nemoci-sympt/PLICNI/alfa-1-antitrypsinova-deficience/terapie-zlepsujici-podpurne-vlivy
Alpha 1-AT and secretory leukoprotease inhibitor (SLPI)
- Are two endogenous serine protease inhibitors which inactivate neutrophil elastase a protease which has been shown to be present in high concentrations in CF sputum and BALFs [29]. Short-term aerosol delivery of ?1-AT to 12 CF patients suppressed neutrophil elastase in the epithelial lining fluid and restored anti-neutrophil elastase capacity [99]. However, a phase II trial to assess the clinical efficacy and safety of nebulised transgenic ?1-AT did not show any evidence of reduction of airway inflammation [100(1b)]. In another open short-term study, a decrease in neutrophil elastase activity, neutrophils, pro-inflammatory cytokines and P. aeruginosa numbers was observed, however, aerosolized ?1-AT treatment had no positive effect on lung function in CF patients [101(2b)]. It is generally agreed, that studies longer than four weeks in young children with moderate lung disease are necessary to show potential drug efficacy of aerosolized ?1-AT [102]. Aerosolized SLPI at a dose of 100 mg twice daily for one week reduced epithelial lining fluid neutrophil elastase in patients with CF, but 50 mg twice daily for two weeks were ineffective [103(2b),104(2b)]. The drug has not been further evaluated in clinical trials.
able 3. Flavonoids measured for anti-elastase activity and their respective IC50 values.Tested compound IC50 value ReferencesLuteolin >300 µM 6712 µM 688.06 ± 2.73 µM 6912.7 ± 0.5 µM 706.91 µM 7136.01 ± 1.15 µM 727.65 ± 0.77 µM 73Luteolin 4'-O-ß-d-glucoside 13.72 ± 5.26 µMLuteolin 4'-methylether 4.13 ± 0.47 µM 74Luteolin 7-O-ß-d-glucoside No significant inhibitory activity 73,75Luteolin 8-C-glucoside 146.1 ± 38.8 µM 76Apigenin 27.6 ± 1.0 µg/mL46.1 ± 0.9 µM 7037.94 ± 2.06 µM 7213.35 ± 0.37 µM 73Apigenin 4'-O-ß-d-glucoside No significant inhibitory activity 77>23.13 µM 73Apigenin 7-O-ß-d-glucoside No significant inhibitory activityApigenin 7-O-rhamnoglucoside >10 µM 78Apigenin 8-C-glucoside 120.95 ± 10.6 µM 76Apigenin 6-C-glucoside 4.34 ± 0.58 µM 79Baicalein 2.2 µM 683.53 µM 8025 µM 67No significant inhibitory activity 81Baicalein 6,7-di-O-methyl >10 µM 82Baicalein 7-O-methylether6-Hydroxy-5,7-dimethoxyflavonDiosmetin 7-O-rutinoside >16.43 µM 73Chrysin 2.44–0.09 µM 826.7 µM 68No significant inhibitory activity 61Norartocarpetin >300 µM 83Cupressuflavone 8.09 ± 0.92 µM 84Amentoflavone 1.27 ± 0.16 µM0.75 ± 0.18 µM 85Robustaflavone 1.33 ± 0.21 µM 840.45 ± 0.11 µM 85Rhusflavanone 19.54 ± 2.4 µM 76Mesuaferrone B 19.06 ± 2.4 µMTricin 17.69 ± 1.71 µM 864'-O-Geranyltricin 12.80 ± 6.84 µM3'-O-Geranylpolloin 17.34 ± 3.81 µMVelutin 4.26 ± 0.12 µMAfrormosin No significant inhibitory activity 87Boeravinone T 88Boeravinone BBoeravinone UBoeravinone JBoeravinone XHypolaetin 7-O-ß-xyloside >100 µM 846,8-Diprenylorobol 1.3 ± 0.3 µM 895,7,3',4'-Tetrahydroxy-2',5'-di(3-methylbut-2-enyl)isoflavon 213.1 ± 1.9 µMFlemiphilippinin A 8.3 ± 0.4 µM5,7,3'-Trihydroxy-2'-(3-methylbut-2-enyl)-4',5'-(3,3-dimethylpyrano)isoflavone 22.4 ± 0.7 µM8-?,?