MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Protizánětlivé a antioxidační působení

LTB4 inhibitory


Řešení alergických reakcí a intolerancí

Kazuistika 1

  • Zhoršení primární lymfedému v den, kdy pacientka konzumuje lepek, aniž by měla celiakii
  • Dietou zlepšení

Kazuistika 2

  • Zhoršení primárního lymfedému konzumací sacharidů, alkoholu a nevyspáním
    • Tedy prozánětlivými vlivy
  • Dietou zlepšení

Kazuistika 3

  • Pociťuje zhoršení lymfedému konzumací mléka
  • Dietou zlepšení

Bestatin (Ubenimex)

  • Inhibition of LTB4
    • A selective LTB4 antagonist with no anti-COX activity

Mouse tail model of lymphedema

Multicenter placebo-controlled trial

Mouse tail model of lymphedema

  • Treatment with bestatin increased lymphatic contractile activity
  • Drug therapy did not modulate the overall leukocyte populations in the draining lymph nodes
  • Did not decrease tail swelling
  • (Cribb et al., 2021)
  • Authors suggested that addressing lymphatic vessel dysfunction is insufficient for lymphedema prevention/treatment.
  • www.frontiersin.org/articles/10.3389/fphar.2022.828513/full

Dupilmab


Histamine Dihydrochloride

  • In mouse models
    • Can protect IL-2 induced rat model of CLS by dose-dependent
    • Reduce the CLS severity and mortality [17]
    • Can reduce the IL-2-induced lung injury, decrease pulmonary edema , pulmonary capillary leakage determinated by Evans blue dye [17]

Ketoprofen




Kurkumin

  • Aktivní složka kurkumy, má silné protizánětlivé a antifibrotické vlastnosti, které mohou pomoci zmírnit zánět a zpomalit tvorbu fibrinu. Kurkumin také podporuje detoxikaci a zlepšuje mikrocirkulaci, což je přínosné při lymfedému.

Tacrolimus

Gardenier et al. experimental study on mice

  • Tacrolimus topically
  • Immunosuppressive potential of this drug affecting T-cells
    • Effective in treating established lymphedema 
    • Preventing the initial development of lymphedema
  • Treated mice presented with decreased tissue swelling, fibrosis, and T-cell infiltration and increased lymphangiogenesis
  • Treated animals also had improved lymphatic function and decreased dermal backflow
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC6897350/

Experimental study

  • Well-established safety and tolerability of this drug
  • Advantage of topical delivery is the fact that it decreases the chance of systemic complications.
  • Has US Food and Drug Administration (FDA) approval for other chronic skin conditions
  • Importance of additional studies to optimize this treatment
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC6897350/

Mouse lymphedema models

  • Promising results when T cell infiltration and activation in the skin are inhibited
    • Using topical medications (Forte et al., 2019b)

Similarities to atopic dermatitis

  • Treated with topical T cell inhibitors and steroids. (Brandt and Sivaprasad, 2011; James and Kwok, 2011; Su et al., 2017; Acevedo et al., 2020)
%%h¨3 Local Tacrplimus
  • Macrolide calcineurin inhibitor
  • Anti-T-cell properties
    • Inhibiting the Nuclear factor of activated T-cells (NFAT) signaling
    • Ultimately decreasing IL-2 expression
  • IL-2 is essential for both T-cell activation differentiation, and proliferation
    • Tacrolimus administration results in profound CD4+ cell immunosuppressive effects
      • (Smith, 1988; Clipstone and Crabtree, 1992; Chow et al., 1999; Rautajoki et al., 2008; Liao et al., 2013)

FDA-approved for:

  • Atopic dermatitis,
  • Psoriasis,
  • Localized scleroderma
  • (Ruzicka et al., 1997; Mancuso and Berdondini, 2005; Wang and Lin, 2014; U.S. Prescribing information, 2021b)

Mouse tails

  • Either before lymphedema development or once it had become established
  • Was highly effective for
    • Reducing fibroadipose tissue deposition
    • Improving lymphatic function. (Gardenier et al., 2017)
  • Treatment significantly decreased
    • Macrophage
    • T cell infiltration
    • Expression of inflammatory cytokines
  • Topical treatments did not result in significant systemic absorption
    • Thus mitigating the potentially toxic effects of this drug on generalized immune responses and kidney function

Other studies

  • Intermittent topical tacrolimus application for up to 1 year
    • Does not result in significant blood concentrations of the drug
  • (U.S. Prescribing information, 2021b)

Clinical studies with periodic blood sampling

Inhibice Thelper CD4+

TH2 Inhibition with Neutralizing Antibodies

  • TH cell differentiation
    • Requires interaction and activation by antigen-presenting cells (APCs) in regional lymph nodes
  • Lymphatic ligation results in rapid activation of APCs in the skin distal to the zone of injury
    • Within 12 h
  • APCs migrate to regional draining lymph nodes
    • Interact with naive CD4+ cells
    • Promote a mixed TH1/TH2 inflammatory response
    • Then released into the systemic circulation
      • (García Nores et al., 2018)

Fingolimod - FTY 720

  • A sphingosine 1-phosphate receptor 1 agonist
  • Inhibition of T cell release by the lymph
  • FDA approved for the treatment of multiple sclerosis

Mouse tail model of lymphedema

  • Prevents lymphedema development in the

T cell differentiation in the lymph node

  • Plays a key role in the pathophysiology of the disease
  • (García Nores et al., 2018; U.S. Prescribing information, 2021)-
  • Activated TH cells
    • Migrate back to the lymphedematous tissues
      • Via the expression of cell surface receptors that recognize their cognate ligands on inflamed blood vessels in the lymphedematous tissues.
    • (García Nores et al., 2018)
  • TH cells can differentiate into various lineages such as
    • TH1, TH2, TH17, and T-regulatory cells
    • (Zhu et al., 2010)
  • TH2 cell differentiation
    • Is a key process in the pathophysiology of lymphedema. (Ly et al., 2019b)

Transgenic mice with impaired TH2 differentiation potential (Stat-6 knockouts)

  • Do not develop lymphedema following skin/lymphatic ablation.

