Hypoxia-inducible factor prolyl hydroxylase inhibitors stabilize levels of hypoxia-inducible factor that upregulate transcription of multiple genes associated with the response to hypoxia, including production of erythropoietin. We conducted two phase 2a studies to explore the relationship between the dose of the hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 and hemoglobin response in patients with anemia of CKD (baseline hemoglobin 8.5-11.0 g/dl) not undergoing dialysis and not receiving recombinant human erythropoietin (nondialysis study) and in patients with anemia of CKD (baseline hemoglobin 9.5-12.0 g/dl) on hemodialysis and being treated with stable doses of recombinant human erythropoietin (hemodialysis study). Participants were randomized 1:1:1:1 to a once-daily oral dose of GSK1278863 (0.5 mg, 2 mg, or 5 mg) or control (placebo for the nondialysis study; continuing on recombinant human erythropoietin for the hemodialysis study) for 4 weeks, with a 2-week follow-up. In the nondialysis study, GSK1278863 produced dosedependent effects on hemoglobin, with the highest dose resulting in a mean increase of 1 g/dl at week 4. In the hemodialysis study, treatment with GSK1278863 in the 5-mg arm maintained mean hemoglobin concentrations after the switch from recombinant human erythropoietin, whereas mean hemoglobin decreased in the lower-dose arms. In both studies, the effects on hemoglobin occurred with elevations in endogenous erythropoietin within the range usually observed in the respective populations and markedly lower than those in the recombinant human erythropoietin control arm in the hemodialysis study, and without clinically significant elevations in plasma vascular endothelial growth factor concentrations. GSK1278863 was generally safe and well tolerated at the doses and duration studied. GSK1278863 may prove an effective alternative for managing anemia of CKD. 27: 123427: -124427: , 201627: . doi: 10.1681 Advanced CKD is frequently associated with anemia 1,2 and its pathogenesis is multifactorial, inclusive of a relative deficiency of erythropoietin (EPO) and impaired absorption and utilization of iron. 3 Current guidelines and recommendations for anemia management in CKD advise treatment with supplemental iron and recombinant human erythropoietins (rhEPOs) if appropriate. rhEPO therapy led to a correction of hemoglobin levels in the majority of dialysis patients 12 and a reduction in the need for red blood cell transfusions. 12 However, several large randomized trials of rhEPO have reported adverse cardiovascular outcomes. The Normal Hematocrit Study, which aimed to normalize hematocrit at 42% versus maintaining it at 30%, was terminated early because of concerns from the independent data monitoring committee around the higher all-cause mortality rate in the normal hematocrit arm compared with the low hematocrit arm, even though the prespecified termination criterion of an overall 5% significance was not met. The Correction of Hemoglobin and Outcomes in Renal Insufficien...

No abstract

BackgroundThis study evaluated the hemoglobin dose response, other efficacy measures and safety of daprodustat, an orally administered, hypoxia-inducible factor prolyl hydroxylase inhibitor in development for anemia of chronic kidney disease.MethodsParticipants (n = 216) with baseline hemoglobin levels of 9–11.5 g/dL on hemodialysis (HD) previously receiving stable doses of recombinant human erythropoietin (rhEPO) were randomized in a 24-week dose-range, efficacy and safety study. Participants discontinued rhEPO and then were randomized to receive daily daprodustat (4, 6, 8, 10 or 12 mg) or control (placebo for 4 weeks then open-label rhEPO as required). After 4 weeks, doses were titrated to achieve a hemoglobin target of 10–11.5 g/dL. The primary outcome was characterization of the dose–response relationship between daprodustat and hemoglobin at 4 weeks; additionally, the efficacy and safety of daprodustat were assessed over 24 weeks.ResultsOver the first 4 weeks, the mean hemoglobin change from baseline increased dose-dependently from −0.29  (daprodustat 4 mg) to 0.69 g/dL (daprodustat 10 and 12 mg). The mean change from baseline hemoglobin (10.4 g/dL) at 24 weeks was 0.03 and −0.11 g/dL for the combined daprodustat and control groups, respectively. The median maximum observed plasma EPO levels in the control group were ∼14-fold higher than in the combined daprodustat group. Daprodustat demonstrated an adverse event profile consistent with the HD population.ConclusionsDaprodustat produced dose-dependent changes in hemoglobin over the first 4 weeks after switching from a stable dose of rhEPO as well as maintained hemoglobin target levels over 24 weeks.

