BACKGROUND: Motion sickness affects millions of people with common symptoms, including nausea and vomiting. Medications used for management of motion sickness since 1870 predominately have anticholinergics and antihistam...BACKGROUND: Motion sickness affects millions of people with common symptoms, including nausea and vomiting. Medications used for management of motion sickness since 1870 predominately have anticholinergics and antihistamines properties. For the past 40 years, there have been no advances in medication options for motion sickness until recently, a novel agent, tradipidant received the Food and Drug Administration approval for symptoms related to motion sickness. MECHANISM OF ACTION, PHARMACODYNAMICS, AND PHARMACOKINETICS: Tradipitant is a selective neurokinin-1 (NK-1) receptor antagonist, blocking the actions of substance P, a neurotransmitter from the tachykinin family. It has high affinity for NK-1 receptors that are present throughout the emetic pathway. The 4 major metabolites of this drug (ie, M2, M3, M4, and M8) have shown a similar affinity to the NK-1 receptor as the parent drug. Pharmacokinetic data have revealed that tradipitant absorption is delayed when administered with food. The volume of distribution is 1956 L and is highly plasma protein bound (∼96%). The half-life is 34 hours. Tradipitant is predominately metabolized by CYP450-mediated pathways and through glucuronidation. Approximately 80% of excretion of tradipitant occurs in the feces. CLINICAL TRIALS: Two phase 3 pivotal trials, Motion Syros (N = 365) and Motion Serifos (N = 316), randomized, double-blinded, placebo-controled, showed significant efficacy for tradipitant in preventing vomiting associated with motion sickness. In Motion Syros, tradipitant groups experienced significantly lower incidences of vomiting than placebo (170 mg tradipitant = 18.3%, 85 mg tradipitant = 19.5%, placebo = 44.3%). In Motion Serifos, 10.4% of the 170-mg tradipitant group and 18.3% of the 85-mg tradipitant group experienced vomiting, compared with 37.7% of the placebo group (P = 0.00002 and P = 0.0014, respectively). The results of the 2 trials validated tradipitant as an effective NK-1 receptor antagonist for motion sickness prevention. The drug was well tolerated with a favorable safety profile and no serious adverse events. THERAPEUTIC ADVANCE: Tradipitant works by blocking the NK-1 receptors found in the emetic pathway and it has been proven in pivotal trials effective for prevention of vomiting due to motion sickness. It reduces motion sickness symptoms in 2 phase 3 trials and offers a revolutionary new treatment option for people who experience motion sickness.
BACKGROUND: Adverse metabolic profile manifested as metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity affect the development and prognosis of heart failure (HF). STUDY QUESTION: Whether treatme...BACKGROUND: Adverse metabolic profile manifested as metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity affect the development and prognosis of heart failure (HF). STUDY QUESTION: Whether treatments targeting metabolic derangements such as sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) and glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) are associated with improved outcomes patients with both HF and MASLD or obesity warrants investigation. STUDY DESIGN: This retrospective study included 7 propensity score matched cohort analyses using deidentified electronic health record data from the TriNetX global health research network. MEASURES AND OUTCOMES: We evaluated the associations between MASLD, obesity, and the use of SGLT2 inhibitors or GLP-1 receptor agonists with adverse outcomes in patients with HF. Cohorts were defined based on combinations of comorbidities (HF subtype, MASLD, obesity, diabetes status) and medication exposure. Time-to-event outcomes with the Kaplain-Meier method and with Cox proportional hazards models for the calculation of hazard ratios (HRs) and 95% confidence intervals. RESULTS: Among patients with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction, MASLD was consistently linked to increased risk of nonfatal cardiovascular events, including HF (HR = 1.09, P < 0.001 and HR = 1.23, P < 0.001), myocardial infarction (HR = 1.03, P = 0.07 and HR = 1.08, P < 0.001), and stroke (HR = 1.04, P = 0.08 and HR = 1.07, P = 0.07). Use of SGLT2 inhibitors in HFpEF and MASLD patients with or without diabetes was associated with reduced all-cause mortality (HR = 0.76, P < 0.001 and HR = 0.69, P < 0.001) and major cardiovascular events. GLP-1 receptor agonists demonstrated a significant survival benefit (HR = 0.38, P < 0.001) in obese patients with HFpEF and MASLD without diabetes. CONCLUSIONS: In patients with HFpEF, pharmacologic interventions targeting metabolic pathways demonstrate meaningful cardioprotective effects, especially in metabolically vulnerable subgroups.
BACKGROUND: Generalized anxiety disorder (GAD) is a prevalent chronic condition affecting quality of life. While pharmacotherapy remains common, its limitations include delayed therapeutic response and intolerable advers...BACKGROUND: Generalized anxiety disorder (GAD) is a prevalent chronic condition affecting quality of life. While pharmacotherapy remains common, its limitations include delayed therapeutic response and intolerable adverse effects. Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuromodulation technique, is emerging as a potential therapeutic option for GAD. However, its comparative efficacy against established pharmacotherapies, such as sertraline, remains unclear. STUDY QUESTION: Is low-frequency right dorsal lateral prefrontal cortex (DLPFC) rTMS, alone or combined with low-dose sertraline, superior to low-dose sertraline monotherapy in reducing anxiety symptoms at 4 weeks in treatment-naïve GAD? STUDY DESIGN: We conducted a randomized, single-blind, exploratory superiority trial comparing two active treatments (low-frequency right DLPFC rTMS monotherapy or combined with low-dose sertraline) against a common reference (low-dose sertraline monotherapy). The study enrolled 35 treatment-naïve patients with GAD randomized to three arms over 4 weeks. MEASURES AND OUTCOMES: Anxiety symptoms were assessed using the Hamilton Anxiety Rating Scale (HARS) at baseline and weeks 1, 2, and 4. The primary end point was change from baseline in HARS total score at week 4 (ΔHARS). RESULTS: In the primary modified intent-to-treat population (n = 32), rTMS monotherapy demonstrated significantly greater symptom reduction compared with sertraline (adjusted mean difference = -3.13, P = 0.018, Cohen d = -0.47), confirmed in the intent-to-treat sensitivity analysis (n = 35). Combination therapy showed no significant advantage over sertraline (P = 0.684). CONCLUSIONS: In this exploratory trial, low-frequency right DLPFC rTMS monotherapy reduced anxiety symptoms more than low-dose sertraline monotherapy during the initial 4-week period, whereas the combination therapy achieved efficacy comparable with sertraline monotherapy. These preliminary findings suggest rTMS may serve as an alternative for treatment-naïve patients with GAD, but larger confirmatory trials are required.
