Evening Dose Research Articles

Non-24-Hour Sleep-Wake Rhythm Disorder in the Totally Blind: Diagnosis and Management.

Several aspects of human physiology and behavior are dominated by 24-h circadian rhythms with key impacts on health and well-being. These include mainly the sleep–wake cycle, vigilance and performance patterns, and some hormone secretions. The rhythms are generated spontaneously by an internal “pacemaker,” the suprachiasmatic nuclei within the anterior hypothalamus. This master clock has, for most humans, an intrinsic rhythm slightly longer than 24 h. Daily retinal light exposure is necessary for the synchronization of the circadian rhythms with the external 24-h solar environment. This daily synchronization process generally poses no problems for sighted individuals except in the context of jetlag or working night shifts being conditions of circadian desynchrony. However, many blind subjects with no light perception had periodical circadian desynchrony, in the absence of light information to the master clock leading to poor circadian rhythm synchronization. Affected patients experience cyclical or periodic episodes of poor sleep and daytime dysfunction, severely interfering with social, academic, and professional life. The diagnosis of Non-24 Sleep–Wake Rhythm Disorder, also named free-running disorder, non-entrained disorder, or hypernycthemeral syndrome, remains challenging from a clinical point of view due to the cyclical symptoms and should be confirmed by measurements of circadian biomarkers such as urinary melatonin to demonstrate a circadian period outside the normal range. Management includes behavioral modification and melatonin. Tasimelteon, a novel melatonin receptor 1 and 2 agonist, has demonstrated its effectiveness and safety with an evening dose of 20 mg and is currently the only treatment approved by the FDA and the European Medicines Agency.

Pharmacist-based antihypertensive medication review and assignment of morning versus evening dosing of once-daily antihypertensive medications: A pilot study to assess feasibility and efficacy in chronic kidney disease patients

ABSTRACTEvening dosing of antihypertensive medications lowers nighttime blood pressure, and in one large randomized trial, it reduced the risk for cardiovascular outcomes. However, the feasibility of nighttime dosing in routine clinical practice is unknown. The purpose of this pilot study was to evaluate the effect of a brief pharmacist intervention to assign patients to take antihypertensive medications at specific times of the day. In this pilot, randomized controlled trial, 79 patients with moderate to severe chronic kidney disease (CKD) taking one or more antihypertensive medications once daily were randomized to take one once-daily antihypertensive either in the morning or in the evening. A total of 79 patients were randomized (39 to morning dosing, 40 to evening dosing). Average (SD) age was 56.5 (14) years, 68% were male, and average (SD) estimated glomerular filtration rate (eGFR) was 36.6 (8.9) mL/min/1.73m2. Adherence, defined as taking the once-daily medication at the time indicated six or seven times in the last 7 days and not taking it at any other time during the day, was 91% in the morning arm and 95% in the evening arm (p = 0.57). This pilot demonstrates the feasibility and efficacy of a pharmacist–physician collaborative to assign once-daily antihypertensive medications to either morning or evening dosing.

The Treatment In Morning versus Evening (TIME) study: analysis of recruitment, follow-up and retention rates post-recruitment

BackgroundThe use of information technology (IT) is now the preferred method of capturing and storing clinical research data. The Treatment In Morning versus Evening (TIME) study predominantly uses electronic data capture and IT to compare morning dosing of hypertensive medication against evening dosing. Registration, consent, participant demographics and follow-up data are all captured via the study website. The aim of this article is to assess the success of the TIME methodology compared with similar studies.MethodsTo assess the TIME study, published literature on similar clinical trials was reviewed and compared against TIME recruitment, follow-up and email interaction data.ResultsThe TIME website registered 31,695 individuals, 21,116 of whom were randomised. Recruitment cost per randomised participant varied by strategy: £17.40 by GP practice, £3.08 by UK Biobank and £58.82 for GoShare. Twelve-month follow-up retention rates were 96%. A total of 1089 participants have withdrawn from their assigned time of dosing, 2% of whom have declined follow-up by record linkage or further contact. When the TIME data are compared with similar study data, study recruitment is very successful. However, TIME suffers difficulties with participant follow-up and withdrawal rates similar to those of conventional studies.ConclusionsThe TIME study has been successful in recruitment. Follow-up, retention rates and withdrawal rates are all acceptable, but ongoing work is required to ensure participants remain engaged with the study. Various recruitment strategies are necessary, and all viable options should be encouraged to maintain participant engagement throughout the life of studies using IT.

