Twice-daily Dosing Research Articles

Long-term stability in randomized and non-randomized patients in the phase 3 randomized, double-blind EDGE trial of once- versus twice-daily dosing of eliglustat in patients with Gaucher disease type 1

Long-term stability in randomized and non-randomized patients in the phase 3 randomized, double-blind EDGE trial of once- versus twice-daily dosing of eliglustat in patients with Gaucher disease type 1

Clinical and genomic safety of treatment with Ginkgo biloba L. leaf extract (IDN 5933/Ginkgoselect\xaePlus) in elderly: a randomised placebo-controlled clinical trial [GiBiEx

BackgroundNumerous health benefits have been attributed to the Ginkgo biloba leaf extract (GBLE), one of the most extensively used phytopharmaceutical drugs worldwide. Recently, concerns of the safety of the extract have been raised after a report from US National Toxicology Program (NTP) claimed high doses of GBLE increased liver and thyroid cancer incidence in mice and rats. A safety study has been designed to assess, in a population of elderly residents in nursing homes, clinical and genomic risks associated to GBLE treatment.MethodsGiBiEx is a multicentre randomized clinical trial, placebo controlled, double blinded, which compared subjects randomized to twice-daily doses of either 120-mg of IDN 5933 (also known as Ginkgoselect®Plus) or to placebo for a 6-months period. IDN 5933 is extracted from dried leaves and contains 24.3% flavone glycosides and 6.1% of terpene lactones (2.9% bilobalide, 1.38% ginkgolide A, 0.66% ginkgolide B, 1.12% ginkgolide C) as determined by HPLC. The study was completed by 47 subjects, 20 in the placebo group and 27 in the treatment group. Clinical (adverse clinical effect and liver injury) and genomic (micronucleus frequency, comet assay, c-myc, p53, and ctnnb1 expression profile in lymphocytes) endpoints were assessed at the start and at the end of the study.ResultsNo adverse clinical effects or increase of liver injury markers were reported in the treatment group. The frequency of micronuclei [Mean Ratio (MR) = 1.01, 95% Confidence Intervals (95% CI) 0.86–1.18), and DNA breaks (comet assay) (MR = 0.91; 95% CI 0.58–1.43), did not differ in the two study groups. No significant difference was found in the expression profile of the three genes investigated.ConclusionsNone of the markers investigated revealed a higher risk in the treatment group, supporting the safety of IDN 5933 at doses prescribed and for duration of six months.Trial registrationClinicalTrials.gov Identifier: NCT03004508, December 20, 2016. Trial retrospectively registered.

Gentamicin in Newborn Sepsis: Once Daily Dose versus Twice Daily Dose

Gentamicin is commonly used as first line drug in neonatal sepsis. It is usually used in combination with other drugs. It is a nephrotoxic and an ototoxic drug. Long term use causes renal failure and hearing impairment. Its efficacy depends on the peak concentration, and its toxicity is related to the trough concentration. There is no set protocol of using gentamicin in neonate in Bangladesh, whether it should be used once daily or twice, it is till debatable in this perspective. In daily practice, it is not followed up trough and peak concentration of gentamicin, so it is not known the renal and hearing status of the baby treated with aminoglycosides. In this regard, primary objectives were to measure the peak level (to observe efficacy) and trough (to observe toxicity) level of gentamicin in once-daily dose (ODD) and in twice-daily dose (TDD) of gentamicin in neonates treated for suspected or culture proven sepsis and finally to assess the renal status and hearing status. This was an open label clinical trial, conducted in the Neonatal Intensive Care Unit, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, during the period of March, 2012 to November, 2012. A total of 50 neonates were included in the study, 25 in ODD group and 25 in TDD group of gentamicin. Serum gentamicin peak and trough were measured in both groups. Mean gestational age were 38.85±1.21Wk and 38.83±1.16Wk in ODD and TDD respectively, and their corresponding mean weights were 2341.66±377 gram and 2307±363 gram. Only a fraction (12 % in ODD group 20% in TDD group) of patients had culture positive sepsis. The mean peak concentration of gentamicin was significantly higher (p value < 0.001) among neonates who received once-daily dose (7.19±1.7 microgram/ml) compare to patients who received the twice-daily dose (4.81±1.8 microgram/ml). The mean trough concentration of gentamicin was significantly lower (p value = 0.04) among neonates who received once-daily dose (1.5±0.78) compared to patients who received the twice-daily dose (2.00±0.9). Serum creatinine concentration raise was statistically non-significant in both group. Only 4% in ODD and 8% in TDD had ototoxicity which was non-significant finding. It may be concluded that ODD of gentamicin had significant higher concentration of peak and lower trough concentration, but no significant difference was in serum creatinine concentration and ototoxicity.

