Efficacy of daprodustat for patients on dialysis with anemia: systematic review and network meta-analysis.

Chronic kidney disease (CKD) is commonly complicated by anemia. Treating dialysis-dependent patients with anemia, including daprodustat and other inhibitors of prolyl hydroxylase of hypoxia-inducible factor, recombinant human erythropoietin (rhEPO), and iron supplements. We conducted this study to test our postulation; daprodustat is superior to rhEPO and other conventional treatments respecting efficacy and safety parameters. We made systematic search through PubMed, Web of Science, Scopus, and Cochrane. Seven unique trials were eventually included for systematic review; six of them with a sample size of 759 patients entered our network meta-analysis (NMA). Daprodustat 25-30 mg was associated with the greatest change in serum hemoglobin (MD=1.86, 95%CI= [1.20; 2.52]), ferritin (MD= -180.84, 95%CI= [-264.47; -97.20]), and total iron binding capacity (TIBC) (MD=11.03, 95%CI= [3.15; 18.92]) from baseline values. Dialysis-dependent patients with anemia had a significant increment in serum Hemoglobin and TIBC and a reduction in serum ferritin, in a dose-dependent manner, when administered daprodustat.

When All Else Fails: Alternative Methods of Euthanasia.

Barbiturate overdose as a method of euthanasia is becoming unacceptable. This has made alternative methods of euthanasia very important. Gunshot or captive bolt euthanasia is among methods that are acceptable, but they may not be esthetically acceptable. This has led to the use of other methods of euthanasia. Inducing anesthesia prior to euthanasia offers an easier method of control. Adjunctive techniques using intravenous potassium or magnesium salts administered intravenously and intracardiac administration of potassium chloride or intrathecal lidocaine offer alternatives that work well and are more environmentally safer than barbiturates. Pithing and exsanguination are also environmentally safer but may not be as esthetically acceptable as the other methods.

Influence of strain, age, origin, and anesthesia on the cardioprotective efficacy by local and remote ischemic conditioning in an ex vivo rat model.

BACKGROUND: Local ischemic preconditioning (IPC) and remote ischemic conditioning (RIC) induced by brief periods of ischemia and reperfusion protect against ischemia-reperfusion injury. METHODS: We studied the sensitivity to IR-injury and the influence of strain, age, supplier, and anesthesia upon the efficacy of IPC and RIC in 7- and 16-weeks-old Sprague-Dawley and Wistar rats from three different suppliers. The influence of sedation with a hypnorm and midazolam mixture (rodent mixture) and pentobarbiturate was compared. RESULTS: IPC attenuated infarct size in both 7-weeks-old Sprague-Dawley (48.4 ± 17.7% vs. 20.3 ± 6.9, p < 0.001) and 7-weeks-old Wistar (55.6 ± 10.9% vs. 26.8 ± 5.0%, p < 0.001) rats. Infarct size was larger in 16-weeks-old Sprague-Dawley rats, however, IPC still lowered infarct size (78.8 ± 9.2% vs. 58.3 ± 12.3%, p < 0.01). RIC reduced infarct sizes in 7-weeks-old Sprague-Dawley (75.3 ± 11.8% vs. 58.6 ± 8.9%, p < 0.05), but not in 7-weeks-old Wistar rats (31.7 ± 17.6% and 24.0 ± 12.6%, p = 0.2). In 16-weeks-old Sprague-Dawley rats, RIC did not induce protection (76.4 ± 5.5% and 73.2 ± 14.7%, p = 0.6). However, RIC induced protection in 16-weeks-old Wistar rats (45.2 ± 8.5% vs. 14.7 ± 10.8%, p < 0.001). RIC did not reduce infarct size in 7-weeks-old Sprague-Dawley rats from Charles River (62.0 ± 13.5% and 69.4 ± 10.4% p = 0.3) or 16-weeks-old Wistar rats from Janvier (50.7 ± 11.3 and 49.2 ± 16.2, p = 0.8). There was no difference between sedation with rodent mixture or pentobarbiturate. CONCLUSION: The cardioprotective effect of IPC is consistent across rat strains independent of age, strain, and supplier. RIC seems to be less reproducible, but still yields protection across different rat strains. However, age, animal supplier, and anesthetics may modulate the sensitivity of IR-injury and the response to RIC.

