Pharmacotherapy最新文献

Background: Levodopa decreases blood pressure (BP) in persons with Parkinson's disease (PwP), but no pharmacodynamic studies integrating systemic levodopa concentration measurements have characterized its hypotensive effects. Understanding this relationship is clinically relevant for guiding therapeutic decisions, such as how aggressively to treat hypotension before initiating or increasing levodopa. In this pilot study, we aimed to determine the acute pharmacodynamic effects of oral immediate-release carbidopa/levodopa on BP in PwP.

Methods: PwP taking chronic oral carbidopa/levodopa with baseline BP ≥ 90/60 mmHg were recruited. Participants withheld antiparkinsonian medications overnight prior to the study visit and received carbidopa/levodopa immediate-release tablets at time 0. Capillary blood levodopa levels, seated BP measurements, and motor symptom assessments were performed at baseline and repeated every 10 min for 70-100 min. Non-compartmental pharmacokinetic parameters of levodopa were determined, including the area under the curve up to the last time point (AUC_{0 → last}), maximum concentration (C_max), and time to maximum concentration (T_max).

Results: Fourteen PwP were enrolled (mean age 69.5 ± 7.6 years, six females). Two participants had orthostatic hypotension at baseline (defined as a sustained drop in systolic BP ≥ 20 mmHg or diastolic BP ≥ 10 mmHg within 3 min of standing), and six were taking antihypertensive medications. Mean arterial pressure (MAP) declined during the study from an average of 105 ± 13.1 mmHg at baseline to a nadir of 84 ± 15.8 mmHg. The maximum MAP drop occurred at 100 min post-dose. Cumulative levodopa AUC negatively correlated with MAP (Pearson's r = -0.30; p = 0.00036).

Conclusions: Oral levodopa is associated with acute hypotension in PwP, and levodopa exposure is inversely correlated with MAP. These effects should be considered when adjusting levodopa dosing, particularly in patients with hypotension, to improve safety outcomes.

Context: To meet the need for effective treatments during the COVID-19 Public Health Emergency, the U.S. government sought to accelerate the discovery and development of new antiviral treatments-a process that normally took 4-12 years. The government changed many features of the established system, selecting the investigational drugs, sponsoring or conducting the clinical testing, and purchasing and managing the distribution of the successful products.

Methods: We focused on novel therapeutic agents for COVID-19 that were funded, clinically tested, and/or received Emergency Use Authorization during the Public Health Emergency from January 2020 to May 2023. The primary sources were the public records of the National Institutes of Health, the U.S. Food and Drug Administration, and the Biomedical Advanced Research and Development Authority. Excluded were vaccines, devices, diagnostic tests, and new indications for approved drugs.

Results: In less than 24 months, the emergency program developed, tested, approved, and distributed eight new therapeutic products, including six monoclonal antibodies and two new oral antivirals. In addition, 11 other investigational agents were funded or tested under the emergency program but did not receive Emergency Use Authorization. More than 30 million courses of treatment were distributed at a cost of $29 billion or $881 per patient. By the end of the emergency, viral mutations and rapidly growing population immunity rendered the new products ineffective in almost all patients.

Conclusions: The emergency program was dramatically effective in finding and testing new drug treatments using a variety of clinically relevant endpoints and serving varied patient populations. Planning for future pandemics should include a global network of clinical testing centers that were key to a rapid response. Research is needed to discover more durable antiviral treatments, especially in settings where mutation and population immunity are subject to rapid change.

Purpose: Filgrastim is administered to shorten the duration of chemotherapy-induced neutropenia. Filgrastim can be administered intravenously or subcutaneously, but different routes of administration may result in different pharmacokinetic properties, which may affect efficacy. The primary objective of this study was to determine if subcutaneous (SQ) filgrastim would be associated with a shorter time to neutrophil recovery in patients with myeloma undergoing autologous hematopoietic stem cell transplantation (autoHSCT) when compared to intravenous piggyback (IVPB) filgrastim.

Methods: This was a single-center, retrospective cohort study of patients undergoing autoHSCT for myeloma admitted and discharged between 2018 and 2019. The primary outcome was the mean number of days from transplant day 0 to absolute neutrophil count (ANC) greater than 500 cells/μL. Secondary outcomes were the incidence of and mean number of days of gram-negative antibiotic treatment and 30-day mortality.