Once- versus twice-daily dosing of eliglustat in adults with Gaucher disease type 1: The Phase 3, randomized, double-blind EDGE trial

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) with compatible CYP2D6-metabolizer phenotypes (>90% of patients). The randomized, double-blind EDGE trial (NCT01074944, Sanofi Genzyme) evaluated once-daily eliglustat dosing compared with the approved twice-daily regimen at the same total daily dose in adults with GD1. Subjects received twice-daily dosing during a 6- to 18-month lead-in period. Only subjects who attained prespecified treatment goals for hemoglobin, platelet count, spleen and liver volumes, and bone symptoms during the lead-in period were randomized to once- or twice-daily dosing. Of 170 enrolled patients, 156 completed the lead-in period and 131 met all requirements to enter the double-blind treatment period. To achieve the composite primary endpoint in the double-blind period, patients had to maintain clinical stability relative to baseline on all five endpoints (hemoglobin, platelet count, spleen and liver volumes, and bone symptoms) and meet pharmacokinetic and other tolerability requirements as determined by the investigator after 1year of eliglustat treatment. After 1year, 80.4% (95% CI: 67.6, 89.8) of once-daily patients were stable compared with 83.1% (95% CI: 71.0, 91.6) of twice-daily patients. The 95% CI for the mean difference of −2.7% between groups was −17.7, 11.9. Because the lower bound of the CI exceeded the pre-defined non-inferiority margin of −15%, once-daily dosing could not be declared non-inferior to twice-daily dosing. Both once-daily and twice-daily patients maintained mean values for hematologic and visceral measures within established therapeutic goals during the double-blind treatment and long-term extension periods. Eliglustat was generally well-tolerated during this long-term trial (mean treatment duration: 3.3years), with just four withdrawals (2%) for related adverse events (AE), and similar AE profiles for both dosing regimens. Patients on twice-daily eliglustat showed more stability overall, and this dose regimen was better tolerated, confirming the dosing regimen for most patients specified in the drug label.

Therapeutic monitoring of amikacin regimen-associated toxicity in febrile neutropenic pediatric cancer patients

Background Amikacin is used in the treatment of fever neutropenia (FN) in pediatric cancer patients. However it may be used once or twice daily, so the explanation of which regimen of amikacin (once or twice) is more effective and less toxic and how to detect renal toxicity early may help in a proper treatment of febrile neutropenia. Aim This study aimed to compare between once-daily versus twice-daily regimens of amikacin to know which regimen is most effective and less toxic. Patients and methods Venous blood from 40 pediatric patients with FN receiving 15 mg/kg amikacin intravenously either once a day (group I) or divided into two equal doses (group II) every 12 h by 30 min infusion. Amikacin was measured by means of homogeneous enzyme immunoassay for all patients. Renal function was assessed by measuring serum creatinine before and after the treatment. Results There were higher significant differences between once-daily versus twice-daily regimens of amikacin in the treatment of FN. The peak levels of amikacin were significantly higher in group I than those in group II (P = 0.001) and the duration of fever in group I was less than that in group II. Conclusion Therapeutic drug monitoring of amikacin should be done to detect its renal toxicity early and the administration of amikacin as a single daily dose may be associated with greater efficacy and less nephrotoxicity compared with that of amikacin administered as twice-daily dose.

Once Versus Twice-Daily Oral Proton Pump Inhibitor Therapy for Prevention of Peptic Ulcer Rebleeding: A Propensity Score-Matched Analysis.