Temporal effects of barbiturate coma on intracranial pressure and compensatory reserve in children with traumatic brain injury.

BACKGROUND: The aim was to study the effects of barbiturate coma treatment (BCT) on intracranial pressure (ICP) and intracranial compensatory reserve (RAP index) in children (< 17 years of age) with traumatic brain injury (TBI) and refractory intracranial hypertension (RICH). METHODS: High-resolution monitoring data were used to study the effects of BCT on ICP, mean arterial pressure (MAP), cerebral perfusion pressure (CPP), and RAP index. Four half hour long periods were studied: before bolus injection and at 5, 10, and 24 hours thereafter, respectively, and a fifth tapering period with S-thiopental between < 100 and < 30 µmol/L. S-thiopental concentrations and administered doses were registered. RESULTS: Seventeen children treated with BCT 2007-2017 with high-resolution data were included; median age 15 (range 6-17) and median Glasgow coma score 7 (range 3-8). Median time from trauma to start of BCT was 44.5 h (range 2.5-197.5) and from start to stop 99.0 h (range 21.0-329.0). Median ICP was 22 (IQR 20-25) in the half hour period before onset of BCT and 16 (IQR 11-20) in the half hour period 5 h later (p = 0.011). The corresponding figures for CPP were 65 (IQR 62-71) and 63 (57-71) (p > 0.05). The RAP index was in the half hour period before onset of BCT 0.6 (IQR 0.1-0.7), in the half hour period 5 h later 0.3 (IQR 0.1-0.7) (p = 0.331), and in the whole BCT period 0.3 (IQR 0.2-0.4) (p = 0.004). Eighty-two percent (14/17) had favorable outcome (good recovery = 8 patients and moderate disability = 6 patients). CONCLUSION: BCT significantly reduced ICP and RAP index with preserved CPP. BCT should be considered in case of RICH.

Possible Role of High-Dose Barbiturates and Early Administration of Parenteral Ketogenic Diet for Reducing Development of Chronic Epilepsy in Febrile Infection-Related Epilepsy Syndrome: A Case Report.

We describe the efficacy of high-dose barbiturates and early administration of a parenteral ketogenic diet (KD) as initial treatments for acute status epilepticus (SE) in an 8-year-old girl with febrile infection-related epilepsy syndrome (FIRES). The patient was admitted to our hospital with refractory focal SE. Abundant epileptic discharges over the left frontal region were observed on electroencephalogram (EEG). Treatment with continuous infusion of thiamylal for 4 hours, increased incrementally to 40 mg/kg/h, successfully ended the clinical SE, and induced a burst-suppression coma. The infusion rate was then gradually decreased to 4 mg/kg/h over the next 12 hours. Parenteral KD was administered from days 6 to 21 of illness. Continuous infusion of thiamylal was switched to midazolam on day 10 without causing seizures or EEG exacerbations. The patient has remained seizure free in the 15 months since hospital discharge. The effectiveness of KD for the treatment of FIRES has attracted attention amongst clinicians, but KD treatment may need to last for 2 to 4 days before it can stop SE, a time period that could cause irreversible brain damage. Considering the severity of SE in our patient and the dose of barbiturates needed to treat it, we consider this case to have had a good clinical outcome. The results suggest that rapid termination of seizure using high-dose barbiturates in conjunction with early administration of parenteral KD could reduce the development of chronic epilepsy in patients with FIRES.

