First evidence of the incorporation of daprodustat and other hypoxia-inducible factor stabilizers into equine hair by passive transfer based on segmental quantitative analysis.

Daprodustat is a hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) inhibitor and is used as an erythropoiesis stimulant for the treatment of anemia in humans. In general, administering daprodustat to horses will result in a lifetime ban from both equestrian sports and horseracing by the International Federation of Horseracing Authorities and the Fédération Équestre Internationale, respectively. To control the misuse/abuse of daprodustat, we conducted nasoesophageal administration of daprodustat (100 mg/day for 3 days) to three thoroughbred mares and the post-administration hair samples collected from the three horses over 6 months were analyzed to demonstrate the potential longer-term detection of daprodustat and its metabolites in hair compared with the detection times of daprodustat of 1 and 2 weeks in plasma and urine respectively. The results of the quantitative 2-cm segmental analysis showed that daprodustat was primarily localized in the proximal region (0-2 cm) at 0.375-0.463 pg/mg at 1 month post-administration. These drug bands were gradually spread out along the hair shaft at a rate consistent with the reported growth rate of horse mane hair (approximately 2.5 cm/month) over the following 6 months. In addition, to attain deeper insight into the mechanism of drug incorporation into hair, a total of 11 relevant parameters, including the actual PK parameters and simulated physicochemical and biopharmaceutical parameters for three HIF stabilizers (i.e., daprodustat, vadadustat, and IOX4), were investigated after normalization of the z-scores of all these parameters. Multiple regression analysis indicated that the major factors contributing to the incorporation of the three drugs into hair were their maximum plasma concentrations and lipophilicities, strongly suggesting that the three HIF stabilizers permeated from the bloodstream into the hair bulb via passive transfer with concentration gradients. This work is the first reported evidence showing the incorporation of HIF stabilizers into hair via passive transfer. In addition, cross-species comparison of drug incorporations into hair between daprodustat in horse and roxadustat in human was made in order to have a better understanding of the interactive interpretations about the analysis results obtained from different species. The above findings are not only useful and beneficial for the purpose of doping control but also provide a better understanding of the mechanism of drug incorporation into horse hair.

Current status and outlook for the management of intracranial hypertension after traumatic brain injury: decompressive craniectomy, therapeutic hypothermia, and barbiturates.

INTRODUCTION: Increased intracranial pressure (ICP) has been associated with poor neurological outcomes and increased mortality in patients with severe traumatic brain injury (TBI). Traditionally, ICP-lowering therapies are administered using an escalating approach, with more aggressive options reserved for patients showing no response to first-tier interventions, or with refractory intracranial hypertension. DEVELOPMENT: The therapeutic value and the appropriate timing for the use of rescue treatments for intracranial hypertension have been a subject of constant debate in literature. In this review, we discuss the main management options for refractory intracranial hypertension after severe TBI in adults. We intend to conduct an in-depth revision of the most representative randomised controlled trials on the different rescue treatments, including decompressive craniectomy, therapeutic hypothermia, and barbiturates. We also discuss future perspectives for these management options. CONCLUSIONS: The available evidence appears to show that mortality can be reduced when rescue interventions are used as last-tier therapy; however, this benefit comes at the cost of severe disability. The decision of whether to perform these interventions should always be patient-centred and made on an individual basis. The development and integration of different physiological variables through multimodality monitoring is of the utmost importance to provide more robust prognostic information to patients facing these challenging decisions.

Evaluating the safety and efficacy of daprodustat for anemia of chronic kidney disease: a meta-analysis of randomized clinical trials.