BackgroundAfter inpatient management of upper gastrointestinal bleeding (GIB) due to peptic ulcer disease (PUD), oral proton pump inhibitor (PPI) therapy is recommended at discharge to decrease rebleeding risk and improve ulcer healing. Our aim is to determine whether once-daily oral PPI dosing at hospital discharge is associated with inferior 30-day rebleeding outcomes as compared to twice-daily dosing.MethodsWe retrospectively identified 233 patients admitted with signs and symptoms of upper GIB found to be due to PUD on upper endoscopy. After inpatient management, patients discharged on once-daily oral PPI were compared to those discharged on twice-daily therapy. We utilized propensity score matching based on Rockall scores to ensure the two groups were closely matched in terms of their baseline rebleeding risk. Primary outcome was the incidence of rebleeding within 30 days. Secondary outcomes were all-cause mortality, blood transfusion requirement, requirement for interventional radiology or surgery.ResultsOverall, 49 patients were discharged on once-daily and 184 on twice-daily PPI. Recurrent bleeding occurred in 18 patients (7.7%) within 30 days. There was no statistically significant difference in recurrent bleeding rates between once-daily (n = 7, 14.3%) as compared to twice-daily PPI (n = 11, 6%) (P = 0.053). In a 1:1 propensity score matched analysis, there was no statistically significant difference in 30-day recurrent bleeding rate between groups (14% once-daily vs. 4% twice-daily, P = 0.159). There were no differences in secondary outcomes.ConclusionsOnce-daily oral PPI dosing at hospital discharge was not associated with inferior outcomes compared to twice-daily dosing in patients hospitalized for upper GIB due to PUD.

EFFECTS OF ONCE-DAILY VERSUS TWICE DAILY DOSING OF CALCIUM FRUCTOBORATE ON KNEE DISCOMFORT. A 90 DAY, DOUBLE-BLIND, PLACEBO CONTROLLED RANDOMIZED CLINICAL STUDY

Importance: Previous research showed that a twice-daily 108 mg dose of calcium fructoborate (CFB) improved knee discomfort during a 2-week supplementation period. This current double-blind, placebo-controlled randomized study investigates the effects of CFB supplementation on knee discomfort during 90 days of supplementation. Purpose: To evaluate the comparative effects of once-daily and twice-daily dosing of calcium fructoborate on knee joint discomfort for ninety days. Design: 120 participants with self-reported knee discomfort were recruited and randomized into three groups (each N=40). Participants received: 108 mg CFB twice per day (CFB-G1); or, 216 mg CFB in a single dose (CFB-G2); or, placebo. Setting: Subjects were recruited through advertisement in local papers. The researchers assessed intake and within-study levels of knee discomfort by using the McGill Pain Questionnaire (MPQ) and the Western Ontario and McMaster University Arthritis Index (WOMAC). Results: 62 female and 59 male subjects completed the study. Subjects’ average age was (52.84 ± 8.19 years) and average BMI was (26.76 ± 2.50 kg/m2). Statistical differences between groups were calculated using a two-sided, two-sample t-test. Analysis of variance (ANOVA) was used to estimate within-group changes in mean WOMAC and MPQ scores as well as against the control group. When compared to placebo, CFB-G1 showed a significant decrease in reported discomfort on day 14 (P=0.02,) day 30 (P=0.003), day 60 (P<0.0001) and day 90 (P<0.0001) according to WOMAC Scores. A similar decrease was observed for CFB-G2 WOMAC Scores on day 14 (P=0.02), day 30 (P=0.0003), day 60 (P<0.0001) and day 90 (P<0.0001). When compared to placebo, the MPQ score for CFB-G1 group decreased on day 7 (P=0.002), day 14 (P=0.001), day 30 (P<0.0001), day 60 (P<0.0001) and day 90 (P<0.0001). MPQ score decreases were also observed for CFB-G2 group on day 7 (P=0.02), day 14 (P=0.01), day 30 (P<0.0001), day 60 (P<0.0001) and day 90 (P<0.0001). When comparing CFB-G1 and CFB-G2, no significant differences were observed. Importantly, no changes were observed in the WOMAC and MPQ scores within the placebo group. Conclusion: Both CFB groups showed early and significantly improved levels of knee comfort. Knee comfort continued to significantly improve throughout the duration of this 90-day study. No significant differences were observed between the once-daily and the twice–daily doses of CFB.

