American journal of therapeutics最新文献

Background: Gonorrhea is a preventable and treatable infection caused by Neisseria gonorrhoeae , remaining a major public health concern because of antibiotic-resistant strains. A milestone was reached with zoliflodacin, the first therapeutic in its class in nearly 2 decades.

Mechanism of action, pharmacodynamics and pharmacokinetics: Zoliflodacin is a first-in-class spiropyrimidinetrione antibacterial agent that targets type II topoisomerases DNA gyrase and topoisomerase IV enzymes essential for DNA synthesis. Its primary target is the GyrB subunit of DNA gyrase, rather than the GyrA or ParC subunits affected by fluoroquinolones. The area under the concentration-time curve/minimum inhibitory concentration is the primary pharmacokinetics and pharmacodynamics index associated with bacterial killing. Zoliflodacin binds approximately 83% to plasma proteins, undergoes extensive metabolism through cytochrome P450-mediated and non-P450-mediated pathways, has a low urinary excretion with a major fecal route elimination pathway, and an elimination half-life of around 5-6 hours.

Clinical trials: Zoliflodacin demonstrated positive results for the treatment of uncomplicated urogenital gonorrhea in phase 2 and subsequently phase 3 trials. In a phase 2, multicenter, open-label RCT, the efficacy and safety of zoliflodacin was compared with ceftriaxone. Cure rates for urogenital infections were 96% (55/57) (2 g), 96% (54/56) (3 g), and 100% (28/28) (ceftriaxone). In a phase 3, multinational, open-label, noninferiority RCT, participants were randomly assigned (2:1) to receive a single 3 g oral dose of zoliflodacin or a single dose of 500 mg intramuscular injection of ceftriaxone plus 1 g oral azithromycin. The primary end point for microbiological cure was achieved in 90.9% (460/506) of patients on zoliflodacin compared with 96.2% (229/238) of the comparator, demonstrating noninferiority and good tolerability.

Therapeutic advance: Oral zoliflodacin represents a novel option for the treatment of uncomplicated urogenital gonorrhea, including antibiotic-resistant strains, providing an important alternative therapy.

Background: Cardiovascular disease remains the leading cause of global mortality (19.8 million deaths in 2022; 32% of all deaths worldwide). Drug repurposing-extending approved agents beyond their original indications-has emerged as a high-impact strategy in cardiovascular prevention, offering reduced development timelines, established safety profiles, and faster implementation than de novo molecular development.

Study question: Which repurposed cardiovascular agents demonstrate the most favorable pharmacoeconomic profiles, and how does the convergence of clinical benefit, patient risk stratification, and economic sustainability define the optimal hierarchy for cardiovascular prevention?

Study design: Narrative review synthesizing evidence from 19 pivotal cardiovascular outcomes trials and European and American guidelines. No formal meta-analysis was applied.

Measures and outcomes: For 13 agents across 8 therapeutic classes, efficacy was quantified as relative and absolute risk reductions, and as the number needed to treat or to harm. Pharmacoeconomic value was assessed via incremental cost-effectiveness ratio in US dollars per quality-adjusted life year, integrating mortality in years of life lost and morbidity in years lived with disability. Primary outcomes included all-cause mortality, cardiovascular mortality, major adverse cardiovascular events, and heart failure hospitalizations.

Results: Three Incremental Cost-Effectiveness Ratio (ICER) tiers were identified: Low-cost (< $20,000/ Quality-Adjusted Life Year (QALY)): ramipril (Number Needed to Treat (NNT) 28), carvedilol (NNT 29), metformin ( NNT 9-15, highest Relative Risk Reduction (RRR) 38-42%), and generic statins - robust mortality benefits at negligible cost; Moderate-cost ($3,000-$50,000/QALY): empagliflozin (↓38% cardiovascular mortality, NNT 61), dapagliflozin (NNT 20 in Heart Failure with Reduced Ejection Fraction), liraglutide (NNT 51), semaglutide (NNT 43), colchicine (NNT 36, morbidity benefit only), and branded statins; High-cost ($80,000-$300,000/QALY): Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors (evolocumab NNT 63; alirocumab NNT 64) - proven benefit compromised by unaffordable biologic pricing.