No abstract

The incidence of dog, cat and human bites has been increasing steadily and represents an important cause of morbidity and mortality in the United States. Approximately half of all Americans will suffer a bite wound during their lifetime, and the annual medical costs of managing these injuries has been estimated to be over $100 million. Possible complications may include disfigurement, dismemberment and infection. Effective management requires rapid medical evaluation and may necessitate surgical intervention and prophylactic antibiotic therapy. As bite wounds are microbiologically diverse and most often polymicrobial in nature, selection of an appropriate antibiotic regimen requires knowledge of common pathogens. Close clinical follow‐up is recommended to minimize the risk of late complications.

BackgroundThis study assessed the short-term safety and efficacy of daprodustat (an oral hypoxia-inducible factor-prolyl hydroxylase inhibitor) to achieve a target hemoglobin in patients with anemia of chronic kidney disease (CKD).MethodsPatients (n = 252) with Stages 3–5 CKD not receiving dialysis were enrolled in this 24-week, multicenter trial [hemoglobin entry criteria: 8–10 g/dL (Cohort 1) or 8–11 g/dL (Cohort 2) for recombinant human erythropoietin (rhEPO)-naïve participants; 9–10.5 g/dL (Cohort 1) or 9–11.5 g/dL (Cohort 2) for rhEPO users]. rhEPO-naïve participants were randomized 3:1 to daprodustat (1, 2 or 4 mg) or control (rhEPO per standard of care). rhEPO users were randomized 1:1 to daprodustat 2 mg or control. Study medication was titrated to maintain hemoglobin 9–10.5 g/dL (Cohort 1) or 10–11.5 g/dL (Cohort 2). Hemoglobin, iron metabolism markers and safety parameters were measured every 4 weeks.ResultsMean hemoglobin levels at Week 24 were 10.2 g/dL (Cohort 1) and 10.9 g/dL (Cohort 2) in the daprodustat group and 10.7 g/dL (Cohort 1) and 11.0 g/dL (Cohort 2) in the control group. Participants had hemoglobin levels within the target range a median of 82% and 66% of the time between Weeks 12 and 24 in the daprodustat and control groups, respectively. The adverse event profile was consistent with clinical events in the CKD population.ConclusionsDaprodustat effectively maintained target hemoglobin over 24 weeks in CKD patients with anemia who were rhEPO naïve or had switched from existing rhEPO therapy.

Key Points Question Is daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, an effective oral alternative to darbepoetin alfa in the treatment of anemia of chronic kidney disease (CKD) in incident dialysis (ID) patients? Findings In this randomized clinical trial of 312 ID patients, daprodustat was noninferior to darbepoetin alfa in treating anemia of CKD; the difference in mean hemoglobin concentration between study arms during the evaluation period was 10.5 g/dL for patients receiving daprodustat and 10.6 g/dL for patients receiving darbepoetin alfa. Meaning The study results suggest that daprodustat represents an oral alternative treatment to a conventional erythropoiesis-stimulating agent in the ID population.

Gender-based differences in cytochrome P450 (CYP) activity may occur due to endogenous hormonal fluctuations with the menstrual cycle, which are altered by oral contraceptives. This study assessed the average activity and within-subject variability in CYP3A4 and CYP2D6 in men, women taking Triphasil, and regularly menstruating women not receiving oral contraceptives. Thirty-three healthy volunteers participated in this 28-day pilot study (12 women receiving Triphasil) (OCs), 11 regularly menstruating women not on exogenous progesterone or estrogen (no OCs), and 10 men. CYP3A4 and CYP2D6 activities were phenotyped with dextromethorphan (DM) on study days 7, 14, 21, and 28 using urinary ratios of DM:3-methoxymorphinan (3MM) and DM:dextrorphan (DX), respectively. Serial blood concentrations of estrogen and progesterone and menstrual diaries were used to determine menstrual phase in both groups of women. Average urinary DM:3MM and DM:DX in the 28 extensive metabolizers of CYP2D6 did not differ between the three study populations (p = 0.86 and 0.93, respectively). Post hoc power analysis indicated that more than 1000 subjects would be needed for 80% power (alpha = 0.05) to detect a +/- 15% difference from the population mean in the urinary ratios of dextromethorphan and its metabolites 3MM and DX. Variability in CYP3A4 and CYP2D6 activity, characterized by intrasubject standard deviation, also did not differ. The varying doses of levonorgesterol and ethinyl estradiol in Triphasil, fluctuations in estrogen and progesterone, and menstrual phase did not influence CYP3A4 or CYP2D6 activity. It was concluded that CYP3A4 and CYP2D6 activity and intrasubject variability were not different in the three study populations, and thus a clinically important difference between men, women on Triphasil, and women not receiving oral contraceptives is unlikely. High inter- and intrasubject variability in DM:3MM and DM:DX were clearly demonstrated and limit the use of dextromethorphan to phenotype endogenous CYP3A4 and CYP2D6 activity.