INTRODUCTION:The absence of guidance on pharmacological management of urinary incontinence (UI) for individuals with dementia may lead to potentially avoidable medication-related harm. This systematic review aimed to evaluate efficacy and safety of medications for managing UI in people living with cognitive impairment, dementia, or in long-term care. METHODS:Four bibliometric databases were searched for randomized control trials (RCTs) from inception to March 2026. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal tool for RCTs. Efficacy, adverse events (ADEs), and cognitive effects were synthesized. RESULTS:Nine RCTs (N = 310 participants) were included (all had possible risk of bias). Efficacy of oral anticholinergics ranged from no significant effects to 17% greater reduction in UI symptoms compared with placebo, while oral estrogen demonstrated no significant effects compared with placebo. Dry mouth was the most common ADE for oral anticholinergics (n = 61/194 participants in intervention vs. 26/194 in control across 4 trials). Oral anticholinergic effects on cognition (reported in three trials) ranged from no significant effects to statistically significant short-term declines in attention/alertness compared with placebo. CONCLUSIONS:UI medications for people with cognitive impairment or dementia should be prescribed cautiously, with consideration of possible benefits and harms. PROSPERO:https://www.crd.york.ac.uk/PROSPERO/view/CRD420251270946.
INTRODUCTION:Parathyroid hormone (PTH) is the primary regulator of calcium and phosphate balance via direct action on the kidneys and bones and indirect action on the intestine. Hypoparathyroidism is caused by insufficient levels of PTH, leading to 1,25-dihydroxy vitamin D (1,25[OH]2D) deficiency. PTH-induced 1,25(OH)2D production is a highly regulated process essential for physiological functions that is reduced or absent in hypoparathyroidism. AREAS COVERED:Physiological synthesis of 1,25(OH)2D requires 25-hydroxy vitamin D (25[OH]D) 1-α-hydroxylation via the renal CYP27B1 enzyme. Enzyme activity is dependent on CYP27B1 transcription, which is induced by specific PTH-1 receptor (PTH1R) activation that results in endosomal-derived intracellular cyclic adenosine monophosphate formation. Palopegteriparatide, a prodrug of PTH(1-34) used as replacement therapy in hypoparathyroidism, is designed to provide active PTH that exerts its physiological effect through the same affinity and binding to receptors as endogenous PTH. Throughout 3.5 years in the phase 3 PaTHway trial, 25(OH)D and 1,25(OH)2D levels were maintained within normal limits as a result of restoring endogenous production of 1,25(OH)2D and physiological signaling with palopegteriparatide treatment, thereby facilitating independence from active vitamin D. EXPERT OPINION:1,25(OH)2D production can be compromised by even small changes to PTH that bias the physiological interaction between PTH and PTH1R. Thus, ensuring formation of 1,25(OH)2D should be a key outcome of interest in drug development of PTH replacement therapies. Data from clinical trials demonstrate active PTH released from palopegteriparatide interacts with PTH1R to ensure adequate 1,25(OH)2D synthesis, enabling independence from active vitamin D analogues, and confirms its position as a PTH replacement therapy.
INTRODUCTION:Trimethoprim-sulfamethoxazole (TMP-SMX) is a widely used and generally well tolerated antibiotic. Its association with life-threatening respiratory failure was described in a 2019 case series showing high rates of morbidity and mortality. Due to this reporting, public awareness increased, leading to a safety label change by the FDA in 2021 and the publication of cases and studies evaluating this rare adverse reaction. AREAS COVERED:In this rapid review, we performed a database search in PubMed and Embase to evaluate the progression of TMP-SMX‑associated respiratory failure research from 1 January 2019 to 27 January 2026. The original case series spurred the publication of other case series that collectively improved understanding of pathology and supportive care, and retrospective studies have recently been published. The wide-reaching impact of case reporting on adverse drug reactions has also been observed historically, such as for chloramphenicol and thalidomide. EXPERT OPINION:Based on expert opinion, continued efforts to evaluate mechanism, clinical course, and risk would be valuable to better understand this underreported and underrecognized reaction. Altogether, the progression of TMP-SMX-associated respiratory failure research since 2019 demonstrates the importance of publishing cases of rare drug reactions and dissemination to the medical community.
