toxicity to green monkey kidney (GMK) cells was noted with increasing concentrations of each extract before 100% plaque reduction could be obtained
  • Dichloromethane extract of Chironia krebsii (EC range = 6.25-12.5 µg/ml);
  • 25% ethanolic extract of Jasminum fluminense (EC range = 50-200µg/ml);
  • Methanolic extract of Mitragyna inermis (EC range = 50-100 µg/ml);
  • 25% ethanolic extract of Polygala virgata (EC range = 400-600 µg/ml);
  • Methanolic extract of Securidaca longepedunculata (EC range = 12.5-25 µg/ml);
  • 25% ethanolic extract of Securidaca longepedunculata (EC range = 2.5-6 µg/ml).
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Beuscher et al.

Helichrysum aureonitens

  • Showed antiviral activity against HSV-1 in human lung fibroblast cells
  • A crude aqueous extract was prepared from plant shoots, excluding its flowers, and simultaneously added with HSV-1 viral suspension to cells.
  • After 1 week of incubation, no cytotoxic effect was noted in cells and significant antiviral activity was exhibited at an extract concentration of 1.35 mg/ml.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Meyer et al.

Bauhinia thonningii, Anacardium occidentale, Dichrostachys glomerata, and Sterculia setigera

  • 17 Nigerian medicinal plants for antiherpetic activity in human colonic cancer cells (HT-29 cells)
  • 4 showed anti-HSV activity:
  • These extracts did not exhibit cytotoxicity to HT-29 cells at a dose of 400 µg/100 µl,
  • Their antiviral effects were noted at a dose of 100 µg/100 µl for each extract.
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Kudi and Myint

Obetia ficifolia

  • (EC50 = 7 µg/ml)
  • Methanolic extracts of each herb were tested against HSV-1 (strain H29)
  • Antiviral activity of acyclovir and found its EC50 to be 3.3 µg/ml.
  • Medicinal plants from La Réunion Island
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Fortin et al.,

Lomatophyllum macrum

  • (EC50 = 64 µg/ml)
  • Methanolic extracts of each herb were tested against HSV-1 (strain H29)
  • Antiviral activity of acyclovir and found its EC50 to be 3.3 µg/ml.
  • Medicinal plants from La Réunion Island
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Fortin et al.,

Citrus hystrix

  • (EC50 = 91 µg/ml)
  • Methanolic extracts of each herb were tested against HSV-1 (strain H29)
  • Antiviral activity of acyclovir and found its EC50 to be 3.3 µg/ml.
  • Medicinal plants from La Réunion Island
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Fortin et al.,

Erythroxylum laurifolium

  • (EC50 = 125 µg/ml)
  • Methanolic extracts of each herb were tested against HSV-1 (strain H29)
  • Antiviral activity of acyclovir and found its EC50 to be 3.3 µg/ml.
  • Medicinal plants from La Réunion Island
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Fortin et al.,

Senecio ambavilla

  • (EC50 = 170 µg/ml)
  • Methanolic extracts of each herb were tested against HSV-1 (strain H29)
  • Antiviral activity of acyclovir and found its EC50 to be 3.3 µg/ml.
  • Medicinal plants from La Réunion Island
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Fortin et al.,