A standardized approach based on dietary and multiple daily insulin injections for the management of diabetes in infants

Plasma glucose control in the neonates and infants with diabetes based on dietary and multiple daily insulin injections is highly difficult. In this study, the infants were fed at 3- to 4-h intervals. All patients were started on insulin therapy with 0.6 U/kg/day divided equally into four doses. The morning, noon, and evening doses were given as premixed insulin (25% insulin lispro and 75% insulin lispro protamin sulphate), while the night insulin dose was given as premixed or neutral protamin Hagedorn (NPH) insulin according to the feeding frequency during the night. Nine-point capillary blood glucose profiles, HbA1c, and anthropometric measurements were evaluated. The study had 15 infants diagnosed with neonatal diabetes (ND) or type 1 diabetes mellitus (T1DM). The mean duration of the follow-up was 22.9 ± 8.7 months. During the follow-up, all patients had experienced sufficient weight and length gains and had experienced neither any episode of ketoacidosis nor wide fluctuations in blood glucose levels. Hypoglycemia, normoglycemia, and hyperglycemia were reported in 9.1, 79.9, and 11% of all the blood glucose measurements, respectively. Severe hypoglycemia was not experienced by any patients. The mean HbA1c levels in the patients with ND and T1DM at the last visit were 7.0 ± 0.2 and 7.6 ± 0.56%, respectively. The findings suggest that our approach is useable for plasma glucose control without wide fluctuations in infants with diabetes.

Influence of cytochrome P450 genotype on the plasma disposition of prochlorperazine metabolites and their relationships with clinical responses in cancer patients

Background Oral prochlorperazine, a dopamine D2 receptor antagonist, is largely metabolized to sulphoxide, 7-hydroxylate and N-desmethylate by cytochrome P450s (CYPs). This study evaluated the influence of CYP genotype on the plasma dispositions of prochlorperazine and its metabolites and their relationships with antiemetic efficacy and prolactin elevation in cancer patients. Methods Forty-eight cancer patients treated with oral prochlorperazine were enrolled. Plasma prochlorperazine and its metabolites concentrations and serum prolactin concentration were determined at 12 h after the evening dosing. The genotypes of CYP2C19, CYP2D6 and CYP3A5 and the incidences of nausea and vomiting were investigated. Results The plasma concentrations of the prochlorperazine metabolites were weakly correlated with that of the parent drug. The CYP genotypes did not affect the plasma concentrations of prochlorperazine and its metabolites. The plasma concentrations of prochlorperazine and its metabolites were not associated with the incidences of nausea and vomiting. The incidence of vomiting was significantly higher in females than in males. The serum prolactin concentration was weakly correlated with the plasma concentrations of prochlorperazine and its metabolites. The plasma concentrations of prochlorperazine metabolites rather than the parent drug had a weaker relation to serum prolactin concentration. Conclusions The CYP genotypes did not affect the plasma dispositions of prochlorperazine and its metabolites. The prochlorperazine metabolites did not have a strong effect on antiemetic efficacy, while they were slightly associated with prolactin secretion in cancer patients.