Treatment with a New Barbituric Acid Derivative Exerts Antiproliferative and Antimigratory Effects against Sorafenib Resistance in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common cause of cancer death worldwide. Sorafenib, a multikinase inhibitor, is the first-line drug approved by the Food and Drug Administration (FDA) for the treatment of patients with advanced HCC. However, most patients who continuously receive sorafenib may acquire resistance to this drug. Therefore, it is important to develop a new compound to treat liver cancer and sorafenib-resistant liver cancer. Barbituric acid derivatives have been used as antiasthmatic drugs in the clinic. We previously reported that a novel barbituric acid derivative inhibited carbon tetrachloride-induced liver fibrosis in mice, but its effects on liver cancer remain unknown. Thus, the purpose of this study was to investigate the antitumor effect of barbituric acid derivatives on HCC cells and sorafenib-resistant HCC cells (HCC-SRs). Our findings reveal that one of the barbituric acid derivatives, BA-5, significantly inhibited HCC and HCC-SR cell viability in a dose- and time-dependent manner. Therefore, compound BA-5 was selected for further experiments. Western blot data revealed that BA-5 treatment decreased the phosphorylation of AKT/p70s6k without affecting the MAPK pathway and increased cleaved PARP and cleaved caspase-7 in both HCC and HCC-SR cells. Since epithelial-mesenchymal transition plays a significant role in regulating cancer invasion and migration, we used the wound healing assay to evaluate the antimigratory effect of compound BA-5. The results showed that BA-5 treatment inhibited HCC and HCC-SR cell migration and reduced Vimentin protein expression. These results were confirmed by microarray analysis showing that BA-5 treatment influenced cancer cell motility and growth-related pathways. In the xenograft mouse model experiment, BA-5 administration significantly inhibited HCC cancer cell growth in mice. Furthermore, the combination of BA-5 with a low dose of regorafenib synergistically inhibited HCC-SR cell proliferation. In conclusion, our study showed that the barbituric acid derivative BA-5 is a new candidate for HCC and sorafenib-resistant HCC therapy.

A Single-Dose, Open-Label, Randomized, Two-Way Crossover Study in Healthy Japanese Participants to Evaluate the Bioequivalence and the Food Effect on the Pharmacokinetics of Daprodustat.

Daprodustat is a prolyl hydroxylase inhibitor that stimulates erythropoiesis in a manner similar to the natural response to hypoxia, whereby inhibition of hypoxia inducible factor (HIF) prolyl-4-hydroxylases by daprodustat ultimately results in increased levels of HIF-responsive genes. Daprodustat is under development as an emerging new class of agents for the treatment of anemia associated with chronic kidney disease (CKD). This was a single-center, single-dose, open-label, randomized, 2-way crossover study in healthy Japanese male participants consisting of 2 parts. The primary objective was to evaluate the bioequivalence (BE) between daprodustat tablet strengths (part 1) and to evaluate the food effect on the pharmacokinetics (PK) of daprodustat (part 2). A total of 64 healthy Japanese male participants were enrolled; 52 participants were included in part 1 and 12 in part 2. BE was demonstrated between the daprodustat 2-mg tablet and the daprodustat 4-mg tablet. A standard CKD meal did not have a large effect on the PK parameters of daprodustat after a single oral dose of daprodustat 4 mg. Administration of single oral doses of daprodustat 4 mg was generally well tolerated in the healthy Japanese participants, and no new safety signals were identified without regard to food.

Management Strategies for Intracranial Pressure Crises in Subarachnoid Hemorrhage.

Objectives: Standard management strategies for lowering intracranial pressure (ICP) in traumatic brain injury has been well-studied, but the use of lesser known interventions for ICP in subarachnoid hemorrhage (SAH) remains elusive. Searches were performed in PubMed and EBSCO Host to identify best available evidence for evaluation and management of medically refractory ICP in SAH. The role of standard management strategies such as head elevation, hyperventilation, mannitol and hypertonic saline as well as lesser known management such as sodium bicarbonate, indomethacin, tromethamine, decompressive craniectomy, decompressive laparotomy, hypothermia, and barbiturate coma are reviewed. We also included dose concentrations, dose frequency, infusion volume, and infusion rate for these lesser known strategies. Nonetheless, there is still a gap in the evidence to recommend optimal dosing, timing and its role in the improvement of outcomes but early diagnosis and appropriate management reduce adverse outcomes.

A randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysis.

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 Emax 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.

Weaning from antiseizure drugs after new onset status epilepticus.