Carissa edulis

  • A medicinal plant that grows locally in Kenya
  • Traditionally for a variety of ailments such as skin conditions and sexually transmitted infections.
  • An aqueous extract was prepared from C. edulis roots, freeze-dried
  • Tested against wild-type HSV-1 (strain 7401 H) and HSV-2 (strain Ito-1262), thymidine kinase-deficient HSV-1 (strain B2006), and acyclovir-resistant 7401 H HSV-1.
  • Extract inhibited plaque formation of all 4 strains
  • Wild-type HSV-2 (EC50 = 6.9 µg/ml and SI = 69.6) and thymidine kinase-deficient HSV-1 strain (EC50 = 8.1 µg/ml and SI = 59.3) were more susceptible to the extract.
  • At 200 µg/ml, the extract reduced viral yields of
    • Acyclovir-resistant HSV-1 strain by 100%,
    • Wild-type HSV-2 strain by 99.5%,
    • Wild-type HSV-1 strain by 97.8%,
    • Thymidine kinase-deficient HSV-1 strain by 96.3%
  • Results are significant considering
    • Acyclovir at 5 µg/ml was tested against thymidine kinase-deficient HSV-1 strain yield reduction of only 3.0%
    • Acyclovir-resistant HSV-1 strain yield reduction of only 1.5%
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Tolo et al
Fifty extracts from 15 Tunisian medicinal plants were studied for their antiviral activity against HSV-1 (strain 17) by Sassi et al.84 Four extracts from 3 plants exhibited antiherpetic activity, defined by the authors as inhibiting more than 50% of HSV-1. These extracts were the methanolic extract of Erica multiflora (EC50 = 132.6 µg/ml and SI >3.77), the acetonic (EC50 = 489.5 µg/ml and SI >1.02) and methanolic (EC50 = 486.2 µg/ml and SI >1.03) extracts of Frankenia pulverulenta, and the acetonic extract of Zygophyllum album (EC50 = 390.7 µg/ml and SI >1.28). Both the methanolic extract of E. multiflora and the acetonic extract of Z. album showed complete cell protection against HSV-1 at 2000 µg/ml.Schnitzler et al.136 tested an aqueous extract of the African medicinal plant Pelargonium sidoides for its ability to act against both HSV-1 (strain KOS) and HSV-2 (strain HG52). The extract was found to have antiviral activity in plaque reduction assays with African green monkey kidney (RC-37) cells. When applied at the maximum non-cytotoxic concentration (not specified), the extract was able to reduce plaque formation by 99% for both HSV-1 and HSV-2. Moreover, the extract was added to RC-37 cells at various times throughout the HSV life cycle and compared to acyclovir. The P. sidoides extract showed antiviral effects if added prior to HSV infection or if added during HSV adsorption, compared to acyclovir that exhibited antiviral effects only during HSV replication. The authors conclude that P. sidoides may be effective if used as a topical antiviral treatment at the onset of HSV infection.Forty-two Egyptian medicinal plants were selected by Soltan and Zaki61 for their traditional uses for infectious diseases, and 80% aqueous ethanolic extracts of either aerial parts, seeds, or tubers were tested against HSV-1. A total of 5 plants showed antiherpetic activity. Moringa peregrina and Ephedra alata were observed to have the highest antiviral activity at concentration ranges 50-100 µg/ml (Rf 104) and 500-1000 µg/ml (Rf 104), respectively. Capparis sinaica, Tamarix nilotica, and Cyperus rotundus showed lesser virucidal activity at concentrations of 1000 µg/ml (Rf 104), 1000 µg/ml (Rf 104), and 500 µg/ml (Rf 102), respectively. It must be noted that all 5 plants are edible except for E. alata, therefore it may not be safe to use E. alata for human HSV-1 infections.Moreover, Behbahani et al.48 found a methanolic extract of Avicenna marina leaves to exhibit antiviral effects against HSV-2. This plant is native to Southern Africa and traditionally used to treat ulcers, rheumatism, and smallpox. The greatest inhibition was seen at a concentration of 20 µg/ml where the extract inhibited 80% of HSV-2 replication. The EC50 and SI values for the extract were determined to be 10 µg/ml and 25, respectively, and no cytotoxic effects were noted up to a concentration of 32 µg/ml.Nauclea latifolia roots were used to make an extraction using a 1:1 mixture of dichloromethane and methanol and tested for anti-HSV-2 activity by Donalisio et al.129 Two HSV-2 strains were used: an acyclovir-sensitive HSV-2 strain and an acyclovir-resistant HSV-2 strain. The IC50 values were found to be 7.17 µg/ml and 5.38 µg/ml for the acyclovir-sensitive and acyclovir-resistant HSV-2 strains, respectively. Time-of-addition experiments revealed that the greatest viral inhibition occurred when the extract was added to cells after HSV-2 infection. The authors note N. latifolia does not block viral attachment or entry into host cells. Additionally, the acyclovir-resistant HSV-2 strain was more susceptible to the extract than the acyclovir-sensitive HSV-2 strain, suggesting a potential different mechanism of action than acyclovir.Hassan et al.188 tested an aqueous extract of Hibiscus sabdariffa for anti-HSV-2 activity, but the extract failed to show any antiviral effects.The most recent African plant to be investigated for its antiherpetic activity was Thymus capitatus, a Tunisian herb that has a long history of use for purposes such as flavoring food, medicines, cosmetics, and perfumes.166 Toujani et al.166 prepared aqueous and ethanolic extracts as well as an essential oil from aerial parts of T. capitatus and found all 3 exhibited antiviral effects against both HSV-1 and HSV-2. The EC50 and SI values, respectively, against HSV-1 were 23.4 µg/ml and >12.7 for the aqueous extract, 16.6 µg/ml and 3.5 for the ethanolic extract, and 17.6 µg/ml and 6.0 for the essential oil. The EC50 and SI values, respectively, against HSV-2 were 23.6 µg/ml and >12.6 for the aqueous extract, 2.3 µg/ml and 26.8 for the ethanolic extract, and 18.6 µg/ml and 6.9 for the essential oil. These results highlight that HSV-2 is more susceptible to the ethanolic extract of T. capitatus compared to HSV-1, while both viruses showed similar susceptibility to the aqueous extract and essential oil. This could be due to differences in susceptibility to antiviral compounds between the 2 viruses and the concentrations of these compounds in the different extracts.AsiaElanchezhiyan et al.146 observed aqueous extracts of Pongamia pinnata to completely inhibit HSV-1 (strain AC) and HSV-2 (strain HV-219) replication at concentrations of 1 mg/ml and 20 mg/ml, respectively. Experiments were carried out using African green monkey kidney (Vero) cells and the seeds of the plant were used to prepare the extracts. Extracts were added to cells after viral inoculation, and complete inhibition was noted at 24 hours. Extract concentrations lower than 1 mg/ml and 20 mg/ml were less effective.Houttuynia cordata, a traditional medicinal plant in Japan and China, was investigated for its antiviral effects against HSV-1 (strain HF) in human epithelial cervical carcinoma (HeLa) cells.105 Hayashi et al.105 found that a steam distillate of aerial parts of H. cordata was effective at inhibiting viral replication (EC50 = 0.0013% and SI >4.4). Neither plaque formation nor viral adsorption were reduced when HeLa cells were pretreated with the distillate. Yet, incubating the distillate with HSV-1 prior to infection prevented viral adsorption, revealing a direct effect on HSV-1 virions as the inhibitory mechanism of action of H. cordata.Chen et al.106 also tested the antiviral effects of H. cordata, but against HSV-2 (strain G ATCC-VR-734). An aqueous extract of the leaves and stems significantly prevented Vero cell death that is associated with HSV-2 infection, and an IC50 value of 50 µg/ml was determined. In addition, the extract significantly inhibited virus production by more than 3 and 4 logs at doses of 150 µg/ml and 450 µg/ml, respectively. The extract demonstrated inhibition of NF-| B, which is activated during HSV-2 infection and required for viral replication. Time-of-addition experiments revealed the extract was able to elicit similar antiviral effects when added to cells before, during, or just after HSV-2 infection, suggesting H. cordata acts early in viral infection.The anti-HSV mechanism of action of H. cordata was further investigated by Hung et al.107 Vero and 2 types of human epithelial carcinoma cells (Hep-2 and A549) were used in experiments with an aqueous extract of the plant against wild-type HSV-1 (strain F ATCC-VR733), acyclovir-resistant HSV-1, and HSV-2 (strain G ATCC-VR734). The extract was able to inhibit all 3 HSV strains. The EC50 and SI values, respectively, were determined to be 0.692 mg/ml and 144.51 for wild-type HSV-1, 1.11 mg/ml and 90.09 for acyclovir-resistant HSV-1, and 0.3 mg/ml and 333.33 for HSV-2. It is interesting to note that the EC50 values were similar for the wild-type and acyclovir-resistant strains of HSV-1, suggesting H. cordata elicits antiviral effects through a different mechanism than acyclovir. Tests using Vero cells revealed the extract likely affects HSV virions directly, interfering with viral binding and penetration, blocking viral entry, and suppressing viral replication and gene expression. This multi-stage inhibition was also observed in HEp-2 and A549 cells. Similar to the previous study, the extract was also found to inhibit NF-kB activation. The authors conclude that H. cordata elicits anti-HSV effects through several mechanisms, which makes it a good candidate for treating HSV infections.Moreover, Kurokawa et al.33,98 tested a wide variety of Asian plants for anti-HSV-1 activity and reported findings in 2 studies. Hot water was used as the solvent for the plant extracts in both studies. In the first study, Kurokawa et al.33 tested antiviral activities of 142 extracts against HSV-1 (strain 7401 H). Extracts that showed 100% of plaque inhibition without any visible cytotoxicity at a dose of 100 µg/ml were Elaeocarpus grandiflorus and Woodfordia floribunda. On the other hand, extracts that showed 100% of plaque inhibition without any visible cytotoxicity at a dose of either 300 or 500 µg/ml were Alpinia officinarum, Brainia insignis, Drynaria fortunei, Geum japonicum, Juglans mandshurica, Polygonum cuspidatum, Prunella vulgaris, Rheum palmatum, Spatholobus suberectus, and Terminalia chebula. In the second study, Kurokawa et al.98 tested antiviral activities of 10 extracts in combination with acyclovir. Acyclovir and extracts were combined at their respective EC50 concentrations and tested against HSV-1 strain 7401 H. The acyclovir-extract combinations that reduced viral plaques to less than 10% of controls were G. japonicum, Rhus javanica, Syzygium aromaticum, and T. chebula. Further experiments revealed that the acyclovir-extract combination elicited stronger antiviral effects than either acyclovir or extract alone, suggesting synergistic activity. No acyclovir-extract combination was more cytotoxic to cells at concentrations lower than the extract alone. Additionally, G. japonicum, R. javanica, S. aromaticum, and T. chebula extracts were tested alone against 2 acyclovir-resistant HSV-1 strains. All 4 extracts were observed to elicit similar antiviral effects on the resistant strains compared to the wild-type strain.Abdul et al.34 tested ethanolic extracts of 61 plants that are commonly used in Malaysian indigenous medicine for their antiviral properties against HSV-1. The plant extracts that showed anti-HSV activity were Alternanthera sessilis, Blumea chinensis, Calotropis gigantea, Costus speciosus, Eleusine indica, Eugenia michelii, Euphorbia hirta, Freycinetia malaccensis, Hedyotis auricularia, Leea indica, Mentha arvensis, Orthosiphon aristatus, Polygonum minus, Ricinus communis, and Solanum americanum. The minimum inhibitory concentration (MIC) for these extracts ranged 0.001-0.01 mg/ml. Furthermore, assays using HeLa cell lines were performed with these plant extracts to test for cytotoxicity. Of the 15 extracts, only E. michelii, M. arvensis, F. malaccensis, and P. minus showed cytotoxicity, with CD50 values ranging 0.05-0.1 mg/ml.Methanolic extracts of 21 plants native to Nepal that are traditionally used to treat bacterial, fungal, or viral infections were examined for antiviral activity against HSV-1 by Taylor et al.36 Assays were performed in the presence of UV-A light, visible light, and darkness to allow for assessment of photosensitive constituents. Four extracts showed 100% viral inactivation at a variety of doses and light conditions: Macaranga pustulata (200 µg/ml in all 3 light conditions), Hypericum cordifolium (50 µg/ml in all 3 light conditions), Maesa macrophylla (100 µg/ml in all 3 light conditions), and Sibbaldia micropetala (200 µg/ml in all 3 light conditions and 100 µg/ml in visible light only). Additionally, 5 extracts were able to partially inhibit HSV-1 at varying doses and light conditions: Hypericum uralum (200 µg/ml in all 3 light conditions), Centipeda minima (13 µg/ml in all 3 light conditions), Corallodiscus lanuginosus (100 µg/ml in visible light only), Anemone obtusiloba (100 µg/ml in all 3 light conditions), and Princepia utilis (200 µg/ml in UV-A and visible light only). Most of the extracts studied exhibited no cytotoxicity up to a dose of 200 µg/ml; however, H. cordifolium, M. macrophylla, and A. obtusiloba showed cytotoxicity at this dose. Additionally, C. minima exhibited cytotoxicity at a dose of 25 µg/ml.Padma et al.38 observed an ethanolic extract of Annona muricata and an aqueous extract of Petunia nyctaginiflora, both at 1 mg/ml, to have total cytopathic effect against HSV-1 (strains 753166 and A-16). The stembark of A. muricata and aerial parts of P. nyctaginiflora were used to create ethanolic and aqueous extracts for both herbs. At the noted concentration of 1 mg/ml, no cytotoxicity to Vero cells was noted. The authors conclude that these 2 herbs have the potential to be used as antiherpetic drugs.Furthermore, aqueous and methanolic extracts of 30 Indonesian medicinal plants were tested for antiviral effects against HSV-1 (strain 7401 H) by Nawawi et al.92 At a concentration of 100 µg/ml, the following extracts inhibited 100% of plaque formation and their IC50 values were subsequently determined: the methanolic extracts of Eurycoma longifolia (IC50 = 62 µg/ml), Filicium decipiens (IC50 = 68 µg/ml), Garcinia mangostana (IC50 = 40 µg/ml), and Toona sureni (IC50 = 37 µg/ml); and the aqueous and methanolic extracts of Nephelium lappaceum (IC50 = 62 µg/ml and 70 µg/ml, respectively) and Punica granatum (IC50 = 68 µg/ml and 64 µg/ml, respectively). All extracts showed no cytotoxicity at 100 µg/ml except for T. sureni.Yoosook et al.53 tested the antiviral effects of Barleria lupulina and Clinacanthus nutans against standard HSV-2 (strain G) and 5 clinical HSV-2 isolates. Methanolic extracts were created from leaves of twigs of B. lupulina and the whole plant of C. nutans. B. lupulina was ineffective at inhibiting plaque formation in cells infected with HSV-2 strain G, but showed antiviral activity against the 5 HSV-2 isolates with EC50 values ranging 442.1-987.7 µg/ml. These doses are significantly below the cytotoxicity value found for the herb (CC50 = 2.64 mg/ml). Acyclovir was tested as a control and showed much greater antiviral activity against all HSV-2 strains with EC50 values ranging 1.9-13.6 µM. C. nutans did not exhibit any antiviral activity against plaque formation. In yield reduction assays, cells were treated with the extracts and acyclovir at various concentrations for either 8 or 24 hours. B. lupulina was able to reduce viral titers of all HSV-2 strains to 0.05-12.7% of control yields at 8 hours with doses ranging 0.25-1 mg/ml. C. nutans exhibited antiviral activity only at 24 hours, reducing viral titers to less than 2% of control yields at its highest non-cytotoxic dose (dose not specified). Treatment with 2.5 µM of acyclovir reduced virus titers to 14.2-43.9% of control yields at 8 hours compared to 0.1-5.3% at 24 hours.C. nutans was also studied by Kunsorn et al.71 that used n-hexane, dichloromethane, and methanol as solvents to create extracts that were tested against HSV-1 (strain KOS) and HSV-2 (strain Baylor 186). Extracts of Clinacanthus siamensis, prepared with the same solvents, were concurrently tested for anti-HSV-1 and anti-HSV-2 effects. All extracts exhibited antiviral activity to different degrees. The most potent extract against HSV-1 was the n-hexane extract of C. nutans (IC50 = 32.05 µg/ml and SI >50.36) followed by the methanolic extract of C. siamensis (IC50 = 37.39 µg/ml and SI >43.52). On the other hand, the most potent extract against HSV-2 was the n-hexane extract of C. siamensis (IC50 = 46.52 µg/ml and SI >34.53). For comparison, the IC50 values for acyclovir were found to be 0.09 µg/ml for HSV-1 and 0.43 µg/ml for HSV-2.In a later study by Yoosook et al.,66 crude water extracts of 8 Thai medicinal plants were evaluated against HSV-1 (KOS strain) and HSV-2 (Baylor 186 strain). Extracts of Centella asiatica, Mangifera indica, and Madura cochinchinensis showed antiviral activity against both viruses. EC50 and SI values, respectively, against HSV-1 were 362.40 µg/ml and 3.9 for C. asiatica, 23.94 µg/ml and 29.5 for M. indica, and 20.19 µg/ml and 8.8 for M. cochinchinensis. EC50 and SI values, respectively, against HSV-2 were 298.84 µg/ml and 4.7 for C. asiatica, 31.83 µg/ml and 22.2 for M. indica, and 68.32 µg/ml and 2.6 for M. cochinchinensis. This was compared to the efficacy of acyclovir that showed EC50 values of 0.14 µg/ml and 0.15 µg/ml for HSV-1 and HSV-2, respectively. Combinations of the extracts and acyclovir were also studied. The combination of C. asiatica and M. indica was shown to exert an additive effect on HSV-2, and each extract with acyclovir resulted in complementary or boosted antiviral effects if the dose of acyclovir was high enough. These results suggest that C. asiatica, M. indica, and M. cochinchinensis may be of use alone or combined for treatment of HSV infections.Furthermore, the effect of 31 Chinese herbs known for their antipyretic and anti-inflammatory actions were studied for their actions against HSV-1 by Hsiang et al.118 Methanolic extracts of the herbs were first tested, and those that exhibited inhibitory effects on viral plaques were subsequently made into extracts using cold water, hot water, ethanol, ethanolic acid, and methanol. Significant reduction in plaque numbers were achieved with the ethanolic extract of Rheum officinale (EC50 = 0.12 µg/ml and SI = 8.3), hot water extract of Sophora flavescens (EC50 = 0.41 µg/ml and SI = 8.4), hot water (EC50 = 0.20 µg/ml and SI = 9.1), cold water (EC50 = 0.36 µg/ml and SI = 8.4), and methanolic (EC50 = 0.06 µg/ml and SI = 12.3) extracts of Paeonia suffruticosa, and methanolic (EC50 = 0.03 µg/ml and SI = 8.0) and ethanolic acid (EC50 = 0.02 µg/ml and SI = 8.0) extracts of Melia toosendan. The authors deemed a SI of 8.0 or greater as being significant. Subsequent testing revealed greater than 95% of inhibition of viral attachment with the aqueous and methanolic extracts of P. suffruiticosa, ethanolic acid extracts of M. toosendan, and ethanolic extract of R. officinale. Also, inhibition of 65% of viral penetration was observed with methanolic extracts of P. suffruticosa and the ethanolic extract of R. officinale. The authors concluded that the studied herbs acted as antiviral agents at various stages of HSV-1 infection, therefore herpes simplex infections may be treated by different herbs at different times during the viral replication cycle.Kuo et al.147 tested ethanolic extracts of 7 Chinese herbs against HSV-1 (strain KOS) and found only Psychotria serpens, at a dose of 100 µg/ml, to significantly reduce plaque number to almost zero. This effect was similar to that of 10 µM of acyclovir. The IC50 value of the extract of P. serpens was determined to be 58.3 mg/ml. The other herbs, which showed little effect on the virus, were Ampelopsis cantoniensis, Melilotus indicus, Verbena bonariensis, Buddleia asiatica, Ruta graveolens, and Tadehagi triquetrum.Of 8 Indonesian medicinal plants studied by Lohezic-Le Devehat et al.,82 the methanolic extracts of Elytranthe tubaeflora and Melastoma malabathricum showed moderate anti-HSV-1 activity, defined by the authors as having SI values >4. On the other hand, the ethanolic and ethyl acetate extracts of Garcinia griffithii and the methanolic extracts of Elytranthe globosa, Elytranthe maingayi, and Piper aduncum showed modest anti-HSV-1 activity, having SI < 4. Neither methanolic extract of Vitex pubescens nor Scurrula ferruginea was active against HSV-1.Chiang and colleagues investigated the antiviral activities of various Asian plants against HSV-1 (strain KOS) and/or HSV-2 (strain 196) in human skin basal cell carcinoma (BCC-1/KMC) cells in several studies. 40,43,57,54,131,189 The authors used hot water and/or ethanolic extracts and seemed to deem extracts with determined EC50 or IC50 values greater than about 200 µg/ml as having little to mild antiherpetic activity. Extracts that showed potent anti-HSV activity were Boussingaultia gracilis (EC50 = 80.7 µg/ml and SI = 37.6 for HSV-1),43 Serissa japonica (EC50 = 67.5 µg/ml and SI = 23.3 for HSV-1; EC50 = 92.1 µg/ml and SI = 17.1 for HSV-2),43 Blumea lacera (IC50 = 83.2 µg/ml and SI >12.0 for HSV-1; IC50 = 43.3 µg/ml and SI >23.1 for HSV-2),54 Tithonia diversifolia (IC50 = 94.4 µg/ml and SI = 9.9 for HSV-1; IC50 = 34.8 µg/ml and SI = 27.1 for HSV-2),54 and Ocimum basilicum (water extract: EC50 = 90.9 µg/ml and SI = 16.2 for HSV-1, EC50 = 51.4 µg/ml and SI = 28.6 for HSV-2; ethanolic extract: EC50 = 108.3 µg/ml and SI = 6.3 for HSV-1).131 Extracts that exhibited moderate antiviral activity were Bauhinia variegata (EC50 = 182.7 µg/ml and SI = 7.4 for HSV-1; EC50 = 117.1 µg/ml and SI = 11.6 for HSV-2),40 Arachis hypogaea (EC50 = 191.1 µg/ml and SI = 18.3 for HSV-2),40 Boussingaultia gracilis (EC50 = 194.7 µg/ml and SI = 15.6 for HSV-2),43 Ardisia squamulosa (EC50 = 168.5 µg/ml and SI = 10.1 for HSV-1),43 Crossostephium chinense (EC50 = 179.2 µg/ml and SI = 4.0 for HSV-2),43 Caesalpinia pulcherrima (EC50 = 166.8 µg/ml and SI = 16.5 for HSV-1; EC50 = 193.1 µg/ml and SI = 14.2 for HSV-2),57 Ixeris chinensis (IC50 = 154.6 µg/ml and SI >6.5 for HSV-1; IC50 = 120.7 µg/ml and SI >8.3 for HSV-2),54 and Senecio scandens (IC50 = 197.6 µg/ml and SI >5.1 for HSV-2).54 The EC50 and SI values of acyclovir, as comparison, ranged 0.61-7.6 µg/ml and 20.3-45.1 for HSV-1 and 0.81-4.7 µg/ml and 32.8-58.9 for HSV-2, respectively. 40,43,57,131,189 Herbs that had little to mild antiherpetic activity were Bidens pilosa,43,54,189 Houttuynia cordata,189 Adenanthera pavonia,40 Bauhinia purpura,40 Desmodium caudatum,40 Desmodium triforum,40 Glycine max,40 Pisum sativum,40 Artemisai princeps,43 Cinnamomum camphora,43 Jasminum sambac,43 Basella rubra,43 Drymaria cordata,43 Portulaca grandiflora,43 Rosa rugosa,43 and Eclipta prostrata.54Moreover, Lipipun et al.28 explored the ability of 20 Thai medicinal plants to work as antivirals against 3 strains of HSV-1. Vero cells infected with wild-type HSV-1 (strain 7401 H) were treated with water, ethanolic, or chloroform plant extracts at a dose of 100 µg/ml. The extracts found to reduce plaque formation by at least 50%, therefore classified by the authors as having antiviral activity against HSV-1, were Aglaia odorata, Cerbera odollam, Harpullia arborea, Ventilago denticulata, Azadirachta indica, Protium serratum, Rinorea anguifera, Hura crepitans, Schima wallichi, and Moringa oleifera. The strongest antiviral effects were noted by the extracts of A. odorata, C. odollam, and V. denticulata that inhibited 100% of plaques at the 100 µg/ml dose. Furthermore, these 3 extracts were assessed for antiviral activity against thymidine kinase-deficient and phosphonoacetate-resistant HSV-1 strains and compared to the wild-type 7401 H strain. The use of acyclovir as a positive control showed that a higher dose of the drug was required to reduce plaque formation of the 2 resistant strains compared to wild-type HSV-1. It was observed that M. oleifera was most effective against the phosphonoacetate-resistant strain (EC50 = 43.5 µg/ml and SI = 20.1), and V. denticulata worked equally as well with all 3 strains (EC50 and SI ranged 42.0-52.0 µg/ml and 16.1-20.0, respectively). However, A. odorata was less effective with the thymidine kinase-deficient strain (EC50 = 24.5 µg/ml and SI = 12.7) than the wild-type (EC50 = 9.5 µg/ml and SI = 32.8) or phosphonoacetate-resistant (EC50 = 10.8 µg/ml and SI = 28.9) strains.Tiwari et al.49 also explored the anti-HSV-1 activity of Azardirachta indica, specifically focusing on the mechanism of action. Aqueous extracts of the plant’s bark at concentrations ranging 50-100 µg/ml were observed to block entry of HSV-1 (strain KOS) into Chinese hamster ovary (CHO-K1), HeLa, Vero, and retinal pigment epithelial (RPE) cells. Experiments using different HSV-1 strains (F, G, MP, and 17) revealed A. incida was not strain-specific as its inhibitory effects were similar toward each strain. The extract blocked the attachment of HSV-1 virions to cells, and when cells were pretreated with the extract, viral glycoprotein mediated cell-cell fusion was inhibited. To note, A. incida was only shown to inhibit viral entry when HSV-1 was pretreated with the extract and not when cells were pretreated, suggesting activity is to due effects on viral particles.Of the 21 Chinese medicinal herbs tested by Li et al.,29 aqueous extracts of Agrimonia pilosa, Pithecellobium clypearia, and Punica granatum showed antiviral activity against different strains of HSV-1 (strain 15577). These 3 extracts showed IC50 values ranging 62.5-125 µg/ml and SI values ranging 4-12 against the standard strain. Additionally, the extracts’ IC50 values ranged 62.5-125 µg/ml and 50-125 µg/ml against the acyclovir-resistant and clinical strain, respectively. While each plant extract was effective against all HSV-1 strains, A. pilosa was most effective against the acyclovir-resistant strain (IC50 = 100 µg/ml and SI = 5), P. clypearia against the standard strain (IC50 = 62.5 µg/ml and SI = 4), and P. granatum against the clinical strain (IC50 = 50 µg/ml and SI = 20).Water and ethanolic extracts of Youngia japonica showed no activity against HSV-1 (strain 15577) in a study conducted by Ooi et al.190 Conversely, Kuo et al.130 found an ethanolic extract of Nelumbo nucifera at a dose of 100 µg/ml inhibited 100% HSV-1 plaque formation in HeLa cells. The extract’s IC50 value was determined to be 50.0 µg/ml.Vijayan et al.76 found potent antiviral activity against HSV-1 from a methanolic extract of Hypericum mysorense (IC50 = 100 µg/ml and SI = 1.2), a methanolic extract of Hypericum hookerianum (IC50 = 50 µg/ml and SI = 2.4), and an acetone and chloroform extract of Usnea complanta (IC50 = 100 µg/ml and SI = 1.2). Virus yield reduction assays revealed H. mysorense and H. hookerianum as the only plant extracts to offer 100% protection from viral particles. Partial anti-HSV activity was noted from an alcoholic and ethyl acetate extract of Melia dubia, a methanolic extract of Cryptostegia grandiflora, and the essential oil of Rosmarinus officinalis. The authors tested a total of 18 plants from Nilgiris, but besides those mentioned, no others exhibited antiherpetic activity.Moreover, an ethyl acetate extract of Euphorbia thymifolia was assessed for inhibitory effects on HSV-2 multiplication by Yang et al.91 E. thymifolia is a widespread herb in Taiwan that is used traditionally for many functions including diuretic, detoxifying, antimalarial, and antidysentery. A negative correlation was observed between the concentration of the extract and the level of HSV-2 multiplication. The ethyl acetate extract was able to substantially decrease HSV-2 infectivity when administered at high concentrations including 2.0, 4.0, and 8.0 µg/ml. Increasing the temperature at which the extract was incubated with the infected cells was not observed to alter inhibitory activity; however, the longer the extract was incubated with the infected cells the more viral inhibition occurred. It was concluded that by inhibiting HSV-2 infectivity, E. thymifolia was able to successfully reduce viral multiplication.In the same year, Yang et al. studied extracts of Phyllanthus urinaria for antiviral effects against HSV-1 (strain KOS) and HSV-2 (strain 196).141 Extracts were made from whole plant parts and various solvents including acetone, benzene, chloroform, ethanol, ethyl acetate, n-hexane, and methanol. At a dose of 10 µg/ml, moderate HSV-1 plaque inhibition was observed from the acetone (31.4%), ethanolic (40.4%), and methanolic (41.3%) extracts. However, these 3 extracts, at the same dose, inhibited greater than 90% of HSV-2 plaques. The IC50 and SI values, respectively, against HSV-2 were determined to be 4.3 µg/ml and 3.5 for the acetone extract, 5.0 µg/ml and 4.0 for the ethanolic extract, and 4.0 µg/ml and 4.1 for the methanolic extract. For comparison, acyclovir at a dose of 0.05 µg/ml inhibited close to 90% of HSV-1 and HSV-2 plaques. Time-of-addition experiments showed that HSV-2 was suppressed the most when extracts were added to cells just after viral infection and effects were greatly reduced if added pre- or post-viral infection. The authors also tested whether lowering the incubation time or temperature affected the HSV-2 virucidal activity of the 3 extracts and found that it did not affect it significantly.Tan et al.138 tested other plants from the genus Phyllanthus, including Phyllanthus urinaria, against HSV-1 and HSV-2. Whole plant aqueous extracts of P. amarus, P. niruri, P. urinaria, and P. watsonii were tested. All extracts inhibited viral replication of both HSV-1 and HSV-2 with IC50 and SI values ranging 11.9-39.5 µg/ml and 12.7 to >33.6, respectively. Of the 4 extracts, P. urinaria demonstrated the highest SI against both viruses (>33.6 for both). It was also found that the extracts exhibited more potent antiviral effects on HSV-1 than HSV-2. Moreover, time-of-addition experiments found that all 4 extracts inhibited viral replication most effectively when introduced to cells at inoculation or post-infection, but not when introduced pre-infection.Moderate anti-HSV-1 and anti-HSV-2 activity of a methanolic extract of Ophirrhiza nicobarica was observed by Chattopadhyay et al.132 At a concentration of 300 µg/ml, the maximum nontoxic concentration, the extract completely inhibited plaque formation of both viruses. Pretreatment of the cells with the extract prior to viral infection did not decrease viral penetration or adsorption, nor did pretreatment of the virus reduce infectivity.Mothana et al.56 tested hot aqueous and methanolic extracts of 25 plant species gathered from the island Soqotra in Yemen against HSV-1 (strain KOS). The strongest antiviral effects were noted by the methanolic extracts of Boswellia elongata (SI not reported), Buxus hildebrandtii (SI = 71.4), and Euryops arabicus (SI not reported), each demonstrating an IC50 value of 0.35 µg/ml. The methanolic extract of Cissus subaphylla also showed promising anti-HSV-1 activity with an IC50 of 0.7 µg/ml (SI not reported). For comparison, the IC50 value of acyclovir was calculated as 0.7 µg/ml. Experiments were recreated with tenfold higher viral counts, and the extracts of B. elongata and B. hildebrandtii maintained their strong antiviral effects. Other methanolic extracts that showed inhibition of HSV-1 were Boswellia ameero, Cassia socotrana, Cissus hamaderohensis, Commiphora parvifolia, Dracaena cinnabari, Exacum affine, Fagonia luntii. Jatropha unicostate, Kalanchoe farinacea, Pulicaria stephanocarpa, Trichocalyx obovatus, Withania adunensis, and Zygophyllum quatarense with IC50 values ranging 1.5-25 µg/ml. Additionally, the hot aqueous extracts of Dorstenia socotrana, P. stephanocarpa, and Punica protopunica were active against HSV-1, but were less potent with IC50 values of 32.1 µg/ml, 50 µg/ml, and 5.8 µg/ml, respectively.Furthermore, Aloe vera was studied by Zandi et al.30 for its effect against HSV-2 infection by administering a crude hot glycerine extract to infected Vero cells at different times during infection. The extract was found to elicit complete cytopathic effects on HSV-2 at a concentration of 700 µg/ml when added at viral inoculation, and the IC50 and SI values were determined to be 428 µg/ml and 7.56, respectively. When the extract was added after the viral attachment stage, a dose of 850 µg/ml entirely prevented the cytopathic effect of HSV-2. The IC50 and SI values were determined to be 536 µg/ml and 6.04, respectively.The anti-HSV-1 activities of the Indian medicinal plant Swertia chirata were examined by Verma et al.161 Water extracts using dried powder of the leaves and stems of the plant were prepared to a total concentration of 1 g/ml. Subsequent dilutions and treatment to cells showed that the extract inhibited plaque formation by more than 70% at a dilution of 1:64. Adding the extract at 4, 8, and 24 hours after infection showed the greatest reduction in infected cells at 4 hours. Additionally, no genetic material amplification was found at 12, 24, 48, or 72 hours after simultaneous HSV-1 infection and S. chirata treatment.Kuo et al.116 investigated the antiviral activity of a methanolic extract of Lobelia chinensis against HSV-1 (strain KOS) in HeLa cells. The extract was found to inhibit plaque formation, demonstrating IC50 and SI values of 139.2 µg/ml and approximately 22.5, respectively. Time-of-addition experiments revealed the extract is effective if added in the window of 0-8 hours post-infection. Additionally, experiments revealed that L. chinensis is able to block HSV-1 replication, likely by impairing DNA synthesis.Three different extracts of Cedrus libani, commonly known as Cedar of Lebanon, were observed to have antiviral activity against HSV-1 (strain F) by Loizzo et al.65 The extracts tested were as follows: ethanolic extract of the plant’s leaves, ethanolic extract of the plant’s cones, and essential oil from the plant’s bark. The 3 extracts demonstrated similar antiviral effects with IC50 and SI values ranging 0.44-0.66 mg/ml and 1.74-2.91, respectively. For comparison, the IC50 value and therapeutic index of acyclovir was found to be 3.77 µM and >27, respectively.Wang et al.137 investigated the antiviral effect of an ethanolic extract of the bark of Phellodendron amurense, a herb that is considered as one of the 50 fundamental herbs in China. The extract’s maximum non-cytotoxic dose was determined as 44.12 µg/ml and was tested at different stages during HSV-1 infection. Pretreatment of cells with the extract only inhibited about 10% of HSV-1 plaques, but pretreatment of HSV-1 resulted in 74% inhibition of plaque formation. Addition of the extract during the viral adsorption and replication inhibited plaques by 10-15%. Acyclovir was also tested and found to inhibit over 90% of plaques only when added during viral replication. These results suggest that P. amurense elicits effects prior to viral infection and acyclovir elicits effects after infection.Two other Chinese medicinal herbs, Radix isatidis and Viola yedoensis, were tested for antiviral activity against HSV-1 by Liao et al.171 Experiments were conducted with infection of the KOS strain of HSV-1 into human neuroblastoma (SK-N-SH) cells and treatment with 600 µg/ml of aqueous extracts of the root of R. isatidis and the whole plant of V. yedoensis. Only V. yedoensis showed inhibition of viral replication. Antiviral effects were similar when the cells were pretreated with the extract 6 hours before infection and treatment to cells 4 hours post-infection. The authors suggested that the mechanism of action is likely not one of direct inactivation of HSV-1.Aqueous and ethanolic extracts of Cajanus cajan, commonly known as pigeon pea, exhibited antiviral effects against both HSV-1 (strain KOS) and HSV-2 (strain HG52).58 Zu et al.58 found both viruses to be more susceptible to the ethanolic extract (IC50 = 0.022 µg/ml and SI = 618.2 for HSV-1; IC50 = 0.10 µg/ml and SI = 136.0 for HSV-2) compared to the aqueous extract (IC50 = 14.93 µg/ml and SI >15 for HSV-1; IC50 = 2.33 µg/ml and SI >100 for HSV-2). The ethanolic extract showed greater antiviral activity than acyclovir (IC50 = 0.59 µg/ml and SI >55.9 for HSV-1; IC50 = 0.62 µg/ml and SI >53.2 for HSV-2). Time-response assays showed 90% plaque inhibition after a treatment duration of 10 minutes with the ethanolic extract and 60 minutes with the aqueous extract. Additionally, the extracts were added at different times during viral infection. Both extracts significantly reduced plaque formation by 95-99% only when either HSV-1 or HSV-2 was pretreated with the extract. When the extracts were added during HSV-2 adsorption, plaque formation was inhibited by about 45-60%. Acyclovir was antiviral when added post-infection, during viral intracellular replication. These results suggest that C. cajan elicits its antiviral effects directly on HSV virions.Arabzadeh et al.173 observed a methanolic extract of Zataria multiflora to significantly inhibit HSV-1 (strain KOS) plaque formation at doses below its maximum non-toxic concentration (1000 µg/ml). When the extract was added to cells during viral adsorption at doses of 800 µg/ml, 500 µg/ml, and 250 µg/ml, inhibition of 100%, 93.2%, and 86.2%, respectively, of HSV-1 plaques was observed. Additionally, the extract was added to cells at 1, 2, and 3 hours after viral infection, and 100% plaque inhibition was observed with all doses, which ranged 250-1000 µg/ml.Moreover, a methanolic extract of Achyranthes aspera was investigated for antiviral effects against HSV-1 (strain F) and HSV-2 (strain G) by Mukherjee et al.24 The extract inhibited HSV plaque formation in a dose-dependent manner with 100% inhibition of HSV-1 and HSV-2 noted at 112.5 µg/ml and 120 µg/ml, respectively. The EC50 and SI values, respectively, of the extract were determined to be 64.4 µg/ml and 10.2 for HSV-1 and 72.8 µg/ml and 9.0 for HSV-2. For comparison, acyclovir was found to have EC50 and SI values, respectively, of 2.1 µg/ml and 61.9 for HSV-1 and 2.9 µg/ml and 44.8 for HSV-2. Time-of-addition experiments revealed that A. aspera elicits its antiviral effects post-infection for both viruses with little inhibition noted before or at the time of infection.The ability of Camellia sinensis, Nerium oleander, and Echium amoenum to prevent HSV-1 (strain KOS) multiplication was explored by Farahani et al.59 The plants were individually extracted using a decoction method to yield aqueous extracts, and Hep-2 cells were used to test for cytotoxicity. It was observed that N. oleander was toxic to cells at all concentrations and therefore was not used in the antiviral assays. Antiviral activity of the other 2 extracts were measured at 1, 2, and 3 hours post-treatment. Significant antiviral effects of C. sinensis were observed at one (IC50 = 20 µg/ml and SI = 50) and 2 (IC50 = 60 µg/ml and SI = 16.7) hours post-treatment, but activity was decreased by the third hour (IC50 = 480 µg/ml and SI = 2.1). E. amoenum was found to be antiviral during the first hour (IC50 = 350 µg/ml and SI = 2.9), but less so than C. sinensis. It was concluded that C. sinensis is an effective treatment to inhibit HSV-1 multiplication within 1 hour.Cho et al.83 found an aqueous extract of Epimedium koreanum to inhibit HSV multiplication in both mouse macrophages (RAW264.7) and human embryonic kidney (HEK293 T) cells. The type of HSV virus used in the experiments was not specified. The virus was more susceptible to the extract in mouse macrophages (EC50 = 0.62 µg/ml and SI = 23.5) than in human embryonic kidney cells (EC50 = 1.41 µg/ml and SI = 5.9). At an extract dose of 1 µg/ml, E. koreanum was able to reduce viral titers 2-fold in both RAW264.7 and HEK293 T cells when compared to control.Pedilanthus tithymaloides demonstrated strong antiviral activity against HSV-2 (strain G), 2 HSV-2 clinical isolates, and a thymidine kinase-deficient strain of HSV-2.134 Ojha et al.134 found that EC50 values for a methanolic extract of the plant ranged 48.5-52.6 µg/ml for the 4 viral strains with SI values of 8.29-9.00. The extract inhibited 99% of HSV-2 multiplication at a dose of 86.5 µg/ml by 2-4 hours post-infection. Acyclovir was tested as a control and shown to have EC50 values of 2.6-2.8 µg/ml and SI values of 46.00-49.53 for strain G and one of the clinical isolates. Further testing revealed the extract was able to inhibit NF-eB, which is activated during HSV-2 infection and required for viral replication.Indigofera heterantha, a common plant in the western Himalayan region, was tested for antiviral activity against HSV-2 (strain G) by Kaushik et al.110 Hydromethanolic extracts of the root, twig, and stem of the plant were separately prepared. The root extract exhibited the strongest antiviral activity of the 3 extracts with IC50 and SI values of 284.2 µg/ml and 13.3, respectively. A subsequent study by the authors showed the extract elicits its effect early in the viral replication cycle by blocking HSV-2 attachment, adsorption, and entry into host cells.191Furthermore, He et al.39 observed an ethanolic extract of the fungus Antrodia camphorata to have antiviral activity against HSV-1 (strain F) and HSV-2 (strain G). Although not nearly as potent as acyclovir, A. camphorata was found to inhibit viral plaque formation with IC50 values of 61.2 µg/ml and 57.5 µg/ml for HSV-1 and HSV-2, respectively. In addition, the SI values for the extract were determined as 7.92 for HSV-1 and 8.43 for HSV-2. For comparison, the IC50 and SI values, respectively, for acyclovir were determined as 2.1 µg/ml and 61.9 for HSV-1 and 2.9 µg/ml and 44.8 for HSV-2.A methanolic extract of Euphorbia spinidens was tested for its ability to act as an antiviral against HSV-1 (strain KOS) by Karimi et al.90 It was observed that the extract was able to inhibit HSV-1 in a dose-dependent manner, but was not as effective as treatment with acyclovir. The EC50 and SI values, respectively, were determined to be 0.34 µg/ml and 14.9 for E. spinidens and 0.028 µg/ml and >178.6 for acyclovir. Time-of-addition experiments revealed that application of the extract at a concentration of 5 mg/ml was most effective at inhibiting the virus within the first 2 hours of its life cycle, demonstrating a total of 70% inhibition. The authors conclude that the extract of E. spinidens may inhibit HSV-1 adsorption and early stages of viral replication.Karimi et al.148 also tested anti-HSV-1 activity of Quercus brantii. A crude extract of the plant’s acorns was prepared using ethyl alcohol, and effects against HSV-1 (strain KOS) were examined in baby hamster kidney (BHK) cells. The extract exhibited antiviral activity against HSV-1 (IC50 = 4.3 µg/ml and SI = 48.4), but was not more potent than acyclovir (IC50 = 1.3 µg/ml and SI = 136.5). Additional experiments found that the greatest viral inhibition occurred when the extract was present both during and after adsorption.Various extracts of Ficus religiosa, commonly known as sacred fig or bodhi tree, showed antiviral activity against HSV-2 (strain MS) and an acyclovir-resistant HSV-2 strain.95 Ghosh et al.95 prepared several extracts using either the leaves or bark of the plant with water, methanol, ethyl acetate, or chloroform as solvents. Extracts from the bark showed more potent antiviral activity against the regular strain compared to leaf extracts. Most notable were the water (EC50 = 9.76 µg/ml and SI = 156.8) and chloroform (EC50 = 6.75 µg/ml and SI = 119.9) bark extracts. These extracts were not as strong as acyclovir, which showed an EC50 value of 0.64 µg/ml and a SI of >468. Against the acyclovir-resistant strain, the water bark extract showed the most potent antiviral activity (EC50 = 6.28 µg/ml and SI = 243.6). These values suggest that the water bark extract elicited more potent antiviral effects against acyclovir-resistant HSV-2 compared to a wild-type HSV-2. Further testing revealed inhibition of HSV-2 by the water bark extract occurred by inactivating virions prior to infection while the chloroform bark extract elicited its effect by inhibiting viral attachment and/or entry into cells.Sakagami et al.155 investigated the antiviral activity of an alkaline water extract of Sasa senanensis leaves against HSV-1 (strain F). They observed the extract to have anti-HSV activity with an SI of 6-7. The extract was also tested in combination with acyclovir, which showed a synergistic effect.Very potent anti-HSV-2 activity was observed by a 50% ethanolic extract of the fruits of Terminalia chebula by Kesharwani et al.165 The extract demonstrated an IC50 of 0.01 µg/ml and a SI of over 40,000 against HSV-2 (strain G ATCC-VR-734), which made it significantly more potent than acyclovir (IC50 = 29.04 µg/ml and SI = 12.1). Pretreatment of the virus with the extract showed significant viral inhibition. This effect was attributed to the extract’s ability to inhibit viral attachment and penetration into host cells. Conversely, the extract was less effective when added to cells post-infection.A hydromethanolic extract of Hemidesmus indicus root was observed to inhibit both HSV-1 and HSV-2 replication to a similar degree.104 Bonvicini et al.104 tested antiviral activity when cells were pretreated with the extract, when the extract was added to cells at and post-infection, and when virions were pretreated with the extract. When the extract was added to cells at the time of infection, the EC50 values of the extract were determined as 66.8 µg/ml and 70.6 µg/ml for HSV-1 and HSV-2, respectively. With treatment post-infection, the extract’s EC50 values were determined as 91.3 µg/ml and 86.1 µg/ml for HSV-1 and HSV-2, respectively. No effect on viral replication was observed when cells were pretreated with the extract. Inhibitory effects were markedly stronger when virions were pretreated with the extract. These results indicate that H. indicus is able to inhibit HSV throughout the infection cycle, but effects are more potent pre-infection. Further pre-infection testing revealed the extract specifically inhibits viral attachment. Viral entry is also inhibited by the extract, but only at higher concentrations. Interestingly, the extract’s inhibitory effects were stronger in the second round of infection compared to the first.Moreover, a chloroform fraction of an ethanolic extract of Arisaema tortuosum leaves demonstrated antiherpetic activity as investigated by Ritta et al.44 Initially, cytotoxicity of A. tortuosum leaves and tubers were assessed using separate ethanolic extracts. The ethanolic extract of the leaves was found to be less toxic and was further fractionated with n-hexane, chloroform, ethyl acetate, and n-butanol. All fractions were found to be highly toxic except for the chloroform fraction, which was assessed for antiviral effects against HSV-1, HSV-2, and an acyclovir-resistant strain of HSV-2. HSV-2 (EC50 = 0.53 µg/ml and SI = 758) and acyclovir-resistant HSV-2 (EC50 = 0.86 µg/ml and SI = 467.4) were more susceptible to the chloroform extract compared to HSV-1 (EC50 = 2.64 µg/ml and SI = 12). The authors note that the chloroform extract was observed to act as a direct virucidal agent as well as inhibit viral attachment, adsorption, and replication.Park et al.81 investigated antiviral effects of methanolic extracts of 5 varieties of marine algae against wild-type (strain 7401 H), thymidine kinase-deficient (strain B2006), and acyclovir and phosphonoacetic acid-resistant HSV-1 strains. All extracts were tested at a dose of 100 µg/ml, and Sargassum ringgoldianum inhibited 100% plaque formation of all 3 HSV-1 strains, but exhibited strong cytotoxicity to Vero cells. Symphyocladia latiuscula demonstrated moderate cytotoxicity, inhibited 100% plaque formation against wild-type HSV-1, and 82.74% against acyclovir and phosphonoacetic acid-resistant HSV-1; however, thymidine kinase-deficient HSV-1 plaques were only inhibited by 38.1%. The IC50 value of S. latiuscula was determined as 56.7 µg/ml (HSV-1 strain not specified). Moderate plaque inhibition was also noted against acyclovir and phosphonoacetic acid-resistant HSV-1 with the extracts of Sargassum thunbergii, Ecklonia stolonifera, and Ulva pertusa, demonstrating 55.99%, 47.79%, and 40.67% inhibition, respectively. S. thunbergii and U. pertusa showed no cytotoxicity, while E. stolonifera was mildly cytotoxic to Vero cells. The methanolic extract of S. latiuscula was successively fractionated into 5 fractions using the following order of solvents: hexane, dichloromethane, ethyl acetate, butanol, and water. The dichloromethanic fraction showed the strongest anti-HSV-1 activity with an IC50 value of 7.73 µg/ml (HSV-1 strain not specified).Another marine algae, Cystoseira myrica, was studied by Zandi et al.77 for antiviral activity against HSV-1 (strain KOS). A hot water extract of the whole plant was prepared and sterilized by 2 methods, filtration and autoclaving. When the extracts were added to cells at the same time of viral inoculation, the IC50 and SI values, respectively, were determined to be 99 µg/ml and 33.4 for the filtered extract and 125 µg/ml and 28.2 for the autoclaved extract. The extracts were less effective when added 2 hours post-inoculation, demonstrating IC50 and SI values, respectively, of 143 µg/ml and 23.1 for the filtered extract and 162 µg/ml and 21.7 for the autoclaved extract.Lastly, Deethae et al.158 created aqueous, ethanolic, and methanolic extracts from the freshwater green algae Spirogyra and investigated antiviral activity against HSV-1 (strain F) and HSV-2 (strain G). Firstly, effects were measured when extracts were added to cells before, during, and after viral attachment. All 3 extracts exhibited their strongest antiviral effects when added to cells during attachment, with HSV-1 being more susceptible to the ethanolic extract (IC50 = 164.20 µg/ml and SI = 2.17) and HSV-2 to the methanolic extract (IC50 = 75.03 µg/ml and SI = 3.34). Moreover, both HSV-1 and HSV-2 virions, when treated with extracts prior to infection, were most strongly inhibited by the methanolic extract. In terms of effects on viral replication, the extracts were able to inhibit HSV yields by 30 hours post-infection. The methanolic extract exhibited the greatest inhibitory effects on HSV-1, and the aqueous extract exhibited the greatest inhibitory effects on HSV-2. When comparing all viral stages tested, the most potent anti-HSV activity was observed during viral attachment.Central America/CaribbeanDel Barrio and Parra139 assessed the antiviral activity of an aqueous extract of the leaves and stems of Phyllanthus orbicularis, a plant native to Cuba, against HSV-2 in human foreskin fibroblast cells. The extract demonstrated EC50 and SI values of 25.7 µg/ml and 26.03, respectively. Direct treatment of HSV-2 virions resulted in a 2 log10 reduction in viral titers with treatment of 5-25 µg/ml of P. orbicularis extract and a 2.75 log10 reduction with 50-75 µg/ml of the extract. The authors suggest that P. orbicularis may elicit its antiherpetic effects by inhibiting virions, either directly or by blocking their entry into host cells.Subsequently, Fernandez Romero et al.140 made the stems and leaves of P. orbicularis into 5 successive extract fractions using the following order of solvents: diethyl ether, chloroform, butanol, 50% ethanol, and an acetic acid/water combination. The butanolic and acetic acid fractions demonstrated significant virucidal activity against acyclovir-sensitive HSV-1 and acyclovir-resistant HSV-1, each in human foreskin fibroblasts and Vero cells. When added to cells at the time of viral infection, the butanolic extract demonstrated EC50 and SI values, respectively, of 30.4-31.3 µg/ml and 21.6-22.8 against acyclovir-sensitive HSV-1 and 32.8-42.5 µg/ml and 15.5-21.8 against acyclovir-resistant HSV-1. The acetic acid extract was not as potent, demonstrating EC50 and SI values, respectively, of 32.5-35.9 µg/ml and 10.3-11.6 against acyclovir-sensitive HSV-1 and 29.4-30.7 µg/ml and 11.3-13.5 against acyclovir-resistant HSV-1. Additionally, extracts were added to virions prior to infection, which showed greater antiviral effects. The acetic acid extract elicited more potent effects against both acyclovir-sensitive HSV-1 (EC50 = 0.47-0.53 µg/ml and SI = 705-785) and acyclovir-resistant HSV-1 (EC50 = 0.40-0.68 µg/ml and SI = 491-1040) compared to the butanolic extract (EC50 = 0.74-1.93 µg/ml and SI = 371-895 for acyclovir-sensitive HSV-1; EC50 = 1.15-1.51 µg/ml and SI = 474-572 for acyclovir-resistant HSV-1). The authors conclude that the butanolic and acetic acid extracts of P. orbicularis may reduce viral adsorption, attachment, or penetration into host cells. They also conclude that the SI values of these 2 extracts were 10-20 times higher than that of the aqueous extract of P. orbicularis used in the study by del Barrio and Parra.139EuropeMuch of the research on European Lamiaceae family herbs is focused on Melissa officinalis. Dimitrova et al.120 explored prophylactic and therapeutic effects of 4 extracts of M. officinalis on HSV-1 (strain DA) using the solvents 50% ethyl alcohol, 50% ethanol, ethyl acetate, and water. When