PURPOSE: Anemia of chronic kidney disease (CKD) has traditionally been treated with recombinant human erythropoietin (rhEPO). Recently, daprodustat, a hypoxia-inducible factor prolyl-hydroxylase inhibitor, has also been shown to increase hematocrit. It remains unclear whether daprodustat or rhEPO should be the treatment of choice for anemia of CKD. We aimed to assess the efficacy and cardiovascular safety of daprodustat versus rhEPO in CKD patients. METHODS: Online databases were queried in April 2022 for articles comparing the efficacy and safety of daprodustat in DD-CKD and NDD-CKD subgroups. Results from trials were pooled using a random-effects model. RESULTS: Data on 8245 CKD patients from eight clinical trials were included. Our results show that in comparison to rhEPO, daprodustat maintained the same efficacy in increasing hemoglobin levels in both the DD-CKD (MD: 0.10; 95% CI [- 0.13,0.34]; p = 0.50) and NDD-CKD (MD: - 0.01; 95% CI [- 0.38,0.35]; p = 0.95) subgroups. Daprodustat significantly lowered hepcidin levels and significantly increased TIBC in both subgroups. Additionally, daprodustat significantly reduced the incidence of major adverse cardiovascular events (MACE) (RR: 0.89; 95% CI: 0.89-0.98; p = 0.02) and its myocardial infarction (MI) component (RR: 0.74; 95% CI: 0.59-0.92; p = 0.006) in the DD-CKD subgroup. CONCLUSION: Daprodustat has similar efficacy compared to rhEPO for the treatment of anemia of CKD. On treatment, the reduced experience of MACE was reported in DD-CKD patients as compared to rhEPO. Furthermore, effects on iron metabolism varied by parameter, with daprodustat being superior to rhEPO in some cases and inferior in others.

Early use of barbiturates is associated with increased mortality in traumatic brain injury patients from a propensity score-based analysis of a prospective cohort.

Barbiturates are proposed as a second/third line treatment for intracranial hypertension in traumatic brain injury (TBI) patients, but the literature remains uncertain regarding their benefit/risk balance. We aimed to evaluate the impact of barbiturates therapy in TBI patients with early intracranial hypertension on the intensive care unit (ICU) survival, the occurrence of ventilator-associated pneumonia (VAP), and the patient's functional status at three months. We used the French AtlanREA prospective cohort of trauma patients. Using a propensity score-based methodology (inverse probability of treatment weighting), we compared patients having received barbiturates within the first 24 hours of admission (barbiturates group) and those who did not (control group). We used cause-specific Cox models for ICU survival and risk of VAP, and logistic regression for the 3-month Glasgow Outcome Scale (GOS) evaluation. Among the 1396 patients with severe trauma, 383 had intracranial hypertension on admission and were analyzed. Among them, 96 (25.1%) received barbiturates. The early use of barbiturates was significantly associated with increased ICU mortality (HR = 1.85, 95%CI 1.03-3.33). However, barbiturates treatment was not significantly associated with VAP (HR = 1.02, 95%CI 0.75-1.41) or 3-month GOS (OR = 1.67, 95%CI 0.84-3.33). Regarding the absence of relevant clinical trials, our results suggest that each early prescription of barbiturates requires a careful assessment of the benefit/risk ratio.

Barbiturate-related hospitalisations, drug treatment episodes, and deaths in Australia, 2000-2018.

OBJECTIVES: To determine the characteristics and population rates of barbiturate-related hospitalisations, treatment episodes, and deaths in Australia, 2000-2018. DESIGN, SETTING: Analysis of national data on barbiturate-related hospitalisations (National Hospital Morbidity Database, 1999-2000 to 2017-18), drug treatment episodes (Alcohol and Other Drug Treatment Services National Minimum Data Set, 2002-03 to 2017-18), and deaths (National Coronial Information System, 2000-01 to 2016-17). MAIN OUTCOME MEASURES: Population rates directly age-standardised to the 2001 Australian standard population; average annual percentage change (AAPC) in rates estimated by Joinpoint regression. RESULTS: We identified 1250 barbiturate-related hospitalisations (791 cases of deliberate self-harm [63%]), 993 drug treatment episodes (195 cases with barbiturates as the principal drug of concern [20%]), and 511 deaths during the respective analysis periods. The barbiturate-related hospitalisation rate declined from 0.56 in 1999-2000 to 0.14 per 100 000 population in 2017-18 (AAPC, -6.0%; 95% CI, -7.2% to -4.8%); the declines in hospitalisations related to accidental poisoning (AAPC, -5.8%; 95% CI, -9.1% to -2.4%) and intentional self-harm (AAPC, -5.6%; 95% CI, -6.9% to -4.2%) were each statistically significant. Despite a drop from 0.67 in 2002-03 to 0.23 per 100 000 in 2003-04, the drug treatment episode rate did not decline significantly (AAPC, -6.7%; 95% CI, -16% to +4.0%). The population rate of barbiturate-related deaths increased from 0.07 in 2000-01 to 0.19 per 100 000 population in 2016-17 (AAPC, +9.3%; 95% CI, +6.2-12%); the rate of intentional self-harm deaths increased (AAPC, +11%; 95% CI, +7.4-15%), but not that of accidental deaths (AAPC, -0.3%; 95% CI, -4.1% to +3.8%). CONCLUSIONS: While prescribing and community use of barbiturates has declined, the population rate of intentional self-harm using barbiturates has increased. The major harm associated with these drugs is now suicide.