OBJECTIVE: In patients with status epilepticus (SE) without prior epilepsy, there are limited data on the safety of discontinuing antiseizure drugs (ASDs) after seizure control. We aimed to describe seizure recurrence when weaning from ASDs following new onset SE (NOSE). METHODS: Retrospective review of adult patients with NOSE admitted to Mayo Clinic, Rochester, Minnesota between January 1, 1990 and December 31, 2015 was performed. Weaning was defined as a discontinuation of ASDs following discharge. Patient demographics, SE characteristics, timing of ASD withdrawal, and seizure recurrence were collected. RESULTS: One hundred seventy-seven patients with mean age 63 ± 18 years were identified; 96 (54.2%) patients had refractory SE (RSE), and 81 (45.8%) had nonrefractory SE. Mean follow-up was 3.8 ± 3.2 years for those successfully weaned off ASDs. One hundred thirty (73.4%) with outpatient follow-up were included in the analysis; 128 (98.5%) patients were discharged on an ASD; 44 of 128 (34.4%) patients underwent weaning from at least 1 ASD following discharge, including 27 of 128 (21.1%) who were completely weaned off of all ASDs. Younger patients (P = 0.009) and those with RSE (P = 0.048, odds ratio = 2.12, 95% confidence interval = 1.00-4.48) tended to undergo weaning. Six of 44 (13.6%) patients had seizure recurrence when weaned off of any ASD, and two of 27 (7.4%) patients completely weaned off all ASDs had seizure recurrence. Two of seven (28.6%) patients who underwent attempted barbiturate weaning experienced seizure recurrence. SIGNIFICANCE: We found a rate of 13.6% for late seizure recurrence after weaning from at least one ASD in patients with NOSE; seizure recurrence was more likely in patients with RSE treated with barbiturates. Systematic collection of longitudinal data in patients requiring multiple ASDs for NOSE control will provide more conclusive guidance on weaning from ASDs.

Barbiturate-induced dyskalaemia in patients with traumatic brain injury patient.

A young man with severe traumatic brain injury and refractory intracranial hypertension was treated with a barbiturate coma. A rare side effect of barbiturates is dyskalaemia. The dyskalaemia presented with acute hypokalaemia that quickly became hyperkalaemia. Both electrolyte disturbances can have serious physiological complications. The cellular cause of the dyskalaemia is not well understood. The correct diagnosis and treatment of barbiturate dyskalaemia is essential in providing care. Clinicians treating patients with barbiturates need to be aware of this rare side effect. Our patient was quickly and correctly treated for the dyskalaemia and suffered no complications related to this side effect.

Early prediction of neurological outcome after barbiturate coma therapy in patients undergoing brain tumor surgery.

After a difficult brain tumor surgery, refractory intracranial hypertension (RICH) may occur due to residual tumor or post-operative complications such as hemorrhage, infarction, and aggravated brain edema. We investigated which predictors are associated with prognosis when using barbiturate coma therapy (BCT) as a second-tier therapy to control RICH after brain tumor surgery. The study included adult patients who underwent BCT after brain tumor surgery between January 2010 and December 2016. The primary outcome was neurological status upon hospital discharge, which was assessed using the Glasgow Outcome Scale (GOS). In the study period, 4,296 patients underwent brain tumor surgery in total. Of these patients, BCT was performed in 73 patients (1.7%). Among these 73 patients, 56 (76.7%) survived to discharge and 25 (34.2%) showed favorable neurological outcomes (GOS scores of 4 and 5). Invasive monitoring of intracranial pressure (ICP) was performed in 60 (82.2%) patients, and revealed that the maximal ICP within 6 h after BCT was significantly lower in patients with favorable neurological outcome as well as in survivors (p = 0.008 and p = 0.028, respectively). Uncontrolled RICH (ICP ≥ 22 mm Hg within 6 h of BCT) was an important predictor of mortality after BCT (adjusted hazard ratio 12.91, 95% confidence interval [CI] 2.788-59.749), and in particular, ICP ≥ 15 mm Hg within 6 h of BCT was associated with poor neurological outcome (adjusted odds ratio 9.36, 95% CI 1.664-52.614). Therefore, early-controlled ICP after BCT was associated with clinical prognosis. There were no significant differences in the complications associated with BCT between the two neurological outcome groups. No BCT-induced death was observed. The active and timely control of RICH may be beneficial for clinical outcomes in patients with RICH after brain tumor surgery.

