CNS drugs最新文献

B-cell depletion with CD20-targeted agents is commonly used for treatment of multiple sclerosis (MS), other autoimmune diseases, and certain hematologic malignancies. Initial apparent success with rituximab in MS and neuromyelitis optica spurred development of the anti-CD20 monoclonal antibody (mAb) therapies ocrelizumab, ofatumumab, and ublituximab as well as the anti-CD19 mAb inebilizumab. While each are effective at targeting and depleting B cells, structural differences translate into different mechanisms of action affecting maintenance of B-cell depletion and safety and tolerability. Although the anti-CD20 mAbs differ in degree of human versus mouse sequences as well as target CD20 epitope, these properties do not appear to substantially affect activity or tolerability. In contrast, an antibody-dependent cell-mediated cytotoxicity (ADCC) versus a complement-dependent cytotoxicity mechanism of action as well as subcutaneous versus intravenous administration may provide improved tolerability. Glycoengineering of the mAbs ublituximab and inebilizumab enhances ADCC and can overcome the reduced responses to mAb-mediated B-cell depletion associated with certain genetic polymorphisms. Other strategies for therapeutic targeting of CD20, including brain shuttle antibodies (e.g., RO7121932), bispecific antibodies, chimeric antigen receptor T-cell therapies, and antibody-drug conjugates, are in active clinical development and may be future treatment approaches in MS and other B-cell-mediated autoimmune diseases.

Opioid analgesics have been used for more than 5000 years and remain the main pain medications prescribed today. Although morphine is considered the gold standard of pain relief, this selective µ-opioid receptor (MOP) agonist provides only moderate relief for many chronic pain conditions and produces a number of unwanted effects that can affect the patient's quality of life, prevent adherence to treatment or lead to addiction. In addition to the lack of progress in developing better analgesics, there have been no significant breakthroughs to date in combating the above-mentioned side effects. Fortunately, a better understanding of opioid pharmacology has given renewed hope for the development of better and safer pain medications. In this review, we describe how clinically approved opioids were initially characterized as biased ligands and what impact this approach might have on clinical practice. We also look at the preclinical and clinical development of biased MOP agonists, focusing on the history of oliceridine, the first specifically designed biased analgesic. In addition, we explore the discrepancies between ligands with low intrinsic efficacy and those with biased properties. Finally, we examine the rationale behind the development of biased ligands during the opioid crisis.

Foslevodopa/foscarbidopa [PRODUODOPA^® (EU); VYALEV^™ (USA, Canada, Japan)] is a soluble formulation of levodopa and carbidopa prodrugs for 24-h continuous subcutaneous (SC) infusion. It is approved for the treatment of motor fluctuations in patients with advanced Parkinson's disease (PD). Administered via an ambulatory infusion pump, it allows for personalized dosing based on individual needs. In a randomized, double-blind, double-dummy trial, continuous SC infusion of foslevodopa/foscarbidopa provided a significant and clinically meaningful increase in hours of 'on' time without troublesome dyskinesia and a reduction in hours of 'off' time compared with oral immediate-release levodopa/carbidopa. The benefits of foslevodopa/foscarbidopa were maintained over the longer term (up to 124 weeks). Continuous SC infusion of foslevodopa/foscarbidopa was generally well tolerated, including over the longer term. However, infusion site events were common, necessitating regular monitoring, cannula replacement, infusion site rotation and aseptic techniques. Although further long-term data are required, foslevodopa/foscarbidopa represents a promising non-surgical alternative to the available device-aided therapies for patients with advanced PD whose motor fluctuations are inadequately controlled by other oral PD medications.

Background: VVZ-2471 is a dual-target compound that simultaneously inhibits both metabotropic glutamate receptor subtype 5 and serotonin receptor subtype 2A. Preclinical studies have supported VVZ-2471 as a promising candidate for opioid use disorder. This study aimed to evaluate the safety and pharmacokinetic (PK)-pharmacodynamic (PD) characteristics of VVZ-2471 capsules in healthy Korean adults.