A Modified Epirubicin and Oxaliplatin Plus Capecitabine (EOX) Regimen as a Second- Line Therapy in Patients with Advanced Gastric Cancer

Objective:We aimed to evaluate the effectiveness of an mEOX (modified epirubicin, oxaliplatin plus capecitabine) regimen as second line therapy after failure of mDCF (modified docetaxel, cisplatin plus fluorouracil).Methods:Gastic cancer patients for whom first-line therapy was unsuccessful and who subsequently received mEOX (epirubicin 50 mg/m2 on day 1, oxaliplatin 85 mg/m² day 1 and capecitabine twice-daily dose of 625 mg/ m2, p.o. for 2 weeks) every 3 weeks until disease progression or unacceptable toxicity, were retrospectively analyzed.Results:The study population comprised 129 cases with a median age of 55 years (range= 27-78), the majority being male (76 %). Most (75.2%) had ≥ 2 sites of metastasis. The median number of chemotherapy courses was five (range= 2–9). Forty-nine achieved a partial response and 33 showed stable disease, resulting in a ORR (overall response rate) of 38% and a DCR (disease control rate) of 63.6%. The most frequent features of grade 3-4 hematological and non-hematological toxicity were neutropenia (8.5%) and nausea/vomiting (5.4%). None of the patients suffered death due to toxicity. The median PFS was 4.7 months (95% CI, 4.1–5.3) and the OS was 7.4 months (95% CI, 6.3–8.5). On multivariate analysis, age ≥ 60 years and ECOG performance status (0-1) were independent prognostic factors affecting PFS and OS.Conslusions:In advanced gastric cancer patients, who progress after first line chemotherapy and have an ECOG performance status of 0-1, mEOX is a well tolerated triple regimen associated with a promising OS and PFS.

Abstract B126: AG-881, a brain penetrant, potent, pan-mutant IDH (mIDH) inhibitor for use in mIDH solid and hematologic malignancies

Abstract AG-881 is an orally available, brain penetrant, potent, small-molecule inhibitor of isocitrate dehydrogenase (IDH) 1 and IDH2 mutant proteins. Small-molecule inhibition of the mutant IDH (mIDH) protein represents a targeted approach to cancer treatment for patients who harbor an IDH1 and/or an IDH2 mutation. Direct inhibition of the gain-of-function activity of the mIDH protein is intended to inhibit the production of the oncogenic metabolite D-2-hydroxyglutarate (2-HG) and induce tumor cell differentiation. Biochemical studies of AG-881 demonstrate that it has low nanomolar potency inhibition (IC50) against multiple mIDH homodimer and heterodimer enzymes. It is a rapid-equilibrium inhibitor of mIDH1-R132H and mIDH2-R172K homodimer enzymes and is a slow-binding inhibitor of mIDH2-R140Q homodimer and wild type (wt) IDH1/mIDH1-R132H, wtIDH2/mIDH2-R140Q, and wtIDH2/mIDH2-R172K heterodimers. The potency against mIDH1 and mIDH2 enzymes has also been shown in cell lines and primary human patient samples. The IC50 range for 2-HG inhibition by AG-881 was 0.04-22 nM in cells expressing mIDH1-R132C, mIDH1-R132G, mIDH1-R132H, or mIDH1-R132S mutations and was 7-14 nM and 130 nM in cells expressing mIDH2-R140Q and mIDH2-R172K mutations, respectively. The treatment of these mIDH cell lines or primary human acute myeloid leukemia samples with AG-881 led to the onset of cellular differentiation. The pharmacokinetics of AG-881 are characterized by rapid oral absorption and low total body plasma clearance in mice (0.406 L/hr/kg) and rats (0.289 L/hr/kg). Because of these favorable properties, a series of in vivo pharmacology studies were conducted with AG-881 in mouse xenograft models. In these studies, dose-response relationships for the reduction in 2-HG in tumor by AG-881 were established. Twice-daily dosing of AG-881 in the HT1080 (mIDH1-R132C) and U87 (mIDH2-R140Q) mouse models reduced tumor 2-HG levels by >96% at doses ≥30 mg/kg. In the orthotopic glioma model (mIDH1-R132H), brain tumor 2-HG levels were reduced by >97% at doses ≥0.1 mg/kg. Based on in vivo exposure-response analyses, plasma AG-881 AUC0-24hr values of 402 hr•ng/mL and 45,200 hr•ng/mL are projected to result in sustained 97% reduction in tumor 2-HG levels in the glioma indication and the non-glioma solid and liquid tumor indications, respectively. AG-881 also exhibits excellent brain penetration, with brain-to-plasma ratios ranging from 0.62 to 1.96 in mice and 1.11 to 1.48 in rats (based on AUC0-24hr), and has an acceptable preclinical safety profile that supports clinical testing. Taken together, these data show that AG-881 is a potent inhibitor of the mIDH1 and mIDH2 proteins and suppresses 2-HG production in enzymatic, cell-based, and in vivo systems. Pharmacology studies support that suppression of 2-HG levels by AG-881 results in alterations of cellular downstream markers, leading to a release from blockage of tumor cell differentiation. AG-881 is currently in phase 1 clinical development in patients with an IDH1 and/or IDH2-mutation who have advanced solid tumors including gliomas (ClinicalTrials.gov NCT02481154), and advanced hematologic malignancies (ClinicalTrials.gov NCT02492737). Citation Format: Katharine Yen, Zenon Konteatis, Zhihua Sui, Erin Artin, Lenny Dang, Kimberly Straley, Erica Tobin, Carl Campos, Hua Yang, Raj Nagaraja, Yue Chen, Hyeryun Kim, Camelia Gliser, Brandon Nicolay, Andrew Olaharski, Lee Silverman, Scott Biller, Shinsan M. Su, Ingo Mellinghoff, Janeta Popovici-Muller. AG-881, a brain penetrant, potent, pan-mutant IDH (mIDH) inhibitor for use in mIDH solid and hematologic malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B126.

