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Xanomeline-Trospium for Adults With Schizophrenia Experiencing Acute Psychosis: A Systematic Review and Meta-Analysis of Safety and Tolerability Outcomes
No full textThe United States Food and Drug Administration approved the xanomeline-trospium combination in September 2024 for treating schizophrenia, based in part on three double-blind, randomized placebo-controlled trials in adults with schizophrenia experiencing acute psychosis. This random-effects model pairwise meta-analysis of those three trials found that xanomeline-trospium was comparable to placebo in terms of all-cause discontinuation, discontinuation rate due to adverse events, Simpson–Angus Scale score change, Barnes Akathisia Rating Scale score change, body weight change, body mass index change, blood pressure change, serum total cholesterol change, blood glucose change, QTc interval changes, and the incidence of headache, somnolence, insomnia, dizziness, akathisia, agitation, tachycardia, gastroesophageal reflux disease, diarrhea, increased weight, and decreased appetite. However, xanomeline-trospium was associated with a higher incidence of at least one adverse event, dry mouth, hypertension, nausea, vomiting, dyspepsia, and constipation, and increased serum triglyceride compared with placebo. Notably, xanomeline-trospium demonstrated superior efficacy than placebo in improving the Positive and Negative Syndrome Scale (PANSS) total score, PANSS positive subscale score, and PANSS negative subscale score
From Patients to Partners: Ethical Complexities of Maintaining Professional Boundaries in a Digital Age: Ethics of Professional Boundaries in Digital Age
No full textProfessional ethics prohibit physicians from dating current patients due to risks of exploitation, compromised objectivity, and power imbalances, conflicting with obligations of beneficence and nonmaleficence. Online dating applications or appls complicate these boundaries, as a physician\u27s online presence may inadvertently enable patient encounters outside professional contexts. To maintain ethical standards, physicians should avoid sharing identifiable information on dating platforms, ensure patient care is transferred before pursuing romantic relationships, and adhere to institutional policies that mitigate risks and uphold transparency
Innovation in the Management of Delayed Cerebral Ischemia in Subarachnoid Hemorrhage
No full textAneurysmal subarachnoid hemorrhage is one of the feared stroke subtypes with a high degree of morbidity and mortality. Even after the initial treatment of the ruptured aneurysm, patients remain critically ill due to numerous neurologic and systemic sequalae. Among them is cerebral vasospasm, which is a key contributor in the development of delayed cerebral ischemia (DCI). Whereas prevention of DCI with oral nimodipine is standard of care, neurointerventional strategies in the management of DCI are varied. Chemical angioplasty with intra-arterial vasodilators has been a conventional approach when noninvasive medical management fails but is associated with the need for retreatment and therefore felt to be least durable. Balloon angioplasty is also another classically employed, but less frequent intervention, and is limited by utility in the proximal arterial segment, a narrower safety profile, and challenging navigability. More recently, the use of retrievable stents is emerging as a novel strategy with the advantages of improved safety profile, and navigability to treat more distal segments. Here, a selective overview of some of these classic and innovative neurointerventional strategies is presented in the treatment of symptomatic vasospasm/DCI
HESI GTTC Ring Trial: Concordance Between Ames and Rodent Carcinogenicity Outcomes for N-Nitrosamines (Nas) With Rat and Hamster Metabolic Conditions
No full textA multi-sector study (i.e., Ring Trial) was designed to improve the in vitro detection of N-nitrosamine (NA)-associated mutagenicity by optimizing the bacterial reverse mutation (i.e., Ames) assay protocol and testing various conditions on the sensitivity and specificity for the prediction of rodent carcinogenicity. A total of 29 NAs and 3 N-nitroso drug-like compounds from different structural classes and carcinogenicity outcomes were tested (two independent laboratories per compound) across 5 bacterial strains using a 30-min pre-incubation protocol. To evaluate the impact of different metabolic activating systems (MASs), testing conditions included the use of 10 or 30 % liver S9 fractions prepared from rats or hamsters pretreated with inducers of enzymatic activity. Results indicate that E. coli and Salmonella typhimurium strains detecting single base pair mutations, coupled with MASs containing 30 % hamster S9s were the most sensitive (90 %) for identifying NAs that are rodent carcinogens. Regarding MAS combinations, the highest sensitivity was 30 % rat and 30 % hamster (93 %), but has low specificity (45 %), with good laboratory agreement for the Ames calls (91 %). DMSO and water were considered suitable solvents, except for small-molecular weight alkyl NAs. These results will support harmonized Ames testing of NAs, giving high confidence for a negative result
Relationship Between Sweat Chloride and Pulmonary Function in Healthy Young Adults – a Single-Center, Pilot Study
