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This trial compared the oral HIF-PHI daprodustat with conventional erythropoiesis-stimulating agents for the treatment of anemia in patients with chronic kidney disease receiving dialysis. Daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes.

This randomized trial compared daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, with darbepoetin alfa for the treatment of anemia in patients with chronic kidney disease who were not undergoing dialysis. Daprodustat was noninferior to darbepoetin alfa with respect to the change in hemoglobin level and cardiovascular outcomes.

Background Refractory status epilepticus (RSE) has a mortality of 16–39%; coma induction is advocated for its management, but no comparative study has been performed. We aimed to assess the effectiveness (RSE control, adverse events) of the first course of propofol versus barbiturates in the treatment of RSE. Methods In this randomized, single blind, multi-center trial studying adults with RSE not due to cerebral anoxia, medications were titrated toward EEG burst-suppression for 36–48 h and then progressively weaned. The primary endpoint was the proportion of patients with RSE controlled after a first course of study medication; secondary endpoints included tolerability measures. Results The trial was terminated after 3 years, with only 24 patients recruited of the 150 needed; 14 subjects received propofol, 9 barbiturates. The primary endpoint was reached in 43% in the propofol versus 22% in the barbiturates arm ( P  = 0.40). Mortality (43 vs. 34%; P  = 1.00) and return to baseline clinical conditions at 3 months (36 vs. 44%; P  = 1.00) were similar. While infections and arterial hypotension did not differ between groups, barbiturate use was associated with a significantly longer mechanical ventilation ( P  = 0.03). A non-fatal propofol infusion syndrome was detected in one patient, while one subject died of bowel ischemia after barbiturates. Discussion Although undersampled, this trial shows significantly longer mechanical ventilation with barbiturates and the occurrence of severe treatment-related complications in both arms. We describe practical issues necessary for the success of future studies needed to improve the current unsatisfactory state of evidence.

Increases in antimicrobial resistance are creating challenges for the treatment of gonorrhea. Zoliflodacin is a new antimicrobial agent that inhibits DNA biosynthesis. In this phase 2 trial, zoliflodacin is shown to have activity against uncomplicated urogenital gonorrhea.