incubated with HSV-1 virions, complete viral inactivation was noted by 3 hours with the water extract and by 12 hours with the non-aqueous extracts. Furthermore, the non-aqueous extracts were added to rabbit kidney (RK) cells pre- and post-infection, but all 3 extracts failed to inhibit viral reproduction.Additionally, Schnitzler et al.122 investigated the antiviral effects of M. officinalis essential oil on HSV-1 (strain KOS) and HSV-2 (strain HG). The essential oil was diluted in up to 1% ethanol. Plaque reduction assays revealed that at a concentration of 0.002% oil, there was a 98.8% reduction of HSV-1 and a 97.2% reduction of HSV-2 titres. At higher doses, the viral infectivity was almost completely absent. The IC50 and SI values, respectively, were calculated to be 0.0004% and 7.5 for HSV-1 and 0.00008% and 37.5 for HSV-2. When HSV-1 and HSV-2 were pretreated with M. officinalis oil at its maximum non-cytotoxic concentration (0.002%), viral infectivity was significantly reduced. However, when the treatment was applied to the viruses during viral adsorption, a moderate reduction in plaque formation of 64.8% and 39.9% for HSV-1 and HSV-2, respectively, was seen. Plaque formation was not affected when RC-37 cells were treated with the essential oil prior to or during infection. The essential oil is highly lipophilic, which the authors proposed as a mechanism by which the active constituents in the oil can be used as a direct antiviral for topical use in humans.Mazzanti et al.123 found that a hydroethanolic extract of M. officinalis elicited significant antiviral effects on HSV-2 after viral penetration. The extract was first tested for cytotoxicity and showed no impairment to cells up to a concentration of 1 mg/ml. When Vero cells were treated with the extract at a dose of 0.5 mg/ml post-infection, the cytopathic effect was reduced by 60%, which was the maximum effect observed. However, incubation of the extract with HSV-2 virions did not reduce viral penetration. The authors suggest that M. officinalis does not bind to HSV-2 to prevent entry into host cells, but elicits its effects after penetration.Research on the antiviral effects of M. officinalis continued to be explored by Astani et al.124 by investigating an aqueous extract of M. officinalis for antiviral activity against HSV-1 (strain KOS). Pretreatment of virions with the extract demonstrated an IC50 and SI of 0.4 µg/ml and 875, respectively, and >99% of viral inactivation was seen at a concentration of 15 µg/ml. Furthermore, the extract inhibited viral attachment to RC-37 cells by 98% at 7.5 µg/ml, a concentration 20 times lower than its maximum non-cytotoxic concentration (150 µg/ml). The authors conclude that since M. officinalis demonstrated both viral inactivation and inhibition of viral attachment, the plant is a good candidate for use as a prophylactic for HSV infections.Nolkemper et al.121 examined the antiviral effects of aqueous extracts from different species in the Lamiaceae plant family, including extracts from M. officinalis, Mentha piperita, Prunella vulgaris, Rosmarinus officinalis, Salvia officinalis, and Thymus vulgaris. All extracts showed inhibitory effects when virions were treated with the extracts pre-infection, but effects were more potent against HSV-1 (strain KOS) compared to HSV-2 (strain HG). From strongest to weakest antiherpetic activity, the extracts were M. piperita (IC50 = 0.041 µg/ml and SI = 2610 for HSV-1; IC50 = 0.227 µg/ml and SI = 471 for HSV-2), M. officinalis (IC50 = 0.025 µg/ml and SI = 2200 for HSV-1; IC50 = 0.027 µg/ml and SI = 2037 for HSV-2), T. vulgaris (IC50 = 0.065 µg/ml and SI = 954 for HSV-1; IC50 = 0.077 µg/ml and SI = 805 for HSV-2), P. vulgaris (IC50 = 0.229 µg/ml and SI = 546 for HSV-1; IC50 = 2.114 µg/ml and SI = 59 for HSV-2), S. officinalis (IC50 = 0.777 µg/ml and SI = 113 for HSV-1; IC50 = 1.359 µg/ml and SI = 65 for HSV-2), and R. officinalis (IC50 = 0.646 µg/ml and SI = 98 for HSV-1; IC50 = 1.055 µg/ml and SI = 60 for HSV-2). Time-of-addition experiments revealed all extracts elicited their strongest antiviral effects when virions were pretreated, and none of the extracts demonstrated an ability to inhibit viral replication if treated post-infection. After treatment of an acyclovir-resistant strain of HSV-1 with maximum non-cytotoxic concentrations of each extract, it was observed that M. piperita and S. officinalis were able to decrease viral infectivity by 85% and 97%, respectively. The authors proposed that aqueous extracts of various species in the Lamiaceae family are able to inhibit HSV adsorption, including strains known to be resistant to pharmaceutical antiviral treatment. As such, these plants may be beneficial as a topical therapeutic treatment to prevent recurrent HSV infections.Moreover, Schnitzler et al.153 found aqueous extracts and multiple ethanolic extracts (20%, 40%, 60%, and 80%) of Salvia officinalis to be antiviral against HSV-1 (strain KOS) and HSV-2 (strain HG). Extracts were made from S. officinalis specimens from 2 geographic locations: the authors’ garden and the Swabian Mountains. When RC-37 cells were pretreated with the extracts, the greatest HSV-2 plaque reduction was seen with the 20% ethanolic extracts of S. officinalis specimens from the garden (94%) and Swabian Mountains (99%). Effects on HSV-1 were significantly weaker. When virions were pretreated with an extract, viral plaques were reduced by 90% and 99% for HSV-1 and HSV-2, respectively, regardless of the location of origin. Each garden extract as well as the aqueous and 40% ethanolic mountain extracts demonstrated stronger antiviral activity against HSV-2 (IC50 = 0.02-3.20 µg/ml and SI = 197-18,345) compared to HSV-1 (IC50 = 0.03-11.18 µg/ml and SI = 56-5463). Conversely, the 20%, 60%, and 80% ethanolic mountain extracts had greater effects on HSV-1 (IC50 = 0.12-0.48 µg/ml and SI = 1135-3755) compared to HSV-2 (IC50 = 0.25-0.64 µg/ml and SI = 865-1802).The authors conclude that the ethanolic extracts were more antiviral than the aqueous extracts, and those made of S. officinalis from the garden had a greater antiviral effect. Therefore, the collection location may play a part in the ability of S. officinalis to act as an antiherpetic treatment.Subsequently, Reichling et al.126 prepared ethanolic extracts of 4 common medicinal plants from the Lamiaceae family and investigated their antiviral activities against HSV-1. The plants tested were Prunella vulgaris, Mentha piperita, Rosmarinus officinalis, and Thymus vulgaris. Two extracts of each plant were prepared using 20% ethanol and 80% ethanol as solvents and tested against acyclovir-sensitive HSV-1 (strain KOS) and acyclovir-resistant HSV-1 (strains Angelotti and 1246/99). A series of dilutions of all extracts were done and tested for viral infectivity. All dilution extracts were effective, even low concentrations of 0.01% almost completely reduced viral infectivity. M. piperita extracts were the most effective against wild-type HSV-1, demonstrating IC50 and SI values, respectively, of 0.06 µg/ml and 7040 for the 20% ethanolic extract and 0.05 µg/ml and 5632 for the 80% ethanolic extract. The other extracts demonstrated IC50 values ranging 0.08-0.82 µg/ml and SI values ranging 90-4530. Moreover, when the extracts were tested against acyclovir-resistant HSV-1, all 80% ethanolic extracts demonstrated complete plaque reduction of both strains. Time-of-addition experiments revealed when host cells were pretreated with the extracts, the 80% ethanolic extracts of P. vulgaris and M. piperita were the only extracts that significantly reduced viral infectivity. When the virus was pretreated, the 20% ethanolic extract of M. piperita and 80% ethanolic extracts of P. vulgaris, M. piperita, and T. vulgaris were effective at entirely reducing viral infectivity. The other extracts were effective at reducing plaques by more than 75%. When the extracts were added during viral adsorption, the 80% ethanolic extracts of P. vulgaris and M. piperita fully suppressed viral infectivity while all other extracts, except the 80% ethanolic extract of R. officinalis, reduced plaque formation by more than 50%. The authors conclude that the 80% ethanolic extracts of M. piperita and P. vulgaris show a dual antiherpetic mechanism of action, and hence are promising candidates for treatment of HSV infections.Another study tested the antiviral activity of M. piperita essential oil against HSV-1 (strain KOS) and HSV-2 (strain HG52).127 Schuhmacher et al.127 found the essential oil, diluted in ethanol, was able to reduce HSV-1 plaque formation by 82% and HSV-2 plaque formation by 92% when virions were pretreated with 0.01% of the oil for 1 hour. The IC50 values for M. piperita against HSV-1 and HSV-2 were calculated as 0.002% and 0.0008%, respectively. When HSV-1 virions were incubated with the essential oil for 3 hours, plaques were reduced by 99%. Time-of-addition experiments revealed the greatest antiviral effects with pretreatment of the viruses with the essential oil and little antiviral activity with pretreatment or post-treatment of host cells. Additionally, pretreatment with the oil, at a concentration of 0.01%, inhibited acyclovir-resistant HSV-1 by 99%. The authors suggest M. piperita elicits antiviral effects by blocking viral adsorption.Lastly, Omidian et al.125 investigated the antiviral effects of a hot water extract of M. piperita at different stages of HSV-1 replication. The extract partially prevented HSV-1 infection when host cells were pretreated (EC50 = 62.70 mg/ml and SI = 1.79) and partially inhibited HSV-1 adsorption (EC50 = 26.65 µg/ml). Addition of the extract after viral adsorption showed viral particles to be completely inactive within 2 hours, and HSV-1 yield was inhibited 30 hours post-infection.Many other European plants that do not belong to the Lamiaceae family have been studied for their antiviral effects. Extracts of Geranium sanguineum were tested by Serkedjieva and Ivancheva97 for their antiviral abilities against HSV-1 (strain KOS) and HSV-2 (strain G) in Vero and human embryonic skin-muscle (E6SM) cells. Five extracts were made with aerial root parts from the early plant and ethanol, methanol, or hydroethanol; overground parts and methanol; and aerial root parts from the late plant and methanol. The strongest antiviral effect was observed by the hydroethanolic extract (EC50 = 5.4 µg/ml and SI = 17.8) and the weakest by the methanolic overground extract (EC50 = 12.1 µg/ml and SI = 5.6). The hydroethanolic extract demonstrated a dose-dependent viral inhibition against HSV-1 and was further tested for virucidal action against HSV-2. HSV-2 showed to be more susceptible to the extract (SI = 27.7) compared to HSV-1. Also, time-of-addition experiments revealed that the hydroethanolic extract only elicits significant antiviral effects when added to cells post-infection, but not when added to cells pre-infection or during viral adsorption or penetration.Subsequently, Serkedjieva145 studied the red algae Polysiphonia denudata for its antiviral effect against 3 HSV-1 strains (KOS, McIntyre, and Kupka) and HSV-2 (strain GC25927). A water extract showed stronger antiherpetic effects against HSV-1 (EC50 = 0.18-0.42 µg/ml and SI = 24.8-47.7) compared to HSV-2 (EC50 = 1.2 µg/ml and SI = 8.7). The antiviral effect differed between the HSV strain and cell type used. For example, the lowest EC50 of 0.18 mg/ml (SI = 47.7) was observed in Vero cells with the Kupka strain of HSV-1, whereas the highest EC50 of 1.2 mg/ml (SI = 8.7) was observed in E6SM cells with the GC25927 strain of HSV-2. The antiviral effect was dose-dependent and at higher concentrations, specifically an MIC90 of 6.5 mg/ml, the water extract was able to act extracellularly and prevent viral adsorption. Time-of-addition experiments demonstrated that the extract had inhibitory effects when added at viral adsorption or post-infection.Serkedjieva67 assessed an additional red algae, Ceramium rubrum, for its antiviral effects against HSV-1 (strain Kupka) in Vero cells, and HSV-1 (strain KOS) and HSV-2 (strain GC25927) in E6SM cells. HSV-1 strain KOS was most susceptible to the C. rubrum water extract (EC50 = 0.5 mg/ml and SI = 10.8), showing dose-dependent direct virucidal activity. The extract was less potent against HSV-1 strain Kupka and HSV-2, demonstrating EC50 and SI values, respectively, of 1.1-1.2 mg/ml and 4.9-5.2.Moreover, dry aqueous extracts of Rhus aromatica, made from the plant’s roots and bark, were studied by Reichling et al.150 for antiherpetic activity against HSV-1 (strain KOS) and HSV-2 (strain HG52). R. aromatica did not significantly decrease infection in cells exposed to virions prior to treatment with the plant extract, however, the extract was shown to significantly decrease plaque formation when incubated with virions pre-infection (IC50 = 0.0005% and SI = 5400 for HSV-1; IC50 = 0.0043% and SI = 628 for HSV-2). HSV-1 was more susceptible to the extract, and when virions were incubated with the extract at a non-cytotoxic dose of 0.0025% for 1 minute, HSV-1 plaques were reduced by 90%.Lazreg Aref et al.94 made 5 different extracts from the latex of Ficus carica and the solvents hexane, ethyl acetate, methanol, chloroform, and hexane-ethyl acetate. None of the extracts showed cytotoxic effects to Vero cells at concentrations up to 100 mg/ml, except 100 mg/ml of the chloroform extract. The hexane and hexane-ethyl acetate extracts showed greatest inhibition of HSV-1 by preventing viral penetration, adsorption, and intracellular replication at all concentrations tested. Specifically, the concentrations of these 2 extracts ranged from 78 µg/ml to 100 mg/ml.Gescher et al.149 observed an aqueous extract made from the aerial parts of Rhododendron ferrugineum to prevent HSV-1 (strain 17 syn+) attachment and penetration into host cells. The extract completely interfered with viral attachment and penetration at concentrations greater than 1 µg/ml and 25 µg/ml, respectively. When virions were pretreated with the extract, antiviral effects corresponded to an IC50 of 7.4 µg/ml and SI of 63.9. The authors suggest that R. ferrugineum directly interacts with the viral envelope to prevent attachment and penetration into host cells.Sarkar et al.112 studied the mycelia of the mushroom Lentinus edodes for antiviral activity against HSV-1 (strain F). L. edodes was cultured, extracted, and filtered with the end product being named JLS-S001. This extract was observed to block the release of HSV-1 particles from cells (EC50 = 20 µg/ml, SI = 40). When cells were pretreated with the extract, viral adsorption was not observed to be prevented.L. edodes, along with other mushrooms, were evaluated for antiherpetic activity by Santoyo et al.55 Water and methanolic extracts were prepared of mushrooms Boletus edulis, L. edodes, and Pleurotus ostreatus. Water extracts exhibited greater virucidal activity than methanolic extracts, but overall effects were low. At a concentration of 3.75 mg/ml, HSV-1 (strain KOS) was inhibited by 50%, 25%, and 15% with the water extracts of L. edodes, B. edulis, and P. ostreatus, respectively, while all methanolic extracts showed 50% inhibition at a concentration of 18.75 mg/ml. Time-of-addition experiments showed that when cells were pretreated with the extracts, viral infection was inhibited by all 3 water extracts by approximately 60% and 90% at concentrations of 75 µg/ml and 100 µg/ml, respectively. The methanolic extracts at concentrations of 100 µg/ml inhibited viral infectivity by 40-50%. The water extracts were also more potent at blocking viral adsorption, demonstrating a 60% and 80% reduction in viral infectivity at concentrations of 50 µg/ml and 75 µg/ml, respectively. Lastly, viral replication was inhibited in a dose-dependent manner more strongly by the water extracts. The IC50 and SI values, respectively, for the water extracts were determined to be 27.04 µg/ml and 14.21 for L. edodes, 35.12 µg/ml and 13.96 for B. edulis, and 26.69 µg/ml and 15.15 for P. ostreatus. Although methanolic extracts were less effective at preventing infection of pretreated cells, preventing viral adsorption, and inhibiting viral replication, they were still more effective than control. In terms of mechanism of action. The authors speculate the mushroom extracts block viral attachment or adsorption at initial HSV-1 infection and further inhibit intracellular viral replication.In another study by Santoyo et al.,78 pressurized liquid extraction was utilized to create hexane, ethanol, and water extracts with the microalgae Haematococcus pluvialis and Dunaliella salina and evaluated for antiviral activity against HSV-1 (strain KOS). When H. pluvialis extracts were added to virally-infected cells, inhibition of intracellular replication was greatest with the ethanolic extract (IC50 = 99.59 µg/ml and SI = 7.39) compared to the hexane (IC50 = 189.58 µg/ml and SI = 3.57) and aqueous (IC50 = 133.98 µg/ml and SI = 12.01) extracts. D. salina extracts showed slightly weaker activity, with the aqueous extract (IC50 = 137.53 µg/ml and SI = 11.48) exhibiting stronger antiviral effects compared to the hexane (IC50 = 168.81 µg/ml and SI = 2.88) and ethanolic (IC50 = 152.73 µg/ml and SI = 4.07) extracts. Time-of-addition experiments revealed the extracts were more effective when cells were treated before infection compared to addition at the time of infection. The ethanolic extract of H. pluvialis was the most effective, showing an 85% reduction in HSV-1 infectivity at a dose of 75 µg/ml with pretreatment, but a 75% reduction at a dose 150 µg/ml with simultaneous addition. The extracts were also tested for virucidal activity, but all extracts exhibited IC50 values greater than 10 mg/ml, which the authors concluded as having virtually no virucidal activity.Furthermore, Civitelli et al.128 compared the antiherpetic activity of Mentha suaveolens essential oil against HSV-1 (strain F) to that of the essential oil from Melaleuca alternifolia. The IC50 and SI values, respectively, were found to be 5.1 µg/ml and 67 for M. suaveolens essential oil and 13.2 µg/ml and 44 for M. alternifolia essential oil. These values suggest greater antiviral capabilities of M. suaveolens compared to M. alternifolia. Interestingly, when each essential oil was combined with acyclovir, additive antiviral effects were observed. Additionally, each extract was shown to inhibit intracellular viral metabolism, but not to prevent viral adsorption.Glycyrrhiza glabra was tested by Ghannad et al.100 for its ability to prevent viral adsorption and delay viral incubation of HSV-1. The greatest antiviral activity was seen when Vero cells were pretreated with an aqueous extract of G. glabra and incubated with HSV-1 for only 1 hour. Additionally, cells were treated with HSV-1, incubated for 1 hour, washed, and treated with a non-cytotoxic dose of the extract after 1, 4, 8, and 12 hours. The most significant results, compared to control, were seen from treatment after hours 1 and 12. The authors speculate that the antiviral capacity of G. glabra comes from either direct viral inhibition or prevention of the viral attachment to host cells. The authors also suggest that G. glabra may interfere with viral gene expression due to results implying the extract was able to delay viral replication.Fukuchi et al.101 studied the ability of aqueous Glycyrrhiza glabra extracts of different pH values to exhibit antiviral activity against HSV-1 (strain F). The neutral water extracts (EC50 = 650 to 740 µg/ml and SI = 2.0 to >4.6) showed greater antiviral activity compared to the alkaline extracts (EC50 = 600 to >3000 µg/ml and SI = <1 to 3.2). An alkaline extract of Sasa senanensis was used as a positive control as the authors demonstrated its anti-HSV activity in a previous study. S. senanensis out-performed all extracts of G. glabra in the context of preserving cell viability after HSV-1 infection (EC50 = 0.033-0.048 µg/ml and SI = 4.5-11.4). Overall, G. glabra has some potential to act as an antiherpetic treatment, but may not be the most promising botanical available.A total of 24 different plant species were tested for antiviral activity against HSV-1 and HSV-2 by Sokmen et al.,192 but all failed to show any effects. The plants studied were Allium macrochaetum subsp. macrochaetum, A. macrochaetum subsp. tuncelianum, A. pustulosum, A. flavum, A. scorodoprosum, A. chrysanthemum, A. dictyoprosum, Rhus coriaria, Bupleurum sulphureum, Cannabis sativa var. sativa, Helianthemum ledifolium, Ecbalium elaterium, Phlomis kurdica, Sideritis libanotica, Thymus fallax, Linum usitatissimum, Urtica dioica, Peganum harmala, Hypericum scabrum, H. Capitatum, Achillea biebersteinii, Pimpinella anisum, and Nigella sativa.North AmericaOpuntia streptacantha is a cactus found in Mexico that has been safely used to treat mild cases of diabetes in humans. Ahmad et al.133 studied the antiviral effects of O. streptacantha against HSV-2 (strain 3345), using extracts of dried powder, acetone, ether, and chloroform. Different concentrations of the extract were added to baby hamster kidney cells (BHK-21) immediately after viral adsorption. A concentration of 3.5 mg/ml reduced viral replication by 2.3 log10, and at 15 mg/ml, viral replication ceased entirely. Also, at a concentration of 15 mg/ml, viral protein synthesis was completely inhibited, but no effects on cellular protein synthesis were observed. More potent effects on viral replication were seen with pretreatment of cells 24 hours prior to viral inoculation, which inhibited replication by 2.6 log10 at a concentration of 3.5 mg/ml. Similar reductions were noted with pretreatment of cells 48 hours pre-infection. Additionally, human cervical cells were inoculated with HSV-2 then incubated with the plant extract or placebo for 2 days. When the extract was delivered at a concentration of 15 mg/ml, the viral replication was reduced by 3.5 log10. Lastly, humans were given either 3 or 6 grams of O. streptacantha for 30 days to assess toxicity. No adverse events were reported from human ingestion of the extract after 30 days.Binns et al.79 made extracts from the roots of 8 different species of Echinacea plants using 70% ethanol and assessed their antiviral activity against HSV-1. Some extracts were further fractionated with n-hexane and/or ethyl acetate. Antiviral assays included exposure to visible and UV-A light to ensure activation of any compounds that may be photosensitizers. The greatest inhibitory activity was elicited by the ethanolic extract of E. pallida var. Sanguinea with a MIC of <0.026 mg/ml and the n-hexane fraction of E. purpurea root with a MIC of 1.56 mg/ml. Additionally, ethanolic extracts of E. atrorubens var atrorubens and E. pallida var angustifolia and the n-hexane fractions of E. pallida var. angustifolia, E. pallida var. pallida, and E. pallida var. tennesseensis each had an MIC of <1 mg/ml.The antiviral activity of E. pallida was also studied by Schneider et al.80 against HSV-1 (strain KOS) and HSV-2 (strain HG52) using a hydroethanolic extract and the plant’s pressed juice. Aerial parts were used to make extracts with 20%, 40%, 60%, and 80% aqueous ethanol as well as a pressed juice that was subsequently mixed with 96% ethanol as a preservative. All hydroalcoholic extracts showed dose-dependent antiviral activity, but the most significant antiviral activity was found from the pressed juice (IC50 = 0.001% and SI = 22,700 for HSV-1; IC50 = 0.0002% and SI = 113,500 for HSV-2). The IC50 values against HSV-1 for the 20%, 40%, 60%, and 80% ethanolic extracts were 0.03% (SI = 506), 0.001% (SI = 8400), 0.005% (SI = 1100), and 0.007% (SI = 514), respectively. Additionally, the IC50 values against HSV-2 for the 20%, 40%, 60%, and 80% ethanolic extracts were 0.007% (SI = 2171), 0.01% (SI = 840), 0.006% (SI = 916), and 0.004% (SI = 900), respectively. Time-of-addition experiments showed that the pressed juice was highly effective against HSV virions both intra- and extracellularly, while the hydroethanolic extracts affected virions extracellularly.Furthermore, Lavoie et al.75 tested Cornus canadensis for its antiviral actions against HSV-1 (strain ATCC-VR733). The extracts were made from dried stems and leaves via decoction or infusion with 3 different solvents each: water, ethanol, and 1:1 of water and ethanol. Viral absorption was best prevented by the simultaneous addition of HSV-1 and the water: ethanol infusion as well as the water decoction, both demonstrating an EC50 of 9 µg/ml. Direct viral inhibition was seen with both the decoctions and infusions of either the water or water: ethanol extracts, EC50 ranging 11-17 µg/ml. No extracts were observed to elicit antiviral effects when cells were pretreated nor when added during viral replication, defined by the authors as having EC50 values >50 µg/ml. Therefore, C. canadensis is most effective when used during or after the initial stages of the viral infection.Recently, Silva-Mares et al.63 screened a variety of plants for antiherpetic activity. Methanol or 1:9 of water: methanol extracts were created from the leaves, aerial parts, or cortex of Juglans mollis, Persea americana, Hamelia patens, Clematis drummondii, Salvia texana, and Salvia ballotaeflora. Also, ethyl acetate and ethyl ether extracts were created from the roots of Ceanothus coeruleus and Chrysactinia mexicana, respectively. The extracts were added after viral infection had been established in the Vero cells. The greatest antiviral activity was observed from the extract of S. ballotaeflora against both HSV-1 and HSV-2 with IC50 values of 31 µg/ml and 16 µg/ml, respectively. This was followed by the extract of J. mollis with IC50 values of 76 µg/ml and 126 µg/ml against HSV-1 and HSV-2, respectively. The SI values toward HSV-1 and HSV-2, respectively, were >26.3 and >15.8 for J. mollis and 7.5 and 14.6 for S. ballotaeflora. SI values toward HSV-1 and HSV-2, respectively, for the other species studied were as follows: 5.0 and <3.4 for P. americana; >4 and >9.4 for H patens, 1.9 and 7.5 for S texana, 5.45 and 3.8 for C. coeruleus, >11.7 and >5.8 for C. mexicana, and >4.3 and >7.8 for C. drummondii.Another recent study by Zaharieva et al.102 assessed a hydromethanolic extract of Graptopetalum paraguayense for antiviral activity against strains of HSV-1 and HSV-2. The extract was found to be antiviral toward wild-type strains of HSV-1 (EC50 = 0.0001 mg/ml, SI = 25,000) and HSV-2 (EC50 = 0.01 mg/ml, SI = 250), and acyclovir-resistant strains of HSV-1 (EC50 = 0.001 mg/ml, SI = 2,500) and HSV-2 (EC50 = 0.1 mg/ml, SI = 25). Interestingly, the