Acute Intracranial Hypertension During Pregnancy: Special Considerations and Management Adjustments.

Pregnancy is associated with a number of pathophysiological changes (including modification of vascular resistance, increased vascular permeability, and coagulative disorders) that can lead to specific (eclampsia, preeclampsia) or not specific (intracranial hemorrhage) neurological complications. In addition to these disorders, pregnancy can affect numerous preexisting neurologic conditions, including epilepsy, brain tumors, and intracerebral bleeding from cerebral aneurysm or arteriovenous malformations. Intracranial complications related to pregnancy can expose patients to a high risk of intracranial hypertension (IHT). Unfortunately, at present, the therapeutic measures that are generally adopted for the control of elevated intracranial pressure (ICP) in the general population have not been examined in pregnant patients, and their efficacy and safety for the mother and the fetus is still unknown. In addition, no specific guidelines for the application of the staircase approach, including escalating treatments with increasing intensity of level, for the management of IHT exist for this population. Although some of basic measures can be considered safe even in pregnant patients (management of stable hemodynamic and respiratory function, optimization of systemic physiology), some other interventions, such as hyperventilation, osmotic therapy, hypothermia, barbiturates, and decompressive craniectomy, can lead to specific concerns for the safety of both mother and fetus. The aim of this review is to summarize the neurological pathophysiological changes occurring during pregnancy and explore the effects of the possible therapeutic interventions applied to the general population for the management of IHT during pregnancy, taking into consideration ethical and clinical concerns as well as the decision for the timing of treatment and delivery.

Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis.

BACKGROUND: Among patients with chronic kidney disease (CKD), the use of recombinant human erythropoietin and its derivatives for the treatment of anemia has been linked to a possibly increased risk of stroke, myocardial infarction, and other adverse events. Several trials have suggested that hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) are as effective as erythropoiesis-stimulating agents (ESAs) in increasing hemoglobin levels. METHODS: In this randomized, open-label, phase 3 trial, we assigned patients with CKD who were undergoing dialysis and who had a hemoglobin level of 8.0 to 11.5 g per deciliter to receive an oral HIF-PHI (daprodustat) or an injectable ESA (epoetin alfa if they were receiving hemodialysis or darbepoetin alfa if they were receiving peritoneal dialysis). The two primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 (noninferiority margin, -0.75 g per deciliter) and the first occurrence of a major adverse cardiovascular event (a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), with a noninferiority margin of 1.25. RESULTS: A total of 2964 patients underwent randomization. The mean (±SD) baseline hemoglobin level was 10.4±1.0 g per deciliter overall. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.28±0.02 g per deciliter in the daprodustat group and 0.10±0.02 g per deciliter in the ESA group (difference, 0.18 g per deciliter; 95% confidence interval [CI], 0.12 to 0.24), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 2.5 years, a major adverse cardiovascular event occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 (26.7%) in the ESA group (hazard ratio, 0.93; 95% CI, 0.81 to 1.07), which also met the prespecified noninferiority margin for daprodustat. The percentages of patients with other adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD undergoing dialysis, daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-D ClinicalTrials.gov number, NCT02879305.).

Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis.

BACKGROUND: Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesis-stimulating agent darbepoetin alfa, are unknown. METHODS: In this randomized, open-label, phase 3 trial with blinded adjudication of cardiovascular outcomes, we compared daprodustat with darbepoetin alfa for the treatment of anemia in patients with CKD who were not undergoing dialysis. The primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 and the first occurrence of a major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Overall, 3872 patients were randomly assigned to receive daprodustat or darbepoetin alfa. The mean (±SD) baseline hemoglobin levels were similar in the two groups. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g per deciliter in the daprodustat group and 0.66±0.02 g per deciliter in the darbepoetin alfa group (difference, 0.08 g per deciliter; 95% confidence interval [CI], 0.03 to 0.13), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 1.9 years, a first MACE occurred in 378 of 1937 patients (19.5%) in the daprodustat group and in 371 of 1935 patients (19.2%) in the darbepoetin alfa group (hazard ratio, 1.03; 95% CI, 0.89 to 1.19), which met the prespecified noninferiority margin of 1.25. The percentages of patients with adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD and anemia who were not undergoing dialysis, daprodustat was noninferior to darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-ND ClinicalTrials.gov number, NCT02876835.).