INTRODUCTION:Bisphosphonates (BPs) have consistently yielded positive results in the treatment of Complex Regional Pain Syndrome (CRPS). However, biochemical and histopathological evidence suggests that osteoclasts, the primary pharmacological target of BPs, is not a key driver in the early pathogenetic steps of CRPS. METHODS:To critically review and integrate current evidence on pharmacological mechanisms of action of BPs in CRPS and to propose unifying hypotheses explaining their clinical efficacy beyond antiosteoclastic activity. Literature from in vitro studies, animal models, and randomized clinical trials was integrated. Approximately 80 primary and review articles were critically reviewed. EXPERT OPINION:BPs efficacy in CRPS is best explained by a bone-driven pharmacological model by which local drug accumulation is achieved in the site of disease. This enables modulation of inflammatory and nociceptive processes on adjacent non-bone cells, including macrophages, neutrophils, keratinocytes, and nociceptive fibers. Inhibition of the mevalonate pathway in these cells may reduce inflammatory cytokines, nerve growth factor (NGF), and reactive oxygen species (ROS), while modulating nociceptive signaling pathways. Additional mechanisms, including modulation of vascular tone and neuropeptide signaling, may further contribute to therapeutic effects. This hypothesis may inform optimal treatment strategies and together improve understanding of CRPS pathophysiology.
INTRODUCTION:Type 2 diabetes mellitus (T2DM) pharmacotherapy guidelines recommend the assessment of individual cardiovascular (CV) risk. However, obesity still seems of lesser importance in the context of CV risk. Importantly, obesity-targeting pharmacotherapy use is limited. AREAS COVERED:A PubMed database search, up to August 2025, was performed. This review explores the rationale for prioritizing weight reduction as a key treatment strategy for overweight/obese T2DM patients and provides evidence supporting a weight-centric approach. Furthermore, it addresses the challenges associated with implementing weight management strategies in clinical practice. Higher doses of medications approved for obesity treatment may be indicated compared with those recommended for T2DM therapy. Additionally, the high cost and the lack of reimbursement policies for these drugs create a significant financial burden. Drug side effects may also minimize their use. EXPERT OPINION:The effectiveness of available pharmacotherapy in treating obesity in T2DM patients is discussed. There is still an urgent need to raise awareness regarding the importance of weight-centric management in overweight/obese T2DM patients. There is a need for a multidisciplinary approach, including health-care providers, the health system and policy makers, taking into consideration the multiple challenges, health inequity concerns and disparities in medication accessibility.
INTRODUCTION:Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is a key therapy in managing type 2 diabetes (T2D), offering significant improvements in glycemic control, weight loss, and cardiovascular protection. Beyond these clinical benefits, multi-omics research is clarifying the molecular mechanisms underlying its systemic metabolic effects. AREAS COVERED:This review synthesizes findings from major clinical trials and recent proteomic and metabolomic studies to explain how semaglutide affects inflammatory, lipid, and extracellular matrix (ECM) pathways in multiple organs. Key molecular mediators, including adiponectin, fibroblast growth factor 21 (FGF21), apolipoprotein C-III (ApoC-III), ceramides, and ECM-remodeling proteins (MMPs, CTGF, α-SMA), are linked to improved insulin sensitivity, reduced adipose inflammation, and restored metabolic flexibility. The review also discusses the use of artificial intelligence (AI) and machine learning (ML) to connect omics biomarkers with clinical outcomes. EXPERT OPINION:Semaglutide exemplifies a precision medicine approach for T2D by linking clinical efficacy to molecular adaptation. Longitudinal validation of omics biomarkers and their integration into AI-driven diagnostic platforms could enable personalized, mechanism-based therapy that goes beyond glucose control to deliver comprehensive cardiometabolic protection.
