Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of ...GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis.
Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks’ dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency MDF; delta+theta/alpha+beta ratio DT/AB) were obtained at baseline, 10, and 21 days.
Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well.
Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone.
Many patients with cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug.
EudraCT 2016-003651-30.
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•Herein, we report findings from a pilot phase IIa study of golexanolone, a GABA-A receptor-modulating steroid antagonist, in clinical development for HE.•Golexanolone was generally well tolerated and seemed to improve neuropsychiatric performance.•These findings support a role for neurosteroids in the pathogenesis of HE-related sleepiness and vigilance.•The results also suggest a role for golexanolone in the treatment of neurosteroid-mediated vigilance and cognitive disorders including HE.
Post-COVID-19 syndrome, also known as long COVID-19 syndrome, is a complex set of symptoms that persist for weeks or months after recovery from an acute phase of COVID-19. These symptoms can affect ...various body systems, including the respiratory, nervous, cardiovascular, and digestive systems. The most common complaints are fatigue, shortness of breath, joint pain, taste and smell disorders, as well as problems with memory and concentration. Pathogenesis of post-COVID-19 syndrome is complicated and not fully understood, but it is likely related to an overactive immune system, disturbances in the intestinal microbiome, and cell and tissue damage caused by the virus. Incorporating a multidisciplinary approach to treating and rehabilitating patients and further research into this syndrome's underlying mechanisms and therapy are crucial for understanding and effectively treating this complex and multifaceted condition.
Tocilizumab, an inhibitor of the interleukin-6 receptor, may decrease the inflammatory response and control the symptoms of severe coronavirus disease 2019 (COVID-19), but the evidence is scarce.
...This retrospective study included patients with severe COVID-19 requiring oxygen therapy who received tocilizumab in seven centers across Poland. We assessed on-treatment changes in clinical status and inflammatory markers.
Twenty-eight patients were included (19 male), with a mean age of 61.7 ± 12.4 years. The mean time from symptom onset to the first tocilizumab dose was 10.5 ± 5.7 days. Clinical status improved within 24 hours in 11 (39%) patients, within one week in 23 (82%) patients, and within two weeks in 25 (89%); one (4%) patient showed no change and two (7%) patients died. Sixteen patients (57%) no longer needed oxygen therapy within a week (p < 0.001). The serum concentrations of C-reactive protein, procalcitonin, and fibrinogen decreased significantly (p ≤ 0.001). Lung changes improved in 21 (84%) patients within two weeks of treatment; 19 had minimal or no changes upon final examination.
Tocilizumab can control the symptoms of severe COVID-19 by reducing the inflammatory response and rapidly improves the clinical status in most patients.
•Glecaprevir/pibrentasvir (G/P) achieved high SVR12 rates (93%) in recent drug users with chronic HCV infection.•Treatment adherence and completion were high (≥96%) regardless of drug use status.•G/P ...was well-tolerated, irrespective of drug use status.
Background: Injection drug use is the primary mode of transmission for hepatitis C virus (HCV), and treatment guidelines recommend treating HCV-infected people who use drugs; however, concerns about adherence, effectiveness, and reinfection have impeded treatment uptake.
Methods: Data were pooled from seven phase III trials that evaluated the efficacy and safety of 8 or 12 weeks of glecaprevir/pibrentasvir (G/P) in patients chronically infected with HCV genotypes 1–6. Patients had compensated liver disease, with or without cirrhosis, and were HCV treatment-naïve or -experienced with interferon or pegylated interferon ± ribavirin, or sofosbuvir plus ribavirin ± pegylated interferon. Patients were grouped into recent drug users (injection drug use ≤12 months before screening, positive urine drug screen UDS, and/or drug-related adverse event), former drug users (>12 months before screening and negative UDS), or non-drug users. Assessments included sustained virologic response at 12 weeks posttreatment (SVR12), treatment adherence, and safety.
Results: Among 1819 patients, 5%, 34%, and 61% were recent, former, and non-drug users, respectively. Treatment adherence and completion were high (≥96%) regardless of drug use status. SVR12 was achieved by 93% (n/N = 91/98), 97% (n/N = 591/610), and >99% (n/N = 1106/1111) of recent, former, and non-drug users, respectively (intention-to-treat analysis). The overall rates of virologic failure were ≤1.5% across all three subpopulations, with no HCV reinfections among recent drug users. Drug-related serious adverse events and adverse events leading to treatment discontinuation were experienced by ≤1% of patients.
Conclusions: G/P is a well-tolerated and efficacious pangenotypic regimen for chronic HCV-infected people with recent or active drug use.
The recommendations set out the principles of diagnosis and treatment of hepatitis C virus (HCV) infections according to the most recent knowledge. The main goal of therapy for HCV infection is to ...eliminate the virus from the body, which consequently leads to arrest of progress or regression of changes in the liver. Current version of the recommendations prioritise pangenotypic regimens and provide guidelines in special populations of patients, such as children, cirrhotics, human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfected, those with renal failure, hepatic decompensation and non-responders to previous therapies.
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