Efficacy of a Novel Prophylactic Barbiturate Therapy for Severe Traumatic Brain Injuries: Step-down Infusion of a Barbiturate with Normothermia.

This study aimed to examine the beneficial effects of a novel prophylactic barbiturate therapy, step-down infusion of barbiturates, using thiamylal with normothermia (NOR+sdB), on the poor outcome in the patients with severe traumatic brain injuries (sTBI), in comparison with mild hypothermia (MD-HYPO). From January 2000 to March 2019, 4133 patients with TBI were admitted to our hospital. The inclusion criteria were: a Glasgow coma scale (GCS) score of ≤8 on admission, age between 20 and 80 years, intracranial hematoma requiring surgical evacuation of the hematoma with craniotomy and/or external decompression, and patients who underwent management of body temperature and assessed their outcome at 6-12 months. Finally, 43 patients were included in the MD-HYPO (n = 29) and NOR+sdB (n = 14) groups. sdB was initiated intraoperatively or immediately after the surgical treatment. There were no significant differences in patient characteristics, including age, sex, past medical history, GCS on admission, type of intracranial hematoma, and length of hospitalization between the two groups. Although NOR+sdB could not improve the patient's poor outcome either at discharge from the intensive care unit (ICU) or at 6-12 months after admission, the treatment inhibited composite death at discharge from the ICU. The mean value of the maximum intracranial pressure (ICP) in the NOR+sdB group was <20 mmHg throughout the first 120 h. NOR+sdB prevented composite death in the ICU in patients with sTBI, and we may obtain novel insights into the beneficial role of prophylactic barbiturate therapy from suppression of the elevated ICP during the first 120 h.

Efficacy and safety of daprodustat in Japanese peritoneal dialysis patients.

Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor for the treatment of anemia of chronic kidney disease. This phase 3 study evaluated the efficacy and safety of daprodustat in an uncontrolled cohort of 56 Japanese peritoneal dialysis patients with anemia over 52 weeks. Subjects received daprodustat 4 mg orally once daily for 4 weeks and the dose was subsequently adjusted every 4 weeks. Mean baseline hemoglobin was 10.9 g/dL (95% CI 10.59, 11.12). Mean hemoglobin reached the target range (11.0-13.0 g/dL) at week 12 and was maintained until week 52. Mean hemoglobin during weeks 40-52 was 12.1 g/dL (95% CI 12.0, 12.2). The most frequent adverse events included nasopharyngitis (29%), catheter-site infection (18%), peritonitis (16%), diarrhea (14%), and nausea (11%). No deaths were reported. Once-daily oral daprodustat treatment was generally well tolerated and mean hemoglobin was achieved and maintained within the target range in Japanese peritoneal dialysis participants.

Daprodustat Compared with Epoetin Beta Pegol for Anemia in Japanese Patients Not on Dialysis: A 52-Week Randomized Open-Label Phase 3 Trial.

BACKGROUND: Daprodustat is an oral agent that stimulates erythropoiesis by inhibiting the prolyl hydroxylases which mark hypoxia-inducible factor for degradation through hydroxylation. Its safety and efficacy (noninferiority) were assessed in this 52-week, open-label study. METHODS: Japanese patients not on dialysis (ND) (N = 299) with anemia of CKD (stages G3, G4, and G5) with iron parameters of ferritin >100 ng/mL or transferrin saturation >20% at screening were randomized to daprodustat or epoetin beta pegol (continuous erythropoietin receptor activator [CERA], also known as methoxy polyethylene glycol-epoetin beta). After initiation of the study, the daprodustat starting dose for erythropoiesis-stimulating agent (ESA)-naïve participants was revised, and daprodustat was started at 2 or 4 mg once daily depending on baseline hemoglobin. ESA users switched to daprodustat 4 mg once daily. CERA was started at 25 µg every 2 weeks for ESA-naïve patients and 25-250 µg every 4 weeks for ESA users based on previous ESA dose. In both treatment groups, dose was adjusted every 4 weeks based on hemoglobin level and changed according to a prespecified algorithm. The primary endpoint was mean hemoglobin level during weeks 40-52 in the intention-to-treat (ITT) population. ESA-naïve patients who entered before the protocol amendment revising the daprodustat starting dose were excluded from the ITT population. RESULTS: Mean hemoglobin levels during weeks 40-52 were 12.0 g/dL in the daprodustat group (n = 108; 95% confidence interval [CI], 11.8-12.1) and 11.9 g/dL for CERA (n = 109; 95% CI 11.7-12.0); the difference between the groups was 0.1 g/dL (95% CI -0.1 to 0.3 g/dL). The lower limit of the 95% CI of the difference was greater than the prespecified margin of -1.0 g/dL. The mean hemoglobin level was within the target range (11.0-13.0 g/dL) during weeks 40-52 for 92% of participants in both groups. There was no meaningful difference in the frequencies of adverse events. CONCLUSIONS: Oral daprodustat was noninferior to CERA in achieving and maintaining target hemoglobin levels in Japanese ND patients. Daprodustat was well tolerated, with no new safety concerns identified.