-Dimethylallylwighteone 6.0 ± 0.3 µMOsajin 26.0 ± 0.6 µMFlemingsin 12.0 ± 0.4 µMFlemichin D 5.3 ± 0.5 µMLupinifolin 13.3 ± 0.1 µMKhonklonginol H 110.2 ± 0.8 µMAuriculasin 3.1 ± 0.2 µM 11Orobol 7,3'-di-O-methyl ether >10 µM 85Genistein 25.87 ± 5.99 µM 73,8251.4 ± 0.5 µM 8963 µM 9042.15 ± 2.88 µM 79Daidzein 4.29 ± 0.49 µMVigvexin A 17.27 ± 4.19 µMVigvexin B 12.62 ± 7.17 µM5,7,4'-Trihydroxy-3'-methoxy isoflavone 19.37 ± 4.16 µMQuercetin 5.51 ± 1.07 µM14.3 ± 0.2 µM 702.6 µM 681.5 µM 91334.18 ± 3.3 µM 9220 µM 672.65 µM 92,93Quercetin 7-O-methylether 18.3 µM 68Quercetin 3-O-rhamnoside 113.29 ± 1.9 µM 7636.98 ± 9.1 µM 81Quercetin 3-methylether 19 µM 94Quercetin 3,3'-dimethylethe 129 µMQuercetin 3-O-rutinoside 6.9 µM 919.8 µM 68Quercetin 3-O-galactoside 0.3 µM0.32 µM 931.94 µM 95Quercitrin 11.1 µM 68>100 µM 84Isoquercitrin1.4 µM 681.5 µM 93,95Quercetagetin 3,6-dimethylether 115 µM 94Fisetin 16 µM 67Myricetin 4 µM21.1 µM 68Myricetin 3-O-rhamnoside No significant inhibitory activity 84Morin 3-O-?-rhamnoside 8.52 ± 0.18 µM 96Morin 4.5 µM 6711.6 µM 68Naringenin 84 µMVitexicarpin >10 µM 78Ugonin M 1.6 ± 0.33 µM 97Ugonin O 3.4 ± 0.50 µMUgonin Q 0.49 ± 0.27 µMUgonin R 4.56 ± 0.32 µMUgonin S 1.9 ± 0.52 µMUgonin T 1.2 ± 0.13 µMUgonin K >10 µMUgonin L 3.8 ± 0.08 µMKaempferol 5000 µM 67Kaempferol 6-hydroxy-3,6-dimethylether 194 µM 94Kaempferol 3,7-dimethylether 61 µM6,8-Diprenylkaempferol 29.3 ± 0.3 µM 89Kaempferol 3-O-?-rhamnoside >100 µM 84154.71 ± 6.48 µM 7638.09 ± 12.19 µM 96Kaempferol 3-O-?-glucoside 19.20 ± 3.08 µM142.28 ± 6.24 µM 76Kaempferol 3-O-rutinoside >100 µM 91Formononetin 7-O-glucoside >232 µM 98Sativanone 7-O-glucoside >215 µMEriodictyol 7-O-rutinoside >400 µM 682-(3,4-Dihydroxy-2-[(2,6,6-trimethylcyclohex-2-enyl)-methyl]phenyl)-3,5,7-trihydroxy-4H-chromen-4-one 0.98 ± 0.15 µM 992-(3,4-Dihydroxyphenyl)-6-
Hepatoprotektiva
- Treatment of A1AD-related liver damage focuses on
- Alleviating the symptoms of the disease [2]
Intravenous infusions of the A1AT protein
- Infusions of alpha-1 antitrypsin
- Derived from donated human plasma
- Augmentation therapy
- To arrest the course of the disease and halt any further damage to the lungs
- Long-term studies of the effectiveness of A1AT replacement therapy are not available
- Currently recommended that patients begin augmentation therapy only after the onset of emphysema symptoms [2]
- 2015 there are four IV augmentation therapy manufacturers in the United States, Canada, and several European countries
- Shown to be clinically identical to one another in terms of dosage and efficacy.
