Buy Harvoni20.03.19Storage active substances: ladizpavir, sofosbuvir; 1 film coated tablet contains 90 mg of lepidapasive and 400 mg of sofosburir; excipients: corn, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silicon dioxide, magnesium stearate; tablet shell: polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), macrogol 3350, talc. Medicinal form Tablets coated with a film coat. Basic physical and chemical properties: white diamond-shaped tablets covered with a film sheath, with the embossed inscription "GSI" on one side and "7985" on the opposite side. Antiviral drugs for systemic use. Antiviral agents of direct action. Antiviral drugs for the treatment of hepatitis C virus (HCV) infection. Code ATX J05A P51. Pharmacological properties Mechanism of action Ladyposvir is an HCV inhibitor whose target is NS5A HCV protein, which is required for RNA replication and HCV virion collection. Since NS5A does not have enzymatic activity, the biochemical confirmation of the inhibition of NS5A under the influence of hydropathy is currently not feasible. In vitro studies of selective and cross-resistance have shown that lasapressur acts on NS5A as an object of its influence. Sophosbuvir is a panenotypic inhibitor of the NS5A RNA-dependent RNA-polymerase of HCV, which is required for the replication of the virus. Sophosbuvir is a nucleotide depot form that, as a result of the intracellular metabolism, is converted into a pharmacologically active uridine nalal triphosphate (GS-461203) that can be incorporated into the NS5B polymeraseous HCA RNA and play the role of the synthesis terminator. GS-461203 (an active metabolite of sofosburir) is not an inhibitor of human DNA and RNA polymerase and is not an inhibitor of mitochondrial RNA polymerase. Antiviral activity The value of the EC50 of lady pasvir and cofosburir for full-chain or chimeric replicons encoding NS5A and NS5B sequences in clinical cultures is given in Table 1. The addition of human serum in 40% concentration did not affect the antiviral activity of cofosburir, but reduced the antidiabetic activity of lidapasvir 12 HCV replicons genotype 1a. Resistance In cell cultures HCV replicons with reduced sensitivity to lepidaphares were selected in cell cultures for genotypes 1a and 1b. Reduced sensitivity to ladyposvir was associated with the primary NS5A substitution of Y93H in genotypes 1a and 1b. In addition, in replicons in the genotype 1a there was a substitution of Q30E. The site-specific mutagenesis of RAV NS5A has shown that substitutions that result in a> 100- and ≤1000-fold change in sensitivity to icepicking are substitution of Q30H / R, L31I / M / V, P32L and Y93T in the genotype 1a and P58D and Y93S in genotype 1b; and substitutions resulting in a 1000-fold change are M28A / G, Q30E / G / K, H58D, Y93C / H / N / S in genotype 1a and A92K and Y93H in genotype 1b. HCV replicons with reduced sensitivity to sofosbuvir are selected in cell cultures for different genotypes, including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced sensitivity to cofosburir was associated with the primary NS5B substitution of S282T in replicons of all studied genotypes. The site-specific mutagenesis of the substituted S282T fragment in replicons of 8 genotypes led to a decrease in the sensitivity to the sofosbuver 2 to 18 times, and a decrease in viral replication ability by 89-99% compared with the corresponding wild type. In clinical studies, genotype 1 The results of the combined analysis of patients treated with lidipasur / cofosburir in phase 3 studies (ION-3, ION-1 and ION-2) showed that 37 patients (29 genotypes 1a and 8 with genotype 1b) were suitable for virologic resistance analysis failure or premature completion of the study drug intake, for the content of RNA HCV> 1000 IU / ml. Details of the sequential sequencing of NS5A and NS5B after baseline (1% limiting value) were obtained for 37/37 and 36/37 patients respectively. Resistance-Associated NS5A variants have been established after isolation in isolates from 29/37 patients (22/29 - genotype 1a and 7/8 - genotype 1b) that have not reached a stable virological response (CVV). Of the 29 patients with resistance genotype 1a, 22 of 29 (76%) patients had one or more NS5A VARs at K24, M28, Q30, L31, S38 and Y93 coordinates at the time of failure, with the remaining 7 / 29 patients at the time of failure did not show any NS5A GAR. The most commonly used variants were Q30R, Y93H and L31M. Of the 8 patients with resistance genotype 1b, 7/8 (88%) of patients had one or more NS5A GARs at positions L31 and Y93 at the time of failure, and in 1/8 of patients at the time of failure, NS5A GAR was not detected . The most widespread variant was the Y93H. Of the 8 patients who had no NS5A BAR at the time of failure, 7 patients received 8 weeks of treatment (n = 3 with lidipasvir / cofosburir; n = 4 with lidipasvir / sophosbuvir + ribavirin) and 1 patient undergoing treatment with lidipasum / cofosbuvir 12 weeks duration.
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