Mice with impaired TH1 differentiation potential (T-bet knockouts)

  • Develop lymphedema indistinguishable from wild-type controls. (Ly et al., 2019b)

Neutralizing antibody inhibition of TH2 differentiation

  • Using interleukin 4 (IL4) or IL13—cytokines
    • Necessary for differentiation of naive CD4+ cells to the TH2

Mouse tail model.

  • Effective in both treatment and prevention of lymphedema
  • Decreased fibroadipose tissue deposition
  • Decreased inflammation,
  • Improved lymphatic collecting vessel pumping capacity
  • Decreased lymphatic leakiness,
  • Overall improved lymphatic function
  • (Zampell et al., 2012a; Avraham et al., 2013)

T cell-derived cytokines

  • Directly affect LECs
    • Decreasing their responsiveness to lymphangiogenic growth factors
    • Actively inhibiting lymphangiogenesis.
      • (Savetsky et al., 2015; Shin et al., 2015; Gardenier et al., 2017)
  • Formation of functional collateral lymphatics
    • Is impaired in patients with lymphedema.

IL4/IL13 neutralizing antibodies

Inhibition of TH2 differentiation - preclinical models

  • Improved lymphedema outcomes

Clinical trial - IL4/IL13 neutralizing antibodies

  • Unilateral BCRL (NCT02494206)
  • (Mehrara et al., 2021)

QBX258 phase I, open-label

  • Humanized monoclonal antibodies that inhibit IL4 (VAK296) and IL13 (QAX576)
  • 9 women stage I/II BCRL
  • (Mehrara et al., 2021)
  • Once-monthly intravenous infusions of QBX258 for 4 months
  • Immediately after and 4 months following cessation of treatment
  • QBX258 treatment was safe,
  • Most adverse events were minor and self-limited.
  • QBX258 improved
    • QoL measurements,
    • Skin stiffness,
    • Histologic changes in the lymphedematous limb
  • Treatment significantly decreased
    • Keratinocyte hyperplasia,
    • Mast cell infiltration,
    • Expression of TH2 inducing cytokines in the skin
  • no significant improvements in arm volumes or bioimpedance
  • Studies with larger patient populations and more effective IL4/IL13 inhibiting compounds (e.g., Dupilmab) are needed.

TH2 Inhibition with Tetracyclines

  • Promise for treating filariasis
      • Anti-parasitic effects of the drug
    • Development of lymphedema due to chronic lymphatic obstruction. (Mand et al., 2012; Debrah et al., 2006; U.S. Prescribing information, 2021c)
    • Filariasis is primarily host-immune mediated
      • Lymphedema severity is closely related to the magnitude of CD4+ T cell immune responses. (Babu et al., 2009; Babu and Nutman, 2014)
  • Filarial infections also increase plasma levels of
    • VEGF-C
    • TH2 cytokines
      • TH2 responses
        • A key role in the development of filarial-induced lymphedema. (Debrah et al., 2006)
  • Tetracyclines to treat filariasis were related to the . (Bandi et al., 1999; Hoerauf et al., 2003)

Double-blind, placebo-controlled trial of 18 patients

  • Bancroftian filariasis in Ghana patients randomized
  • 6-weeks 200 mg/day doxycycline x placebo (ISRCTN 14757)
  • (Debrah et al., 2006)
  • All patients were also treated with standard anti-parasitic treatment
  • Lymphedema outcomes were analyzed 12 and 24 months later
  • 1-year time point
    • Patients treated with Doxycycline
      • Had decreased serum levels of VEGF and soluble VEGFR3 + correlated with:
        • Reduction in the mean stage of lymphedema
        • Improved skin texture
        • Reduced skin folds
  • Soluble VEGFR3
    • Is related to impaired lymphangiogenesis in preclinical models
    • This is the first clinical trial to utilize soluble VEGFR3 levels as a clinical outcome measure.
      • (Mäkinen et al., 2001a)

162 patients with mild to moderate lymphedema

  • Randomized to 3 treatment arms -6-weeks course of treatment with
    • Amoxicillin (1000 mg/d)
    • Doxycycline (200 mg/d)
    • Placebo (ISRCTN 90861344)
  • (Mand et al., 2012)
  • At 1 and 2-years follow-up
    • Nearly 44% of patients treated with Doxycycline showed improvements in their disease status.
    • Improvements were noted in only 3.2 and 5.6% of patients treated with amoxicillin or placebo
  • Leading the authors to recommend a 6-weeks course of doxycycline treatment every year or every other year for patients with mild-to-moderate filarial lymphedema
  • Beneficial effects of Doxycycline
    • May be related to anti-inflammatory rather than anti-microbial activity
    • Doxycycline was more effective than amoxicillin

Mouse model of filarial lymphedema

  • (Furlong-Silva et al., 2021)
  • Associated with
    • Impaired lymphatic function
    • Increased circulating levels of VEGF-C
    • Filarial-induced lymphatic dysfunction was dependent on
      • IL-4 receptor immune responses
  • Beneficial effects of tetracycline in this model were related to
    • Decreased monocyte recruitment,
    • Inhibition of alternatively activated macrophage polarization
    • Decreased TH2 differentiation. (Furlong-Silva et al., 2021)
  • www.frontiersin.org/articles/10.3389/fphar.2022.828513/full
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Poslední aktualizace: 6. 10. 2024 23:37:48