Results: A total of 196 patients with myeloma met the inclusion criteria. No significant differences in time to neutrophil recovery between IVPB and SQ filgrastim were observed (11.0 ± 0.7 days vs. 10.8 ± 0.8 days, p = 0.15, respectively). No significant differences were observed in any of the secondary outcomes between IVPB and SQ filgrastim.

Conclusion: In patients with myeloma undergoing autoHSCT, no differences in time to neutrophil recovery, incidence of or duration of gram-negative antibiotic treatment, or 30-day mortality were observed between IVPB and SQ routes of filgrastim administration.

Background: Although randomized controlled trials (RCTs) have established evidence regarding thromboembolic risks of thrombopoietin receptor agonists (TPO-RAs) in immune thrombocytopenia (ITP) during short-term follow-up, the long-term risks remain uncertain. This meta-analysis integrates data from prospective studies and RCTs to provide a comprehensive evaluation of thromboembolic risks associated with TPO-RA therapy.

Methods: PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to January 23, 2025 for RCTs and prospective studies reporting thromboembolic events in patients treated with TPO-RAs. The primary outcome was the risk of any thromboembolism. Subgroup analyses separately assessed the incidence of venous and arterial thrombosis. Short-term (≤ 6 months) evidence was derived from RCTs, while long-term (6-12 months and > 12 months) evidence was supplemented by prospective studies. Data from RCTs were analyzed using the Peto odds ratio (OR) with 95% confidence intervals (CIs), and data from prospective studies were pooled to calculate the incidence of thromboembolic events.

Results: The analysis included 12 RCTs (involving 1530 patients) and 11 prospective studies (involving 1820 patients). TPO-RAs significantly increased thromboembolic risk compared to placebo in the short-term (0.72% vs. 0.23%, Peto OR = 3.25, 95% CI = 1.11-9.51, p = 0.03). Pooled results from prospective studies demonstrated thromboembolism incidence of 3.84% at 6 to 12 months and 5.59% beyond 12 months of treatment with TPO-RAs. The reported incidence of arterial thrombosis increased from 0.14% (≤ 6 months) to 1.51% (6-12 months), and further to 4.2% (> 12 months). Whereas the reported incidence of venous thrombosis increased from 0.18% (≤ 6 months) to 2.50% (6-12 months), and plateaued at 2.55% beyond 12 months.

Conclusion: This analysis demonstrates that TPO-RAs therapy increases the risk of thromboembolism, with the risk of arterial events becoming particularly pronounced during long-term use. These findings highlight the need for individualized risk assessment and vigilant monitoring in patients receiving TPO-RAs.

Background: There are sparse data to guide resumption of direct oral anticoagulants (DOACs) versus warfarin in patients with atrial fibrillation (AF) who survive a major gastrointestinal bleeding (GIB) event.

Objective: To compare the risk-benefit profile of restarting DOACs versus warfarin among patients with AF following hospitalization for major GIB.

Methods: Using claims submitted to a commercial health insurance database from January 2010 to December 2017, we identified adult patients with AF hospitalized for a major GIB while receiving oral anticoagulants. Eligible patients were required to have survived and restarted oral anticoagulation with DOACs or warfarin within 90 days following hospital discharge for major GIB. The outcomes of interest were subsequent hospitalization for major bleeding, hospitalization for ischemic stroke/systemic embolism (SE), all-cause mortality, and net adverse clinical effect (NACE), which was a composite of all-cause mortality, hospitalization for ischemic stroke/SE, and hospitalization for major bleeding. Stabilized inverse probability of treatment weighting was used to balance measured covariates.

Results: Overall, 4,389 patients resumed oral anticoagulation, with 3016 (68.7%) on warfarin and 1373 (31.3%) on DOACs, within 90 days of hospital discharge for major GIB. The median (interquartile range) time from hospital discharge for major GIB to resumption of oral anticoagulant was 24 (10, 47) days. The weighted hazards ratio (HR) among individuals that resumed DOACs versus warfarin after major GIB was 0.76 (95% confidence interval, CI: 0.60, 0.96) for subsequent hospitalization for major bleeding, 0.91 (95% CI: 0.53, 1.55) for subsequent hospitalization for ischemic stroke/SE, and 0.83 (95% CI: 0.72, 0.97) for NACE.