Risk factors contributing to a low darunavir plasma concentration.

Darunavir is an efficacious drug; however, pharmacokinetic variability has been reported. The objective of this study was to find predisposing factors for low darunavir plasma concentrations in patients starting the once‐ or twice‐daily dosage. Darunavir plasma concentrations from January 2010 till December 2014 of human immunodeficiency virus‐infected individuals treated in the outpatient clinic of the University Medical Center Groningen were retrospectively reviewed. The first darunavir plasma concentration of patients within 8 weeks after initiation of darunavir therapy was selected. A dichotomous logistic regression analysis was conducted to select the set of variables best predicting a darunavir concentration below median population pharmacokinetic curve. In total 113 patients were included. The variables best predicting a darunavir concentration besides food intake included age together with estimated glomerular filtration rate (Hosmer–Lemeshow test P = 0.945, Nagelkerke R 2 = 0.284). Systematic evaluation of therapeutic drug monitoring results may help to identify patients at risk for low drug exposure.

Influence of corticosterone treatment on nestling begging in Florida scrub-jays (Aphelocoma coerulescens)

Altricial young are dependent on adults for protection and food, and they display nutritional need by begging to elicit feeding from parents. Begging at high levels can be energetically expensive and attract predators; thus, an individual must balance its nutritional needs with these potential costs. Further, because a parent is limited in the amount of food it can provide, begging can contribute to both parent-offspring conflict and sibling-sibling competition. Many extrinsic and intrinsic factors may contribute to begging behavior. One intrinsic factor of interest is corticosterone (CORT), a metabolic hormone hypothesized to play a role in regulating a nestling’s begging behavior. We investigated the hypothesis that increased exposure to CORT influences nestling begging behavior in an altricial species, the Florida scrub-jay (Aphelocoma coerulescens). We treated one nestling per treatment nest with a twice-daily dose of exogenous hormone via a CORT-injected waxworm, whereas a second individual received a vehicle-injected waxworm. We monitored individual nestling and adult behavior at all nests with the use of high-definition video cameras on several days during treatment. We found no difference in begging rate between CORT fed and vehicle fed nestlings within a treatment nest. Further, to determine whether CORT treatment had indirect effects on the entire brood, we monitored additional nests, in which nestlings were not manipulated. When treatment and controls were compared, overall begging rates of nestlings in treatment nests were greater than those in control nests. This result suggests that CORT treatment of an individual altered its behavior, as well as that of its siblings.

Rifaximin Fails to Prevent Campylobacteriosis in the Human Challenge Model: A Randomized, Double-Blind, Placebo-Controlled Trial.