Methods: A phase I, double blind, placebo controlled, single ascending dose (SAD) and multiple ascending dose (MAD) study was conducted in healthy adult males. In the SAD study, participants received a single oral dose of VVZ-2471 ranging from 25 to 600 mg, including a satellite food-effect group receiving 200 mg. In the MAD study, participants received 200 mg once daily (QD), 200 mg twice daily, and 400 mg QD for 7 days. Plasma and urine samples were collected for the PK analyses. Safety analysis was based on adverse events, clinical laboratory tests, vital signs, physical examinations, 12-lead electrograms, oxygen saturation monitoring, and the Beck Depression Inventory-II test. The potential of VVZ-2471 for treating addiction was explored using a well-established questionnaire on smoking urges (QSU-Brief) consisting of ten items.

Results: A total of 49 and 24 healthy Korean adult males completed the SAD and MAD study, respectively. The overall demographic characteristics of participants who received VVZ-2471 or placebo in the SAD and MAD studies were generally comparable. Following a single oral dose of VVZ-2471 up to 600 mg, the area under the concentration-time curve (AUC) increased proportionally with the dose. After repeated administration, the accumulation ratio of VVZ-2471 ranged from 1.4 to 2.0. In the fed state, the maximum plasma concentration and AUC of VVZ-2471 decreased to 0.78-fold and 0.61-fold, respectively, compared with the fasting state. Urinary excretion was marginal. The most common adverse events were nausea and dizziness. Among 29 smokers, participants given VVZ-2471 at 200 mg or higher had reduced smoking urges compared with the placebo.

Conclusions: VVZ-2471 was well tolerated up to a single oral dose of 600 mg and a daily oral dose of 400 mg for 7 days. While preliminary, a trend of reducing smoking urges was observed in the VVZ-2471 group.

Registration: Clinical Research Information Service (CRiS), Republic of Korea (a primary registry in the World Health Organization (WHO) Registry Network) identifier no. KCT000889.

Background and objectives: Sinus tachycardia commonly occurs at the start of clozapine treatment, often leading to discontinuation owing to perceived adverse cardiovascular effects. However, little evidence exists on its natural course after clozapine initiation. We aimed to determine the frequency and course of clozapine-induced tachycardia over the first month of treatment and to identify possible risk factors METHODS: In this cross-sectional study, we serially monitored heart rates (HRs) and other clinical variables of psychiatric inpatients commencing clozapine over the first 28 days. HRs were plotted over time and modelled by explanatory variables, including age group, sex, body mass index (BMI), smoking status and prescribed medications for HR.

Results: In total, 123 consecutive inpatients undergoing clozapine titration were assessed daily, with 2901 HR measures collected. After starting clozapine, mean HR increased from 83.7 to 99.5 beats per minute (bpm). Almost all participants (93.5%) had at least one recorded HR > 100 bpm, and 68% had three consecutive days with HR > 100 bpm (being then defined as tachycardic). At least one HR > 120 bpm was recorded in 35.8%, and 8% had persistent HRs > 120 bpm. Tachycardia occurred early during clozapine titration, with a dose response effect at lower doses, which plateaued between 150 and 350 mg daily. Tachycardia spontaneously resolved for some but 44% remained tachycardic at day 28. Female sex was associated with early tachycardia at day 14 (p = 0.008) but not at day 28, while age, smoking status, and BMI were not significantly associated with tachycardia.

Conclusions: Sinus tachycardia occurred in over two thirds of participants during the first month of clozapine titration. Spontaneous resolution of tachycardia in some suggests watchful monitoring may be appropriate prior to treatment with rate-controlling agents such as β-blockers or ivabradine. Long term follow-up is required to determine the effects of sinus tachycardia on cardiovascular outcomes in patients treated with clozapine.

Background: Ketamine and esketamine are increasingly used to manage treatment-resistant depression and have also been shown to reduce symptoms of posttraumatic stress disorder (PTSD). Little is known about how common comorbidities in the veteran population, such as traumatic brain injury (TBI) or obstructive sleep apnea (OSA), may influence ketamine and esketamine treatment outcomes.

Methods: In this retrospective study, we analyzed clinical outcomes from Veterans Affairs (VA) San Diego Healthcare System's ketamine program to assess the relationship between ketamine or esketamine treatment and changes in depression and PTSD symptoms, while also examining how common medical comorbidities influence treatment outcomes. We specifically examined whether a patient's history of TBI or OSA would affect ketamine or esketamine treatment outcomes. Linear mixed-effects models were used to examine how TBI and OSA history interacted with ketamine/esketamine treatment to change PTSD Checklist for DSM-5 (PCL-5) and Patient Health Questionnaire-9 (PHQ-9) scores.