extract had greater antiherpetic action than acyclovir in all 4 strains tested.OceaniaSchnitzler et al.87 compared the antiherpetic effect of tea tree oil, from Melaleuca alternifolia, to that of eucalyptus oil, from Eucalyptus globulus. Tea tree oil (IC50 = 0.0009% and SI = 6.7 for HSV-1; IC50 = 0.0008% and SI = 7.5 for HSV-2) demonstrated more potent antiviral activity than eucalyptus oil (IC50 = 0.009% and SI = 3.3 for HSV-1; IC50 = 0.008% and SI = 3.75 for HSV-2). Additionally, tea tree oil had significantly greater virucidal activity when virions were pretreated, eliminating over 90% of each HSV strain at non-cytotoxic concentrations. Eucalyptus oil showed 58% and 75% reduction in viral titers of HSV-1 and HSV-2, respectively. Time-of-addition experiments revealed that both oils have the ability to impact viral adsorption, but not after viral penetration. The authors conclude that oils from either M. alternifolia or E. globulus have potential to be effective topical treatments for HSV infections.Another 3 species from the Melaleuca family, M. ericifolia, M. leucadendron, and M. armillaris, were studied for the ability of their essential oils to act against HSV-1.119 Farag et al.119 observed a 99% virucidal effect with M. armillaris, a 92% virucidal effect with M. leucadendron, and a 91.5% virucidal effect with M. ericifolia. The authors explain that the variation in plaque reduction could be due to the different make up of each plant’s essential oils as well as the time of year the leaves were collected.Moreover, Reichling et al.113 investigated antiviral effects of the essential oil of Leptospermum scoparium, commonly known as Manuka oil, against both HSV-1 (strain KOS) and HSV-2 (strain HG52). Manuka oil, which is commercially used as an anti-infective oil in New Zealand, was diluted with ethanol to a final ethanol concentration of 1% for all assays. L. scoparium essential oil inhibited plaque formation for both viruses in a dose-dependent manner when virions were pretreated with the oil. The IC50 and SI values, respectively, were determined to be 0.96 µg/ml and 40 for HSV-1 and 0.58 µg/ml and 66.2 for HSV-2. Furthermore, manuka oil was added at the non-cytotoxic concentration of 28.8 µg/ml to HSV-treated cells at different stages of the viral infection cycle. Pretreatment of cells with the oil prior to viral infection did not reduce plaque formation. However, pretreatment of viruses prior to infection reduced infectivity by 99.5% and 98.9% for HSV-1 and HSV-2, respectively. Manuka oil was less effective as the viral life cycle progressed. Therefore, L. scoparium essential oil has the potential to be effective as a prophylactic for HSV infection rather than a treatment.South AmericaHayashi et al.74 observed a chloroform and ethanolic extract from dried leaves and twigs of Cordia salicifolia to have antiviral activity against HSV-1 (strain HF). The ED50 and SI values were found to be 0.85 µg/ml and 261, respectively, when the extract was added post-infection. Time-of-addition experiments showed the extract inhibited viral penetration and replication, but not attachment, and had a direct virucidal effect on HSV-1 virions. A clinically relevant finding was that the extract exhibited 99% inhibition of HSV-1 when added between 3 hours pre-infection to 8 hours post-infection.Pacheco et al.45 assessed aqueous and hydroalcoholic extracts of 36 species of Chilean plants for antiviral activity against HSV-1 (strain F) and HSV-2 (strain 333). Hydroalcoholic extracts of Cassia stipulaceae (IC50 = 80 µg/ml) and Illinita sp. (IC50 = 40 µg/ml) were found to have antiviral activity against HSV-1. Antiviral activity against HSV-2 was observed from the hydroalcoholic extracts of Aristotelia chilensis (IC50 = 40 µg/ml), Drimys winteri (IC50 = 35-80 µg/ml), and Elytropus chilensis (IC50 = 100 µg/ml) and the aqueous extract of Luma apiculata (IC50 = 100 µg/ml).Aqueous extracts of the leaves and aerial parts of plants native to Argentina were prepared and assessed for antiviral activity against HSV-1 (strain F) by Kott et al.115 The plants tested were Polygonum punctatum, Lithraea molleoides, Sebastiania brasiliensis, Myrcianthes cisplatensis, and Sebastiania klotzschiana. All extracts were found to have an antiviral effect except for M. cisplatensis. The greatest viral inhibition was observed by S. klotzschiana with an EC50 of 39 µg/ml. Other observed EC50 values ranged 51-169 µg/ml. The maximal non-cytotoxic concentrations were found to be 450 µg/ml for P. punctatum and 250 µg/ml for L. molleoides, S. brasiliensis, and S. klotzschiana.Ethanolic and aqueous extracts of Baccharis genistelloides, Baccharis rubricaulis, Ambrosia arborescens, Phoradendron crassifolium, Rumex obtusifolius, Plantago australis, and Satureja boliviana, plants native to Bolivia, were tested by Abad et al.51 for antiviral effects against HSV-1. Ethanolic extracts demonstrated high cytotoxicity, for example, the ethanolic extract of B. rubricaulis was cytotoxic at concentrations as low as 5 µg/ml. Only aqueous extracts were observed for antiviral effects, however, their maximum non-cytotoxic concentrations were at the upper limit of their effective concentration ranges The aqueous extracts that demonstrated inhibition of HSV-1 were S. boliviana, B. genistelloides, and P. crassifolium. Concentrations that were observed to show antiherpetic effects were 10-125 µg/ml, 25-50 µg/ml, and 125-500 µg/ml for S. boliviana, B. genistelloides, and P. crassifolium, respectively.Subsequently, Abad et al.52 assessed 10 plants from South America for anti-HSV-1 activity. Aqueous and ethanolic extracts of Baccharis trinervis, Baccharis teindalensis, Eupatorium articulatum, Eupatorium glutinosum, Tagetes pusilla, Neurolaena lobata, Conyza floribunda, Phytolacca bogotensis, Phytolacca rivinoides, and Heisteria acuminata were tested. At concentrations of 50-200 µg/ml, the aqueous B. trinervis extract was able to inhibit 80-100% of viral replication. Two other extracts were observed to inhibit viral replication, but demonstrated cytotoxicity at concentrations that closely paralleled effective concentrations. These extracts were the ethanolic H. acuminata extract and the aqueous E. articulatum extract, which inhibited less than 60% of viral replication at concentrations ranging 125-250 µg/ml.Aerial parts from Achyrocline flaccida were made into an aqueous extract and tested against radiolabeled HSV-1 (strain F) by Garcia et al.193 The extract was observed to inhibit >95% viral adsorption when 200 µg/ml was applied during infection, but had no inhibitory effect when applied as a pretreatment to cells. Through the use of radiolabeled virions, it was observed that penetration was reduced by 50% with a concentration of 200 µg/ml of the extract.Goncalves et al.172 used an acyclovir-resistant strain of HSV-1 to assess the antiherpetic activity of leaf and fruit ethyl acetate extracts of Vitex polygama. Maximum non-cytotoxic concentrations were determined as 25 µg/ml and 50 µg/ml for the leaf and fruit extracts, respectively, and used for all testing. Both extracts were observed to inhibit HSV-1 when cells were pretreated. The leaf extract showed 73.7% inhibition while the fruit extract showed 85.2% inhibition. Additionally, the leaf extract was able to disrupt intracellular activity by 60.2% while the fruit extract had a direct virucidal effect by inhibiting 73.1% of virions. Neither extract could prevent HSV-1 attachment to host cells. As such, the leaf extract would likely be more applicable to use during HSV infection, whereas the fruit extract may have more of an effect when used to prevent infection.Methanolic extracts of 24 plants traditionally used for skin infections from various regions within Columbia were tested for ability to inhibit HSV-1 by Lopez et al.27 A total of 13 extracts demonstrated complete inhibition of viral cytopathic effects. These included extracts from Vismia macrophylla (MIC = 5.5 µg/ml), Symphonia globulifera (MIC = 25 µg/ml), Eschweilera rufifolia (MIC = 8 µg/ml), Byrsonima verbascifolia (MIC = 6.5 µg/ml for root bark extract; MIC = 2.5 µg/ml for leaf extract), Iryanthera megistophylla (MIC = 10 µg/ml), Virola multinervia (MIC = 11.5 µg/ml for resin extract; MIC = 17 µg/ml for bark extract), Myrteola nummulari (MIC = 10.5 µg/ml), Polygonum punctatum (MIC = 20 µg/ml), Adiantum latifolium (MIC = 11.5 µg/ml), Ampelozizyphus amazonicus (MIC = 22 µg/ml), and Duroia hirsuta (MIC = 10.5 µg/ml). Of these extracts, the most notable was the B. verbascifolia leaf extract, which completely inhibited HSV-1 activity at a low concentration of 2.5 µg/ml.Moreover, Betancur-Galvis et al.89 made petroleum ether, dichloromethane, ethanolic and/or water extracts from 10 Columbian medicinal plants from the Euphorbia genus and assessed antiherpetic activity against HSV-2. The species assessed were E. cestrifolia, E. cotinifolia, E. tirucalli, E. arenaria, and E. pulcherrima, E. heterophyla, E. cyatophora, E. graminea, E. cf. cotinifolia, and Euphorbia sp. Additional water-methanol (20:80) extracts were made from fresh parts of E. tirucalli and E. cotinifolia. Strong antiviral activity was seen from the hydromethanolic extracts of the leaves and stems of E. tirucalli (IC50 = 140.2 mg/ml and SI >7.13) and E. cotinifolia (IC50 = 104.6 mg/ml and SI >9.56), and moderate antiviral activity was seen from the ethanolic extracts of the stems of E. cotinifolia (IC50 = 75.6 mg/ml and SI = 1.59), E. cestrifolia (IC50 = 160.1 mg/ml and SI = 1.41) and E. tirucalli (IC50 = 64.3 mg/ml and SI = 3.46) and the dichloromethane extracts of the leaves of E. cotinifolia (IC50 = 36.8 mg/ml and SI = 4.08) and E. cestrifolia (IC50 = 59.8 mg/ml and SI = 2.83). The greatest inhibitory effects were observed from the hydromethanolic extracts of E. tirucalli and E. cotinifolia. It is important to note that these 2 extracts were not found to be cytotoxic at any dose studied, but their inhibitory action was lower than that of acyclovir (IC50 = 2.8 mg/ml and SI = 31,600). The authors believe that the antiviral activity of E. tirucalli and E. cotinifolia is acceptable and that these plants are good candidates for further research.Significant inhibitory and virucidal action against acyclovir-resistant HSV-1 was observed from a 1:1 sodium chloride: glycerol extract of the seeds of Licania tomentosa by Miranda et al.114 The ED50 and SI values of 9 µg/ml and 851, respectively, were calculated. Further experiments were conducted at the extract’s maximum non-cytotoxic concentration, which was determined as 625 µg/ml. Viral inhibition of 90% was observed when the cells were pretreated with the extract for 3-4 hours at 37°C prior to infection, but the extract was cytotoxic if cells were pretreated at 4°C. When the extract was added to acyclovir-resistant HSV-1 directly, 59% of virions were inactivated. Addition of the extract after viral attachment resulted in 92.7% inhibition, but addition 2 hours post-infection only inhibited 74.4% of the virus.Garcia et al.25 assessed virucidal activity of essential oils from various medicinal plants found in Argentina. Viral inactivation of HSV-1 (strain F) was observed from the essential oils of Aloysia gratissima (IC50 = 65 ppm and SI = 2.31),32 Artemisia douglasiana (IC50 = 83 ppm and SI = 3.77),32 Eupatorium patens (IC50 = 125 ppm and SI = 2.35),32 Tessaria absinthioides (IC50 = 105 ppm and SI = 2.50),32 Lepechinia floribunda (IC50 = 20.3 ppm and SI = 3.80),25 Lantana grisebachii (IC50 = 26.1 ppm and SI >19.16),25 Lantana camara (IC50 = 43.3 ppm and SI = 2.48),25 Eupatorium catarium (IC50 = 47.9 ppm and SI = 10.09),25 Eupatorium arnottianum (IC50 = 52.1 ppm and SI = 7.61),25 and Trixis divaricata (IC50 = 37.8 ppm and SI = 4.22).25 Since L. grisebachii essential oil showed the strongest virucidal activity, the authors tested it against HSV-2 (strain G) and acyclovir-resistant HSV-1 (strain Field). The oil was found to elicit virucidal effects against both viruses with IC50 and SI values, respectively, of 44.3 ppm and >11.29 against HSV-2 and 79.7 ppm and >6.27 against acyclovir-resistant HSV-1.A methanolic extract of the leaves of Trichilia glabra was made by Cella et al.168 and further fractionated with different proportions of chloroform-methanol ranging from 100:0-90:10. The extracts exhibited virucidal activity against HSV-1 (strain F) in a dose-dependent manner. At a dose of 0.25 mg/ml, the 95:5 and 90:10 chloroform-methanolic fractions reduced viral titers by 2.4 log10 and 1.5 log10, respectively. Additionally, 33% reduction of HSV titers was observed with 0.27 mg/ml of the 95:5 chloroform-methanolic fraction, 0.35 mg/ml of the 90:10 chloroform-methanolic fraction, and 0.5 mg/ml of the methanolic extract.A total of 51 aqueous and hydroethanolic extracts from plants native to Southern Brazil were tested for antiviral activity against HSV-1 by Montanha et al.31 Extracts were tested against HSV-1 strain KOS, and those that exhibited anti-HSV activity were subsequently tested against the HSV-1 strains ATCC-VR733 and 29-R/acyclovir-resistant. The aqueous extracts of Ilex brevicuspis (5 mg/ml), Ilex theezans (0.25 mg/ml), and Maytenus ilicifolia (1.25 mg/ml) and the hydroethanolic extracts of Aloysia gratissima (1.25 mg/ml), Baccharis megapotamica (0.0048 mg/ml), and M. ilicifolia (0.5 mg/ml) inhibited 100% of viral cytopathic effects at their determined maximum tolerated concentrations. The hydroethanolic extracts of Baccharis erioclada (0.25 mg/ml), Glechon marifolia (0.625 mg/ml), and Glechon spathulata (0.25 mg/ml) inhibited 100% of viral cytopathic effects at half of their maximum tolerated concentrations. The aqueous extract of B. erioclada (0.312 mg/ml) and the hydroethanolic extract of Baccharis uncinella (0.312 mg/ml) inhibited 100% of viral cytopathic effects at a quarter of their maximum tolerated concentrations. Additionally, complete inhibition of cytopathic effects from HSV-1 strain ATCC-VR733 was observed from the aqueous extracts of I. brevicuspis (5 mg/ml), I. theezans (0.25 mg/ml), B. erioclada (0.625 mg/ml), and M. ilicifolia (1.25 mg/ml) and the hydroethanolic extracts of B. erioclada (0.5 mg/ml), M. ilicifolia (0.5 mg/ml), G. marifolia (0.625 mg/ml), G. spathulata (0.25 mg/ml), and A. gratissima (1.25 mg/ml). Lastly, the extracts that showed complete inhibition cytopathic effects of the 29-R/acyclovir-resistant HSV-1 strain were the aqueous extract B. erioclada (1.25 mg/ml) and the hydroethanolic extracts of B. erioclada (0.5 mg/ml), B. uncinella (1.25 mg/ml), and G. spathulata (0.25 mg/ml).Furthermore, 15 medicinal plants from Argentina were assessed for antiherpetic activity against HSV-1 (strain F) and HSV-2 (strain G) by Ruffa et al.85 Extracts were prepared with methanol, and the methanolic extract was subsequently dried, dissolved in hot water, and lyophilized to create an infusion. Only the methanolic extract and infusion of Juglans australis (methanolic: EC50 = 96.0 µg/ml and SI = 5.9 for HSV-1; infusion: EC50 = 65.3 µg/ml and SI = 8.1 for HSV-1, EC50 = 114.1 µg/ml and SI = 4.3 for HSV-2) and the methanolic extract of Eriobotrya japonica (EC50 = 183.2 µg/ml and SI = 2.4 for HSV-1, EC50 = 146.1 µg/ml and SI = 3.0 for HSV-2) were found to be antiherpetic. Only the infusion of J. australis showed effective antiviral activity as defined by the authors as a SI > 8 against HSV-1.Andrighetti-Frohner et al.41 made hydroethanolic extracts that were subsequently extracted with dichloromethane, ethyl acetate, and n-butanol using 6 medicinal plants from the Brazilian Atlantic Tropical Forest. The plants studied were Cuphea carthagenensis, Lippia alba, Tillandsia usneoides, Bromelia antiacantha, Araucaria angustifolia, and Wilbrandia ebracteata, and the HSV-1 strains used to test antiviral activity were wild-type strain KOS and 29-R/acyclovir-resistant strain. The most potent extracts were the ethyl acetate extracts of C. carthagenensis (EC50 = 2 µg/ml and SI = 90) and T. usneoides (EC50 = 3 µg/ml and SI = 65) against strain KOS. Other extracts that showed activity against strain KOS were the dichloromethane extracts of C. carthagenensis (EC50 = 4 µg/ml and SI = 49) and T. usneoides (EC50 = 10 µg/ml and SI = 18), the ethyl acetate extracts of A. angustifolia (EC50 = 35 µg/ml and SI = 9) and W. ebracteata (EC50 = 62 µg/ml and SI = 4), and the n-butanolic extracts of A. angustifolia (EC50 = 13 µg/ml and SI = 11), C. carthagenensis (EC50 = 31 µg/ml and SI = 12), T. usneoides (EC50 = 3 µg/ml and SI = 8), and W. ebracteata (EC50 = 125 µg/ml and SI = 1). The acyclovir-resistant strain was most strongly affected by W. ebracteata, demonstrating EC50 and SI values, respectively, of 25 µg/ml and 10 for the ethyl acetate extract and 12 µg/ml and 10 for the n-butanolic extract. Other extracts that showed activity against strain 29-R/acyclovir-resistant were the n-butanolic extracts of L. alba (EC50 = 2 µg/ml and SI = 8) and the dichloromethane, ethyl acetate, and n-butanolic extracts of T. usneoides (EC50 = 26 µg/ml and SI = 7, EC50 = 23 µg/ml and SI = 8, EC50 = 12 µg/ml and SI = 2, respectively).Eight South American plant extracts were assessed for antiviral activity against HSV-1 strains KOS and 29-R/acyclovir-resistant by Muller et al.108 Extracts were prepared with water, ethanol, 40% hydroethanol, or methanol. Antiherpetic activity, defined by the authors as a SI >7, was exhibited toward HSV-1 strain KOS by the aqueous extract of Ilex paraguariensis (EC50 = 80.0 µg/ml and SI = 15.8) and the methanolic extracts of Rubus imperialis (EC50 = 70.0 µg/ml and SI = 19.8) and Lafoensia pacari (EC50 = 60.0 µg/ml and SI = 19.0). Additionally, antiherpetic activity against strain 29-R/acyclovir-resistant was observed by the aqueous extracts of I. paraguariensis (EC50 = 100.0 µg/ml and SI = 12.6) and Passiflora edulis (EC50 = 89.9 µg/ml and SI = 17.8) and the methanolic extracts of R. imperialis (EC50 = 90.0 µg/ml and SI = 15.4) and Sloanea guianensis (EC50 = 140.0 µg/ml and SI = 10.0).I. paraguariensis was also studied by Luckemeyer et al.109 A hydroethanolic extract of the plant’s leaves was prepared and further partitioned into butanol, aqueous residual, butanol residual, and ethyl acetate fractions. The extract and fractions were observed for antiherpetic action against HSV-1 (strain KOS) and HSV-2 (strain 333). The extract and all fractions, except for the aqueous residual fraction, showed antiherpetic activity against both strains, with the strongest inhibitory action observed from the ethyl acetate fraction (IC50 = 6.6 µg/ml and SI = 188.7 against HSV-1; IC50 = 7.1 µg/ml and SI = 264.7 against HSV-2). Additionally, the hydroethanolic extract showed strong inhibition toward HSV-2 (IC50 = 14.1 µg/ml and SI = 171.3) and HSV-1 (IC50 = 22.2 µg/ml and SI = 68.9). For comparison, acyclovir was also tested and demonstrated an IC50 of 0.5 µg/ml and a SI >2000 against HSV-1 as well as an IC50 of 1.2 µg/ml and SI >833.4 against HSV-2. Through other experiments in this study, the authors were able to show that the ethyl acetate fraction can prevent viral attachment and penetration into host cells and can reduce lateral spread of virions.Valadares et al.157 observed an ethanolic extract of Solanum paniculatum leaves to have antiviral activity against HSV-1. The extract demonstrated an EC50 of approximately 298 µg/ml and a SI of 1.4. For comparison, acyclovir was also tested and was found to have an EC50 of 40 µg/ml.Moreover, 34 ethanolic extracts of 18 species of Brazilian medicinal plants were tested against HSV-1 by Brandao et al.37 A total of 30 extracts were found to be non-cytotoxic at reasonable or ideal doses, and 10 of these were found to exhibit some antiherpetic activity. Extracts that showed moderate effects were Arrabidaea formosa (leaves: EC50 = 82.2 µg/ml and SI >6.1; stems: EC50 = 90.2 µg/ml and SI >5.5) and Zeyheria tuberculosa (leaves: EC50 = 81.8 µg/ml and SI = 2.1). Low activity was observed by Anemopaegma setilobum (leaves: EC50 = 138.1 µg/ml and SI >1.4; stems: EC50 = 168.2 µg/ml and SI >3.0), Arrabidaea craterophora (stems: EC50 = 188.1 µg/ml and SI = 1.9), A. formosa (fruit: EC50 = 148.5 µg/ml and SI >3.4), Arrabidaea pulchra (leaves: EC50 = 232.1 µg/ml and SI >2.2), Arrabidaea sceptrum (stems: EC50 = 375.3 µg/ml and SI >1.3), and Stizophyllum perforatum (stems: EC50 = 338.7 µg/ml and SI >1.5).Faral-tello et al.26 created ethanolic extracts from 24 South American plants and 4 South American algal species and tested for antiviral activity against HSV-1 (strain F). None of the algal species offered inhibitory action toward HSV-1, however, 14 of the plant extracts demonstrated viral inhibition. These plants were Achyrocline satureioides, Bauhinia candicans, Chenopodium ambrosioides, Limonium brasiliense, Margyricarpus pinnatus, Phyllanthus niruri, Polygonum punctatum, Psidium incanum, Psidium luridum, Schinus molle, Sesbania punicea, Smilax gracilis, Tillandsia aeranthos, and Tillandsia usneoides. EC50 values of these plant extracts ranged 50-1500 µg/ml, and the highest SI values calculated were from P. niruri (42.37), P. incanum (14.89), and L. brasiliense (4.58). These 14 extracts were also tested for ability to directly inactivate HSV-1 virions at their respective maximum non-cytotoxic concentrations, and 6 showed virucidal activity, which was defined by the authors as inactivating ?90% of viral particles. These extracts were C. ambrosioides, L. brasiliense, M. pinnatus, S. gracilis, T. aeranthos, and T. usneoides.Thirty-six varieties of marine algae from Brazil were investigated for antiherpetic activity against acyclovir-resistant HSV-1 and HSV-2 by Soares et al.69 Extracts were prepared using either dichloromethane and methanol in a 1:1 ratio or dichloromethane alone and added to Vero cells at determined maximum non-cytotoxic concentrations at the same time as viral infection. Strong antiviral activity against acyclovir-resistant HSV-1, defined as greater than 90% percent inhibition of viral titers, was exhibited by the dichloromethanic and methanolic extracts of Laurencia dendroidea (97.5% inhibition at 3.1 µg/ml), Hypnea spinella (92% inhibition at 200 µg/ml), Lobophora variegata (92% inhibition at 6.2 µg/ml), Stypopodium zonale (96.8% inhibition at 50 µg/ml), Sargassum cymosum (98.2% inhibition at 50 µg/ml), Ulva fasciata (99.9% inhibition at 200 µg/ml), and Codium decorticatum (99.9% inhibition at 200 µg/ml) as well as the dichloromethanic extract of Penicillus capitatus (93.0% inhibition at 250 µg/ml). Moreover, strong antiviral activity against acyclovir-resistant HSV-2 was exhibited by the dichloromethanic and methanolic extracts of Chondracanthus acicularis (92.4% inhibition at 100 µg/ml) and Stypopodium zonale (95.8% inhibition at 50 µg/ml) as well as the dichloromethanic extract of Penicillus capitatus (96% inhibition at 250 µg/ml). Cytotoxicity was not noted by the extracts that exhibited strong anti-HSV activity (CC50 > 200 µg/ml), except the extract of L. dendroidea (CC50 = 48.2 µg/ml).Moura-Costa et al.60 assessed aqueous and hydroalcoholic (50% and 70%) extracts from 6 Brazilian plants against HSV-1. The plants studied were Campomanesia eugenioides, Luehea paniculata, Ocimum gratissimum, Cordia americana, Schinus terebinthifolius, and Zanthoxylum rhoifolium. All extracts, except the aqueous extracts of C. americana and Z. rhoifolium bark, showed anti-HSV-1 activity. The hydroalcoholic extracts (EC50 and SI ranged 1.4-26 µg/ml and 6.9-21.3, respectively) were observed to have greater antiviral effects compared to the aqueous extracts (EC50 and SI ranged 0.6-20 µg/ml and 13-62, respectively). The highest SI values observed were from the 70% hydroalcoholic extracts of C. eugenioides (52) and C. americana bark (55) and the 50% hydroalcoholic extracts of O. gratissimum,190 C. americana leaves,82 S. terebinthifolius (>48), and Z. rhoifolium leaves .146S. terebinthifolia was also tested by Nocchi et al.156 for antiherpetic activity against the HSV-1 KOS strain, 29-R/acyclovir-resistant strain, and a clinical strain. A crude hydroethanolic extract of the plant demonstrated EC50 and SI values, respectively, of 10.20 µg/ml and >49 against strain KOS, 13.9 µg/ml and >35.9 against strain 29-R, and 14.2 µg/ml and >34.9 against the clinical strain. Further testing revealed the extract elicited its antiviral effects by inhibiting viral attachment and penetration when the extract was added during the adsorption and infection viral stages. However, little effects were noted on viral infectivity when virions were pretreated with the extract. Interestingly, the extract showed to have a synergistic effect with acyclovir when the 2 were tested in combination.Furthermore, Petronilho et al.64 found a hydroethanolic extract of Cecropia glaziovii leaves to inhibit viral replication of the HSV-1 strain 29-R/acyclovir-resistant. This extract demonstrated an EC50 of 40 µg/ml and SI of 50, suggesting strong viral inhibitory capacity.Silva Junior et al.96 found a dichloromethane extract from the roots of Gallesia gorazema to elicit 93% viral inhibition of HSV-1 at its maximum non-cytotoxic concentration of 100 µg/ml, but had no effect against HSV-2. An ethanolic extract from the leaves of Gallesia gorazema was also tested, but failed to demonstrate any antiherpetic activity against HSV-1 or HSV-2.A crude extract of Trichilia catigua bark was prepared using 7:3 acetone: water and further partitioned with water or ethyl acetate by Espada et al.167 Antiviral and virucidal activity as well as inhibition of viral adsorption of HSV-1 were investigated. The crude extract (IC50 = 4.59 µg/ml and SI >87) demonstrated stronger antiviral activity than the aqueous fraction (IC50 = 12.5 µg/ml and SI >32) or ethyl acetate fraction (IC50 = 11.1 µg/ml and SI >35.97). Time-of-addition experiments revealed the extract and fractions were most effective when added to cells at the time of infection. Greater inhibition of viral adsorption was seen with the ethyl acetate fraction, demonstrating 96.45% inhibition at 100 µg/ml. Moreover, 100% direct viral inhibition was elicited by 100 µg/ml, 50 µg/ml, and 25 µg/ml of the crude extract, aqueous fraction, and ethyl acetate fraction, respectively. The crude extract was also found to act as an antagonist to acyclovir while the 2 fractions acted synergistically.Boff et al.160 assessed the antiviral actions of an ethyl acetate extract from the stem bark of Strychnos pseudoquina against HSV-2 strain 333, and HSV-1 strains KOS and 29-R/acyclovir-resistant. When extract and virus were administered simultaneously to cells, the extract demonstrated IC50 and