Development of new treatments for gonorrhoea is a global public health priority. We aimed to evaluate the efficacy and safety of zoliflodacin versus ceftriaxone plus azithromycin in patients with uncomplicated urogenital gonorrhoea. In this phase 3, multinational, randomised, controlled, open-label, non-inferiority clinical trial, participants aged 12 years and older with clinical suspicion of uncomplicated urogenital gonorrhoea were eligible for inclusion. The trial was done in 17 outpatient clinics in Belgium, the Netherlands, South Africa, Thailand, and the USA. Participating countries with high disease prevalence were identified for participation in the study. Sites selected for participation were led by principal investigators with research experience, who were knowledgeable in HIV or sexually transmitted infections and treatment. Feasibility questionnaires and prestudy visits assessed sexually transmitted infection case management guidelines, clinical services, and resources (ie, facility, staff, proposed composition of the study team, standard sexually transmitted infection services offered at the site, assessment of laboratory capacity, research experience and ethical review of clinical trials). Eligible participants were randomly assigned (2:1) to receive a single dose of zoliflodacin 3 g (oral) or ceftriaxone 500 mg (intramuscular) plus azithromycin 1 g (oral). Treatment assignment was known to the participants and their treating clinicians; however, microbiology laboratory staff were masked and the sponsor's central study team were masked until after database lock. The primary endpoint was the proportion of patients with microbiological cure (eradication of Neisseria gonorrhoeae, determined by urethral or endocervical culture) at test of cure (TOC; day 6 ± 2) in the microbiological intention-to-treat population. The primary efficacy analysis declared non-inferiority if the upper bound of the two-sided 95% CI for the treatment difference (comparator minus zoliflodacin) fell below the 12% non-inferiority margin. The trial is registered with ClinicalTrials.gov, NCT03959527, and EudraCT, 2019-000990-22. Between Nov 6, 2019, and March 16, 2023, 1011 patients were screened. 81 patients did not meet screening criteria and 930 participants were randomly assigned to zoliflodacin (n=621) or comparator (n=309). The mean participant age was 29·7 years (SD 9·4). 815 (88%) of 930 participants were assigned male at birth and 115 (12%) participants were assigned female at birth. 514 (55%) of 930 participants were Black or African American, 285 (31%) were Asian, and 113 (12%) were White. Microbiological cure rates at TOC in the microbiological intention-to-treat (urogenital) population (primary efficacy endpoint) were 460 (90·9%, 95% CI 88·1–93·3) of 506 participants for zoliflodacin and 229 (96·2%, 92·9–98·3) of 238 participants for comparator. The estimated difference between groups was 5·3% (95% CI 1·4–8·6) and the upper confidence interval limit was within the prespecified non-inferiority margin of less than 12%. Zoliflodacin was generally well tolerated and adverse events were similar between treatment groups. The most frequently reported treatment-emergent adverse events included headache (61 [10%] of 619 patients), neutropenia (42 [7%]), and leukopenia (24 [4%]) in the zoliflodacin group and injection site pain (38 [12%] of 308 patients), neutropenia (24 [8%]), and diarrhoea (22 [7%]) in the comparator group. The majority of adverse events were mild or moderate in severity. No serious adverse events were reported. Zoliflodacin was non-inferior to ceftriaxone plus azithromycin for the treatment of uncomplicated urogenital gonorrhoea and had a similar safety profile. These data suggest a potential role for zoliflodacin as an effective oral treatment option for uncomplicated urogenital gonorrhoea. German Federal Ministry of Research, Technology and Space, UK Department of Health and Social Care as part of the Global Antimicrobial Resistance Innovation Fund, Japan Ministry of Health, Labour and Welfare, Netherlands Ministry of Health, Welfare and Sport and Directorate-General for International Cooperation, Switzerland Federal Office of Public Health, and the Canton of Geneva, Switzerland.

•Trend data from DFSA cohort studies is reported for the first time.•Why certain compounds are detected in the DFSA cases is explored in detail.•The mechanism of action of drugs associated with DFSA is reported.•Attempt is made to identify compounds more likely to be used in predatory DFSA.•A critical multifactorial review of compounds detected in DFSA cases is included. Drug-facilitated sexual assault (DFSA) is a sexual act in which the victim is unable to give or rescind consent due to intoxication with alcohol and/or drugs that have been self-administered (opportunistic DFSA) or covertly administered by the perpetrator (predatory DFSA). The drugs that are most commonly associated with DFSA are flunitrazepam and gamma-hydroxybutyric acid (GHB). They cause sedation and amnesia, are readily dissolved in beverages and are rapidly eliminated from the system. However, drugs such as amphetamine and cocaine, which are central nervous system (CNS) stimulants, have also been encountered in DFSA cases. This paper critically evaluates trend data from cohort studies, identifying drugs that have been detected in DFSA cases and reports on the differences in drugs used between opportunistic and predatory DFSA. This is the first time that a critical multifactorial review of drugs used in DFSA has been conducted. The pharmacology of each identified group of drugs is presented, showing why these compounds are of interest and used in the perpetration of DFSA. Furthermore, the pharmacology and mechanisms of action are described to explain how the drugs cause their effects. It is also apparent from this study that if meaningful data is to be exchanged between law enforcement agencies then it is necessary to agree on protocols for the collection of evidence and the drugs for which analysis should be performed and indeed on the analytical methods used.