- Standard mode of augmentation therapy
- Not appropriate for people with liver disease [3]
- Most direct and efficient means of elevating AAT levels in the plasma and the lung interstitium.
American Thoracic Society suggests
- Weekly augmentation therapy with human pooled AAT for individuals who have
- Plasma levels of AAT less than 11 micromols/L
- Established airflow obstruction
- FEV1 less than 80% predicted [3]
Canadian Thoracic Society suggests
- AAT augmentation therapy if AAT level less than 11 micromols/L
- FEV1 of 25% - 80% predicted
- Who have quit smoking and are on optimal medical therapy [3]
The selection criteria for augmentation therapy include:
- High-risk phenotype
- Plasma AAT level below 11 micromols/L
- Airflow obstruction by spirometry (e.g., FEV1 less than 80% of predicted)
- Likely compliance with the protocol
- Age equal to or greater than 18 years
- Nonsmoker or ex-smoker.
Augmentation therapy is not recommended
- Patients with heterozygous phenotypes
- Plasma AAT level exceeds 11 micromols/L
Side effects associated
- Uncommon
- no long-term reactions have been noted
- Some side effects can occur :
- Low-grade fever and mild flu-like symptoms are usually self-limited
- Anaphylaxis with IgE antibody formation to AAT has been reported
- Extremely rare
- A syndrome of transient fever, chest and low back pain, and thrombocytopenia
- Due to a high molecular weight contaminant in the stabilizer added to the AAT product in the late 1980s
- Pooled human plasma alpha 1-antiprotease contains small amounts of IgA
- IgA-deficient individuals with anti-IgA antibodies are at risk of anaphylaxis
- Before initiating intravenous AAT therapy, it is recommended to check for IgA deficiency or anti-IgA antibodies [3]
NAC
- The daily administration of NAC (600 mg) to postmenopausal women
- Strengthened the immune defenses
- Decreasing the probability of immune system-related diseases in aging, such as infections [210]
- Binding of DNA reactive metabolites and in blocking reactive intermediates
- Exert antioxidant activity via p53-mediated apoptosis
- L-Cys, derived by NAC catabolism, is readily bioconverted to the vasodilator, anti-inflammatory and readily diffusible hydrogen sulfide.
- Therefore, NAC should be regarded as a hydrogen sulfide donor [210]
- Potent scavenger of ROS and especially of hypochlorous acid (HOCl) and •OH [210]
- Inhibition by NAC of the ROS-producing vascular NAD(P)H oxidases is relevant to prevention of hypertension [210]
- NAC potentiates the vasodilator and antiaggregatory effects of nitric oxide
- Inhibition by NAC of epidermal growth factor receptor (EGFR), a tyrosine kinase involved in inflammation
- Results in a decreased inactivation of alpha 1-antitrypsin [210]
- Efficacy and structural conformational integrity of alpha 1-antitrypsin via a GSH-mediated mechanism
- It enhances ?1-antitrypsin transcytosis thus improving its cellular uptake and functions [210]
- Administration of NAC to pregnant mice enhanced the expression of the gene encoding for an ?1-antitrypsin precursor in the fetal liver [210]
- NAC was found to
Vaccination
- Influenza
- Pneumococcus
- Hepatitis [2]
Prevence polymerizace v játrech
- Experimental therapies are aimed at the prevention of polymer formation in the liver [2]
Liver transplantation
- In severe liver disease may be an option [2]
Lung transplantation
- May also be recommended in severe deficiences [2]