Unexpected in utero exposure to psychotropic medications

Introduction Pregnancies in the world each year involve women who have or who will develop psychiatric illness during the pregnancy. Psychotropics in gestation could produce adverse perinatal and postnatal outcomes, however counseling these women to discontinue medication presents new risks associated with untreated or inadequately treated mental illness, such as poor prenatal care, inadequate nutrition, and increased alcohol and tobacco use. The single administration at a higher dosage over multiple medications, active pharmaceutical compounds with fewer metabolites and higher protein binding are preferred. Nevertheless all psychotropic medications cross the placenta, are present in amniotic fluid, and can enter breast milk. Case description The FDA, the Australian Drug Evaluation Committee and Micromedex have categorized medications according to risk during pregnancy. Based on these classifications Benzodiazepines, have been demonstrated possibly teratogenic however they are still used for treating anxiety, panic, seizures and insomnia. International Pharmacopoeia reported an increased risk of intrauterine growth retardation, hypotonia, bradycardia, respiratory depression, low Apgar and preterm delivery for fetal plasma drug concentrations equivalent to the therapeutic range of maternal prescription. Very few data are published on sudden intrauterine death (SIUD) for intrauterine exposure to psychotropic medication. We describe a SIUD correlated with unexpected toxic plasmatic fetal concentration of Lorazepam. Results and conclusions The pregnant manifested anxiety, panic attack and deficiency of emotional transport for the fetus. She was treated with Lorazepam evening dose of 2mg from 24 to 40 gestational weeks, according to therapeutic range prescription, when suddenly and unexpectedly fetus died in utero just before the delivery. We evaluated the maternal and fetal pharmacological plasmatic concentration and observed a fetal plasmatic level of Lorazepam of 330mcg/l greater the toxic cutoff of 45mcg/l, suggested by Micromedex to cause floppy infant syndrome. By autoptic diagnosis we hypothesized neuropathological signs of sudden cardiac arrest in health fetus. Take-home message We propose that the monitoring of the maternal plasma levels of benzodiazepines during pregnancy and assessment of the concentration umbilical cord at birth, have to be correlated with the fetal vital signs. Nevertheless, it is difficult to define the metabolic fate of drugs in utero. Each of the major metabolic pathways can be promoted by placental and/or fetal enzymes and the metabolite concentration in the fetus does not ineludibly reflect the ability of the fetus to metabolize drugs. For this reason it has to be strictly evaluated the toxicological etiopathogenesis of some cases of SIUD and still birth.

Combination treatment with valsartan and amlodipine intensifies evening suppression of Bmal1 clock gene in kidneys of spontaneously hypertensive rats

Abstract Blood pressure (BP) rhythm is exhibited in a circadian pattern regulated by complex system of endogenous factors. Administration of pharmacological treatment at the right time can influence the efficacy of treatment; but while kidneys play significant role in BP regulation, little is known about their role in chronopharmacotherapy. This study aimed to compare differences between morning and evening dosing with valsartan and amlodipine combination in both short-term and long-term settings and to elucidate the role of kidneys in chronopharmacology. Spontaneously hypertensive rats aged between 8 and 10 weeks were daily treated with 10mg/kg of valsartan and 4 mg/kg of amlodipine, either in the morning or in the evening with treatment duration of 1 and 6 weeks. After short-term treatment, only morning treatment group demonstrated significantly better outcomes in terms of BP control when compared to placebo. After long-term treatment, both treatment groups gained superior results in BP control against placebo; however, no significant difference was seen between morning and evening treatment. Interestingly, clock gene expression in kidney has been significantly modulated only in the evening-treated groups, with treatment intensifying the reduced Bmal1 levels, while Per2 expression was less altered. However, no direct relation with the outcomes of the therapy has been observed, suggesting that pharmacotherapy may serve as an independent modulator of peripheral circadian clock in the kidney.

24-h bronchodilation and inspiratory capacity improvements with glycopyrrolate/formoterol fumarate via co-suspension delivery technology in COPD