SI values, respectively, of 5.29 µg/ml and 10.16 for HSV-1 strain KOS and 6.55 µg/ml and 8.21 for HSV-2. When the extract was administered post-infection, it demonstrated IC50 and SI values, respectively, of 22.2 µg/ml and 3.84 for HSV-1 strain KOS, 17.62 µg/ml and 3.05 for HSV-1 strain 29-R, and 8.64 µg/ml and 6.22 for HSV-2. Time-of-addition experiments revealed the extract had antiherpetic activity during viral adsorption (IC50 = 1.96 µg/ml and SI = 27.43 for HSV-1 strain KOS; IC50 = 6.02 µg/ml and SI = 8.92 for HSV-2), post-adsorption (IC50 = 3.12 µg/ml and SI = 17.23 for HSV-1; IC50 = 3.15 µg/ml and SI = 17.07 for HSV-2), and penetration (IC50 = 7.33 µg/ml and SI = 7.34 for HSV-1; IC50 = 4.47 µg/ml and SI = 12.03 for HSV-2). Pretreatment of cells with the extract inhibited HSV-2 replication (IC50 = 7.56 µg/ml and SI = 7.11), but had no effect on HSV-1 replication.Antiviral activity against HSV-2 (strain 333) of hydroethanolic extracts of Equisetum giganteum, Croton lechleri, Uncaria tomentosa, and Copaifera reticulata was investigated by Churqui et al.73 Viral plaques were reduced by 100% by extracts of E. giganteum, U. tomentosa, and C. reticulata at a concentration of 100 µg/ml and the C. lechleri extract at 30 µg/ml. IC50 values for the E. giganteum, U. tomentosa, C. reticulata, and C. lechleri extracts were found to be 18 µg/ml, 28 µg/ml, 50 µg/ml, and 10 µg/ml, respectively, and SI values were calculated as >55.56, >35.71, 10, and >100, respectively. All extracts demonstrated virucidal effects and prevented viral adsorption, but were not effective at inhibiting viral replication or preventing infection with pretreatment of cells.An aqueous extract from Baccharis anomala was studied by Venturi et al.50 for its effect on ATCC-VR733 and 29-R/acyclovir-resistant strains of HSV-1. The aqueous extract demonstrated EC50 and SI values, respectively, of 0.0088 mg/ml and 49.14 against the wild-type strain and 0.065 mg/ml and 66.53 against the 29-R strain. Additionally, pretreatment of cells with the extract did not prevent HSV infection, therefore the extract likely does not act by inhibiting viral attachment.Aerial parts of Tanacetum parthenium were used to create a hydroethanolic extract that was tested against HSV-1 (strain KOS) in Vero and mouse fibroblast (L-929) cells by Benassi-Zanqueta et al.162 The extract encouraged wound healing in L-929 cells, demonstrating a fivefold increase in wound healing at 48 hours and a 3-fold increase at 72 hours compared to control. In addition, the extract inhibited viral replication in Vero cells, demonstrating EC50 and SI values of 3.1 µg/ml and 18.1, respectively.Most recently, Fahmy et al.86 found a methanolic extract of Erythrina speciosa leaves that was further partitioned with ethyl acetate to inhibit HSV-1, demonstrating EC50 and SI values, respectively, of 94 µg/ml and 2.65.Multiple Geographic LocationsThe antiviral activity of Macrocystidia cucumis mycelia was assessed against HSV-1 (strain F) in BHK-21 cells by Saboulard et al.117 The mycelia were grown in a culture broth and were found to possess antiviral activity, specifically, a decrease in expression of the HSV-1 antigen after 21 days of cultivation. This activity was maintained when the culture broth was diluted up to 64-fold, and there was no cytotoxicity observed. The authors proceeded to isolate the active compound from this broth and determined it to be a novel nucleoside analogue. This compound was found to have a MIC of 0.72 µg/ml against HSV-1.Pan et al.111 assessed an aqueous extract of another mushroom, Inonotus obliquus, for antiviral activity against HSV-1. The extract was found to have an IC50 value of 12.29 µg/ml and a SI of > 80, and primarily acted through prevention of viral entry.Furthermore, a variety of mushrooms were assessed for antiviral activity against HSV-2 (strain BH) in RK-13 cells by Krupodorova et al.47 The mushrooms were cultured as biomass and the mycelia were made into aqueous extracts using a 0.9% sodium chloride solution. Four species were found to inhibit HSV-2 replication, namely Fomes fomentarius (EC50 = 0.62 mg/ml and SI = 40.32), Pleurotus ostreatus (EC50 = 0.155 mg/ml and SI = 80.64), Auriporia aurea (EC50 = 0.155 mg/ml and SI = 161.29), and Trametes versicolor (EC50 = 0.077 mg/ml and SI = 324.67).Chiang et al.144,143 tested aqueous extracts of Plantago major and Plantago asiatica against HSV-1 (strain KOS) and HSV-2 (strain 196) in BCC-1/KMC cells. Both P. asiatica (EC50 = 1318 µg/ml and SI = 46.5)143 and P. major (EC50 = 843 µg/ml and SI = 2.2)144,143 demonstrated antiviral activity against HSV-2, but neither extract was active against HSV-1. The authors described the observed antiviral activity as weak, therefore P. major and P. asiatica are likely poor candidates for further HSV research.An extract of Sambucus nigra was assessed for antiherpetic activity against HSV-1 (strain VR-3), acyclovir-resistant HSV-1 (strain VRTK-), and HSV-2 (strain UW-268) by Suzutani et al.154 The extract’s antiviral effects were compared to that of an extract of Ribes nigrum, called Kurokarin. The S. nigra extract was shown to have a SI of 2.14 against acyclovir-resistant HSV-1, but SI <1 against the other 2 strains. The SI values of Kurokarin were determined to be 1.19 against wild-type HSV-1, 2.19 against acyclovir-resistant HSV-1, and 1.72 against HSV-2. Both extracts offered more potent viral inhibition against acyclovir-resistant HSV-1 compared to the wild type HSV-1.Ozcelik et al.142 created 15 lipophilic extracts from Pistacia vera using n-hexane and different plant parts (seed, kernel, leaf, stem, branch, and shell skins) and assessed for antiviral effects against HSV (type not specified) Inhibition of viral cytopathic effects was observed from 6 of the 15 extracts. The most effective extracts were those made from the plant’s fresh kernels, skins of processed woody shells, and unripe seeds, each with MIC <0.00006 µg/ml.Moreover, Eugenia caryophyllus flower buds were extracted by Tragoolpua et al.88 with ethanol and assessed against HSV-1 (strain F and 5 isolates) and HSV-2 (strain G and 5 isolates). The extract had similar antiviral activity against HSV-1 strain F (ED50 = 72.8 µg/ml and SI = 1.55) and HSV-2 strain G (ED50 = 74.4 µg/ml and SI = 1.52). HSV-1 isolates and HSV-2 isolates that also showed activity had similar antiviral effects (ED50 = 62.0-73.1 µg/ml and SI = 1.54-1.82; ED50 = 42.6-52.9 µg/ml and SI = 2.13-2.65, respectively). Both HSV-1 strain F and HSV-2 strain G were completely inactivated after exposure to the extract for 3 hours at a concentration of 78.1 µg/ml. Additionally, when administered 30 hours after infection, the extract was able to inhibit 10-27% of replication of HSV-1 and HSV-1 isolates and 16-35% of replication of HSV-2 and HSV-2 isolates.Onozato et al.163 observed aqueous and ethyl acetate extracts of Tanacetum vulgare to exhibit antiherpetic activity against HSV-1. The ethyl acetate extract (EC50 = 40 µg/ml and SI = 3.9) showed slightly more potent effects than the aqueous extract (EC50 = 55 µg/ml and SI = 2.2). Further experiments were conducted with an isolated compound, and the authors concluded that T. vulgare most likely exhibits antiviral activity by interfering with HSV-1 replication.T. vulgare was also studied by Alvarez et al.164 The plant’s aerial parts and rhizomes were extracted with methanol and aerial part extracts were fractionated with petroleum ether, chloroform, ethyl acetate, butanol, and water. The chloroform fraction was found to be cytotoxic and therefore was not assessed for antiviral capacity. Each extract/fraction was investigated against HSV-1 and HSV-2. The greatest antiviral effects were observed by the petroleum ether (EC50 = 69.9 µg/ml and SI = 3.37 for HSV-1; EC50 = 61.16 µg/ml and SI = 3.85 for HSV-2) and ethyl acetate (EC50 = 95.7 µg/ml and SI = 2.03 for HSV-1; EC50 = 59.4 µg/ml and SI = 3.27 for HSV-2) fractions and the methanolic rhizome extract (EC50 = 295.8 µg/ml and SI = 3.68 for HSV-1; EC50 = 500.0 µg/ml and SI = 2.18 for HSV-2). A strong antiviral effect was observed when petroleum ether or ethyl acetate extracts were added up to 6 hours after initial infection. The methanolic rhizome extract showed viral inhibition when added up to 2 hours after initial infection. Additionally, the ethyl acetate and petroleum ether extracts were able to inhibit >80% viral adsorption when added at concentrations of 50 µg/ml.Yarmolinsky et al.93 studied the ethanolic extracts of Ficus benjamina (leaf, fruit, stem) and Lilium candidum (leaf, petal, bulb) for antiviral effect on HSV-1 (strain ATCC-VR-735) and HSV-2. Leaf extracts of both plants showed strong viral inhibition toward both viruses, while the other extracts failed to show significant effects. The most pronounced effects were observed when the extracts were added simultaneously with the virus, rather than being added to cells post-infection. The leaf extract of F. benjamina (SI = 980 for HSV-1; SI ~800 for HSV-2) was found to have a greater SI for both viruses than acyclovir (SI ~700 for HSV-1; SI ~300 for HSV-2), and significantly greater than the leaf extract of L. candidum (SI = 87.5 for HSV-1; SI = 35 for HSV-2). Both extracts were also found to be synergistic with acyclovir.A total of 31 medicinal plants were extracted with acetone and methanol by Jaeger Greer et al.,46 and each extract was tested against HSV-1 (McIntyre strain) and HSV-2 (strain 333). Extracts from 8 plants varied in 10-98% inhibition of plaque formation at concentrations ranging 0.025-0.2 mg/ml. These extracts were the acetonic extracts of Atractylis macrophylla, Clematis cirrhosa, Gnaphalium chilense, Hymenoclea salsola, Kalanchoe pinnata, Lithospermum officinale, Psilostrophe cooperi, and Tetraclinis articulata and the methanolic extracts of H. salsola and K. pinnata. The acetonic extract of K. pinnata offered the safest antiviral effect with 95% and 98% inhibition of HSV-1 and HSV-2, respectively, at a concentration of 0.2 mg/ml, without being cytotoxic at this concentration. In subsequent experiments, the acetonic extract of K. pinnata demonstrated an EC50 of 0.025 mg/ml and SI of 50 for both HSV-1 and HSV-2. Although not as potent, the methanolic extract of K. pinnata demonstrated an EC50 of 0.05 mg/ml and SI of 19 for HSV-1 and EC50 of 0.2 mg/ml and SI of 4.75 for HSV-2. Another notable SI was demonstrated by the acetonic extract of A. macrophylla (EC50 = 0.05 mg/ml and SI = 5) against HSV-2.Furthermore, Danaher et al.152 found an ethanolic extract of Rubus eubatus berries to elicit direct virucidal effects and prevent viral adsorption and replication of HSV-1 (strain 17+) in oral epithelial (OKF6) cells. Specifically, 56 µg/ml of extract was able to reduce viral yield by 99%. When the extract was added 1 hour post-infection, a concentration of 280 µg/ml was required to significantly reduce viral yields. Additionally, the extract was not found to be cytotoxic at high concentrations.A hydroethanolic extract of Arctium lappa fruits was shown to have antiviral effects against HSV-1 (strain ATCC-VR733) by Dias et al.42 All tested concentrations of the extract (3.125-400 µg/ml) were non-cytotoxic, and the extract showed a dose-dependent reduction in viral loads. At 400 µg/ml, A. lappa prevented cellular damage from viral infection and showed similar, although slightly better, antiviral capacity to 50 µg/ml of acyclovir.Various plant parts from Peganum harmala were used to create extracts with a combination of solvents (hexane, dichloromethane, ethyl acetate, methanol, and ethanol) that were assessed by Benzekri et al.135 for antiviral activity against HSV-2. Only the seed extract demonstrated viral inhibition (IC50 = 161 µg/ml and SI = 13.19). Time-of-addition experiments showed that the seed extract offered direct virucidal activity (IC50 = 49 µg/ml and SI = 43.46) and interfered with viral adsorption and lysis, but it did not protect pretreated cells from viral infection.Donalisio et al.169 found Vachellia nilotica bark extracts prepared with methanol (EC50 = 4.71 µg/ml and SI = 30.6), water (EC50 = 10.2 µg/ml and SI = 18.6), and chloroform (EC50 = 12.3 µg/ml and SI = 15.4) exhibited antiviral activity against HSV-2 (strain ATCC-VR540). Acyclovir was also tested and demonstrated EC50 and SI values of 3.17 µg/ml and >468, respectively. Against an acyclovir-resistant strain of HSV-2, the methanolic extract showed antiviral activity (EC50 = 6.71 µg/ml and SI = 21.5), suggesting a different mechanism of action compared to acyclovir. Additionally, the methanolic extract was observed to reduce viral load when added during infection, but only mildly reduce viral load when added after infection. The methanolic extract did not prevent infection in pretreated cells.Lastly, an ethanolic extract of Veronica persica was tested by Sharifi-Rad et al.170 for antiviral effects on HSV-1 and HSV-2. The extract was able to reduce viral load in a dose-dependent manner when added after infection. The SI was found to be 65 for HSV-1 and 45 for HSV-2. The ethanolic extract was further fractionated with 0%, 20%, 40%, 60%, 80%, and 100% methanol. The most notable antiviral effect was observed by the 80% methanolic fraction (IC50 = 0.62 µg/ml and SI = 451.6 for HSV-1; IC50 = 0.73 µg/ml and SI = 383.5 for HSV-2), whereas all other fractions demonstrated SI <4. It should be acknowledged that the SI values achieved by the 80% methanolic fractions were greater than those observed by acyclovir (SI = 320 for HSV-1; SI = 300 for HSV-2). Moreover, time-of-addition experiments revealed that the greatest viral inhibition occurred when cells were treated with the 80% methanolic fraction at inoculation and again post-infection. Single treatment at or post-infection demonstrated weaker effects. Additionally, the 80% methanolic fraction demonstrated synergistic antiviral effects with acyclovir.Single Herbs In VivoDimitrova et al.120 investigated the antiviral effects of 4 extracts of Melissa officinalis on HSV-1 (strain DA) infection in rabbits. Extracts were prepared with either 50% ethyl alcohol, 50% ethanol extract, ethyl acetate, or water. Rabbits were infected with HSV-1 into their eyes and treated 1 of the 4 extracts, 8 or 9 times a day at 1-hour intervals. Tear secretions were taken from each rabbit daily for 7 days and analyzed. No differences were found between treated and control rabbits for any outcome measure. The authors were unable to demonstrate antiviral effects of M. officinalis extracts in vivo.A wide variety of aqueous Asian plant extracts were tested by Kurokawa et al.33,98,99 in 3 studies for their ability to delay development of lesions and prolong survival time of female BALB/c mice infected with HSV-1 (strain 7401 H). Many of these extracts were previously found by the authors to exhibit antiviral effects against HSV-1 in vitro, either alone or in combination with acyclovir. In the first study, Kurokawa et al.33 cutaneously inoculated mice with HSV-1 and aqueous plant extracts were orally administered at a dose of 1-10 mg in a volume of 0.25 ml/mouse once at 8 hours prior to inoculation and then 3 times daily for 10 days after inoculation. The extracts of Alpinia officinarum, Caesalpinia sappan, Geum japonicum, Paeonia suffruticosa, Phellodendron amurense, Polygala tenufolia, Punica granatum, Rhus javanica, Syzygium aromaticum, Terminalia arjuna, and Terminalia chebula significantly delayed the development and progression of herpes lesions. The only extract to prolong mean survival time was Phellodendron amurense.In the second study, Kurokawa et al.98 tested the antiviral activities of 4 aqueous extracts of G. japonicum, R. javanica, S. aromaticum, and T. chebula each in combination with acyclovir. Extracts were dosed at 250 mg/kg and acyclovir at 2.5 mg/kg. The combination of acyclovir with G. japonicum, S. aromaticum, and T. chebula showed to significantly delay the development and progression of herpes lesions and/or mean survival time compared to acyclovir or extract alone. The combination of acyclovir with R. javanica did not show significant antiviral effects compared to acyclovir or extract alone. No significant toxicity was found for any of the combinations tested. Additionally, the 4 extracts and acyclovir were tested on viral yields in the skin and brain of mice. The extracts showed 2.5-20 times greater antiviral activity in the brain than skin. On the other hand, acyclovir was observed to elicit stronger anti-HSV effects in the skin than the brain. The combination of acyclovir with each of the extracts exhibited stronger antiviral effects than acyclovir or extract alone, and these effects were stronger in the brain than skin.In the third study, Kurokawa et al.99 tested hot water extracts of G. japonicum, R. javanica, S. aromaticum, and T. chebula for their ability to prevent recurrent HSV-1 infection in BALB/c mice that were infected with the virus 4 months prior and exposed to ultraviolet irradiation. The extracts, or water as control, were administered orally to the mice 3 times per day for 10 days at a total dose of 750 mg/kg/day. The UV irradiation began on day six. The extracts were shown to reduce incidence of recurrence, reduce the severity of vesicles, and decrease the duration of lesions if they occurred. The prophylactic treatment also reduced the ability to detect viral DNA in the trigeminal ganglion or pinna of the mice. The strongest prophylactic response was observed in mice treated with the S. aromaticum extract.Nakano et al.151 also investigated the antiviral effects of R. javanica and its prophylactic ability with recurrent HSV-2 (strain Ito-1262) herpes genitalis in guinea pigs in a crossover study. First, female guinea pigs were intravaginally infected with HSV-2 and monitored for 1.5 months until lesions healed. After primary infection was alleviated, guinea pigs were given an aqueous extract of R. javanica or water for 2 months. R. javanica was administered through drinking water at an average dose of 625 mg/kg/day. After 2 months, there were notable decreases in the number of vesicles, time to heal, and severity of lesions. The second part of the crossover design was conducted once secondary infection was cleared. Guinea pigs that received placebo treatment were administered R. javanica for 2 to 3 months, and those that previously received R. javanica were given either water or a new extract of T. chebula for the same duration. Both extracts were dosed on average at 625 mg/kg/day. In guinea pigs who received R. javanica followed by water, infection was not immediately triggered by discontinuation of the extract. However, treatment with R. javanica reduced the number, severity, and prevalence of lesions. The authors note that by maintaining similar results after crossover, R. javanica potentially provided prophylactic relief from recurrent HSV-2 infection.Furthermore, Nawawi et al.92 investigated the antiherpetic effects of methanolic extracts of 7 Indonesian medicinal plants in BALB/c mice. The plants studied were Eurycoma longifoli, Filicium decipiens, Garcinia mangostana, Melaleuca leucadendron, Nephelium lappaceum, Punica granatum, and Toona sureni. Extracts were dissolved in 2% dimethyl sulfoxide and orally administered to mice 8 hours before HSV-1 (strain 7401 H) inoculation and 3 times daily post-inoculation. All extracts were able to significantly delay the appearance of vesicles in the local region, but only M. leucadendron and N. lappaceum were able to both limit further development to mild zosteriform lesions and reduce mortality when compared to control. Specifically, N. lappaceum completely inhibited development of mild zosteriform lesions and was the only extract to exhibit similar antiherpetic activity as acyclovir (0.1 mg/mouse was given as comparison). The authors conclude that N. lappaceum has the potential to be used as an anti-HSV-1 treatment in humans.A later study by Nawawi et al.159 explored the efficacy of a methanolic extract of the root tubers of Stephania cepharantha at fighting off HSV-1 (strain 7401 H) infection in BALB/c mice. After cutaneously infecting mice with HSV-1, the extract was orally administered at 125 or 250 mg/kg of body weight. The extract led to a decrease in the number and development of vesicles and an increase in survival time of mice.Lipipun et al.28 assessed the water, ethanolic, or chloroform extracts of Aglaia odorata, Moringa oleifera, Ventilago denticulata, Cerbera odollam, and Willughbeia edulis for antiherpetic properties in female BALB/c mice. The mice were shaved and cutaneously infected with wild-type HSV-1 (strain 7401 H) and administered an extract orally in a dose of 250 mg/kg 8 hours prior to infection and then every 8 hours for 5 days. The size and development of skin lesions was significantly reduced in mice that were treated with A. odorata, M. oleifera, and V. denticulata. New female BALB/c mice were then virally infected and given either 5 mg/kg of acyclovir or 250 mg/kg of either A. odorata, M. oleifera, or V. denticulata every 8 hours for 2 weeks. All 3 plant extracts significantly reduced the development of vesicles in the local region, but only M. oleifera reduced mortality of the mice and increased survival times. The antiviral activities of A. odorata, M. oleifera, and V. denticulata were comparable to that of acyclovir.Moreover, Park et al.81 found a methanolic extract of Symphyocladia latiuscula to significantly delay the appearance and limit further progression of HSV-1 infection in female BALB/c mice. Mice were inoculated with wild-type HSV-1 (strain 7401 H) and orally administered the extract at a dose of 0.5 mg/mouse 4 hours pre-inoculation and then 3 times a day for 6 to 10 days post-inoculation. The extract significantly delayed the appearance of local vesicles and further progression to mild zosteriform lesions compared to control. Although survival time increased with the extract compared to control, the mortality rate was 100% in both groups. Further experiments evaluated viral yields in the skin and brain of mice treated with the extract at 3 and 6 days post-inoculation. At both 3 and 6 days post-infection, the extract significantly reduced viral yields in the skin, but not in the brain.The therapeutic effect of Carissa edulis extract in BALB/c mice infected with wild-type HSV-1 (strain 7401 H), wild-type HSV-2 (strain Ito-1262), or acyclovir-resistant 7401 H HSV-1 was investigated by Tolo et al.62 The extract was previously found by the authors to exhibit antiviral effects against HSV-1 and HSV-2 in vitro. Mice were treated post-infection with 250 mg/kg of the extract 3 times a day for 1 week. Onset of infection was significantly delayed by 2 days in both the wild-type and acyclovir-resistant HSV-1 infected mice. Delay of onset of infection in wild-type HSV-2 mice was not significantly different from control. Notably, the delay in onset of infection in wild-type HSV-1 infected mice was similar to the delay observed with treatment with acyclovir. Additionally, a longer survival time and lower mortality rate was observed in wild-type HSV-1 infected mice treated with the herbal extract compared to control.A methanolic extract of Lobelia chinensis demonstrated antiviral effects against HSV-1 infection in BALB/c mice by Kuo et al.116 The extract was previously found by the authors to exhibit anti-HSV-1 activity in vitro, likely by blocking viral DNA synthesis. Mice were inoculated with HSV-1 (strain KOS) and treated orally with either 20 or 50 mg/kg of the extract or 60 mg/kg of acyclovir 3 times a day for 7 days. No differences were observed in the development of lesions in mice treated with 20 mg/kg of extract and control. However, lesions completely disappeared in mice treated with 50 mg/kg of the extract or acyclovir, suggesting both are effective at preventing lesion formation. Further experiments revealed L. chinensis disrupts HSV-1 replication in mice, likely by reducing viral DNA expression. The extract was found not to have any toxic effects on the liver or kidneys of mice treated with the extract.Kaushik et al.110 tested the therapeutic effect of a hydromethanolic extract of Indigofera heterantha on HSV-2 infection in BALB/c mice. The authors had previously found the extract to demonstrate antiviral activity in vitro by blocking HSV-2 attachment, adsorption, and entry into host cells. The extract was formulated into a cream to be used for topical application at the genital region of mice. Mice were vaginally inoculated with HSV-2 (strain G) and administered 375, 750, or 1500 mg/kg of cream 3 times a day for 5 days, starting at 30 minutes post-infection. Treatment with 375 and 1500 mg/kg of cream resulted in 100% survival for the mice, and treatment with 750 mg/kg resulted in 87.5% survival. In terms of effects on lesion formation, clinical symptoms, and extravaginal disease, only treatment with 1500 mg/kg showed 100% reduction. Further experiments tested the prophylactic ability of the extract cream. Treatment with 125 mg/kg and 500 mg/kg at 2 and 4 hours pre-infection resulted in 100% survival and significant reductions in lesion scores. The authors conclude that I. heterantha has the potential to both treat and prevent genital herpes infection.Nocchi et al.156 investigated the anti-HSV activity of a crude hydroethanolic extract of Schinus terebinthifolia in female BALB/c mice. The extract was previously found by the authors to exhibit antiviral effects against HSV-1 in vitro by inhibiting viral attachment and penetration. Mice were infected with HSV-1 (strain KOS) and either given no treatment, 2% crude extract, 5% crude extract, or acyclovir cream 5 times per day for 10 days. The lesions developed more slowly and cleared up more quickly on mice who were treated with the crude extract versus no treatment. Additionally, the authors report no statistically significant differences between the lesions in mice treated with crude extract versus acyclovir. It is important to acknowledge that the authors also verified an absence of genotoxicity from the crude extract on bone marrow of the rodents.Hydroethanolic extracts of Equisetum giganteum, Croton lechleri, Uncaria tomentosa, and Copaifera reticulata were investigated by Churqui et al.73 against HSV-2 infection in female C57bl/6 mice. The extracts were previously found by the authors to exhibit antiviral effects against HSV-2 (strain 333) in vitro by preventing viral adsorption. When each of the extracts were administered simultaneously with the virus to mice, HSV infection was successfully prevented by all 4 extracts via viral inhibition.

