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Browsing by Subject "Phenylpropionates"
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Item A Multicenter, Open-Label, Single-Arm Study to Evaluate the Efficacy and Safety of Saroglitazar in Patients With Primary Biliary Cholangitis(Wolters Kluwer, 2021-03-26) Vuppalanchi, Raj; González-Huezo, Ma Saraí; Payan-Olivas, Ramon; Muñoz-Espinosa, Linda E.; Shaikh, Farheen; Pio Cruz-Lopez, Jose L.; Parmar, Deven; Medicine, School of MedicineIntroduction: Patients with primary biliary cholangitis (PBC) without biochemical response to ursodeoxycholic acid (UDCA) are at increased risk of liver-related mortality. Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual PPAR agonistic properties (α/γ). There is a strong mechanistic rationale for studying saroglitazar in PBC because PPARα is a molecular target of fibrates that showed improvements in liver tests in patients with PBC. Methods: In this 16-week, open-label, phase 3 study, 37 patients were screened across 3 clinical centers to enroll 7 patients. All patients received daily dose of saroglitazar 4 mg for 16 weeks in addition to their ongoing treatment with UDCA. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at week 16 as compared to baseline. Results: Mean age of the study population was 51.1 ± 10.0 years, all patients were female of Mexican descent, and mean body mass index was 25.5± = 4.8 kg/m2. Six (85.7%) patients reported taking ursodiol at baseline and continued throughout the study with a mean daily dosage of 417 mg. Among these, the daily dosage of UDCA 500 mg in 4 and 250 mg in 2 subjects, respectively. The mean baseline ALP level was 230 ± 103 U/L. The primary efficacy endpoint, mean change (reduction) from baseline in ALP concentration at week 16 based on the modified intent-to-treat population was -94 ± 53 U/L (P = 0.003), corresponding to a reduction of 48 ± 23%. Treatment with saroglitazar 4 mg resulted in a rapid and sustained decrease of ALP levels at week 4 (-84 ± 47 U/L, P = 0.003). Six patients who completed the study achieved mean ALP reduction of at least 40% at week 4 and all subsequent visits. Discussion: Although the study was terminated because of lack of enrollment, saroglitazar daily for 16 weeks resulted in rapid and sustained improvements in ALP with an acceptable safety profile in patients with PBC.Item Pharmacokinetic, Safety, and Pharmacodynamic Profiles of Saroglitazar Magnesium in Cholestatic Cirrhosis With Hepatic Impairment and Participants With Renal Impairment(Wiley, 2025) Vuppalanchi, Raj; Cruz, Mary M.; Momin, Taufik; Shaikh, Farheen; Swint, Kimberly; Patel, Harilal; Parmar, Deven; Medicine, School of MedicineSaroglitazar magnesium, a dual PPAR α/γ agonist, currently in Phase III for treating primary biliary cholangitis (PBC), was evaluated for its pharmacokinetic (PK) profile, safety, and pharmacodynamics in participants with cholestatic liver disease (CLD) across different levels of hepatic impairment (HI) and participants with severe renal impairment (RI). Three PK studies comparing saroglitazar with healthy controls were conducted: Study 1 involved daily oral doses of 1 or 2 mg for 4 weeks in 12 PBC cirrhosis participants with mild or moderate HI; Study 2 assessed single-dose PK (2 or 4 mg) in eight non-cirrhotic CLD participants; Study 3 evaluated single-dose PK (2 mg) in eight participants with severe RI. On day 1, saroglitazar exposure increased by 14.6-42% in mild HI vs. normal, but by day 28, levels were similar, indicating no accumulation. In moderate HI, exposure was significantly increased by 50.4-85% on days 1 and 28, with 34-46% lower clearance despite a similar half-life. The moderate HI group had a 59% higher exposure than the non-cirrhotic group. Saroglitazar (1 and 2 mg) reduced alkaline phosphatase (ALP) levels by 17-40% after 4 weeks in participants with abnormal baseline ALP. Single-dose PK in non-cirrhotic CLD (2 and 4 mg) and severe RI (2 mg) was comparable to matched controls without significant safety issues. Overall, saroglitazar (1 and 2 mg) was safe and well-tolerated in cholestatic cirrhosis with mild HI and participants with severe RI without major PK changes. Moderate HI increased exposure and decreased clearance without any safety concerns.Item Race and sex differences in response to endothelin receptor antagonists for pulmonary arterial hypertension(Elsevier, 2012-01) Gabler, Nicole B.; French, Benjamin; Strom, Brian L.; Liu, Ziyue; Palevsky, Harold I.; Taichman, Darren B.; Kawut, Steven M.; Halpern, Scott D.; Biostatistics, School of Public HealthBackground Recently studied therapies for pulmonary arterial hypertension (PAH) have improved outcomes among populations of patients, but little is known about which patients are most likely to respond to specific treatments. Differences in endothelin-1 biology between sexes and between whites and blacks may lead to differences in patients' responses to treatment with endothelin receptor antagonists (ERAs). Methods We conducted pooled analyses of deidentified, patient-level data from six randomized placebo-controlled trials of ERAs submitted to the US Food and Drug Administration to elucidate heterogeneity in treatment response. We estimated the interaction between treatment assignment (ERA vs placebo) and sex and between treatment and white or black race in terms of the change in 6-min walk distance from baseline to 12 weeks. Results Trials included 1,130 participants with a mean age of 49 years; 21% were men, 74% were white, and 6% were black. The placebo-adjusted response to ERAs was 29.7 m (95% CI, 3.7-55.7 m) greater in women than in men (P = .03). The placebo-adjusted response was 42.2 m for whites and −1.4 m for blacks, a difference of 43.6 m (95% CI, −3.5-90.7 m) (P = .07). Similar results were found in sensitivity analyses and in secondary analyses using the outcome of absolute distance walked. Conclusions Women with PAH obtain greater responses to ERAs than do men, and whites may experience a greater treatment benefit than do blacks. This heterogeneity in treatment-response may reflect pathophysiologic differences between sexes and races or distinct disease phenotypes.