Current treatment practices for anemia in patients with chronic kidney disease and future opportunities with hypoxia-inducible factor prolyl hydroxylase inhibitors: a narrative review.

PURPOSE: To investigate current treatment practices for anemia in patients with chronic kidney disease (CKD), issues surrounding current treatment practices, and the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) that are currently in clinical trials. Treatment of anemia in patients with CKD has traditionally included iron supplementation and erythropoiesis-stimulating agents (ESAs). However, due to adverse cardiovascular (CV) events and hypo-responsiveness to ESA therapy, new agents are currently in clinical trials to treat anemia in patients with CKD. The HIF-PHIs stimulate erythropoiesis and regulate iron metabolism and are attractive alternatives to iron supplementation and ESAs.

Development of a Polo-like Kinase-1 Polo-Box Domain Inhibitor as a Tumor Growth Suppressor in Mice Models.

Polo-like kinase-1 (Plk1) plays a key role in mitosis and has been identified as an attractive anticancer drug target. Plk1 consists of two drug-targeting sites, namely, N-terminal kinase domain (KD) and C-terminal polo-box domain (PBD). As KD-targeting inhibitors are associated with severe side effects, here we report on the pyrazole-based Plk1 PBD inhibitor, KBJK557, which showed a remarkable in vitro anticancer effect by inducing Plk1 delocalization, mitotic arrest, and apoptosis in HeLa cells. Further, in vivo optical imaging analysis and antitumorigenic activities in mouse xenograft models demonstrate that KBJK557 preferentially accumulates in cancer cells and selectively inhibits cancer cell proliferation. Pharmacokinetic profiles and partition coefficients suggest that KBJK557 was exposed in the blood and circulated through the organs with an intermediate level of clearance (t1/2, 7.73 h). The present investigation offers a strategy for specifically targeting cancer using a newly identified small-molecule inhibitor that targets the Plk1 PBD.

Characterization of a Novel Barbituric Acid and Two Thiobarbituric Acid Compounds for Lung Cancer Treatment.

BACKGROUND/AIM: Previously, we reported the identification of a cytotoxic chemotype compound CC-I (1a), a derivative of thiobarbituric acid. We also reported the anticancer activity of a series of novel thio- and seleno-barbituric acid analogs. MATERIALS AND METHODS: We herein evaluated the effect of 1a and its modified compounds on in vitro and in vivo lung cancer models. RESULTS: The compounds 1b and 2a showed more potent cytotoxicity than 1a to lung cancer cells. Moreover, 1b did not have any cytotoxicity on normal cells, such as fibroblasts. In the human lung cancer A549 mouse tumor xenograft model, 1b and 2a showed more pronounced antitumor effects than 1a In the A549 lung cancer cells, 1a induced cell death mainly via JNK and p38 MAPK activation. However, compound 1b and 2a induced lung cancer cell death mostly through JNK activation. CONCLUSION: The results suggest that 1b and 2a can be useful therapeutic agents for lung cancer.