Management of Pediatric Severe Traumatic Brain Injury: 2019 Consensus and Guidelines-Based Algorithm for First and Second Tier Therapies.

OBJECTIVES: To produce a treatment algorithm for the ICU management of infants, children, and adolescents with severe traumatic brain injury. DATA SOURCES: Studies included in the 2019 Guidelines for the Management of Pediatric Severe Traumatic Brain Injury (Glasgow Coma Scale score ≤ 8), consensus when evidence was insufficient to formulate a fully evidence-based approach, and selected protocols from included studies. DATA SYNTHESIS: Baseline care germane to all pediatric patients with severe traumatic brain injury along with two tiers of therapy were formulated. An approach to emergent management of the crisis scenario of cerebral herniation was also included. The first tier of therapy focuses on three therapeutic targets, namely preventing and/or treating intracranial hypertension, optimizing cerebral perfusion pressure, and optimizing partial pressure of brain tissue oxygen (when monitored). The second tier of therapy focuses on decompressive craniectomy surgery, barbiturate infusion, late application of hypothermia, induced hyperventilation, and hyperosmolar therapies. CONCLUSIONS: This article provides an algorithm of clinical practice for the bedside practitioner based on the available evidence, treatment protocols described in the articles included in the 2019 guidelines, and consensus that reflects a logical approach to mitigate intracranial hypertension, optimize cerebral perfusion, and improve outcomes in the setting of pediatric severe traumatic brain injury.

Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: Update of the Brain Trauma Foundation Guidelines, Executive Summary.

OBJECTIVES: The purpose of this work is to identify and synthesize research produced since the second edition of these Guidelines was published and incorporate new results into revised evidence-based recommendations for the treatment of severe traumatic brain injury in pediatric patients. METHODS AND MAIN RESULTS: This document provides an overview of our process, lists the new research added, and includes the revised recommendations. Recommendations are only provided when there is supporting evidence. This update includes 22 recommendations, nine are new or revised from previous editions. New recommendations on neuroimaging, hyperosmolar therapy, analgesics and sedatives, seizure prophylaxis, temperature control/hypothermia, and nutrition are provided. None are level I, three are level II, and 19 are level III. The Clinical Investigators responsible for these Guidelines also created a companion algorithm that supplements the recommendations with expert consensus where evidence is not available and organizes possible interventions into first and second tier utilization. The purpose of publishing the algorithm as a separate document is to provide guidance for clinicians while maintaining a clear distinction between what is evidence based and what is consensus based. This approach allows, and is intended to encourage, continued creativity in treatment and research where evidence is lacking. Additionally, it allows for the use of the evidence-based recommendations as the foundation for other pathways, protocols, or algorithms specific to different organizations or environments. The complete guideline document and supplemental appendices are available electronically from this journal. These documents contain summaries and evaluations of all the studies considered, including those from prior editions, and more detailed information on our methodology. CONCLUSIONS: New level II and level III evidence-based recommendations and an algorithm provide additional guidance for the development of local protocols to treat pediatric patients with severe traumatic brain injury. Our intention is to identify and institute a sustainable process to update these Guidelines as new evidence becomes available.

Assessing evidence-based medicine and opioid/barbiturate as first-line acute treatment of pediatric migraine and primary headache: A retrospective observational study of health systems data.