Conclusions: Pharmacoeconomic stratification of repurposed cardiovascular agents identifies 3 distinct tiers. Generic agents-ramipril, carvedilol, metformin, and statins-demonstrate the most favorable cost-effectiveness profiles and should form the basis of any prevention protocol. SGLT2 inhibitors and GLP-1 receptor agonists offer clinically meaningful benefits in secondary prevention when applied to populations meeting pivotal trial eligibility criteria. PCSK9 inhibitors remain cost-effective only in patients with very high cardiovascular risk and inadequate LDL control on maximally tolerated statin therapy.

Background: Propofol is widely used for deep sedation during endoscopic retrograde cholangiopancreatography (ERCP) due to its rapid onset and favorable recovery profile; however, it is associated with dose-dependent cardiopulmonary adverse effects, particularly hypoxia and hypotension.

Areas of uncertainty: Significant heterogeneity persists in the definition, severity classification, and reporting of these adverse events, limiting comparability across studies and hindering reliable risk stratification. Therefore, the aim of this systematic review was to evaluate the incidence and clinical characteristics of propofol-associated hypoxia and hypotension in adult patients undergoing ERCP, and to assess variability in reporting practices across studies.

Data sources: A systematic review was conducted and reported in accordance with PRISMA guidelines. PubMed was searched for English-language studies published between 1995 and 2025 involving adult patients undergoing ERCP under propofol-based sedation.

Results: Across studies reporting extractable data, oxygen desaturation occurred in 16.9% of aggregated cases (1194/7049), whereas hypotension occurred in 13.0% (187/1440). These values represent descriptive estimates and should not be interpreted as meta-analytic pooled incidences. Both events were predominantly mild and transient, responding to standard supportive measures, whereas severe complications, including cardiopulmonary arrest, were exceptionally rare. Considerable variability in definitions, outcome reporting, and study design was observed across studies.

Conclusions: Propofol sedation during ERCP is associated with frequent but generally manageable hypoxia and hypotension. Continuous respiratory and hemodynamic monitoring facilitates early recognition and prompt intervention. Standardization of outcome definitions and reporting, along with the development of structured risk stratification tools, may improve patient selection and enhance procedural safety.

Background: Acute myocardial infarction (MI) is associated with a high incidence of morbidity and mortality. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic medications known for their favorable effects on cardiovascular disease. However, evidence regarding their effects in acute MI is limited.

Study question: Whether early administration of dapagliflozin could affect the cardiovascular outcome of patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).

Study design: We randomly allocated 101 patients with nondiabetes, nonheart failure STEMI undergoing primary PCI to receive dapagliflozin (10 mg/d started before PCI and continued for 40 days) or placebo.

Measures and outcomes: The primary outcomes were changes in left ventricular ejection fraction (LVEF) 40 days after PCI, changes in cardiac troponin I (cTnI) levels, estimated infarct size using the peak and area under the curve (AUC) of cTnI, and ST-segment resolution. Secondary outcomes included high-sensitivity C-reactive (hs-CRP) protein levels at discharge and health-related quality of life (HRQoL) 40 days after acute MI.

Results: The results revealed a significant increase in LVEF in dapagliflozin-treated patients with baseline LVEF ≤40% compared with the placebo group (41.1 ± 5.5 vs. 38.1 ± 6.9; P = 0.037). No significant difference was observed regarding ST-segment resolution, cTnI levels, AUC, and peak between the 2 groups. We did not observe a significant difference regarding secondary outcomes.

Conclusions: This study showed that dapagliflozin could significantly improve LVEF among patients whose LVEF dropped to ≤40% post-STEMI. However, further studies are required to confirm the study findings.