Results: This study included 119 veterans who received eight sessions of ketamine or esketamine treatment at the San Diego VA Medical Center. Using linear effects modeling, we found that repeated ketamine or esketamine sessions were significantly correlated with reductions in both depression (p < 0.005) and PTSD (p < 0.05) symptom scores. However, in veterans with comorbid TBI (n = 38) and severe OSA (n = 9), depression symptoms did not improve over the course of ketamine or esketamine treatment, suggesting this subgroup may require alternative treatments or OSA treatment prior to starting ketamine or esketamine treatment.

Conclusions: Ketamine and esketamine treatment did not improve symptoms of depression in veterans with comorbid TBI and severe OSA. Thus, our findings generally support ketamine and esketamine as effective interventions for depression and PTSD, while emphasizing the consideration of comorbidities such as OSA and TBI.

Background: Huntington's disease (HD) is a rare, fatal, chronic progressive neurodegenerative disorder with a significant unmet medical need for effective treatments. Pridopidine is a novel, first-in-class, highly selective and potent sigma-1 receptor (S1R) agonist in development for HD. Pridopidine has been extensively studied in adult HD across the full spectrum of disease severity and age ranges, and its safety profile has been characterized in approximately 1600 participants across multiple studies and a broad range of doses. The specific objective of this study was to gain an in-depth understanding of pridopidine's safety profile at the recommended human dose of 45 mg twice daily (bid) in patients with HD.

Methods: An integrated safety analysis of pooled data from 1067 patients with HD enrolled in four double-blind, placebo-controlled studies was performed. The safety profile of pridopidine was compared with placebo.

Results: Pridopidine was found to be generally safe and well tolerated with an adverse event (AE) profile comparable to that of placebo. Moreover, there were no significant differences observed in the safety profile of pridopidine compared with placebo when analyzed by age, sex, baseline total functional capacity (TFC), cytosine-adenine-guanine (CAG) repeat length, use of antidopaminergic medications (ADMs), and region.

Conclusions: The integrated analysis replicated and corroborated the good safety profile observed in the individual studies. Despite the larger sample size, no new safety signals emerged. Long-term exposure to pridopidine, up to 6.5 years in open-label extension studies, revealed no new safety concerns, supporting its potential for long-term use in patients with HD.

BACKGROUND AND OBJECTIVES: Intensive or conventional antihypertensive treatment for acute intracerebral hemorrhage is still controversial. This study aimed to compare those antihypertensive regimens and analyze the efficacy of antihypertensive drugs.

Methods: Retrieval was conducted through four databases. Meta-analysis and Bayesian network meta-analysis were performed to evaluate the safety of antihypertensive treatments and the efficacy of antihypertensive drugs.

Results: A total of 9271 patients were included. Intensive strategy showed an advantage in 24-h hematoma enlargement (relative risk, RR = 0.76; 95% confidence intervals, CI = 0.67-0.87; P < 0.0001) and 90-day intracranial rebleeding (RR = 0.71, 95% CI = 0.52-0.96, P = 0.03) compared with conventional strategy. Meanwhile, the 90-day renal insufficiency (RR = 2.31, 95% CI = 1.05-5.05, P = 0.04) and renal failure (RR = 2.42, 95% CI = 1.20-4.86, P = 0.01) were increased. When cerebral hematoma volume was less than 15 ml, intensive strategy had a protective effect on 24-h hematoma enlargement (RR = 0.77, 95% CI = 0.67-0.89, P = 0.0003), but it increased 90-day renal failure (RR = 2.33, 95% CI = 1.07-5.04, P = 0.03). For the volume greater than 15 ml, it enhanced 90-day functional independence (RR = 0.78, 95% CI = 0.65-0.94, P = 0.01) and decreased intracranial rebleeding (RR = 0.68, 95% CI = 0.49-0.94, P = 0.02). Labetalol was the best, with the mortality risk probability of 0.09 and the surface under the cumulative ranking curve of 0.33.

Conclusions: This meta-analysis suggests that for intracerebral hematoma volume greater than 15 ml, intensive antihypertensive treatment can improve functional independence and reduce intracranial bleeding. Labetalol has the best effect among the four antihypertensive regimens studied.