Campylobacter species are a leading cause of diarrheal disease globally with significant morbidity. Primary prevention efforts have yielded limited results. Rifaximin chemoprophylaxis decreases rates of travelers' diarrhea and may be suitable for high-risk persons. We assessed the efficacy of rifaximin in the controlled human infection model for Campylobacter jejuni. Twenty-eight subjects were admitted to an inpatient facility and randomized to a twice-daily dose of 550 mg rifaximin or placebo. The following day, subjects ingested 1.7 × 105 colony-forming units of C. jejuni strain CG8421. Subjects continued prophylaxis for 3 additional days, were followed for campylobacteriosis for 144 hours, and were subsequently treated with azithromycin and ciprofloxacin. Samples were collected to assess immunologic responses to CG8421. There was no difference (P = 1.0) in the frequency of campylobacteriosis in those receiving rifaximin (86.7%) or placebo (84.6%). Additionally, there were no differences in the clinical signs and symptoms of C. jejuni infection to include abdominal pain/cramps (P = 1.0), nausea (P = 1.0), vomiting (P = .2), or fever (P = 1.0) across study groups. Immune responses to the CG8421 strain were comparable across treatment groups. Rifaximin did not prevent campylobacteriosis in this controlled human infection model. Given the morbidity associated with Campylobacter infection, primary prevention efforts remain a significant need. NCT02280044.

Darunavir for use in pregnant women with HIV

ABSTRACTIntroduction: Combination antiretroviral therapy is recommended during pregnancy to decrease the rate of HIV transmission to the baby and reduce morbidity in the mother. More than 50% of women are prescribed a protease inhibitor-based regimen during pregnancy. Darunavir was recently reclassified as a first-line protease inhibitor for use in pregnancy in the US Department of Health and Human Services Perinatal Guidelines.Areas covered: This is a brief review of the use of protease inhibitor therapy during pregnancy, and a discussion of darunavir’s utility in this area. Clinical pharmacology and trial data are reviewed, and the safety, efficacy and dosing of darunavir during pregnancy is discussed.Expert commentary: Darunavir has become an important option in the management of HIV during pregnancy. Both once-daily dosing and twice-daily dosing regimens have shown efficacy in clinical studies. Although a significant reduction in total (protein bound and unbound) plasma concentrations of darunavir has been noted during pregnancy, antiviral activity appears to be maintained with standard dosing. This is likely due to diminished changes in unbound drug concentrations. Preterm delivery and low birth weight have been noted for pregnancies of women on darunavir-containg regimens, but a causal relationship has not yet been demonstrated.

Randomized, Placebo-controlled Crossover Study of Dalfampridine Extended-release in Transverse Myelitis.

BackgroundDalfampridine has the potential to be effective in patients with transverse myelitis (TM) as this rare disorder shares some clinical and pathogenic similarities with multiple sclerosis.MethodsThis is a randomized, double-blind, placebo-controlled crossover study of dalfampridine extended-release (D-ER, Ampyra®). Sixteen adult study participants with monophasic TM confirmed by MRI were enrolled if their baseline timed 25-foot walking speed was between 5 and 60 seconds. Participants were randomized to receive 10 mg twice-daily doses of either D-ER or placebo control for eight weeks, then crossed over to the second arm of placebo or dalfampridine for eight weeks. The primary outcome measure was the timed 25-foot walk.ResultsOf 16 enrolled participants, three withdrew and 13 completed the trial. Among the 13 completers, nine individuals showed an average timed walk that was faster in the D-ER arm compared to the placebo arm, but only four participants met the stricter statistical threshold to be classified as a responder. Analyses of secondary clinical outcome measures including strength, balance assessments, spasticity, and Expanded Disability Status Scale (EDSS) score showed trends toward improvement with D-ER.ConclusionsD-ER may be beneficial in TM to improve walking speed and other neurological functions.

Gastrointestinal Involvement in Systemic Sclerosis: An Update.

Gastrointestinal Involvement in Systemic Sclerosis: An Update.

Safety, tolerability and pharmacokinetics of 21 day multiple oral administration of a new oxazolidinone antibiotic, LCB01-0371, in healthy male subjects.

LCB01-0371 is a new oxazolidinone antibiotic, which targets most Gram-positive organisms. High rates of adverse reactions including myelosuppression have been reported for existing oxazolidinones, limiting their long-term use. The safety, tolerability and pharmacokinetics (PK) of 21 day multiple oral administrations of LCB01-0371 in healthy male subjects (clinicaltrials.gov: NCT02540460) were investigated. In this randomized, double-blind, placebo-controlled study, subjects received 800 mg of LCB01-0371 once or twice daily or 1200 mg of LCB01-0371 twice-daily for 21 days in a fasting state. Safety and tolerability profiles including laboratory tests were evaluated during the study and on a post-study visit and the results were analysed using repeated-measures analysis of variance (RM-ANOVA). Serial blood samples for PK analysis were collected up to 12 h after dosing on day 21. A total of 40 subjects were enrolled and 34 subjects completed the study. Two subjects dropped out according to stopping rules. In the 1200 mg twice-daily dose group, the absolute value of red blood cell count, haematocrit and haemoglobin decreased by 500 × 106/L (6.5%), 4.5% (6.8%) and 1.6 g/dL (6.9%), respectively, after 21 day administrations of LCB01-0371. However, mean relative changes from baseline of all haematology values were not significantly different among doses, including placebo (all, P < 0.05). PK profiles of LCB01-0371 in the dose range of 800 mg once daily to 1200 mg twice daily were consistent with previous studies. LCB01-0371 is well tolerated in healthy male subjects with comparable haematology profiles to placebo, after multiple doses of up to 1200 mg twice daily for 21 days.

Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials

Current guidelines to treat iron deficiency recommend daily provision of ferrous iron divided through the day to increase absorption. However, daily dosing and split dosing might increase serum hepcidin and decrease iron absorption from subsequent doses. Our study aim was to compare iron absorption from oral iron supplements given on consecutive versus alternate days and given as single morning doses versus twice-daily split dosing. We did two prospective, open-label, randomised controlled trials assessing iron absorption using (54Fe)-labelled, (57Fe)-labelled, or (58Fe)-labelled ferrous sulfate in iron-depleted (serum ferritin ≤25 μg/L) women aged 18-40 years recruited from ETH Zurich and the University of Zurich, Switzerland. In study 1, women were randomly assigned (1:1) to two groups. One group was given 60 mg iron at 0800 h (±1 h) on consecutive days for 14 days, and the other group was given the same doses on alternate days for 28 days. In study 2, women were assigned to two groups, stratified by serum ferritin so that two groups with similar iron statuses could be formed. One group was given 120 mg iron at 0800 h (±1 h) and the other was given the dose split into two divided doses of 60 mg at 0800 h (±1 h) and 1700 h (±1 h) for three consecutive days. 14 days after the final dose, the groups were each crossed over to the other regimen. Within-individual comparisons were done. The co-primary outcomes in both studies were iron bioavailability (total and fractional iron absorption), assessed by measuring the isotopic label abundance in erythrocytes 14 days after administration, and serum hepcidin. Group allocations in both studies were not masked and primary and safety analyses were done on an intention-to-treat basis. The studies were registered at ClinicalTrials.gov, numbers NCT02175888 (study 1) and NCT02177851 (study 2) and are complete. For study 1, 40 women were enrolled on Oct 15-29, 2015. 21 women were assigned to the consecutive-day group and 19 to the alternate-day group. At the end of treatment (14 days for the consecutive-day group and 28 days for the alternate-day group), geometric mean (-SD, +SD) cumulative fractional iron absorptions were 16·3% (9·3, 28·8) in the consecutive-day group versus 21·8% (13·7, 34·6) in the alternate-day group (p=0·0013), and cumulative total iron absorption was 131·0 mg (71·4, 240·5) versus 175·3 mg (110·3, 278·5; p=0·0010). During the first 14 days of supplementation in both groups, serum hepcidin was higher in the consecutive-day group than the alternate-day group (p=0·0031). In study 2, 20 women were enrolled between Aug 13 and 18, 2015. Ten women were assigned to receive once-daily dosing and ten were assigned to receive twice-daily divided dosing. No significant differences were seen in fractional (day 1-3 geometric mean: 11·8% [7·1, 19·4] once daily vs 13·1% [8·2, 20·7] twice daily; p=0·33) or total iron absorption (day 1-3: 44·3 mg [29·4, 66·7] once daily vs 49·4 [35·2, 69·4] twice daily; p=0·33) between the two dosing regimens. Twice-daily divided doses resulted in a higher serum hepcidin concentration than once-daily dosing (p=0·013). No grade 3 or 4 adverse events were reported in either study. In iron-depleted women, providing iron supplements daily as divided doses increases serum hepcidin and reduces iron absorption. Providing iron supplements on alternate days and in single doses optimises iron absorption and might be a preferable dosing regimen. These findings should be confirmed in iron-deficient anaemic patients. Swiss National Science Foundation, Bern, Switzerland.

Safety of once- or twice-daily dosing of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with nonvalvular atrial fibrillation: A NOAC-TR study.