BackgroundSymptoms of chronic obstructive pulmonary disease may vary throughout the day and it is important that therapeutic approaches provide 24-h symptom control. We report the results of two phase IIIb crossover studies, PT003011 and PT003012, investigating the 24-h lung function profile of GFF MDI (glycopyrrolate/formoterol fumarate 18/9.6 μg delivered using innovative co-suspension delivery technology) administered twice daily.MethodsPatients with moderate-to-very severe chronic obstructive pulmonary disease received 4 weeks’ treatment with each of GFF MDI, placebo MDI, and open-label tiotropium (PT003011 only). Lung function was assessed over 24 h on day 29 of each treatment period. The primary outcome was forced expiratory volume in 1 second area under the curve from 0 to 24 h (FEV1AUC0–24). Other outcomes included change from baseline in average daily rescue medication use over the treatment period. In addition, we conducted a post-hoc analysis of data pooled from both studies to further characterize the effect of GFF MDI on inspiratory capacity.ResultsGFF MDI treatment significantly increased FEV1AUC0–24 versus placebo in studies PT003011 (n = 75) and PT003012 (n = 35) on day 29 (both studies p < 0.0001), with similar improvements in FEV1AUC versus placebo for hours 0–12 and 12–24. In PT003011, improvements with GFF MDI versus tiotropium in FEV1AUC were greater during hours 12–24 compared to 0–12 h. GFF MDI treatment also resulted in a significant reduction in rescue medication use versus placebo (−0.84 [p<0.0001] and −1.11 [p=0.0054] puffs/day in PT003011 and PT003012, respectively), and versus tiotropium in PT003011 (−0.44 [p=0.017] puffs/day). A post-hoc pooled analysis showed patients treated with GFF MDI were more likely to achieve a >15% increase from baseline in inspiratory capacity than patients treated with placebo or tiotropium (72.1%, 19.0% and 47.0% of patients, respectively after the evening dose on day 29). There were no significant safety/tolerability findings.ConclusionsGFF MDI significantly improved 24-h lung function versus placebo in patients with moderate-to-very severe chronic obstructive pulmonary disease, with similar benefits in the second 12-h period compared to the first, supporting twice-daily dosing of GFF MDI.Trial registrationPearl Therapeutics, Inc.; www.clinicaltrials.gov; NCT02347072 and NCT02347085. Registered 21 January 2015.

Evening versus morning dosing regimen drug therapy for chronic kidney disease patients with hypertension in blood pressure patterns: a systematic review and meta-analysis.

Evening dosing regimen drug therapy on blood pressure (BP) control is used widely, but its clinical benefits and preservation or re-establishment of the normal 24-h BP dipping pattern in chronic kidney disease (CKD) patients is not known. To investigate the effect of an evening dosing regimen of antihypertensive drugs on BP patterns of CKD patients with hypertension. A systematic review was conducted by searching PUBMED, EMBASE, ASN-ONLINE, the Cochrane Library and the reference lists of relevant articles of published papers. All trials designed to evaluate the effects of evening versus morning dosing regimen drug therapy for CKD patients with hypertension were included. Meta-analysis was performed using random or fixed effects models. Five randomised controlled trials and one comparative study, including 3732 patients, met the inclusion criteria. Compared with morning dosing regimen drug therapy, evening administration of antihypertensive medication was associated with a significant reduction of 40% in non-dipper BP patterns (risk ratio (RR), 95% CI, (0.43, 0.84)). We noted a significant decrease in nocturnal systolic blood pressure (SBP) (MD -3.17 mmHg, 95% CI (-5.41, -0.94)), a significant reduction in nocturnal diastolic blood pressure (DBP) (MD -1.37 mmHg, 95% CI (-2.05, -0.69)) and a significant increase in awake SBP (MD 1.15 mmHg, 95% CI (0.10, 2.19)) in patients assigned to the evening dosing regimen drug therapy group. Patients showed no significant differences for all-cause mortality and cardiovascular mortality. This review shows that evening dosing regimen drug therapy could reverse non-dipper BP patterns in hypertensive CKD patients.

Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes

Hypoglycemia, a serious risk for insulin-treated patients with type 2 diabetes, negatively affects glycemic control. To test whether treatment with basal insulin degludec is associated with a lower rate of hypoglycemia compared with insulin glargine U100 in patients with type 2 diabetes. Randomized, double-blind, treat-to-target crossover trial including two 32-week treatment periods, each with a 16-week titration period and a 16-week maintenance period. The trial was conducted at 152 US centers between January 2014 and December 2015 in 721 adults with type 2 diabetes and at least 1 hypoglycemia risk factor who were previously treated with basal insulin with or without oral antidiabetic drugs. Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 361) or to receive insulin glargine U100 followed by insulin degludec (n = 360) and randomized 1:1 to morning or evening dosing within each treatment sequence. The primary end point was the rate of overall symptomatic hypoglycemic episodes (severe or blood glucose confirmed [<56 mg/dL]) during the maintenance period. Secondary end points were the rate of nocturnal symptomatic hypoglycemic episodes (severe or blood glucose confirmed, occurring between 12:01 am and 5:59 am) and the proportion of patients with severe hypoglycemia during the maintenance period. Of the 721 patients randomized (mean [SD] age, 61.4 [10.5] years; 53.1% male), 580 (80.4%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were 185.6 vs 265.4 episodes per 100 patient-years of exposure (PYE) (rate ratio = 0.70 [95% CI, 0.61-0.80]; P < .001; difference, -23.66 episodes/100 PYE [95% CI, -33.98 to -13.33]), and the proportions of patients with hypoglycemic episodes were 22.5% vs 31.6% (difference, -9.1% [95% CI, -13.1% to -5.0%]). The rates of nocturnal symptomatic hypoglycemia with insulin degludec vs insulin glargine U100 were 55.2 vs 93.6 episodes/100 PYE (rate ratio = 0.58 [95% CI, 0.46-0.74]; P < .001; difference, -7.41 episodes/100 PYE [95% CI, -11.98 to -2.85]), and the proportions of patients with hypoglycemic episodes were 9.7% vs 14.7% (difference, -5.1% [95% CI, -8.1% to -2.0%]). The proportions of patients experiencing severe hypoglycemia during the maintenance period were 1.6% (95% CI, 0.6%-2.7%) for insulin degludec vs 2.4% (95% CI, 1.1%-3.7%) for insulin glargine U100 (McNemar P = .35; risk difference, -0.8% [95% CI, -2.2% to 0.5%]). Statistically significant reductions in overall and nocturnal symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were also seen for the full treatment period. Among patients with type 2 diabetes treated with insulin and with at least 1 hypoglycemia risk factor, 32 weeks' treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemia. clinicaltrials.gov Identifier: NCT02030600.

MRNA levels of circadian clock components Bmal1 and Per2 alter independently from dosing time-dependent efficacy of combination treatment with valsartan and amlodipine in spontaneously hypertensive rats

ABSTRACTChronopharmacological effects of antihypertensives play a role in the outcome of hypertension therapy. However, studies produce contradictory findings when combination of valsartan plus amlodipine (VA) is applied. Here, we hypothesized different efficacy of morning versus evening dosing of VA in spontaneously hypertensive rats (SHR) and the involvement of circadian clock genes Bmal1 and Per2. We tested the therapy outcome in short-term and also long-term settings. SHRs aged between 8 and 10 weeks were treated with 10 mg/kg of valsartan and 4 mg/kg of amlodipine, either in the morning or in the evening with treatment duration 1 or 6 weeks and compared with parallel placebo groups. After short-term treatment, only morning dosing resulted in significant blood pressure (BP) control (measured by tail-cuff method) when compared to placebo, while after long-term treatment, both dosing groups gained similar superior results in BP control against placebo. However, mRNA levels of Bmal1 and Per2 (measured by RT-PCR) exhibited an independent pattern, with similar alterations in left and right ventricle, kidney as well as in aorta predominantly in groups with evening dosing in both, short-term and also long-term settings. This was accompanied by increased cardiac mRNA expression of plasminogen activator inhibitor-1. In summary, morning dosing proved to be advantageous due to earlier onset of antihypertensive action; however, long-term treatment was demonstrated to be effective regardless of administration time. Our findings also suggest that combination of VA may serve as an independent modulator of circadian clock and might influence disease progression beyond the primary BP lowering effect.

Plasma concentrations of atovaquone given to immunocompromised patients to prevent Pneumocystis jirovecii.