Hydroethanolic extract of Tanacetum parthenium

  • Benassi-Zanqueta et al. anti-HSV-1 activity of oral and topical administrations of a hydroethanolic extract of Tanacetum parthenium in BALB/c mice
    • Extract was previously found by the authors to exhibit antiviral effects against HSV-1 (strain KOS) in vitro
  • Oral administration was given once daily and mice were administered either no treatment, control treatment, acyclovir at 10 mg/kg body weight, hydroethanolic extract at 4 mg/kg body weight, or hydroethanolic extract at 8 mg/kg body weight
  • Topical administration was given 4 times a day and mice were administered either no treatment, control treatment, 5% acyclovir, 2.5% hydroethanolic extract, or 5% hydroethanolic extract.
  • Both arms were carried out for 10 days.
  • The hydroethanolic extract was determined not to be genotoxic nor irritating.
  • Oral and topical treatment with the extract or acyclovir was found to yield similar results
    • But improvement of HSV lesions was mild compared to inactive treatments

Herbal Combinations In VitroSerkedjieva et al.174 prepared an aqueous extract from 100 g Sambucus nigra, 70 g Hypericum perforatum, and 40 g Saponaria officinalis and investigated the herbal combination’s antiviral effects against HSV-1 (McIntyre strain). The extract was assessed for cytotoxicity in human fetal lung fibroblast (MRC-5) cells and a maximum tolerated concentration was determined to be 250 µg/ml. At a concentration of 200 µg/ml, the extract showed virucidal effects to a 0.01/ml viral dose, but the ability to inactivate virions was only seen at a 0.1/ml viral dose. Moreover, MRC-5 and rabbit kidney (RK-13) cells were infected with HSV-1 and incubated with the extract or control for 24 hours. The extract at a concentration of 250 ug/ml was tested in MRC-5 cells, and concentrations of 100, 150, or 200 ug/ml were tested in RK-13 cells. There was a 2.4 log difference and a 1-3 log difference between control and treatment viral titres in MRC-5 and RK-13 cells, respectively.Cheng et al.178,179 investigated the antiherpetic activity of 2 traditional Chinese medicinal formulas in 2 studies. In the first study, Cheng et al.178 prepared an aqueous extract of Yin Chen Hao Tang, which consisted of 108 g Artemisia capillaries, 36 g Gardenia jasminoids, and 36 g Rheum officinale. The extract was tested against HSV-1 (strain KOS) and HSV-2 (strain 196 and strain G) and found to inhibit both viruses to different degrees. The IC50 and SI values against HSV-1 ranged 145.5-150.1 µg/ml and 5.7-6.0, respectively. Antiviral activity was more potent against the HSV-2 strains, with IC50 and SI values ranging 19.6-29.4 µg/ml and 28.9-43.4, respectively. Time-of-addition experiments revealed antiviral effects of the extract on HSV-2 were only noted when the extract was added simultaneously with the virus to cells or added 2 hours post-infection and presence maintained for 48 hours. In addition, pretreatment of HSV-2 virions with the extract showed to inhibit viral infectivity, and this inactivation was observed to be irreversible.In the second study, Cheng et al.179 made an aqueous extract of Long Dan Xie Gan Tang, which consisted of the following 10 Chinese herbs and weights: 32 g Alisma plantago-aquatica, 16 g Akebia quinata, 16 g Angelica sinensis, 32 g Bupleurum chinense, 16 g Gardenia jasminoides, 32 g Gentiana scabra, 16 g Glycyrrhiza uralensis, 16 g Plantago asiatica, 16 g Rehmannia glutinosa, and 16 g Scutellaria baicalensis. The extract showed to inhibit both HSV-1 (strain KOS) and HSV-2 (strain 196) in a dose-dependent manner, but HSV-1 was more susceptible to the extract. The IC50 and SI values, respectively, were determined to be 257.5 µg/ml and 15.8 against HSV-1 and 494.6 µg/ml and 8.2 against HSV-2. Additionally, HSV-2 virions were pretreated with the extract and a decrease in viral infectivity was observed. The authors conclude that Long Dan Xie Gan Tang likely inactivates herpes viruses directly, which is a different mechanism of action than acyclovir.An aqueous extract of Chui-Uren-Chien, another traditional Chinese medicine formula that is considered to be immunomodulatory, was tested for anti-HSV-1 activity by Liao et al.171 The extract was prepared from 7.5 g Panax ginseng, 11.25 g Astragalus membranaceus, 7.50 g Glycyrrhiza uralensis, 3.75 g Cimicifuga foetida, and 11.25 g Atractylodes macrocephala. HSV-1 (strain KOS) inhibition was not noted when the extract, at a dose of 600 µg/ml, was treated to virally infected SK-N-SH cells.
Lastly, Mishra et al.180 investigated the ability of a herbal gel formulation to act as an antiviral on HSV-2 (strain G ATCC-VR-734). The gel was previously studied on ulcers caused by HIV-1, and the authors propose that there is a strong link between ulcers caused by HIV-1 and HSV-2. The gel contained 50% ethanolic extracts of Acacia catechu, Lagerstroemia speciosa, Terminalia chebula, and Phyllanthus emblica. The use of this gel formulation resulted in a greater decrease in HSV-2 attachment (IC50 = 46.55 µg/ml and SI = 68.30) and penetration (IC50 = 54.94 µg/ml and SI = 57.87) than seen when treating infected cells with acyclovir. When cells were treated post-infection, acyclovir (IC50 = 0.065 µg/ml SI = 69,082) had significantly greater inhibition than the formulation (IC50 = 469.05 µg/ml and SI = 6.78). However, when testing virucidal activity, the gel formulation (IC50 = 27.26 µg/ml and SI = 116.63) was significantly more potent on virions than acyclovir (IC50 = 124.50 µg/ml and SI = 3.61). Moreover, physiological effects were explored by applying the gel to normal human vaginal mucosa (Vk2/E6E7) cells. The gel did not decrease viability of local vaginal flora or the integrity of vaginal keratinocytes. It also did not increase mutagenic behavior or secretion of inflammatory cytokines. The authors conclude that these results are more applicable to patient care than results from non-human cell lines.Herbal Combinations In VivoIkemoto et al.175 investigated the antiviral activity of Shigyaku-to in mice and tissue culture cells. Shigyaku-to is the Japanese name for the traditional Chinese herbal medicine Si Ni Tang, which is a combination of Glycyrrhiza glabra, Zingiberis siccatum, and Aconitum carmichaelii at a ratio of 3:2:1. It has been traditionally used for thousands of years in China to treat a variety of infections. To test the antiviral activity of this herbal combination, mice were infected with lethal amounts of HSV-1 (strain KOS) and treated with various doses of Shigyaku-to (1.25-80mg/kg). The strongest antiviral activity was seen with a dose of 20mg/kg where 74% of mice survived infection compared to 100% mortality of mice treated with saline control. Moreover, when infected mice were inoculated with whole spleen cells from uninfected mice treated with Shigyaku-to, survival rate was significantly higher compared to non-inoculated controls. Shigyaku-to’s antiviral mechanism was investigated in Vero cells, but the herbal combination did not show any virucidal or virostatic activities in vitro. The authors suggest that the antiviral mechanism of this herbal combination may be due to stimulation of the body’s antiviral functions in mice.Another traditional Chinese herbal formula, Kanzo-bushi-to, was studied for antiviral effects in thermally-injured BALB/c mice by Matsuo et al.176 Kanzo-bushi-to is the Japanese name for the Chinese formula Gan Cao Fu Zhi Tang. The authors chose to use thermally-injured mice because they are approximately 100 times more susceptible to herpes infection than non-thermally-injured mice. A hot water extract was made from Kanzo-bushi-to, which is a combination of Aconitum carmichaelii, Atractyloidis lanceae, Cinnamomum verum, and Glycyrrhiza glabra at a ratio of 2:12:7:4. Mice were thermally injured and 1 day later were inoculated with HSV-1 (strain KOS). The extract was administered intraperitoneally on days one and 4 post-injury at a dose of 5 mg/kg. The extract significantly reduced the mortality rate of mice, demonstrating a rate of 10% compared to 95% in controls. Further experiments showed that CD8+ ST-cell activities were reduced in mice treated with the extract. This is an important finding because an increase in CD8+ ST cell activity is involved in the increased susceptibility to infection of thermally-injured mice. Additionally, an accelerated generation of Contra-ST-cells was observed in mice treated with the extract, which likely explains the reduction in CD8+ ST cell activity. The authors conclude that an aqueous extract of Kanzo-bushi-to reduced the susceptibility to HSV-1 infection in thermally-injured mice by expanding the generation of Contra-ST-cellsLastly, Nagasaka et al.177 studied a Chinese herbal combination called Kakkon-to for its antiherpetic properties. Kakkon-to, which is the Japanese name for the Chinese formula Ge Gan Tang, is a mixture of 24 g Pueraria pseudo-hirsuta radix, 12 g Ephedra sinica herba, 12 g Zizyphi jujuba fructus, 9 g Cinnamomi cassia cortex, 9 g Paeoniae lactiflora radix, 6 g Glycyrrhizae uralensis radix, and 3 g Zingiberis officinale rhizoma. A hot water extract of the herbal mixture was prepared and female BALB/c mice were orally given either 300mg/kg of the extract or water 4 hours pre-infection. Mice were subjected to cutaneous HSV infection by inoculation with HSV-1 strain 7401 H and treated with the same 300mg/kg of extract or water every 8 hours for 7 days. Mice treated with Kakkon-to showed 33% mortality compared to 100% mortality in those untreated. Additionally, the size and severity of lesions significantly decreased in mice treated with Kakkon-to versus those untreated. To study the antiviral effect on an established HSV-1 infection, separate female mice were inoculated with HSV-1 strain 7401 H and were either treated with 330mg/kg Kakkon-to at zero or 18 hours post-infection or were non-treated controls. The appearance of skin lesions was significantly reduced in the treatment groups compared to controls. However, the lesions developed along the same course from vesicular to ulcerated lesions in all groups. The only noted difference was smaller lesion sizes in treated mice regardless of treatment time. The authors concluded that Kakkon-to acted as both a therapeutic and prophylactic agent against HSV-1 cutaneous infection.Human TrialsThe effect of Melaleuca alternifolia oil gel on recurrent herpes labialis was studied via a randomized, placebo-controlled, investigator-blinded trial conducted by Carson et al.181 Participants were not blinded to their treatment due to the unique smell of M. alternifolia oi, and 20 participants with a history of recurrent herpes labialis were recruited. Treatment was either a 6% M. alternifolia oil aqueous gel or placebo gel. Participants were instructed to apply the gel 5 times daily as close to onset of infection as possible. Those treated with M. alternifolia oil gel had a shorter duration of infection (9 days) compared to participants treated with placebo (12.5 days), and the viral load present in lesions was lower in those treated with M. alternifolia oil gel than with placebo. However, both groups had similar results for HSV presence (via PCR) and time to crust formation. Study results were not statistically significant, which the authors owe to the small population studied. However, Melaleuca alternifolia oil has potential to be a cost effective alternative topical treatment for herpes labialis infections.Two human trials, carried out by Wolbling et al.,182 demonstrated the antiviral effects of Melissa officinalis on HSV lesions. Lomaherpan cream containing 1% dried extract of M. officinalis was tested. The first trial tested the cream on HSV lesions without the use of a placebo-control group. The trial was conducted at 3 dermatology clinics on a total of 115 patients with HSV lesions of the skin or transitional mucosa for not more than 72 hours. Subjects were instructed to apply the cream to lesions 5 times daily until lesions completely healed. Lesions completely healed by day 4, 6, and 8 in 60%, 87%, and 96% of subjects, respectively. The authors believed the cream reduced healing time as HSV lesions naturally heal within 10 to 14 days. The second trial was a randomized, double-blind, placebo-controlled study of 116 patients with HSV lesions with the same inclusion criteria as the trial before. A cream that did not contain M. officinalis was used as placebo. Subjects were instructed to apply the cream to lesions 2 to 4 times daily for a period of 5 to maximum 10 days. Clinical symptoms between the treatment and placebo groups were not statistically different at baseline. On day two, significant reductions in symptoms and lesion swelling was noted in the treatment compared to the placebo group. On day five, complete resolution of symptoms was noted by 24 subjects in the treatment group compared to 15 subjects in the placebo group. Subjects’ and physicians’ assessments of healing were significantly greater for the treatment group compared to the placebo group. The trial provided evidence for the use of M. officinalis as a treatment for HSV lesions. The antiviral effect was found to be most significant if treatment was commenced as early as possible during the course of infection.Koytchev et al.183 also assessed the antiviral activity of M. officinalis on HSV infections in a randomized, double-blind, placebo-controlled trial. The study included 66 patients based on the criteria of at least 4 episodes of herpes labialis per year. A cream was created to have 1% active ingredient, described as the dried extract of M. officinalis at a 70:1 concentration. Subjects were given either the treatment or a placebo cream and instructed to apply the cream to lesions 4 times daily for a duration of 5 days. Symptom scores were measured on the second day of treatment because most symptoms in patients with recurrent herpes labialis have the greatest severity around this time. Treatment with the M. officinalis cream resulted in significantly lower scores of symptom severity compared to placebo. The authors report that the M. officinalis cream resulted in a shortened healing time, decreased spread of virus to neighboring cells, and reduced symptoms such as itching, burning, swelling and erythema. Additionally, it is speculated that the M. officinalis cream may elongate the asymptomatic stage in individuals with recurrent herpes labialis.Furthermore, the efficacy of Echinacea purpurea at reducing the frequency and severity of herpes genitalis was studied by Vonau et al.194 using a placebo-controlled, double blind, crossover trial with 50 participants. The strain of HSV present in each participant was confirmed and found to be a mix of HSV-1 and HSV-2. The extract used was a marketed compound called Echinaforce, made of the plant and root of E. purpurea. Treatment with placebo or 800 mg bid orally of the extract was given for 6 months followed by 6 months of treatment with the opposite arm. There was no significant difference found between E. purpurea or placebo at preventing or reducing the frequency of recurrence of herpes genitalis. Additionally, there were no significant differences between pain scores, duration of infection, or neutrophil count between placebo or extract.Clewell et al.184 explored the effect of a topical formulation of Hypericum perforatum and copper sulfate pentahydrate compared to that of topical 5% acyclovir on HSV lesions. The formulation is marketed as Dynamiclear and aims to treat HSV lesions with a one-time application. The authors explain that Dynamiclear would be a more cost-effective treatment compared to the topical 5% acyclovir as the latter requires multiple applications. A total of 149 participants with active HSV-1 or HSV-2 lesions between the ages of 18-55 were randomized to receive either a single treatment of Dynamiclear or topical 5% acyclovir for 14 days. Participants reported their symptoms and physical exams were evaluated on days 1, 2, 3, 8, and 14. The Dynamiclear group had lower reports of burning or stinging sensation and decreased ratings of acute pain, erythema, and vesiculation compared to the acyclovir group. In fact, the acyclovir group was 4 times more likely to have vesiculation than those treated with Dynamiclear. It is important to note that the Dynamiclear treatment was not associated with any adverse events or toxicity.The therapeutic antiviral effects of 2 herbal combinations were assessed by Hijikata et al.185,186 in 2 trials. In the first trial, Hijikata et al.185 prepared an aqueous extract to contain a daily dose of 4 g Coicis semen, 2 g Elfuinga applanata, 4 g Ganoderma lucidum, 2 g Terminalia chebulae, 2 g Trapa natans, and 2 g Wisteria floribunda. One male and 4 females, aged 31-60 years, with recurrent herpes labialis were treated orally with the extract, either taking a single, double, or triple daily dose. For all 5 patients, use of the herbal combination extract significantly reduced the healing time of herpes lesions compared to previous outbreaks when no treatment was used. Lesions crusted and resolved within a few days compared to resolving within approximately 2 weeks with no treatment. In addition, pain associated with outbreaks was significantly reduced for one patient with use of the extract.In the second trial, Hijikata et al.186 prepared an aqueous extract that was subsequently dried to a powder to contain a daily dose of 2 g Wisteria floribunda, 2 g Trapa natans, 2 g Terminalia chebulae, 4 g Coicis lachryma-jobi, 4 g Ganoderma lucidum, and 2 g Elfuinga applanata. Study participants had recurrent HSV infections for at least 1 year and had been treated by external medical professionals without improvement. The study recruited 15 patients with herpes genitalis and 13 patients with herpes labialis. Patients were instructed to take a double daily dose of the herbal combination on days one and 2 of infection and a single daily dose for subsequent days until complete relief. At baseline, the mean time to relief from infection was 10.9 ± 6.3 days for herpes genitalis and 7.8 ± 4.3 days for herpes labialis. After treatment with the herbal combination, the mean time to relief was reduced to 4.9 ± 1.3 days for herpes genitalis and 4.0 ± 1.1 days for herpes labialis. Both reductions were statistically significant. The authors concluded that treatment with this herbal combination provided fast and effective relief from recurrent HSV infections.Lastly, Saller et al.187 conducted a double-blind, randomized, comparative trial to assess the efficacy of 2 herbal creams on herpes labialis lesions. The first cream contained sage extract from leaves of Salvia officinalis, and the second cream contained sage extract and rhubarb extract from the roots of Rheum palmatum and Rheum officinale. The reference treatment was Zovirax, which contained acyclovir (50 mg/g). All subjects were provided a topical treatment. A total of 145 subjects participated in the trial and were split into 3 treatment groups so that 64 received the rhubarb-sage cream, 40 received the sage cream, and 41 received the Zovirax cream. Participants’ HSV status was assessed by the amount of swelling present and pain associated with lesions. Mean time to healing for the sage, sage-rhubarb, and Zovirax cream groups was 7.1, 6.7, and 6.5 days, respectively, and mean time to crust formation was 7.8, 7.2, and 6.3 days, respectively. Mean time to healing and crust formation were not statistically different between treatments. Additionally, the participants who used the rhubarb-sage extract cream reported less pain than those using the sage extract cream. This study provides a basis of knowledge that herbal remedies, specifically the combination of rhubarb and sage, may be as effective as current pharmacological topical therapies for the treatment of HSV lesions.Identified ConstituentsA wide variety of phytochemicals and constituents can be found within medicinal plants. Several studies within this review have identified constituents found in their plants of interest. Compounds isolated from multiple antiviral plants included phenolic acids56,90,108,136–138,174,180 such as cichoric acid,79,80 gallic acid,92,138,150,180 rosmarinic acid,63,120,121,123,124,126,153,173,182,187 caffeic acid,94,109,120,121,124,126,153,182 catechinic acid,72 coumaric acid,94,124,153 ferulic acid,94,120 carnosic acid,153 chlorogenic acid,109,162,182 atomaric acid,69 and caffeoyl acids.108 Flavonoids were identified,24,41,56,70,82,90,95,97,101,107,108,121,126,132,136–138,148,150,160,163,174,180 specifically luteolin,44,48, 94,121,126,134,153,164,172 quercetin,57,83,102,106,172 quercitrin,106 apigenin,44,121,126,131,153 rutin,57, 109,138 myricetin,57 and kaempferol.102 Other constituents included alkaloids, 56,24,41,49,95,107,129,132, 135,158,159 tannins, 29, 56,70,75,82,92, 95, 97, 138,141, 148,165,150,174,180,190 xanthones,66,82 saponins,41,95,100,101,108,109,129,174 sesquiterpenes,78 halogenated sesquiterpenes,69 sesquiterpene lactones,162,163 monoterpenes, 131,65,166 triterpenoids, 24,41,56,57,66,70,95,96,131,132, 158,150 sterols,24,41,56,96,132,166,180 phenols,78 bromophenols,81 coumarins,41,136 lignans,42,112 aldehydes,105,104,166 alkanes,78 polysaccharides,30,49, 55,68,78,83,100,158,171 carbohydrates,112 protein,112 ketones,82,105 triacylglycerols,69 fatty acids,69,78 carboxylic acids,39 hydroxyanthracene.187 Lastly, constituents identified in antiviral essential oils were bicyclogermacrene,25 germacrene-D,25 spathulenol,25 ß-caryophyllene,25 piperitenone,25 ?–copaene,25 eugenol,119 1,8-cineole,119 1,8-cineole,119 terpinen-4-ol,119 flavesone,113 leptospermone,113 citral a,122 caryophyllen,122 citral b,122 citronellal,122 ß-cubeben,122 menthylheptenon,122 caryophyllenoxid,122 and ocimen.122LimitationsThis review has several limitations. First of all, the use of different outcome measures among the studies reviewed poses a challenge to compare results. Several studies calculated SI values of plant extracts against herpes simplex virus infections, while others only reported their CC50, TD50, IC50, and/or ED50 values. Furthermore, some of the studies reviewed reported none of these outcome measures. Reporting the CC50 or TD50 with the IC50 or ED50 is important to be able to fully evaluate the therapeutic potential of an extract and compare potential between extracts. For example, if an extract has a high ED50, but a low CC50, it will be cytotoxic to cells before it shows significant antiviral activity, and this will correspond to a low SI. On the other hand, a low ED50 with a high CC50 would give an extract a high safety profile, as it would elicit antiviral effects before any signs of cytotoxicity, which would correspond to a high SI. In some studies, missing SI values could be calculated, but in others, this was not possible if only the CC50/TD50 or IC50/ED50 was reported. In these cases, efficacy is open to interpretation.Secondly, SI ranges or cut-off values that represent mild, moderate, or strong antiviral activity varied among studies. A possible reason for this discrepancy could be the dose of virus used in the studies. For example, an extract demonstrating an SI of 20 may be considered as having strong antiviral activity by one group of authors, while another group may classify it as having moderate effects. This, paired with varying doses of HSV-1 and HSV-2 virions administered to cells, makes it difficult to compare the absolute antiviral effects of extracts.Thirdly, comparing the absolute antiviral effect of botanicals between studies is challenging because extracts were prepared with different solvents as well as type and amount of plant material. The antiviral activity of a plant is due to its active constituents. Without knowing what these constituents are, their polarity, and which part of the plant they are contained in, it is difficult to determine the ideal method of extraction. As such, plants which have antiviral potential may be found to not possess effects if its extract was prepared with a solvent that was not ideal to extract its active constituents.Lastly, the majority of the studies conducted on botanicals were done in vitro. While many show promising anti-HSV activity, the results cannot be extrapolated to how the botanicals would perform clinically. The low number of human clinical trials limits conclusions that can be made on the efficacy of various botanicals on HSV prevention and treatment. Therefore, more in vivo research is needed in the form of randomized clinical trials.ConclusionHerpes simplex virus affects many individuals around the world as it is easily transmitted from person-to-person due to viral shedding in the absence of symptoms.1 While HSV infection is not fatal, it is recurrent and as such it can negatively affect an individual’s quality of life. There is no cure for HSV, therefore management strategies are important to prevent and treat HSV outbreaks. The efficacy of current treatments has begun to falter, as seen by emerging viral resistance to nucleoside analogues.12 Research has studied the ability of various botanicals to fight HSV infections and possibly uncover higher efficacy treatments than currently utilized. HSV may be less likely to develop resistance to botanicals because their various active constituents have various mechanisms of action, for example by targeting viral attachment, penetration, DNA replication, gene expression, or by directly inactivating virions. This gives botanicals a potential benefit over the conventional therapy for HSV, acyclovir, which specifically targets viral replication. Additionally, results suggest that combination therapies have the potential to elicit greater benefits over single therapies. Future research should include human clinical trials that study the combination of botanicals that demonstrate anti-HSV activity in vitro.

