Evaluation of an International Pharmacopoeia method for the analysis of ritonavir by liquid chromatography

A gradient LC method for the determination of related substances in ritonavir (RTV) has been recently published in the International Pharmacopoeia. The method uses a base-deactivated reversed-phase C18 column kept at a temperature of 35 degrees C. The mobile phases consist of acetonitrile, phosphate buffer pH 4.0 and water. UV detection is performed at 240 nm. A system suitability test (SST) is described to govern the quality of the separation. Since no brand names of columns are mentioned in pharmacopoeial texts, analysts often have problems to select a suitable stationary phase which is only described in general terms. So, the separation towards RTV components was investigated on 18 C18 columns and correlation was made with the column classification system developed in our laboratory. The method was further evaluated using a Hypersil BDS C18 column (25 cm x 4.6mm i.d.), 5 microm, which was also used for the development of the method. A central composite design was applied to examine the robustness of the method. The method shows good precision, linearity, sensitivity and robustness. Four commercial samples were examined using this method.     

Ombitasvir/paritaprevir/ritonavir + dasabuvir +/-ribavirin in real world hepatitis C patients

BACKGROUND The hepatitis C virus(HCV) NS5A inhibitor ABT-267(ombitasvir, OBV), the HCV NS4/4A protease inhibitor ABT-450(paritaprevir, PTV), the CYP3A inhibitor ritonavir(r) and the non-nucleoside NS5B polymerase inhibitor ABT-333(dasabuvir, DSV)(OBV/PTV/r + DSV) with or without ribavirin(RBV) is a direct-acting antiviral regimen approved in the United States and other major countries for the treatment of HCV in genotype 1(GT1) infected patients. Patients with HCV who are considered "hard-to-cure" have generally been excluded from registration trials due to rigorous study inclusion criteria, presence of comorbidities and previous treatment failures.AIM To investigate the efficacy of this regimen in HCV G1-infected patients historically excluded from clinical trials.METHODS Patients were ≥ 18 years old and chronically infected with HCV GT1(GT1a, GT1b or GT1a/1b). Patients were treatment-na?ve or previously failed a regimen including pegylated interferon/RBV +/-telaprevir, boceprevir, or simeprevir.One hundred patients were treated with the study drug regimen, which was administered for 12 or 24 wk +/-RBV according to GT1 subtype and presence/absence of cirrhosis. Patients were evaluated every 4 wk from treatment day 1 and at 4 and 12 wk after end-of-treatment.RESULTS Many of the patients studied had comorbidities(44.2% hypertensive, 33.7%obese, 20.2% cirrhotic) and 16% previously failed HCV treatment. Ninety-six patients completed study follow-up and 99% achieved 12-wk sustained virologic response. The majority(88.4%) of patients had undetectable HCV RNA by week 4. The most common adverse events were fatigue(12%), headache(10%),insomnia(9%) and diarrhea(8%); none led to treatment discontinuation. Physical and mental patient reported outcomes scores significantly improved after treatment. Almost all(98%) patients were treatment compliant.CONCLUSION In an all-comers HCV GT1 population, 12 or 24-wk of OBV/PTV/r + DSV +/-RBV is highly effective and tolerable and results in better mental and physical health following treatment.     

The role of interleukin-18 in glioblastoma pathology implies therapeutic potential of two old drugs-disulfiram and ritonavir

Based on reporting in the last several years, an impressive but dismal list of cytotoxic chemotherapies that fail to prolong the median overall survival of patients with glioblastoma has prompted the d...     

Interferon-free treatment choice according to baseline RASs leads to high SVR rates in HCV genotype 1 infected patients

Aim

Different combinations of direct antiviral agents (DAA) lead to high SVR rates in HCV genotype 1 infected patients. However, presence of baseline resistance-associated substitutions (RASs) represents a major risk factor for treatment failure. It is unknown whether choice of treatment based on RASs has the potential to decrease virologic failure rates.

达诺瑞韦联合长效α-干扰素治疗基因3型慢性丙型肝炎患者疗效研究

目的 研究在达诺瑞韦基础上联合长效α-干扰素治疗基因3型慢性丙型肝炎(CHC)患者的临床疗效。方法 2017年10月～2019年5月我院收治的132例基因3型CHC患者,其中66例(对照组)接受聚乙二醇干扰素α-2a联合利巴韦林治疗24周,另66例(观察组)接受聚乙二醇干扰素α-2a和利巴韦林治疗的基础上,加用利托那韦和达诺瑞韦联合治疗12周。所有患者随访24周。结果 在治疗2 w、4 w和12 w末,观察组病毒学应答率分别为90.9%、97.0%和100.0%,显著高于对照组的66.7%、75.8%和81.8%(P＜0.05);在治疗结束后24 w随访时,观察组持续病毒学应答率(SVR)为92.4%,显著高于对照组的74.2%(P＜0.05);在治疗12 w末,两组外周血白细胞计数、血小板计数和血红蛋白水平变化无统计学差异(P＞0.05),两组不良反应发生率比较差异也无统计学意义(P＞0.05)。结论 应用利托那韦和达诺瑞韦联合标准治疗方案治疗基因3型CHC患者临床疗效确切,安全性较好,值得进一步观察。     

Direct interference of HIV protease inhibitors with pancreatic β-cell function

The aim of the present study was to evaluate whether HIV protease inhibitors directly interfere with stimulus-secretion coupling in pancreatic -cells. Insulin secretion was determined by a radioimmunoassay (RIA), cytosolic free Ca²⁺ concentration ([Ca²⁺]_c) with the fluorescence dye fura-2 and whole-cell membrane currents with the patch-clamp technique.Glucose-induced insulin secretion was inhibited in a concentration-dependent manner by ritonavir and nelfinavir but not by indinavir. Ritonavir and nelfinavir lowered [Ca²⁺]_c in the presence of a stimulatory glucose concentration whereas indinavir again had no effect. Ritonavir and nelfinavir completely inhibited the effect of tolbutamide, which normally increases [Ca²⁺]_c by blocking K_ATP channels. This observation points to an action of both drugs on K_ATP channels or a step distal to these channels in stimulus-secretion coupling. Ritonavir was used to further evaluate the direct effects of HIV protease inhibitors on -cell ion channel currents. Unexpectedly, ritonavir inhibited neither the whole-cell K_ATP current nor the whole-cell L-type Ca²⁺ current. Tolbutamide almost completely suppressed the K_ATP current in the presence of ritonavir excluding that ritonavir alters the tolbutamide sensitivity of the K_ATP channel. Ritonavir increased the length and decreased the frequency of glucose-induced action potentials. This effect can be attributed to inhibition of voltage-dependent K⁺ currents. Intracellular stores seem not to be involved in the ritonavir-induced lowering of [Ca²⁺]_c.In conclusion, different HIV protease inhibitors surprisingly reveal distinct effects on insulin secretion. Ritonavir inhibits insulin secretion by lowering [Ca²⁺]_c but this effect is evidently independent of the opening of K_ATP channels or the closure of voltage-dependent Ca²⁺ channels, which are commonly considered to play a key role in stimulus-secretion coupling.Abbreviations [Ca²⁺]_c Cytosolic Ca²⁺ concentration - RIA Radioimmunoassay