Atovaquone is one of the alternatives to trimethoprim/sulfamethoxazole for prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients. In volunteers, there was wide inter-individual variability in atovaquone bioavailability. The aim of this study was to assess the plasma concentrations of atovaquone in immunocompromised patients under PCP prophylaxis. Adult haematology or HIV-positive patients receiving atovaquone (750 mg oral suspension twice a day) for PCP prophylaxis were included. Plasma concentrations were assessed using UV-HPLC, around 12 h after the evening dose (Cmin) and 1-5 h after the morning dose (Cmax). A total of 82 measurements were performed in 33 patients. This included 19 HSCT recipients, 7 haematology non-transplant patients and 7 HIV-positive patients. The median Cmin (IQR) was 11.3 μg/mL (6.2-27.8) and the median Cmax was 13.4 μg/mL (6.0-28.3). The Cmin and Cmax of atovaquone were not different between HIV-negative and HIV-positive patients, or between HSCT and non-HSCT patients. Atovaquone concentrations were not influenced by the co-administration of valaciclovir (n = 20) or ciclosporin (n = 11), by gut graft-versus-host disease (n = 7) or by the intake of atovaquone with food. Nineteen of the 33 (58%) patients had Cmin <15 μg/mL, a threshold associated with a low rate of clinical response in PCP treatment. Atovaquone is poorly absorbed in more than half of immunocompromised patients and its bioavailability varies between individuals. These unpredictable variations raise the question of therapeutic drug monitoring, in order to identify patients with low concentrations and those who could benefit from regimen adaptation or from alternatives.

Effects of morning vs evening statin administration on lipid profile: A systematic review and meta-analysis

Evidence about the optimal time of day at which to administer statins is lacking. The objective of this study is to synthesize evidence about effects of morning vs evening statin administration on lipid profile. We searched PubMed, SCOPUS, Web of Science, and Embase databases (from inception up to July 24, 2016) to identify the relevant studies. Mean differences (MDs) between the change scores in lipid parameters were pooled using a fixed-effect model. Eleven articles with 1034 participants were eligible for the analysis. The pooled analysis comparing effects of morning vs evening administration of statins on plasma total cholesterol (TC; P=.10), high-density lipoprotein cholesterol (P=.90), and triglycerides (P=.45) was not statistically significant. Low-density lipoprotein cholesterol (LDL-C) lowering was statistically greater in the evening-dose group (MD: 3.24mg/dL, 95% CI: 1.23-5.25, P=.002). Subgroup analysis according to statin half-lives showed that evening dose of statins was significantly superior to morning dose for lowering LDL-C in case of both short and long half-life statins (MD: 9.68mg/dL, 95% CI: 3.32-16.03, P=.003 and MD: 2.53mg/dL, 95% CI: 0.41-4.64, P=.02, respectively) and also for TC reduction in case of short half-life statins only (P=.0005). LDL-C and TC lowering was significantly greater in the evening dose than in the morning dose in case of short-acting statins. Besides slight but significant effect on LDL-C, the efficacy of long-acting statins was equivalent for both regimens. Therefore, long-acting statins should be given at a time that will best aid compliance. Short-acting statins should be given in the evening.

Evaluation of the effect of time dependent dosing on pharmacokinetic and pharmacodynamics of amlodipine in normotensive and hypertensive human subjects

ABSTRACTIn clinical practice, circadian rhythms play a prominent role in pharmacokinetics and cell responses to therapy, hence necessitating in designing a defined protocol for drug administration. Clinical evidence for chronopharmacological behavior of cardiovascular active drugs in human subjects has been limited for amlodipine. Hence, the present study was undertaken to study the chronopharmacokinetic and chronopharmacodynamic phenomena of amlodipine and evaluate the effect of time of dosage in hypertensive subjects. Single oral dose of amlodipine was administered to the hypertensive/normotensive subjects either morning or evening to assess the pharmacokinetic profile after morning dosing or evening dosing, respectively. PK parameters obtained revealed that Tmax was shorter and Cmax was greater after evening dosing than the morning dosing in both hypertensive and normotensive subjects. These observations were comparable with the hypothesis that amlodipine is absorbed rapidly when it is given during the night time. Also, the changes in systolicBP, DiastolicBP, and heart rate in comparison to the respective circadian baseline values were markedly different depending on the time and dosing. SBP and HR were significantly reduced after evening dosing with slight difference in measurement of DBP in hypertensive patients. Hence, it can be concluded that prescription of antihypertensive medications containing amlodipine, to be administered at night offers highly efficacious means to control BP without the need to increase either the dose or number of medications. The current treatment strategy method involves delivery of medications, so that they are synchronized in time to biological need that varies according to the chronobiology of the targeted tissues.

Zolpidem prescribing practices before and after Food and Drug Administration required product labeling changes.