OBJECTIVES: To evaluate providers' use and predictors of evidence-based medicine or opioid/barbiturate as first-line acute treatment for children's initial presentation of acute migraine or primary headache. METHODS: This retrospective, observational study utilized patient (children ages 6-17) and provider/encounter characteristics extracted from the patient's Electronic Health Record from 2008-2014 during an initial encounter for migraine or primary headache. The primary outcome was provider evidence-based medicine utilization; overall prescriptions and opioid/barbiturate prescriptions were also evaluated. Hierarchical linear modeling examined whether Level 1 (patient: Demographic, insurance type) and Level 2 (provider/encounter: Treatment setting/location, encounter diagnoses) characteristics influenced outcomes. RESULTS: In all, 38,926 patients (56.7% female, mean age = 12.1) and 1617 providers were evaluated. Only 17.7% of patients were diagnosed with migraine; 16.1% received evidence-based medicine. Older children (OR = 1.07, p < 0.001), females (OR = 1.14, p < 0.001), and those diagnosed with migraine (OR = 4.71, p < 0.001) were more likely to receive evidence-based medicine. Among prescriptions, 15.8% were for opioids/barbiturates. Older children (OR = 1.14, p < 0.001) and those cared for in the emergency department/urgent care (OR = 2.02, p < 0.001) were at increased risk. CONCLUSIONS: Demographics and migraine diagnosis are associated with evidence-based medicine and opioid/barbiturates. Primary care provides an opportunity to target provider interventions to enhance effective pediatric headache treatment.

Randomized Phase I Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Topical Daprodustat in Healthy Volunteers and in Patients With Diabetic Foot Ulcers.

Daprodustat, a small-molecule inhibitor of prolyl hydroxylases, prevents breakdown of hypoxia-inducible factor (HIF), leading to increased transcription of HIF-responsive genes. This randomized, placebo-controlled study evaluated the safety, tolerability, and pharmacokinetics of a topical formulation of daprodustat in healthy volunteers (intact skin) and in patients with diabetic foot ulcers (DFUs) following single and/or 14-day repeat-dose administration. In the diabetic patients, exploratory assessments of wound area, volume, and depth were made to qualitatively assess effectiveness. Systemic absorption via topical application was limited across doses up to 1.0% at 100 mg/cm2 for 14 days. Systemic pharmacokinetics were quantifiable in a few samples from a few patients. Because only sporadic concentrations were observed versus pharmacokinetic profiles, pharmacokinetic parameters were not determined. Wound area, depth, and volume showed consistent but weak improvements in the treatment arm; however, the variability in response and small sample size of the standard-of-care and placebo arms limited the ability to assess trends in wound healing compared with the daprodustat arm. Overall, topically applied daprodustat was well tolerated, raised no safety concerns, and provided limited to nonquantifiable systemic exposures. The healing of DFUs will need to be evaluated in studies designed to test this hypothesis over a longer treatment duration.

Single-Dose Zoliflodacin (ETX0914) for Treatment of Urogenital Gonorrhea.

BACKGROUND: Antibiotic-resistant Neisseria gonorrhoeae has prompted the development of new therapies. Zoliflodacin is a new antibiotic that inhibits DNA biosynthesis. In this multicenter, phase 2 trial, zoliflodacin was evaluated for the treatment of uncomplicated gonorrhea. METHODS: We randomly assigned eligible men and women who had signs or symptoms of uncomplicated urogenital gonorrhea or untreated urogenital gonorrhea or who had had sexual contact in the preceding 14 days with a person who had gonorrhea to receive a single oral dose of zoliflodacin (2 g or 3 g) or a single 500-mg intramuscular dose of ceftriaxone in a ratio of approximately 70:70:40. A test of cure occurred within 6±2 days after treatment, followed by a safety visit 31±2 days after treatment. The primary efficacy outcome measure was the proportion of urogenital microbiologic cure in the microbiologic intention-to-treat (micro-ITT) population. RESULTS: From November 2014 through December 2015, a total of 179 participants (167 men and 12 women) were enrolled. Among the 141 participants in the micro-ITT population who could be evaluated, microbiologic cure at urogenital sites was documented in 55 of 57 (96%) who received 2 g of zoliflodacin, 54 of 56 (96%) who received 3 g of zoliflodacin, and 28 of 28 (100%) who received ceftriaxone. All rectal infections were cured in all 5 participants who received 2 g of zoliflodacin and all 7 who received 3 g, and in all 3 participants in the group that received ceftriaxone. Pharyngeal infections were cured in 4 of 8 participants (50%), 9 of 11 participants (82%), and 4 of 4 participants (100%) in the groups that received 2 g of zoliflodacin, 3 g of zoliflodacin, and ceftriaxone, respectively. A total of 84 adverse events were reported: 24 in the group that received 2 g of zoliflodacin, 37 in the group that received 3 g of zoliflodacin, and 23 in the group that received ceftriaxone. According to investigators, a total of 21 adverse events were thought to be related to zoliflodacin, and most such events were gastrointestinal. CONCLUSIONS: The majority of uncomplicated urogenital and rectal gonococcal infections were successfully treated with oral zoliflodacin, but this agent was less efficacious in the treatment of pharyngeal infections. (Funded by the National Institutes of Health and Entasis Therapeutics; ClinicalTrials.gov number, NCT02257918 .).

