ABSTRACT
Background & Aims: The safety, tolerability, and efficacy of the non-bile acid farnesoid X receptor agonist tropifexor were evaluated in a phase II, double-blind, placebo-controlled study as potential second-line therapy for patients with primary biliary cholangitis (PBC) with an inadequate ursodeoxycholic acid response. Methods: Patients were randomised (2:1) to receive tropifexor (30, 60, 90, or 150 µg) or matched placebo orally once daily for 28 days, with follow-up on Days 56 and 84. Primary endpoints were safety and tolerability of tropifexor and reduction in levels of γ-glutamyl transferase (GGT) and other liver biomarkers. Other objectives included patient-reported outcome measures using the PBC-40 quality-of-life (QoL) and visual analogue scale scores and tropifexor pharmacokinetics. Results: Of 61 enrolled patients, 11, 9, 12, and 8 received 30-, 60-, 90-, and 150-µg tropifexor, respectively, and 21 received placebo; 3 patients discontinued treatment because of adverse events (AEs) in the 150-µg tropifexor group. Pruritus was the most frequent AE in the study (52.5% [tropifexor] vs. 28.6% [placebo]), with most events of mild to moderate severity. Decreases seen in LDL-, HDL-, and total-cholesterol levels at 60-, 90-, and 150 µg doses stabilised after treatment discontinuation. By Day 28, tropifexor caused 26-72% reduction in GGT from baseline at 30- to 150-µg doses (p <0.001 at 60-, 90-, and 150-µg tropifexor vs. placebo). Day 28 QoL scores were comparable between the placebo and tropifexor groups. A dose-dependent increase in plasma tropifexor concentration was observed, with 5- to 5.55-fold increases in AUC0-8h and Cmax between 30- and 150-µg doses. Conclusions: Tropifexor showed improvement in cholestatic markers relative to placebo, predictable pharmacokinetics, and an acceptable safety-tolerability profile, thereby supporting its potential further clinical development for PBC. Lay summary: The bile acid ursodeoxycholic acid (UDCA) is the standard-of-care therapy for primary biliary cholangitis (PBC), but approximately 40% of patients have an inadequate response to this therapy. Tropifexor is a highly potent non-bile acid agonist of the farnesoid X receptor that is under clinical development for various chronic liver diseases. In the current study, in patients with an inadequate response to UDCA, tropifexor was found to be safe and well tolerated, with improved levels of markers of bile duct injury at very low (microgram) doses. Itch of mild to moderate severity was observed in all groups including placebo but was more frequent at the highest tropifexor dose. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT02516605).
ABSTRACT
PURPOSE: The aim of this study was to determine the impact of ABCB1 (MDR1) rs1045642 polymorphisms on the efficacy and safety of amlodipine in Caucasian patients. PATIENTS AND METHODS: The 12-week study included 100 patients. Patients with the newly diagnosed stage I-II hypertension (HT) were recruited to complete genotyping of the rs1045642 single-nucleotide polymorphism (SNP). The study design did not include a control group. Before treatment, all patients either did not undergo antihypertensive treatment at all or did not receive regular antihypertensive therapy. The initial dose was 5 mg/day. Four office blood pressure measurements, two 24-hour noninvasive ambulatory blood pressure measurements, and questionnaires of Tsvetov were used to evaluate the efficacy and safety of amlodipine. RESULTS AND CONCLUSION: The highest antihypertensive effect in combination with the lowest incidence of adverse reactions was observed in the TT group, while patients with the CC genotype showed a low antihypertensive effect and the highest incidence of adverse effects. Patients with the CC genotype presented with adverse effects predominantly in the form of edema. A total of 33 patients reached the target blood pressure (SBP <140 mmHg; DBP <90 mmHg): two patients with the CC genotype (12%); 18 patients with the CT genotype (34%); and 13 patients with the TT genotype (43%). The intergroup differences were: CC vs CT, P=0.02; CC vs TT, P=0.02; and CT vs TT, P=0.05. The results of this study indicate the potential of pharmacogenetic testing for rs1045642 SNP when prescribing amlodipine for the first time in Caucasian patients with stage I-II arterial HT.
ABSTRACT
Chronic hepatitis B (CHB) is a widespread infectious disease with unfavorable outcomes and life-threatening consequences for patients, in spite of modern vaccination and antiviral treatment modalities. Cutting-edge experimental approaches have demonstrated key pathways that involve cross-talk between viral particles and host immune cells. All events, including penetration of hepatitis B virus (HBV) particles into host cells, establishing persistence, and chronization of CHB infection, and possibility of complete elimination of HBV particles are controlled by the immune system. Researchers have paid special attention to the replication capacity of HBV in host cells, which is associated with cellular changes that reflect presentation of viral antigens and variability of HBV antigen features. In addition, specific HBV proteins have an immune-modulating ability to initiate molecular mechanisms that "avoid" control by the immune system. The relationship between immunological shifts and chronic infection stages has been intensively studied since it was recognized that the immune system is a direct participant in the recurrent (cyclic) nature of CHB. Understanding the wide diversity of molecular pathways and the crosstalk between innate and adaptive immune system components will provide fresh insight into CHB immune pathogenesis and the possibilities of developing new treatment strategies for this disease.