Background:Women have higher morning serum zolpidem concentrations than men after taking an evening dose, potentially leading to increased risk of harm. On 19 April 2013, the United States Food and Drug Administration required labeling changes for zolpidem, recommending an initial dose of no greater than 5 mg (immediate release) or 6.25 mg (controlled release) per night in women.Objectives:The primary objective of this study was to compare prescribing practices before and after the 2013 zolpidem labeling change. A secondary objective was to evaluate serious adverse events potentially related to zolpidem.Methods:Electronic medical records of adults receiving care through the University of Colorado Health system were accessed for study inclusion if patients were provided a first-time prescription for zolpidem either prior to or after the Food and Drug Administration labeling change. Patients were randomly chosen from eight strata based on age, gender, and date of zolpidem initiation (before/after the labeling change). Demographic and zolpidem prescribing data were collected. Low-dose zolpidem was considered 5 mg (immediate release) or 6.25 mg (controlled release) daily or less. Documentation of potentially related serious adverse events within the patients’ records was also evaluated.Results:A total of 400 patients were included in the study. The overall percentage of patients prescribed low-dose zolpidem increased from 44% to 58% after the labeling change (p = 0.0020). In a pre-specified subgroup analysis, the percentage of patients prescribed low-dose zolpidem increased in all groups, including young men (38%–50%, p = 0.23), elderly men (34%–40%, p = 0.53), and elderly women (60%–74%, p = 0.14), but the change was only significant in young women (42%–70%, p = 0.0045).Conclusion:After Food and Drug Administration–mandated labeling changes for zolpidem in 2013, the percentage of overall patients in our health system, and specifically young women, with initial prescriptions for low-dose zolpidem significantly increased as compared to before the labeling change.

Tolerability of Switch to Macitentan from Bosentan in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease that can be treated with several medications. Macitentan, an endothelin receptor antagonist (ERA), has received approval as a PAH therapy. We report our data regarding the tolerability in patients with PAH who were switched from bosentan to macitentan. At the Baylor Pulmonary Hypertension Program, 24 patients with PAH who had been taking bosentan and were switched to macitentan were identified in this retrospective study. Data from these patients who switched from bosentan 125 mg orally twice per day to macitentan 10 mg orally daily (between October 2013 and February 2015) when macitentan became commercially available were collected. Patients were advised to take their last evening dose of bosentan and then take the first dose of macitentan the following morning within 12 to 24 hours of the last bosentan dose. Baseline data and postswitch data, including 6-minute walk distance, brain naturietic peptide, alanine transaminase (ALT) and aspartate transaminase (AST) levels, World Health Organization Functional Class (WHO FC), Borg dyspnea score, presence of peripheral edema. At the time of the switch, the mean age was 58 ± 13 (mean ± standard deviation) years, the duration of disease was 6.6 ± 4.4 years, 21 patients were women, 54% were white, and 25% had idiopathic PAH. The mean duration of follow-up after the switch was 5.7 ± 1.5 months. The 6-minute walk distance was 344 ± 106 m preswitch and 319 ± 85 m postswitch (P = 0.18). Brain naturietic peptide levels were 91 ± 170 pg/mL preswitch and 90 ± 137 pg/mL postswitch (P = 0.93). At the time of the switch, 42% were WHO FC II and 50% had edema, and 55% had edema. AST and ALT remained unchanged postswitch. Two patients did not tolerate the switch to macitentan and had to be returned to bosentan: one patient with portopulmonary hypertension developed elevated AST and ALT and the second patient's macitentan was stopped because of malaise and tachyarrhythmia. One patient who underwent a successful liver transplant had macitentan stopped following the transplant. A rapid switch from bosentan to macitentan was well tolerated and safe with maintained WHO FC, with no significant change in edema and liver enzyme levels. The switch from bosentan to macitentan eliminates the need for monthly liver function test monitoring and removes the potential for bosentan treatment interruption.

Effect of melatonin different time administration on the development of diet-induced obesity in rats

In recent years much attention has been paid for study of the melatonin use possibilities for improving obesity comorbidities. The aim of our study was to determine the influence of melatonin different time treatment on body weight changes of dietinduced obesity in rats. The administration by gavage of melatonin in dose 30 mg/kg for 7 weeks had the potential to decrease visceral fat weight, Lee index (both after morning and evening treatment) and body weight gain rate (only after evening dose).

