Effects of Alcohol Administered With Flibanserin in Healthy Premenopausal Women: A Randomized, Double-Blind, Single-Dose Crossover Study.

INTRODUCTION: Flibanserin is approved in the United States and Canada for the treatment of hypoactive sexual desire disorder in premenopausal women. AIM: The purpose of this trial was to evaluate the safety of concomitant administration of flibanserin with alcohol. METHODS: In this single-center, randomized, double-blind, single-dose, crossover study, participants were randomly assigned to 1 of 12 sequences to receive each of 7 treatments: flibanserin 100 mg or placebo with ethanol 0.2 g/kg, 0.4 g/kg, or 0.6 g/kg, or flibanserin 100 mg only. Treatments were administered using a worst-case approach that included morning dosing and consumption of alcohol within 10 minutes. MAIN OUTCOME MEASURE: The primary end point was the proportion of participants who experienced dizziness, syncope, or hypotension. Safety end points included orthostatic vital signs. RESULTS: The study included 96 premenopausal women (mean age 31 ± 8 years). The incidence of dizziness for ethanol + flibanserin was 39.8% for ethanol 0.6 g/kg, 34.1% for 0.4 g/kg, and 27.4% for 0.2 g/kg compared with 31.1% for flibanserin without ethanol. Based on the available vital signs data, there was no effect of ethanol concentration on orthostatic blood pressure, vertigo, or hypotension; no instances of syncope were observed. The overall incidence of adverse events (AEs) was similar when flibanserin was administered alone (96.7%) or with ethanol (90.5-97.6%). CLINICAL IMPLICATIONS: Consumption of the tested amounts of alcohol (0.2-0.6 g/kg) does not have an additive effect on the AE profile of flibanserin 100 mg in healthy premenopausal women. STRENGTHS & LIMITATIONS: Strengths include the study population (premenopausal women, as indicated for flibanserin) and range of ethanol doses. Limitations include the morning dosing of study medication, which is inconsistent with the bedtime dosing recommended for flibanserin, and the method of handling missing vital sign measurements. CONCLUSION: Co-administration of flibanserin 100 mg with varying doses of ethanol resulted in few AEs of special interest, with no notable alcohol dose response. However, a significantly greater percentage of participants administered flibanserin with 0.6 g/kg and 0.4 g/kg of alcohol were characterized as "Participants in Whom Standing Blood Pressure Was Not Obtained" compared with participants administered flibanserin alone. Simon JA, Clayton AH, Parish SJ, et al. Effects of Alcohol Administered With Flibanserin in Healthy Premenopausal Women: A Randomized, Double-Blind, Single-Dose Crossover Study. J Sex Med 2020;17:83-93.

Efficacy and Safety of High-Specific-Activity 131I-MIBG Therapy in Patients with Advanced Pheochromocytoma or Paraganglioma.

Patients with metastatic or unresectable (advanced) pheochromocytoma and paraganglioma (PPGL) have poor prognoses and few treatment options. This multicenter, phase 2 trial evaluated the efficacy and safety of high-specific-activity 131I-meta-iodobenzylguanidine (HSA 131I-MIBG) in patients with advanced PPGL. Methods: In this open-label, single-arm study, 81 PPGL patients were screened for enrollment, and 74 received a treatment-planning dose of HSA 131I-MIBG. Of these patients, 68 received at least 1 therapeutic dose (∼18.5 GBq) of HSA 131I-MIBG intravenously. The primary endpoint was the proportion of patients with at least a 50% reduction in baseline antihypertensive medication use lasting at least 6 mo. Secondary endpoints included objective tumor response as assessed by Response Evaluation Criteria in Solid Tumors version 1.0, biochemical tumor marker response, overall survival, and safety. Results: Of the 68 patients who received at least 1 therapeutic dose of HSA 131I-MIBG, 17 (25%; 95% confidence interval, 16%-37%) had a durable reduction in baseline antihypertensive medication use. Among 64 patients with evaluable disease, 59 (92%) had a partial response or stable disease as the best objective response within 12 mo. Decreases in elevated (≥1.5 times the upper limit of normal at baseline) serum chromogranin levels were observed, with confirmed complete and partial responses 12 mo after treatment in 19 of 28 patients (68%). The median overall survival was 36.7 mo (95% confidence interval, 29.9-49.1 mo). The most common treatment-emergent adverse events were nausea, myelosuppression, and fatigue. No patients had drug-related acute hypertensive events during or after the administration of HSA 131I-MIBG. Conclusion: HSA 131I-MIBG offers multiple benefits, including sustained blood pressure control and tumor response in PPGL patients.