Conclusions: Among patients with AF who survived and resumed oral anticoagulation within the first 90 days after hospitalization for a major GIB event, restarting oral anticoagulation treatment with DOACs was associated with a lower risk of subsequent hospitalization for major bleeding and the composite outcome of ischemic stroke, SE, all-cause mortality, and recurrent or incident major bleeding.

We describe a case of a 56-year-old male who developed severe, refractory hypotension after an intentional ingestion of clozapine and who became hemodynamically stable after one session of therapeutic plasma exchange (TPE). The patient, who presented after an ingestion of clozapine, was found to have altered mental status and hypotension in the emergency department. Escalating catecholamine vasoactive agents were necessary to maintain adequate hemodynamics. Angiotensin II was added and rapidly up titrated in efforts to maintain adequate blood pressure. Due to persistent hemodynamic instability despite four vasoactive agents, TPE was attempted to enhance the elimination of the highly protein bound medication. Within 2 h of completing TPE, the catecholamines and vasopressin were stopped, and angiotensin II dosing was significantly decreased. This is the first report of utilizing TPE as a method of enhanced elimination of a toxic clozapine ingestion resulting in severe hemodynamic compromise. Further study is necessary to determine if TPE should be incorporated into the care of patients experiencing clozapine toxicity.

Depression is the leading cause of disability worldwide, affecting people of all ages. Both pharmacological and non-pharmacological therapies are available for its treatment. However, some patients do not respond to first-line pharmacological interventions, referred to as treatment-resistant depression (TRD). Individuals with TRD face a significantly higher risk of mortality, including an increased risk of suicide. Additionally, TRD poses a substantial economic burden on health care systems. Various treatment options have been explored for TRD, including augmentation of an antidepressant through the use of an additional agent. Lithium salts have shown promising benefits in the TRD. Lithium requires close therapeutic monitoring due to its narrow therapeutic range, with well-defined thresholds for efficacy and toxicity, in addition to its pharmacokinetic characteristics. Furthermore, lithium has been associated with a reduced risk of mortality by lowering aggression, impulsivity, and suicide rates. Compared with other agents used in the management of TRD-such as atypical antidepressants, second-generation antipsychotics (SGAs), ketamine, and thyroid hormones-lithium is considered a cost-effective augmentation option, alongside other evidence-based strategies, and has a well-established efficacy profile. This literature review examines the role of lithium as an augmentation agent in TRD, with a focus on its pharmacological and clinical properties, as well as the current evidence supporting its use.

Introduction: Pediatric plastic bronchitis (PB) is a rare complication of surgically palliated congenital heart disease (CHD). Fibrin casts obstruct airways and can cause respiratory distress. There are no therapeutics approved by the United States Food and Drug Administration to treat PB, but inhaled tissue plasminogen activator (tPA) has been anecdotally used to relieve symptoms. We conducted a phase II open-label clinical trial to test the safety of inhaled tPA in pediatric PB.

Methods: Patients with an acute exacerbation of PB requiring hospitalization were enrolled to test the safety of an inhaled tPA regimen (5 mg every 6 h). The primary end point was to assess the safety and tolerability of repeated doses of nebulized, inhaled tPA in pediatric patients with acute PB. Safety parameters consisted of clinical laboratories to assess bleeding, which were measured prior to, during, and after tPA treatment. To benchmark efficacy using spirometry and oxygen saturation, children with Fontan-palliated CHD without a history of PB, with and without protein losing enteropathy (PLE), and healthy children were enrolled in a control arm that did not receive tPA.

Results: Of the 10 patients with PB screened for enrollment, eight qualified for immediate treatment with inhaled tPA. A total of 29 non-PB participants (PLE, n = 8 [10-18 yo]; CHD, n = 9 [8-17 yo]; and healthy, n = 12 [7-16 yo]) were enrolled. There were no differences in pretreatment clinical blood laboratory values of hemostasis and those during and after treatment with the study drug (primary safety outcome). However, there were four episodes of self-limiting epistaxis related to the study drug. Inhaled tPA statistically improved oxygen saturation although this was moderate and likely not clinically significant; inhaled tPA did not alter spirometry values.

Conclusion: In this small, phase II study, repeated doses of inhaled tPA in patients with an acute exacerbation of PB did not result in disrupted systemic coagulation or hematological homeostasis or serious bleeding. However, patients should be monitored for localized bleeding. Larger, randomized trials are needed to provide more comprehensive assessments of bleeding risk and to further assess efficacy.

Trial registration: ClinicalTrials.gov identifier: NCT02315898.