Once-daily dosing of non-vitamin K antagonist oral anticoagulants (NOACs) may increase patient adherence to treatment but may also be associated with a higher risk of bleeding. In this study, we investigated the adherence to once- or twice-daily dosing of NOACs and the risk of bleeding in nonvalvular atrial fibrillation (NVAF) patients. This multicenter cross-sectional study, conducted between 1 September 2015 and 28 February 2016, included 2214 patients receiving NOACs for at least 3 months, due to NVAF. Patients receiving once-daily or twice-daily NOAC doses were 1:1 propensity score matched for baseline demographic characteristics and the presence of other diseases. The medication adherence was assessed by the 8-item Morisky Medication Adherence Scale. Risk factors were investigated in relation to minor and major bleeding. The mean age of patients was 71 ± 10 years, and 53% of the patients were women. The medication adherence was lower in patients receiving twice-daily NOAC doses compared to once-daily-dose group (47% versus 53%, p = 0.001), and there was no difference between the groups in terms of minor (15% versus 16%, p = 0.292) and major bleeding (3% versus 3%, p = 0.796). Independent risk factors for bleeding were non-adherence to medication (OR: 1.62, 95% CI: 1.23-2.14, p = 0.001), presence of 3 or more other diseases (OR: 10.3, 95% CI: 5.3-20.3, p < 0.001), and HAS-BLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INR, Elderly, Drugs or alcohol) score (OR: 4.84, 95% CI: 4.04-5.8, p < 0.001). In summary, the once-daily dose of NOACs was associated with increased patient adherence to medication, while it was not associated with bleeding complications.

Antihypertensive Drug Prescription Patterns and their Impact on Outcome of Blood Pressure in Ethiopia:A Hospital-Based Observational Study

Irrational prescription is strongly associated with poor control of hypertension. The present study aimed to evaluate antihypertensive drug prescription trends and to measure their impact on the level of blood pressure (BP) control in Gondar University Hospital, Gondar, Ethiopia. A hospital-based retrospective cross-sectional study was conducted from May 30 to June 30, 2016. All hypertensive patients on medication were included. A structured data abstraction form was prepared to gather the necessary information. The prescription patterns and BP level were measured retrospectively. A binary logistic regression was computed to determine the effect of different prescription patterns on BP control. A total of 596 hypertension patients were recruited for the study; of them, 561(94%) met the study criteria. The mean age of the respondents was 55.96±14.6 years. Females constituted 58.2% of the study population. Approximately ffty percent of the prescriptions were monotherapies. Twice-daily dosing was associated with lower risk of uncontrolled hypertension (crude odds ratio [COR] =0.51[0.15–0.73], adjusted odds ratio [AOR] =0.69[0.163–0.91]). Monthly appointment was linked with a nearly 90% reduced incidence of uncontrolled BP (COR =0.15[0.04–0.73], AOR =0.093[0.024–0.359]). Monotherapies were the most frequently prescribed regimens. Twice-daily dosing and monthly appointments were associated with low incidence of uncontrolled BP. Clinicians should be vigilant in adjusting the frequency of dosing and should fx appointment date in consultation with their patients.

Effect of three different regimens of repeated methamphetamine on rats' cognitive performance.

Neurocognitive impairment in response to methamphetamine (MA) has been proven in a variety of experimental and clinical studies. Elucidation of the underlying mechanisms of MA-induced cognitive deficits and finding preventive/therapeutic approaches need best-suited animal models. In modeling repeated MA exposure, while some believes that escalating doses simulate drug abuse conditions, others believe this regimen confers a preconditioning protection. The present study aimed to compare the effects of three different regimens of repeated MA administration on memory and cognitive function of adult rats. Rats in two different experimental groups were treated with escalating paradigms consisted of twice-daily i.p. injections; 1-4mg/kg over 7days or 1-10mg/kg over 10days. The third group received twice-daily doses of 15mg/kg every other day over 14days. Spatial working memory, novel object recognition task and anxiety-like behavior were measured sequentially in all MA-treated rats and vehicle-treated controls started from day 8 after last injection. All MA regimens decreased rates of spontaneous alternation in Y-maze and increased anxiety-like response. Short-term recognition memory was unchanged across all MA-treated animals, while long-term memory was impaired in the second and third MA regimen. Though MA deleterious effect especially in recognition memory is somehow dose dependent, preconditioning effect of increasing doses may be ruled out at least in the case of parameters measured here.