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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.

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.

Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA A ) receptors to dampen neuronal activity in the brain 1 – 5 . However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABA A receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABA A receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain. Cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetics and benzodiazepines reveal both common and distinct transmembrane binding sites, and show that the mechanisms of action of anaesthetics partially overlap with those of benzodiazepines.

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.

In this randomized trial involving patients with traumatic brain injury and elevated intracranial pressure, therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone. In Europe, traumatic brain injury is the most common cause of permanent disability in people younger than 40 years of age, with the annual cost exceeding €33 billion (approximately $37.5 billion in U.S. dollars). 1 , 2 Recent statistics show a 21% increase in the incidence of traumatic brain injury during the past 5 years — three times greater than the increase in population. Despite this, management of traumatic brain injury has been underrepresented in medical research as compared with other health problems. 3 Consequently, there are few data to support the commonly used stage 2 interventions (Figure 1) for the management of . . .

Background and Objective Daprodustat is a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) approved in the USA for treatment of anemia owing to chronic kidney disease (CKD) in dialysis-dependent adults and in Japan for treatment of CKD in dialysis- and non-dialysis dependent adults. This analysis characterized the population pharmacokinetics (PopPK) of daprodustat in adults with CKD and evaluated the influence of intrinsic and extrinsic factors. Methods This PopPK analysis included data from one phase 2B and four phase 3 studies comprising 707 CKD subjects dose titrated to prespecified target hemoglobin levels with daprodustat doses ranging from 1 to 24 mg once daily and 2 to 48 mg given three times a week (TIW). Model development leveraged a previous phase 1/2 PopPK model. Stepwise covariate analysis included 20 extrinsic and intrinsic factors. Model evaluation used standard goodness-of-fit and visual predictive checks. Results Daprodustat PopPK was adequately characterized using a three-compartment distribution model with first-order elimination. The absorption phase was described using five transit compartments. Oral clearance and volume of distribution was 24.6 L/h and 26.9 L, respectively. Body weight dependence (with fixed allometric coefficients) of clearance and volume terms was a statistically significant covariate. Concomitant use of clopidogrel (moderate CYP2C8 inhibitor) decreased oral clearance, resulting in higher area under the plasma concentration-time curve (AUC) ratio of 1.59 (90% CI: 1.39–1.82), subjects’ dialysis status (non-dialysis versus dialysis) had an effect on absorption, with C max ratio of 1.19 (90% CI: 1.09–1.30). None of the other investigated intrinsic or extrinsic covariates, including concomitant administration with phosphate binders, oral iron and acid reducing agents resulted in a significant change in daprodustat systemic exposure. Conclusion The PopPK of daprodustat in the CKD population with anemia was adequately characterized. Allometrically-scaled body weight on clearance and volume, dialysis status on absorption and clopidogrel on clearance were statistically significant covariates.

General anesthesia induced by etomidate, barbiturates and propofol is associated with positive modulation of synaptic αβγ GABAA receptors, inhibitory hetero-pentameric ligand-gated ion channels formed from homologous subunits arranged β-α-β-α-γ around a central gated chloride channel. Approaches based on mutations, amino-acid level analysis of photolabel incorporation, and cryo-electron micrography (cryo-EM) all indicate that etomidate binds selectively in two outer transmembrane β+/α- inter-subunit sites per receptor. These approaches also reveal that the potent barbiturate photolabel R-mTFD-MPAB binds selectively in homologous sites formed at α+/β- and γ+/β- interfaces. The anesthetic photolabel, pTFD-di-iPr-BnOH, was proposed to bind selectively in α+/β- and α+/γ- homologs of the etomidate sites, based largely on functional analysis of only 5 point mutations in α1β3γ2L receptors. To further test the interactions of receptor-bound pTFD-di-iPr-BnOH with outer transmembrane inter-subunit sites, we used voltage-clamp electrophysiology in substituted cysteine modification and protection (SCAMP) experiments at 8 residues located in the five homologous sites, focusing on α+ and γ- loci. Control SCAMP studies were performed using etomidate and R-mTFD-MPAB. Incorporation of single cysteine mutations (α1M236C, α1S280C, α1A291C, β3L231C, β3M286C, γ2I242C, γ2L246C, and γ2S301C) produced functional GABA-responsive receptors that retained sensitivity to pTFD-di-iPr-BnOH modulation and displayed increased GABA sensitivity following exposure to the covalent sulfhydryl modifier p-chloromercuribenzenesulfonate (pCMBS). In the presence of pTFD-di-iPr-BnOH, pCMBS modification effects were reduced (evidence of steric protection) in receptors with cysteine mutations in α+ , β-, and γ-, but not in α-, β+ , or γ+ interfacial loci. Protection patterns with etomidate and R-mTFD-MPAB mirrored prior results. SCAMP results further support the hypothesis that pTFD-di-iPr-BnOH binds selectively in α+/β- and α+/γ- interfacial sites that are homologs of the β+/α- etomidate sites.

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.

Some series of arylidene barbiturates and thiobarbiturates were evaluated for their antibacterial, antioxidant, and urease inhibition activities. The arylidene barbiturates and thiobarbiturates were tested for antimicrobial activity using the agar well diffusion technique against 13 bacteria. The synthesized compounds (1a–g) were screened for antiurease and antioxidant activities. The results showed that the synthesized compounds (1a–g) had effective antiurease, antioxidant, and antibacterial activities.

In continuation of our efforts to identify novel herbicide lead compounds, twenty new 5-(1-amino-4-phenoxybutylidene)barbituric acid derivatives containing an enamino diketone motif were synthesized and evaluated for their herbicidal activities. The greenhouse bioassay results indicated that several of the target compounds, including BA-1, BA-2, BA-5, BA-18, and BA-20, exhibited notable post-emergence herbicidal activity, with sum inhibition rates exceeding 70% at a dosage of 150 g ha−1, which was superior to that of the commercial herbicide flumiclorac-pentyl (FP). The structure–activity relationship analysis demonstrated that the steric and electronic effects of the R group, as well as the lipophilicity of the target compounds, significantly influenced herbicidal activity. Among these, BA-1 was identified as a promising herbicide lead compound due to its high total herbicidal efficacy, broad-spectrum activity, and favorable crop safety profile. Molecular simulation studies indicated that BA-1 binds effectively to Nicotiana tabacum protoporphyrinogen IX oxidase (NtPPO), suggesting its potential as a novel PPO inhibitor. This study highlights BA-1 as a promising lead compound for the development of novel PPO-inhibiting herbicides.