BACKGROUND:Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized treatment for type 2 diabetes mellitus (T2DM), obesity and beyond. Current research focuses on the use of the dual agonist of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR), tirzepatide. AREAS COVERED:This narrative review focuses on the clinical potential of tirzepatide in type 1 diabetes mellitus (T1DM). A literature search in PubMed/MEDLINE, Scopus and Google Scholar until March 2026 was conducted using appropriate keywords. Glycated hemoglobin (HbA1c) was reduced by up to 0.9% and body weight by up to 23.4% corresponding to a reduction in body-mass index by up to 9.0 kg/m2. Continuous glucose monitoring (CGM) has shown that time in range (TIR) increased by up to 18.0%, almost exclusively due to reduced time above range (TAR). Daily insulin requirements were reduced by up to 38 units/day. EXPERT OPINION:Tirzepatide was associated with optimized glycemic control and reduced insulin requirements. These benefits were partly, but not exclusively, mediated by weight loss. Currently available studies are largely observational and have included subjects with overweight or obesity. Future randomized controlled trials are now required to further corroborate these promising findings.
INTRODUCTION:Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disease characterized by hemolytic anemia, bone marrow failure, and thrombosis. Some PNH patients carrying the C5 mutation (Arg885) show poor response to eculizumab and ravulizumab. AREAS COVERED:The US FDA approved PiaSky (crovalimab-akkz) on 20 June 2024, for use in adults or adolescents with PNH. It is a humanized anti-C5 monoclonal antibody, formerly known as SKY59. The main objective of this review is to examine the pharmacological properties of crovalimab and its clinical efficacy and safety. EXPERT OPINION:Crovalimab inhibits the cleavage of complement C5 into C5a and C5b by specifically binding to complement C5, thus preventing terminal complement-mediated intravascular hemolysis in patients with PNH. Based on the pivotal trials COMMODORE 1 and COMMODORE 2, crovalimab had clinical efficacy not inferior to that of eculizumab and exhibited good tolerability and safety, including in controlling hemolysis, avoiding transfusions, and reducing or maintaining lactate dehydrogenase levels. Additionally, crovalimab showed a favorable response in PNH patients carrying C5 variants, and the response in adolescents aged ≥13 years was similar to that in adults. Common adverse events associated with crovalimab include infusion-related reactions, respiratory tract infections, and Type III hypersensitivity reactions.
BACKGROUND:Warfarin dosing varies widely due to genetic, demographic, and clinical factors, but it is unknown whether the importance, equilibrium, and prediction uncertainty of established pharmacogenetic predictors (VKORC1 and CYP2C9) differ between arterial (AF/stroke) and venous (DVT/PE) thromboembolic indications. RESEARCH DESIGN AND METHODS:This exploratory study (early clinical evaluation) synthesizes findings from the International Warfarin Pharmacogenetics Consortium dataset. We evaluated five machine learning (ML) models, and SHapley Additive exPlanations (SHAP) and Bayesian Additive Regression Trees (BART) analyses were carried out. RESULTS:Random Forest demonstrated slightly better predictive performance than other ML models. SHAP analysis quantified feature contributions, revealing that VKORC1 G/G genotype as the most influential in AF/Stroke, while VKORC1 A/A genotype followed by age in the DVT/PE group. BART provided probabilistic predictions and identified indication-specific uncertainty drivers. Age possibly has an interaction effect in the requirements of reduced warfarin doses with AF/Stroke. CONCLUSIONS:Our findings reveal that while core genetic and anthropometric predictors of warfarin dose transcend thromboembolic indication, the equilibrium among these factors and sources of prediction uncertainty possibly differ between arterial and venous disease. Integration of ML with SHAP offers a roadmap for personalized warfarin dosing, though prospective validation is needed before clinical implementation.
INTRODUCTION:Despite the availability of drugs which prevent vomiting, treatment gaps in controlling nausea and vomiting remain. New approaches are needed. AREAS COVERED:We identify unmet clinical needs by examining clinical reviews (last 5-years), adding our experience in drug discovery/emesis research. Mechanisms of nausea and vomiting are given. We identify emerging research and new approaches before discussing the challenges of quantifying nausea and vomiting in future trials. EXPERT OPINION:As single agents, drugs which prevent vomiting have efficacy in some but not all groups of patients, with NK1 receptor antagonists possessing the widest spectrum of action. Drug combinations have improved efficacy in specific clinical settings. However, treatment gaps remain (e.g. gastroparesis, cyclic vomiting syndrome) and efficacy is lower against nausea compared with vomiting. The latter requires greater attention in trial design and regulatory assessments. The issue of nausea is difficult because in humans it is inadequately quantified (with high temporal resolution), there is a lack of clinical research into nausea, and animal models only measure 'nausea-like behaviours,' with challenges in translating to humans. In drug discovery, more systematic and critical analysis of the pharmacology of the diverse agents which induce or reduce nausea and vomiting may help identify new therapeutic mechanisms.