Effect of Flibanserin Treatment on Body Weight in Premenopausal and Postmenopausal Women with Hypoactive Sexual Desire Disorder: A Post Hoc Analysis.

BACKGROUND: Flibanserin, a 5-HT1A agonist and 5-HT2A antagonist, is indicated for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. This post hoc analysis evaluated the effect of flibanserin treatment on body weight in premenopausal and postmenopausal women with HSDD. MATERIALS AND METHODS: This analysis included three 24-week, double-blind, placebo-controlled studies of flibanserin 100 mg each bedtime (qhs) in premenopausal women, a similarly designed study in postmenopausal women, and a 52-week, open-label extension study in premenopausal women. RESULTS: In a pooled analysis of premenopausal women, mean baseline body mass index (BMI) was 27.0 kg/m2 in the flibanserin group (n = 1227) and 26.8 kg/m2 in the placebo group (n = 1238). Among patients who completed 24 weeks of treatment, least squares (LS) mean weight change was -1.4 kg in the flibanserin group (n = 1010) and -0.1 kg in the placebo group (n = 1066; p < 0.0001). Weight loss ≥5% from baseline was reported in 21.0% of patients who received flibanserin and 7.8% of patients who received placebo; weight loss ≥10% was reported in 3.8% and 2.0% of patients, respectively. In postmenopausal women, mean baseline BMI was 27.7 kg/m2 in the flibanserin group (n = 467) and 27.3 kg/m2 in the placebo group (n = 480). LS mean weight change at week 24 was -1.8 kg in the flibanserin group (n = 385) and -0.1 kg in the placebo group (n = 425; p < 0.0001), with weight loss ≥5% reported in 24.7% and 7.3% of patients, respectively, and weight loss ≥10% reported in 5.2% and 1.7%, respectively. In HSDD patients with >12 months (n = 880) and >18 months (n = 637) of exposure to flibanserin, mean weight change was -1.0 and -1.2 kg, respectively; 25.4% and 26.9% of patients, respectively, experienced weight loss ≥5% from baseline, and 7.8% and 8.4%, respectively, experienced weight loss ≥10%. CONCLUSIONS: Women treated with flibanserin for HSDD may experience weight loss.

Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold?

Since their discovery in the 1950s, neurotrophic factors have raised expectations that their clinical application to neurodegenerative diseases might provide an effective therapy for what are now untreatable conditions. Nerve growth factor (NGF) was the first neurotrophic factor to be discovered and was one of the earliest to proceed to clinical trials. NGF, which is selectively trophic for small fiber sensory and sympathetic neurons, was selected as a potential theraphy for diabetic polyneuropathy becaus of the serious consequences associated with degeneration of those neuronal populations in this condition. In addition, evidence shows that reduced availability of NGF may contribute to the pathogenesis of diabetic neuropathy, and animal models of neuropathy respond to the exogenous administration of NGF. Two sets of phase II clinical trails suggested that recombinant human NGF (rhNGF) administration was effective at ameliorating the symptoms associated with both diabetic polyneuropathy and HIV-related neuropathy. These early studies, however, revealed that painful side effects were dose limiting for NGF. A large-scale phase III clinical trail of 1019 patients randomized to receive either rhNGF or palcebo for 48 weeks failed to confirm the earlier indications of efficacy. Among the explanations offered for the discrepancy between the two sets of trails was a robust palcebo effect, inadequate dosage, different study populatioms, and changes to the formulation of rhNGF for the phase III trail. As a result of the phase III outcome, Genentech has decided not to proceed with further development of rhNGF.