BACKGROUND: Laboratory changes after antiobesity drugs in routine care are not well-described. STUDY QUESTION: In adults with obesity and no diabetes, how do 2-year laboratory trends and major clinical outcomes compare a...BACKGROUND: Laboratory changes after antiobesity drugs in routine care are not well-described. STUDY QUESTION: In adults with obesity and no diabetes, how do 2-year laboratory trends and major clinical outcomes compare after starting semaglutide versus naltrexone-bupropion or phentermine-topiramate? STUDY DESIGN: Retrospective cohort study in the TriNetX US Collaborative Network (2021-2025). New users were propensity-score matched 1:1 and followed for up to 24 months in an intention-to-treat framework. A prespecified 3-month landmark analysis and a global network replication were performed. MEASURES AND OUTCOMES: Lipids, HbA1c, ALT, AST, lipase, creatinine, and estimated glomerular filtration rate were assessed at baseline and at 6, 12, and 24 months. Outcomes were all-cause mortality, major adverse kidney events (MAKEs), major adverse liver outcomes, and acute pancreatitis. Cox models estimated hazard ratios (HRs); 24-month absolute risk differences (ARDs) were derived from Kaplan-Meier estimates. RESULTS: Matching yielded 11,484 semaglutide-naltrexone-bupropion pairs and 16,316 semaglutide-phentermine-topiramate pairs. Compared with each comparator, semaglutide users had lower total cholesterol and LDL-C across follow-up; triglycerides were lower versus naltrexone-bupropion. HDL-C was higher with phentermine-topiramate at 12-24 months. HbA1c was lower with semaglutide versus naltrexone-bupropion at 12 and 24 months and slightly higher versus phentermine-topiramate. Between-group differences in creatinine and estimated glomerular filtration rate were limited. Semaglutide use was associated with lower hazards of mortality (vs. naltrexone-bupropion: HR 0.51; ARD -0.4%; vs. phentermine-topiramate: HR 0.62; ARD -0.2%) and MAKE (vs. naltrexone-bupropion: HR 0.47; ARD -0.5%; vs. phentermine-topiramate: HR 0.48; ARD -0.4%). Major adverse liver outcome and pancreatitis estimates were near the null, and landmark results were similar. CONCLUSIONS: Over 2 years in routine care, semaglutide use was associated with lower atherogenic lipid levels and lower hazards of death and MAKEs than naltrexone-bupropion or phentermine-topiramate, while kidney laboratory differences were limited.
BACKGROUND: Adjustment disorder with mixed anxiety and depressed mood lacks established treatment protocols, despite its clinical significance. Repetitive transcranial magnetic stimulation (rTMS) has demonstrated efficac...BACKGROUND: Adjustment disorder with mixed anxiety and depressed mood lacks established treatment protocols, despite its clinical significance. Repetitive transcranial magnetic stimulation (rTMS) has demonstrated efficacy in stress-related conditions, yet its application in adjustment disorder remains limited. STUDY QUESTION: This retrospective chart review examined the safety and clinical benefit of rTMS for this condition in a Romanian health care context. STUDY DESIGN: Sixty adults with adjustment disorder with mixed anxiety and depressed mood were identified from outpatient clinic records and grouped by treatment received: rTMS alone (n = 20), rTMS with medication (n = 10), or medication only (n = 30). MEASURES AND OUTCOMES: Low-frequency 1-Hz stimulation at 110% of the motor threshold was applied to the right dorsolateral prefrontal cortex in 10 sessions over 2 weeks. Depressive and anxiety symptoms were measured at baseline and at day 30 using the Hamilton Depression Rating Scale and the Hamilton Anxiety Scale. Logistic regression analysis was used to identify factors associated with treatment outcomes. RESULTS AND DISCUSSION: Significant symptom improvements occurred across all groups ( P < 0.001). Complete remission rates varied substantially: rTMS monotherapy achieved 80% remission, medication alone 40%, and combined treatment 20% (χ 2 = 13.714, P = 0.008). Sixty percent of participants showed clinical response. Treatment modality predicted response, with rTMS monotherapy increasing odds of improvement 5.7-fold versus medication alone ( P = 0.017). Lower baseline anxiety predicted combined remission (OR = 0.779, P = 0.001), while demographic factors showed no predictive value. Adverse events were mild and transient, with no serious complications or discontinuations. Urban residence significantly influenced rTMS uptake ( P = 0.011). CONCLUSIONS: rTMS seems effective and may be considered alongside conventional pharmacotherapy for adjustment disorder with mixed anxiety and depressed mood. The intervention showed good tolerability. Geographic barriers to access warrant attention in service planning. Larger randomized controlled trials with extended follow-up are needed to confirm these findings and establish optimal protocols.