A multifactorial critical appraisal of substances found in drug facilitated sexual assault cases.

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.

The drug interaction potential of daprodustat when coadministered with pioglitazone, rosuvastatin, or trimethoprim in healthy subjects.

This study was conducted to evaluate the likelihood of daprodustat to act as a perpetrator in drug-drug interactions (DDI) with the CYP2C8 enzyme and OATP1B1 transporter using the probe substrates pioglitazone and rosuvastatin as potential victims, respectively. Additionally, this study assessed the effect of a weak CYP2C8 inhibitor, trimethoprim, as a perpetrator of a DDI with daprodustat. This was a two-part study: Part A assessed the effect of coadministration of daprodustat on the pharmacokinetics of pioglitazone and rosuvastatin in 20 subjects; Part B assessed the coadministration of trimethoprim on the pharmacokinetics of daprodustat in 20 subjects. Coadministration of 100 mg of daprodustat with pioglitazone or rosuvastatin had no effect on the plasma exposures of either probe substrate. When trimethoprim was coadministered with 25-mg daprodustat plasma daprodustat AUC and Cmax increased by 48% and 28%, respectively. Additionally, AUC and Cmax for the metabolite GSK2531401 were decreased by 32% and 40%, respectively. Cmax for the other metabolites was slightly decreased (~8-15%) but no changes in AUC were observed. As 100-mg daprodustat exceeds the planned top therapeutic dose, interaction potential of daprodustat as a perpetrator with substrates of the CYP2C8 enzyme and OATP1B1 transporters is very low. Conversely, daprodustat exposure (AUC and Cmax) is likely to increase moderately with coadministration of weak CYP2C8 inhibitors.

Does the doctrine of double effect apply to the prescription of barbiturates? Syme vs the Medical Board of Australia.

The doctrine of double effect (DDE) is a principle of crucial importance in law and medicine. In medicine, the principle is generally accepted to apply in cases where the treatment necessary to relieve pain and physical suffering runs the risk of hastening the patient's death. More controversially, it has also been used as a justification for withdrawal of treatment from living individuals and physician-assisted suicide. In this paper, I will critique the findings of the controversial Victorian Civil and Administrative Tribunal (VCAT) hearing Syme vs the Medical Board of Australia In that hearing, Dr Rodney Syme, a urologist and euthanasia advocate, was defending his practice of prescribing barbiturates to terminally ill patients. Syme claimed that he prescribed the drugs with the intention of relieving their existential suffering and not to assist in suicide; he argued that the DDE could be applied. Pace VCAT, I argue that this is an illegitimate application of DDE. I argue that a close scrutiny of Syme's actions reveals that, at the very least, he intended to give patients the option of suicide. He furthermore used what on a traditional definition of DDE would be considered a 'bad' means-the prescription of Nembutal-to achieve a 'good' end-the relief of suffering. The case demonstrates the crucial importance of analysing an agent's 'intention' and the 'effects' of their actions when applying DDE. Ethicists and, indeed, the judiciary need to attend to the ethical complexities of DDE when they assess the applicability of DDE to end of life care. If they fail to do this, the doctrine risks losing its legitimacy as an ethical principle.