Measuring women’s experience of induction of labor using prostaglandin vaginal gel

ObjectiveTo describe and examine the EXIT (EXperiences of Induction Tool), and report on the experience of women undergoing PGE2 vaginal gel IOL, who were participants in a randomized controlled trial comparing early amniotomy with repeat-PGE2. Study designFollowing an evening dose of PGE2 vaginal gel, 245 women with live singleton term pregnancies were randomized to amniotomy or repeat-PGE2. Women’s experience of IOL was a secondary outcome measure, assessed using the self-report EXIT administered by phone at 7–9days post-partum. The 10-item EXIT assessed women’s experiences in multiple domains using a 5-point agreement scale. Principal components analysis with orthogonal varimax rotation was undertaken to examine the scale structure. Internal consistency, face, content, construct and discriminant validity were also assessed. ResultsThe final 3-component solution comprised 8 of the 10 EXIT items, explained 76.1% of the variance and had a good fit to model (p<0.001). The three resulting components were representative of women’s experience of the time taken to give birth, discomfort with IOL, and subsequent contractions. The items loading to each component showed good internal consistency for time taken to give birth (α=0.88), discomfort with IOL (α=0.78), and experience of subsequent contractions (α=0.87). Women in the repeat-PGE2 group reported a less favorable experience with the time taken to give birth (mean (SD): 3.5 (1.4) vs 3.9 (1.2); p=0.04) and more discomfort with IOL (2.9 (1.1) vs 2.5 (1.0); p=0.04) compared to women in the amniotomy group. At the individual item level, women in the amniotomy group responded more positive about the time taken to have their baby (median (IQR): 4 (3–5) vs 3 (2–5); p<0.01); and less negative to the question about the number of vaginal examinations (2 (1–3) vs 2 (1–4); p=0.05). ConclusionsThe EXIT shows promise as an instrument for assessing women’s experience of IOL. Women undergoing PGE2 vaginal gel IOL reports a more positive experience with an early amniotomy rather than with repeat-PGE2.

Chronotherapy for hypertension in obstructive sleep apnoea (CHOSA): a randomised, double-blind, placebo-controlled crossover trial

BackgroundObstructive sleep apnoea (OSA) is an important cause of secondary hypertension. Nocturnal hypertension is particularly prevalent in OSA and is a strong predictor of cardiovascular mortality. Studies in patients with...

Novel Gastroretentive Controlled Release Formulations for Once-Daily Administration: Assessment of Clinical Feasibility and Formulation Concept for Raltegravir.

Raltegravir is an integrase strand transfer inhibitor indicated in combination with other anti-retroviral medicinal products for the treatment of HIV-1 infection, given twice daily. Although a BCS class II compound, raltegravir exhibits low colonic absorption, thus making development of modified release formulations challenging. It was hypothesized that a gastroretentive (GR) formulation would increase trough (C24 h) concentrations of raltegravir, hence being amenable to a once-daily (QD) regimen. Iterative prototype GR formulations were developed in monolithic, bilayer, and trilayer tablet designs. Four phase I studies in healthy subjects were conducted to provide proof of formulation concept. Raltegravir C24 h was increased by a GR formulation with scintigraphy data supporting gastric retention. Single-dose exposures from a trilayer tablet administered in the morning with a high-fat meal resulted in acceptable C24 h values. However, C24 h values for evening dosing with a high-fat meal did not meet the success criteria for QD administration. Raltegravir C24 h and area under the curve (AUC) values after AM dosing with a low-fat meal were significantly lower than after dosing with a moderate-fat meal. Skipping, delaying, or giving a low-fat, low-calorie lunch after dosing with a high-calorie breakfast also resulted in an unacceptable decline in C24 h values. The requirements for consistent product performance under varying conditions of diet, timing of dosing, and dose were not favorable when given as GR tablets. The findings from these studies offer valuable insights into modifying the absorption of candidate drugs with limiting colonic permeability and solubility characteristics and the interplay between meal, dose timing, and GR formulation performance.