Hypoxia‐inducible factor prolyl hydroxylase (HIF‐PH) inhibitors are a new class of agents for the treatment of anemia in chronic kidney disease (CKD). Unlike traditional treatments such as erythropoiesis‐stimulating agents (ESAs), HIF‐PH inhibitors are orally administered drugs and may increase endogenous erythropoietin and improve iron homeostasis. However, a significant concern is their possible side effect on blood pressure. The current mini‐review summarizes the data of 26 randomized controlled (placebo or ESAs) trials on six different HIF‐PH inhibitors with regard to their potential influence on blood pressure and hypertension in the management of anemia in CKD. Overall, the use of HIF‐PH inhibitors was associated with a higher risk of hypertension than placebo (pooled risk ratio 1.36, 95% confidence interval [CI] 1.16–1.59), but a lower risk of hypertension than ESA treatment (pooled risk ratio 0.92, 95% CI 0.86–0.98), especially in CKD patients not undergoing dialysis (pooled risk ratio 0.85, 95% CI 0.73–0.98). This review highlights the importance of blood pressure monitoring during the treatment of HIF‐PH inhibitors, especially out‐of‐office blood pressure measurement.

Background Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor currently being investigated as a treatment for anemia of chronic kidney disease (CKD) in both dialysis and nondialysis patients. In clinical studies to date, daprodustat has been administered orally as a once-daily regimen. This randomized, double-blind, placebo-controlled study characterized the initial dose-hemoglobin response as well as the efficacy and safety of three times weekly (TIW) daprodustat in hemodialysis patients switched from stable recombinant human erythropoietin (rhEPO), in accordance with a TIW hemodialysis schedule. Methods 103 patients on hemodialysis with baseline hemoglobin of 9.0 to 11.5 g/dL and previously receiving a stable dose of rhEPO or its analogs were randomized 1:1:1:1:1 to receive daprodustat 10, 15, 25, or 30 mg or placebo TIW over 29 days. Results Mean baseline hemoglobin was 10.6 g/dL for the placebo group and each daprodustat cohort. Daprodustat produced dose-dependent changes in mean hemoglobin from baseline to day 29. Using a Bayesian approach, the estimated dose conversion ratio between once-daily and TIW daprodustat was ~ 2.0 across the evaluated dose range using an E max model. Daprodustat was generally well tolerated, with an adverse event (AE) profile consistent with the hemodialysis population. Conclusions These data help inform the appropriate dose conversion ratio to be applied to daily doses to obtain equivalent daprodustat TIW doses and suggest TIW treatment with daprodustat can treat anemia of CKD safely, supporting future long-term studies for this indication using a TIW dosing regimen. Trial registration ClinicalTrials.gov Identifier: NCT02689206 ; date registered: 02/11/2016.

The guidelines for management of traumatic brain injury (TBI) recommend that high-dose barbiturate therapy may be considered to lower intracranial pressure (ICP) that is refractory to other therapeutic options. Lower doses of barbiturates may be used for sedation of patients with TBI, although there is no mention of this in the published guidelines. The goal of this study was to analyze the use of barbiturates in patients with severe TBI in the European centers where the International Neurotrauma Research Organization introduced guideline-based TBI management and to analyze the effects of barbiturates on ICP, use of vasopressors, and short- and long-term outcome of these patients. Data on 1172 patients with severe TBI were collected in 13 centers located in five European countries. Patients were categorized into three groups based on doses of barbiturates administered during treatment. Univariate and multivariate statistical methods were used to analyze the effects of barbiturates on the outcome of patients. Fewer than 20% of all patients with severe TBI were given barbiturates overall, and only 6% was given high doses. High-dose barbiturate treatment caused a decrease in ICP in 69% of patients but also caused hemodynamic instability leading to longer periods of mean arterial pressure <70 mm Hg despite increased use of high doses of vasopressors. The adjusted analysis showed no significant effect on outcome on any stage after injury.Thiopental and methohexital were equally effective. Low doses of thiopental and methohexital were used for sedation of patients without side effects. Phenobarbital was probably used for prophylaxis of post-traumatic seizures.