BACKGROUND:Dolutegravir (DTG) is an integrase strand transfer inhibitor indicated for human immunodeficiency virus (HIV) infection. Although intrinsic factors show no ethnic-specific impact on DTG pharmacokinetics, extrinsic factors may modulate its pharmacokinetic profile. RESEARCH DESIGN AND METHODS:This study developed a population pharmacokinetic model for DTG in Chinese adults living with HIV and identified key covariates influencing its pharmacokinetics using nonlinear mixed-effects modeling. RESULTS:A total of 302 DTG concentrations from 293 Chinese patients receiving once-daily 50 mg DTG were analyzed. A one-compartment model with first-order absorption and elimination characterized the data. The estimated parameters were as follows: an absorption rate constant of 0.222 h-1, an apparent clearance of 0.843L·h-1, and a volume of distribution of 9.32 L. Body weight (WT) was identified as a significant (p < 0.01) covariate influencing apparent clearance. Monte Carlo simulations indicated that under the standard 50 mg once-daily regimen, DTG exposure was comparable across the WT range of 40-100 kg. CONCLUSION:The findings may contribute to more personalized and effective treatment for Chinese adults living with HIV. In this predominantly male cohort, WT-based dose adjustment was generally not warranted among patients weighing 40-100 kg who received DTG 50 mg once daily.
BACKGROUND:Terlipressin is recommended for acute kidney injury (AKI) in cirrhosis, but its role in those with ascites but without AKI is unclear. METHODS:We retrospectively enrolled 905 cirrhotic patients with ascites from three hospitals, of whom 250 received terlipressin and 655 standard medical therapy. Patients were stratified by baseline serum creatinine (Scr) into stable renal function (Scr < 133 μmol/L; n = 784) and renal dysfunction (Scr ≥ 133 μmol/L; n = 121) cohorts. Primary outcomes included AKI, renal dysfunction, and renal function improvement. Propensity score matching (PSM) was performed. Multivariable logistic regression was further performed in the stable renal function cohort to assess the independent association between terlipressin and AKI. Odds ratio (OR) was calculated. RESULTS:In the stable renal function cohort, after PSM (n = 120), terlipressin group had lower incidence of AKI (1.67% vs. 16.67%, p = 0.004) and renal dysfunction (0% vs. 8.33%, p = 0.068); and multivariate logistic regression analysis confirmed that terlipressin was independently associated with lower incidence of AKI (OR = 0.093, p = 0.027). In the renal dysfunction cohort, after PSM (n = 34), terlipressin was associated with higher incidence of renal function improvement (70.59% vs. 23.53%, p = 0.006). CONCLUSION:Terlipressin may be associated with favorable renal outcomes in cirrhotic patients with ascites, regardless of baseline renal function.
INTRODUCTION:The number of patients with adult congenital heart disease (ACHD) is gradually increasing worldwide due to advances in surgical techniques and pharmacological therapies. ACHD can lead to pulmonary arterial hypertension (PAH), and treatment strategies for PAH associated with ACHD have also evolved. AREAS COVERED:Several PAH-targeted drugs including endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclin analogs are available for treatment of PAH. In this review, we summarized the current evidence regarding the use of PAH-targeted drugs in patients with PAH associated with ACHD. We also propose a 'treat and repair' strategy, which involves initial medical treatment to improve PAH followed by surgical or interventional repair of the systemic-to-pulmonary shunt. A PubMed literature search was conducted from 2000 to 2025. EXPERT OPINION:In cases of PAH associated with a systemic-to-pulmonary cardiac shunt, advanced PAH-targeted drugs can improve hemodynamics, and reduce the risk of cardiac defect repair and further improvement in PAH. The treat and repair strategy represents a promising therapeutic approach for PAH patients associated with systemic-to-pulmonary shunts.