Carissa edulis

  • A medicinal plant that grows locally in Kenya
  • Traditionally for a variety of ailments such as skin conditions and sexually transmitted infections.
  • An aqueous extract was prepared from C. edulis roots, freeze-dried
  • Tested against wild-type HSV-1 (strain 7401 H) and HSV-2 (strain Ito-1262), thymidine kinase-deficient HSV-1 (strain B2006), and acyclovir-resistant 7401 H HSV-1.
  • Extract inhibited plaque formation of all 4 strains
  • Wild-type HSV-2 (EC50 = 6.9 µg/ml and SI = 69.6) and thymidine kinase-deficient HSV-1 strain (EC50 = 8.1 µg/ml and SI = 59.3) were more susceptible to the extract.
  • At 200 µg/ml, the extract reduced viral yields of
    • Acyclovir-resistant HSV-1 strain by 100%,
    • Wild-type HSV-2 strain by 99.5%,
    • Wild-type HSV-1 strain by 97.8%,
    • Thymidine kinase-deficient HSV-1 strain by 96.3%
  • Results are significant considering
    • Acyclovir at 5 µg/ml was tested against thymidine kinase-deficient HSV-1 strain yield reduction of only 3.0%
    • Acyclovir-resistant HSV-1 strain yield reduction of only 1.5%
  • journals.sagepub.com/doi/10.1177/2515690X20978394 Tolo et al

Celecoxib

Inonotus obliquus - Chaga mushroom

N-chlorotaurine

  • An essential weak oxidant produced by stimulated human leukocytes
  • Known to have bactericidal, fungicidal and vermicidal properties
  • Its virucidal activity
  • 5 and 60 min, virus titers of both Herpes simplex virus type 1 and 2
    • Were reduced about 1.3-2.9 log10 and 2.8-4.2 log10 by 0.1 and 1%, (5.5 and 55 mM) N-chlorotaurine
  • Virus titer reduction of adenovirus type 5 between 15 and 60 min was 0.5-2.0 and 0.6-4.0 log10, respectively, by the same concentrations of N-chlorotaurine
  • N-chlorotaurine in destruction of pathogens during inflammatory reactions and also the possibility of its application as an antiviral agent in human medicine.
  • pubmed.ncbi.nlm.nih.gov/9614001/

5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU)

  • Highly specific COX-2 inhibitor is even more effective than ASA
  • DFU resulted in a 68% reduction in recurrences
    • When given before the stress was applied
  • 50% reduction
    • When given after the stress was applied (Gebhardt BM, unpublished data, 2001)
  • Inhibition of recurrences
    • Reduction of virus on the corneal surface
    • Reduction of virus DNA in the ganglion
  • iovs.arvojournals.org/article.aspx?articleid=2123004


Ethynylthymidine

  • Inhibitor of viral thymidine kinase
  • Thymidine kinase occurs in non-neural cells
    • Selective inhibitor of viral thymidine kinase would not inhibit viral multiplication in these cells
      • Because the cellular enzyme would be available
  • Central nervous system did not normally contain thymidine kinase
    • Viral mutants deficient in thymidine kinase generally do not recur frequently
  • Ethynylthymidine reduced the recurrence rate of herpes
    • Is insoluble and difficult to administer
  • iovs.arvojournals.org/article.aspx?articleid=2123004

Fluoxetine

Herbal-based ointment: lysine + zinc oxide + echinacea + goldenseal

In HIV infection



Interferon gamma (IFN-g)

  • Suppresses pathogen replication, including
    • Chlamydia, Hepatitis B virus, and Parainfluenza virus,
  • By depleting L-Trp
    • Through activation of
      • Indoleamine-pyrrole 2,3-dioxygenase (IDO)
        • Initial KP rate-limiting enzyme (Carlin et al., 1989; Lepiller et al., 2015; Rabbani et al., 2016; Yoshio et al., 2016; Raniga and Liang, 2018)

HSV u imunokomprimovaných

  • WHO STI expert consultation in Montreux, Switzerland, in April 2008
    • Longer duration of treatment with aciclovir should be explored
  • Genital HSV infection is more severe in people who are immunocompromised
    • Recommendations for treatment of HSV-2 infections in people living with HIV should also be updated
  • Suppressive therapy has been shown to
    • Reduce HIV viral shedding
    • HSV-2 viral shedding and recurrences [1]
  • 1st. epizode of genital herpes
  • Most infections are transmitted via asymptomatic viral shedding.

Oral antiviral medications are available for:

  • Initial,
  • Episodic,
  • Suppressive therapy;
  • However, there is no cure for the infection.

In 2003, World Health Organization (WHO) guidelines recommended dosages are:

  • Aciclovir
    • 200 mg orally, 5 times daily for 7 days
    • 400 mg orally, 3 times daily for 7 days
  • Valaciclovir
    • 1 g orally, twice daily for 7 days
  • Famciclovir
    • 250 mg orally, 3 times daily for 7 days [2]

Inhibition of HCF-1-associated H3K9 demethylases or UTX/JMJD3 H3K27 demethylases

Inhibitors of LSD1

  • Have been shown to suppress HSV infection and reactivation from latency
  • Enhances epigenetic repression of the latent HSV genomes
    • Correlates with a reduction of reactivation and viral shedding
  • journals.asm.org/doi/10.1128/mBio.01141-17

EZH2/1 inhibitors

  • Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens
  • Histone H3K27 methyltransferases EZH2 and EZH1 (EZH2/1)
  • Epigenetic repressors
  • Suppress gene transcription via propagation of repressive H3K27me3-enriched chromatin domains
  • EZH2/1 are implicated in the repression of herpesviral gene expression
  • Inhibitors of these enzymes suppressed primary herpes simplex virus (HSV) infection in vitro and in vivo
  • Compounds blocked lytic viral replication following induction of HSV reactivation in latently infected sensory ganglia
  • Suppression correlated with the induction of
    • Multiple inflammatory,
    • Stress,
    • Antipathogen pathways
    • Enhanced recruitment of immune cells to in vivo infection sites
  • EZH2/1 inhibitors
    • Induced a cellular antiviral state
    • Also suppressed infection with DNA (human cytomegalovirus, adenovirus) and RNA (Zika virus) viruses
    • Have considerable potential as general antivirals through the activation of cellular antiviral and immune responses.
  • journals.asm.org/doi/10.1128/mBio.01141-17
  • Most widely utilized antiherpetic pharmaceuticals target the viral DNA polymerase to interfere with late-stage viral replication
    • Drug-resistant strains emerge
    • Compounds do not adequately control subclinical infectious viral shedding
      • The most prevalent means of transmission.
  • Epigenetic regulation is mediated by
    • Families of histone modification enzymes
    • Adaptor recognition proteins
    • Chromatin remodelers
  • Inhibitors of the histone H3K27 methyltransferases EZH2 and EZH1 (EZH2/1)
  • Potential therapeutics for treating cancers with EZH2 gain-of-function mutations
  • Components of Polycomb repressive complex 2 (PRC2)
    • EZH2/1 mediate gene repression primarily through propagation of H3K27me3
      • Results in domains of nucleosomal compaction
  • EZH2 and EZH1
    • Modulate genes whose promoters exhibit bivalent histone markers (H3K27me3 and H3K4me3)
      • That enable the transition to either an active or a repressed state during environmental signaling and differentiation
  • EZH2/1 PRC2 complexes
    • Regulation of the lytic-latency cycles of multiple members of the herpesvirus family, including HSV
  • journals.asm.org/doi/10.1128/mBio.01141-17
  • EZH2/1 inhibition
    • Reduced HSV gene expression and lytic infection in vitro and in vivo
  • Inhibitors did not induce reactivation
    • But rather suppressed the spread of viral reactivation in a ganglion explant model
    • Treatment induces multiple components of antipathogen pathways that result in an enhanced cellular antiviral state
      • Not limited to HSV but also other representative nuclear DNA viruses
        • Human cytomegalovirus [hCMV],
        • Adenovirus 5 [Ad5]),
        • Unrelated RNA virus (Zika virus [ZIKV])
  • journals.asm.org/doi/10.1128/mBio.01141-17
  • Inhibitors of the histone H3K27 methyltransferases EZH2/1 have been developed on the basis of the potential to treat
    • Some diffuse large B-cell,
    • Follicular,
    • Non-Hodgkin’s lymphomas
    • Kaposi’s sarcoma-associated herpesvirus
    • Epstein-Barr virus, and hCMV
  • Two natural compounds ZINC000004217536 (Tetragastrin) and ZINC000003938642 (Thymopentin )
    • Could bind tightly to EZH2,
    • Calculated to be nontoxic
    • High degree of intestinal absorption and high bioavailability.
  • In vitro experiments confirmed that drug ZINC000003938642 could inhibit
    • The proliferation and migration of osteosarcoma
    • Providing new clues for the treatment or adjuvant treatment of tumors
  • GSK126 significantly reduces the level of H3K27me3 in tumor cells by inhibiting the methyltransferase activity of EZH2
    • Thereby inhibiting the growth of tumor cells such as
      • Human tongue squamous cell carcinoma
      • Multiple myeloma cells
  • EZH2 may promote tumor invasion and metastasis
    • By downregulating downstream targets such as E-cadherin and vascular endothelial growth factor (VEGF)-A
  • EZH2 inhibitor GSK126 had made notable progress in different kinds of cancers
    • Prostate cancer cells
    • Gastric cancer cells
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC8560702/

Tetragastrin - Cholecystokinin tetrapeptide (CCK-4) - ZINC000004217536

Markery EZH2 inhibice

  • EZH2 inhibition, alone and in combination with cisplatin
  • Induces immune signaling
    • Largest changes interferon gamma upregulation
      • Result of activated natural killer (NK) signaling
      • Increase in NK cell-associated genes MIP-1alpha, ICAM1, ICAM2, and CD86 in xenografts treated with EZH2 inhibitors
  • EZH2 inhibition results in decreased expression of
    • Pluripotency markers, ALDH2 and CK5
    • Increased cell death
  • Mediated through increased NK cell-related signaling
    • Resulting in tumor cell differentiation and cell death
  • //ri.conicet.gov.ar/handle/11336/123264

Inhibitors of the JMJD2 family of histone H3K9 demethylases


Inhibitors of prostaglandin synthesis

Jasminum fluminense - Brazilian jasmine

Oral lysine

  • An amino acid
  • In preventing and treating HSV infections
  • Found to be ineffective at doses of 1 gram per day
    • Without consumption of a low arginine diet
  • Comes from tissue culture findings
    • Viral replication is suppressed when the ratio of lysine-to-arginine is high
    • Also the rationale for why a diet low in arginine can help manage outbreaks
    • Evidence does not support the use of one without the other
  • Treatment with greater than 3 grams of lysine per day
    • Has shown to improve the subjective experience associated with HSV infections
  • journals.sagepub.com/doi/10.1177/2515690X20978394

  • The supplementation of L-lysine is safe
  • A 70 kg man may use 800-3000 mg / day
  • Doses of up to 3g per day are well tolerated;
  • Higher doses (10-15g per day) can cause gastrointestinal disturbances, including
    • Nausea, abdominal cramps and diarrhea.
  • Prophylactic L-lysine to patients with recurrent herpes range from 500-3000 mg/day
  • A reasonable recommendation is 500 -1000 mg daily for prophylaxis,
    • Keeping higher doses (3,000 mg / day) for active outbreaks and only for a limited time to the acute phase
  • L-Lysine has a significant effect on reduction of virus replication HSV1 in animals
    • Also reduces the healing time
      • Lesion cycles as in its incidence

Clinical trial

  • After 12 months from the first cycle of L-lysine
    • An average reduction of 49% in time for the damage repair in one year
    • This reduction was statistically significant (p <0.01)
    • In one year, a decrease of 63% in the lesions incidence was observed
      • This reduction was statistically significant (p <0.01)
  • A paired t test was used to compare the incidence and duration of the cycle before and after this first treatment
  • Annual incidence reduction of recurrent herpes in a 8-year follow up
  • 12 individuals
  • During the lesion crust phase using one capsule of 500 mg daily for 30 days
  • Taken fasting with water, one hour before a meal or two hours minimum after.
  • Continue the use of the same acyclovir cream they were using prior to Lysine
  • A new 30-day course of 500 mg L-lysine was prescribed 12/12 months with the same dosing guidelines.
  • As well as avoiding the consumption of foods rich in Arginine was prescribed
  • Following years every 4 months
  • The amino acid lysine has an antagonistic relationship with the amino acid arginine which is an amino acid required for the replication of HSV virus

Double blind controlled study with 27 patients

  • 1000 mg of lysine three times a day for six months
  • Reduction in the incidences of lesions (p <0.05)
  • Substantial reduction in symptom severity (p <0.05)
  • Reduced healing time (p <0.05)
  • Compared with the group receiving placebo

Prospective study with 9 subjects receiving 500 mg of lysine daily

  • In conjunction with a diet low in arginine
  • Reduction in recurrence, severity, and duration of lesions

Multicenter study with 45 patients

  • 320 to 1.200 mg / day of Lysine for two months + restriction rich in arginine food
  • Reduction in infection recurrence

Group of 65 patients

  • Control group with placebo and the test group with 500 mg of L-Lysine
  • Reduction in recurrence of lesions
    • Test group (27.7%)
    • Control group (12.3%), p <0.05.
  • Dose was equally administered twice a day for 12 weeks

26 volunteers with a record of frequently recurring herpetic lesions

Double-blind crossovers study

  • Daily oral supplements of 1,000 mg L-Lysine
  • Serum samples were analyzed at scheduled intervals
  • Members of the lysine group reported significantly fewer lesions
  • Those who were taken off lysine supplementation
    • Generally showed a significant increase in lesion occurrence
  • When a person's serum lysine concentration exceeded 165 nmol/ml
    • There was a corresponding significant decrease in recurrence rate.
  • Frequency rate increased significantly as concentration levels fell below 165 nmol/ml
    • Prophylactic lysine may be useful in managing selected cases of recurrent herpes simplex labialis if serum lysine levels can be maintained at adequate concentrations
  • www.scielo.br/j/rgo/a/PdPQSGKWFGpsRwZsXRGnVks/?lang=en

Foods rich in lysine

Food containing the amino acid arginine to reduce

Mangifera indica - Mango


Leptospermum scoparium - Manuka oil

Treatment of a first clinical episode of genital HSV x no treatment

Aciclovir

  • Eight randomized controlled trials reported in six articles comparing aciclovir to no treatment or placebo
  • Various oral dosages of aciclovir were used over periods of 5–10 days
  • Duration of symptoms and lesions is probably reduced (2–4 days fewer) with aciclovir compared to placebo
  • Pain may be reduced by two more days
  • Duration of viral shedding may be reduced by nine more days
  • Adverse events may also be reduced with treatment compared to placebo
  • Benefits of treatment was moderate and the adverse events trivial.
  • Reducing the number and frequency of tablets taken
  • Adherence to treatment regimens may be improved with simpler regimens
  • Different regimens and medicines are probably acceptable to most people
  • Valaciclovir and famciclovir are more expensive than aciclovir
    • Famciclovir is more expensive than valaciclovir [2]
  • Effects of treatment would likely be similar in other populations
    • E.g. people with positive HIV status
    • People who are immunocompromised
    • Pregnant women
  • Severe infections have traditionally not been well defined
    • First clinical episodes can often be severe
  • Benefits would likely apply to people with “severe infections” [2]

Propranolol

 

Sandalwood oil

  • Essential oil of Santalum album L.

In vitro

  • Antiviral activity against Herpes simplex viruses-1 and -2.
  • Replication of these viruses was inhibited in the presence of the oil.
  • Effect was dose-dependent and more pronounced against HSV-1.
  • Oil was not virucidal
  • Showed no cytotoxicity at the concentrations tested.
  • pubmed.ncbi.nlm.nih.gov/10374251/

Lentinus edodes - Shiitake mushroom

SSRI

  • Pharmacological inhibition of serotonin reuptake by selective serotonin reuptake inhibitors (SSRI)
    • Can both suppress replication of viral pathogens
      • Inhibit virus-mediated inflammatory disease (Zuo et al., 2012; Ulferts et al., 2013; Young et al., 2014; Medigeshi et al., 2016; Chang et al., 2017; Benkahla et al., 2018; Schneider-Schaulies and Beyersdorf, 2018; Bauer et al., 2019; Almeida et al., 2020; Calusic et al., 2021; Dechaumes et al., 2021; Meikle et al., 2021; Zimniak et al., 2021; Kummer et al., 2022).
  • SSRI’s have been shown to suppress efficient replication of many viruses
    • Enteroviruses, Dengue, Coxsackie virus, HIV, and SARS-CoV-2
  • Prolonged SSRI use, which enhances 5-HT signaling through cell surface receptors
    • Linked to ocular hypertension, decreased tear production, and damage to ocular surface cells (Acan and Kurtgoz, 2017).
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC8982329/

Tamoxifen

  • Ncreased circulating sex hormones may be associated with increased susceptibility to HSV recurrences
  • 55-year-old woman taking tamoxifen whose labial HSV infections recurred after she missed 3 daily doses of the drug
  • Within 24 hours of restarting tamoxifen administration, the lesions resolved.
  • Benson and Baum posited that the antiviral effect of this drug may rest with
    • Induction of interferons or additional viral inhibitors or a modification of the T-suppressor to T-helper cell ratio.
  • www.jaad.org/article/S0190-9622(02)70159-X/fulltext

Melaleuca alternifolia - Tea tree

  • Leaf Gel In vivo  

20 subjects with recurrent herpes labialis


Pregnant women



HSV vakcína

Valacyclovir and acyclovir

  • Safe and well-tolerated drug
  • no associated toxicities
  • Minimal adverse effects aside from crystalluria and increased creatinine levels
    • Can be mitigated
      • With fluid administration prior to taking acyclovir
      • Adjustment in acyclovir dosage according to renal function
  • Options for prophylaxis in patients needing long-term suppression
  • Equally efficacious in the treatment and prophylaxis of herpes simplex virus
  • Valacyclovir requires less frequent dosing due to the increased bioavailability
  • Twice daily dosing of 500 mg of valacyclovir
    • Effectively prevents herpes simplex virus reactivation
  • www.tandfonline.com/doi/full/10.1080/09546634.2021.1978665

Zinc-containing cream

  • Zinc salts irreversibly inhibit herpes virus replication in vitro
  • Effective in treating herpes infections in vivo
  • Shown in a clinical trial to be a effective topical treatment for HSL
  • Applied to herpetic lesions
    • Decrease viral load
    • Markedly improve healing rates
    • Relieving the symptoms of herpes as healing occurs
  • Zinc swabs contain
    • 33 mmol/l of ionic Zinc in an emulsification of Benzalkonium chloride, glycerin, hydroxyethylcellulose, sodium chloride, and sodium hydroxide (ph 7.2).
    • Zinc gluconate is monographed in the Homeopathic Pharmacopoeia of the United States (HPUS) and one of OTC indications for Zinc and its salts is for the treatment of cold sores.
  • clinicaltrials.gov/ct2/show/NCT00809809
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Poslední aktualizace: 18. 12. 2022 3:38:13