Severe hypokalemia and rebound hyperkalemia during barbiturate coma in patients with severe traumatic brain injury / Hipopotasemia grave e hiperpotasemia de rebote durante el coma terapéutico inducido por barbitúricos en pacientes con lesiones cerebrales traumáticas

OBJECTIVES: To evaluate the incidence of severe potassium disturbances during barbiturate coma therapy in patients with severe traumatic brain injury (TBI), and the characteristics of these patients. METHODS: The study comprised 37 patients with severe TBI who were treated for barbiturate coma between 2015 and 2017 in level 3 intensive care units of two hospitals. RESULTS: No potassium disturbance occurred in 14 patients. Seventeen patients developed mild-moderate hypokalemia (2.6-3.5 mEq/L), and 6 patients developed severe hypokalemia (< 2.5 mEq/L) following the induction of barbiturate therapy. The incidence of mild-to-severe barbiturate-induced hypokalemia was 62.2% and the rate of severe hypokalemia was 16.2%. The mean potassium supply per day during thiopentone therapy was statistically significantly different between patients with mild-to-moderate hypokalemic and those with severe hypokalemic (p < 0.001). Four of 6 patients with severe hypokalemia developed rebound hyperkalemia exceeding 6mEq/L following the cessation of barbiturate infusion. The nadir potassium concentration was 1.5 mEq/L and the highest value was 6.8 mEq/L. The mean time to reach nadir potassium concentrations was 2.8 days. The mortality rate of the 6 patients was 66.7%. Of the 2 survivors of severe hypokalemia, the Glasgow Outcome Scale (GOS) on discharge and the extended GOS one year after the trauma were 5 and 8 respectively. CONCLUSIONS: Severe hypokalemia refractory to medical treatment and rebound hyperkalemia is a serious adverse effect of thiopentone coma therapy in patients with severe TBI. Excessive and aggressive potassium replacement during the barbiturate-induced hypokalemia period must be avoided. Weaning barbiturate treatment over time may be advantageous in the management of severe serum potassium disturbances

OBJETIVOS: Evaluar la incidencia de alteraciones graves de los niveles de potasio durante el coma terapéutico inducido por barbitúricos en pacientes con lesiones cerebrales traumáticas (LCT) graves y las características de estos pacientes. MÉTODOS: El estudio incluyó 37 pacientes con LCT grave que habían sido tratados mediante coma terapéutico inducido por barbitúricos entre 2015 y 2017 en unidades de cuidados intensivos de nivel 3 de dos hospitales. RESULTADOS: En 14 pacientes no se observaron alteraciones de los niveles de potasio. Diecisiete pacientes desarrollaron hipopotasemia leve o moderada (2,6-3,5 mEq/l), y 6 pacientes desarrollaron hipopotasemia grave (< 2,5 mEq/l) después de la inducción de la terapia con barbitúricos. La incidencia de hipopotasemia de leve a grave inducida por barbitúricos fue del 62,2% y la tasa de hipopotasemia grave fue del 16,2%. El aporte medio de potasio al día durante el tratamiento con tiopentona fue diferente de forma estadísticamente significativa entre los pacientes con hipopotasemia leve o moderada y entre los que tenían hipopotasemia grave (p < 0,001). Cuatro de los 6 pacientes con hipopotasemia grave desarrollaron hiperpotasemia de rebote que superó los 6 mEq/l después de la suspensión de la infusión de barbitúricos. La concentración mínima de potasio fue de 1,5 mEq/l y el valor máximo de potasio fue de 6,8 mEq/l. El tiempo medio hasta alcanzar las concentraciones mínimas de potasio fue de 2,8 días. La tasa de mortalidad de los 6 pacientes fue del 66,7%. En los 2 supervivientes con hipopotasemia grave, los resultados de la Escala de Resultados de Glasgow (Glasgow Outcome Scale, GOS) en el alta y la GOS extendida un año después del traumatismo fueron 5 y 8, respectivamente

Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia: A Randomized, Double-Blind, Phase 3 Trial.