No full textBackground: The role of Cystic Fibrosis Transmembrane Conductance regulator (CFTR) dysfunction in non-cystic fibrosis lung diseases, including COPD, is not well understood. The objective of this study was to assess the prevalence of intermediate sweat chloride levels, 30–59 mmol/L, in healthy young adults and the relationship between sweat chloride and pulmonary function. Methods: Healthy volunteers \u3e18 years of age were enrolled in this single center, prospective, cross-sectional pilot study. Sweat chloride testing was performed by pilocarpine iontophoresis. Study participants completed the ATS-DLD LHS-III modified general respiratory symptom questionnaire, spirometry pre- and post-inhaled bronchodilator, and Lung Clearance Index. Results: 93 subjects were enrolled. 1 subject withdrew and 2 had insufficient sweat volumes collected. Median (IQR) age was 27 years (25, 33) and 40 % were male. Median (IQR) sweat chloride was 21 mmol/L (12, 29). 25/90 subjects (28 %) had intermediate sweat chloride values, median 37 (33, 40) mmol/L. 60 % of individuals with intermediate sweat chloride values were male as compared to 34 % of individuals with normal sweat chloride values, p \u3c 0.001. Median FEV1 (% predicted) was 100 (90, 109), FEV1/FVC 0.83 (0.81, 0.86), and LCI was 6.01 (5.38, 6.98). There were no differences in pulmonary function between those with normal and intermediate sweat chloride values. Conclusions: A significant number of healthy young adults have intermediate sweat chloride levels, but no differences in spirometry and LCI were found. Larger studies, including genetic analyses, are needed to determine if mild CFTR dysfunction impacts respiratory health, especially in older individuals with respiratory co-morbidities
State-Dependent Central Synaptic Regulation by GLP-1 Is Essential for Energy Homeostasis
No full textCentral glucagon-like peptide-1 (GLP-1), secreted by a distinct population of nucleus tractus solitarius neurons, suppresses feeding but the exact mechanisms of action in the brain remain unclear. Here, we investigate a descending circuit formed by GLP-1 receptor (GLP-1R) neurons in the paraventricular hypothalamic nucleus (PVNGLP-1R) projecting to the dorsal vagal complex (DVC) of the brain stem in mice. PVNGLP-1R→DVC synapses release glutamate and are augmented by GLP-1. Chemogenetic activation of PVNGLP-1R→DVC suppresses feeding. Under an energy deficit (that is, hunger) state, synaptic strength is weaker but is more profoundly augmented by GLP-1R activation than under energy-replete state. In an obese condition, the dynamic synaptic changes in this circuit are disrupted. Optogenetic activation of PVNGLP-1R→DVC projections suppresses food intake energy state dependently, and blocking its synaptic release or ablating GLP-1Rs in the presynaptic neurons impairs metabolic health. These findings indicate that the state-dependent synaptic regulation by GLP-1 in PVNGLP-1R→DVC descending circuit is important for energy homeostasis
Long-Acting Oral Weekly Risperidone (LYN-005) for Schizophrenia in the USA (STARLYNG-1): A Multicentre, Open-Label, Non-Randomised Phase 3 Trial
No full textBackground: Medication non-adherence and insufficiently managed disease worsen outcomes in people with schizophrenia. We aimed to compare the bioavailability of a long-acting oral weekly formulation of risperidone, LYN-005, with daily oral risperidone at steady state. Methods: In this open-label, non-randomised, phase 3 trial, clinically stable participants with schizophrenia or schizoaffective disorder were enrolled from five sites across the USA while residing in an inpatient facility for 5 weeks (with the exception of days 9–13). After a 7-day run-in period with immediate-release risperidone (2 mg or 6 mg), participants received five doses of long-acting oral weekly LYN-005 (15 mg or 45 mg, respectively), with a supplemental half dose of daily immediate-release risperidone during week 1. Primary endpoints compared pharmacokinetic parameters of LYN-005 (minimum concentration [Cmin] at weeks 1 and 5, and maximum concentration [Cmax] and average concentration [Cavg] at week 5) with those of immediate-release risperidone on the last day of the run-in period. Prespecified primary endpoint criteria were geometric mean ratios for Cmin at week 1 and week 5 (90% CI ≥0·8), Cmax at week 5 (90% CI ≤1·25), and Cavg at week 5 (0·8 ≤90% CI ≤1·4). No people with lived experience were involved in the study design. This study was registered with ClinicalTrials.gov, NCT05779241, and has been completed. Findings: Between April 13, 2023 and Dec 1, 2023, 83 participants were enrolled in the study (62 [75%] male and 21 [25%] female; 67 [81%] Black or African American, mean age 49·3 years [SD 11·5]), of whom 47 participants completed the 5-week study. In the pharmacokinetic analysis (n=44), sustained release of the active moiety was observed across all doses of LYN-005. Geometric mean ratios of LYN-005 versus immediate-release risperidone were 1·02 (90% CI 0·93–1·12) for Cmin at week 1, and 1·04 (90% CI 0·87–1·23), 0·84 (0·77–0·92), and 1·03 (0·93–1·13) for Cmin, Cmax, and Cavg, respectively, at week 5 and met predetermined criteria. In individuals taking LYN-005 (n=67), gastrointestinal treatment-emergent adverse events were most common (44 [66%] participants), with one serious treatment-emergent adverse event reported. Interpretation: Weekly LYN-005 provided sustained release of risperidone at therapeutic concentrations with similar bioavailability to immediate-release risperidone. Patients remained clinically stable and no unexpected safety signals emerged. This offers a novel long-acting oral drug delivery technology for schizophrenia and schizoaffective disorder. Funding: Lyndra Therapeutics