BACKGROUND AND OBJECTIVES: Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates genes related to iron metabolism. The efficacy (noninferiority) and safety of daprodustat compared with standard therapy (darbepoetin alfa) was evaluated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a randomized, phase 3, double-blind, active-control study in Japanese patients receiving hemodialysis with anemia of CKD. Participants' treatment was switched from current erythropoiesis-stimulating agents (ESAs) to daprodustat 4 mg once daily or darbepoetin alfa 10-60 µg once weekly (on the basis of the prestudy ESA dose). Dose was adjusted every 4 weeks for daprodustat or every 2 weeks for darbepoetin alfa, according to a protocol-specified algorithm. The primary end point was mean hemoglobin during weeks 40-52 in the intent-to-treat population. RESULTS: Of 332 participants screened, 271 participants were randomized (safety evaluation: 271 participants; efficacy evaluation: 267 intent-to-treat population). The mean hemoglobin during weeks 40-52 were maintained within the target range in both groups (10.9 g/dl [95% confidence interval (95% CI), 10.8 to 11.0] for daprodustat, and 10.8 g/dl [95% CI, 10.7 to 11.0] for darbepoetin alfa). Daprodustat was noninferior to darbepoetin alfa, as the lower bound of the confidence interval for the treatment difference (0.1 g/dl; 95% CI, -0.1 to 0.2 g/dl) was greater than the noninferiority criterion of -1.0 g/dl. For most participants, hemoglobin was maintained within the target range (10.0-12.0 g/dl) during weeks 40-52 (88% daprodustat; 90% darbepoetin alfa). Geometric mean hepcidin levels decreased more at week 52 with daprodustat (-37%; 95% CI, -49 to -23) than with darbepoetin alfa (-20%; 95% CI, -36 to -1), and an increase in total iron-binding capacity was observed in the daprodustat group. Frequency of adverse events were generally similar between daprodustat and darbepoetin alfa. CONCLUSIONS: Oral daprodustat was noninferior to darbepoetin alfa as measured by mean hemoglobin over weeks 40-52 in Japanese patients receiving hemodialysis switched from ESAs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: 201754, Clinicaltrials.gov, NCT02969655.

Long-term prognosis related to deep sedation in refractory status Epilepticus.

OBJECTIVE: To evaluate long-term prognosis in patients with refractory status epilepticus according to the level of sedation reached during drug-induced coma. MATERIALS AND METHODS: Longitudinal study of patients with status epilepticus who received anesthetics to induce therapeutic coma. Demographic data, clinical, and electroencephalographic characteristics were collected, as well as variables related to sedation. We considered as deep sedation the EEG burst-suppression patterns (suppression ratio > 50%). A GOSE (Glasgow Outcome Scale Extended) score of 7 or 8 was considered as good prognosis. A comparative study was carried out to identify predictors of good or poor prognosis at discharge, at 1 and 2 years of follow-up. RESULTS: We included 61 patients: 63.9% were men; mean age 53.5 ± 16.8 years (range 16-86 years), 39.3% reached deep sedation; 62.3% had > 48 h induced coma. The median hospital stay was 21 days, while 10 days in the intensive care unit (ICU). In the multiple regression analysis, an ICU length of stay ≥ 7 days was associated with poor prognosis at discharge and at long-term (P < .05), while deep sedation was associated only with poor long-term prognosis (1 and 2 years, P < .05). The Kaplan-Meier curve showed higher survival in the group that did not undergo deep sedation (P < .05). CONCLUSIONS: In refractory status epilepticus, deep sedation is associated with poor prognosis at long-term.

Characterization of Acute Prescription Migraine Medication Use: Results From the CaMEO Study.

OBJECTIVE: To characterize self-reported use of acute prescription medication for migraine in a sample representing the US population. PATIENTS AND METHODS: Data were obtained from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study. The CaMEO Study is an Internet-based cross-sectional longitudinal survey administered between September 17, 2012, and November 19, 2013. Demographic characteristics, migraine-related disability, symptom severity, quality of life, and psychiatric comorbidity profiles were evaluated. RESULTS: Data from 13,624 respondents were analyzed, including 3121 (22.9%) self-reported current users of acute prescription medication for migraine, 1719 (12.6%) previous/discontinued users, and 8784 (64.5%) who had never used acute prescription medication for migraine. Mean ± SD monthly headache frequency was 7.3±7.1 days for current users, 5.6±6.6 days for those who discontinued, and 3.9±4.9 days for respondents who never used acute prescription medication for migraine. Current users experienced the highest degree of migraine-related disability based on Migraine Disability Assessment scores and the highest levels of migraine symptom severity based on Migraine Symptom Severity Scale scores. Current users also had the highest scores on the depression and anxiety questionnaires. The most commonly reported prescription medications used or "kept on hand" by current users were triptans (47.2%; 1474 of 3121), opioids (37.3%; 1164 of 3121), nonsteroidal anti-inflammatory drugs (31.9%; 997 of 3121), and barbiturates (12.8%; 399 of 3121), with many people reporting more than 1 medication. CONCLUSION: Despite reporting moderate to severe migraine-related disability and impairment, many people with migraine have never used acute prescription migraine medication. The burden related to migraine is great, especially among individuals currently using acute prescription medication for migraine.