Morning Trough Research Articles

What are the ideal metrics for assessing the quality of long-term stabilized "perfect" 24-h BP control after renal denervation?

A significant number of individuals being treated for hypertension still have uncontrolled blood pressure (BP). In Japan, renal denervation (RDN) is being introduced into clinical practice as an adjunctive treatment for hypertension that is uncontrolled despite adequate lifestyle changes and maximal antihypertensive drug therapy. The pivotal SPYRAL ON-MED trial showed that there was a significant reduction in trough office and nighttime ambulatory BP values in the RDN group compared with sham control group, although 24-h and daytime BP values were not significantly different between the two groups. The trough office BP measurement (taken before morning antihypertensive dosing) is similar to guideline recommendations for taking morning home BP before taking the morning antihypertensive drug dose. Recent guidelines recommend the measurement of nighttime BP because nighttime BP is a stronger predictor of cardiovascular event risk than daytime BP. It is particularly important to assess nighttime BP in medicated individuals with hypertension because the up- or down-titration of antihypertensive drug dosing is primarily based on office and daytime BPs in clinical practice. This means that there may be significant risk relating to nocturnal hypertension during longer follow-up. Because RDN results in persistent, "always-on" 24-h BP-lowering effects, the best BP metrics to assess the potential benefit of RDN are nighttime BP (determined using home or ambulatory BP monitoring) and morning BP (determined using home BP monitoring or morning trough office BP measurement). The variability of office, home, and ambulatory BP values is another important metric to assess the quality of RDN-related BP lowering.

Population pharmacokinetics of posaconazole in Chinese pediatric patients with acute leukaemia: Effect of food on bioavailability and dose optimization

This study aimed to investigate the effect of food on the pharmacokinetics of posaconazole suspension in pediatric patients with acute leukaemia and to recommend optimal dosing strategies. This single-site, prospective, open-label, observational study was conducted in 42 patients and included 186 plasma concentrations of posaconazole. Sparse data were analyzed using population pharmacokinetic modeling. Monte Carlo simulations were conducted to predict the morning trough concentrations at steady-state with the proposed dose of 2–7 mg/kg three times daily (tid) or four times daily (qid) for bodyweights of 10–36 kg. The target concentrations were 700 ng/mL for prophylaxis and 1000 ng/mL for treatment. Dosage regimens with percentage of target attainment (PTA) ≥70% were recommended. A one-compartment model with allometric scaling adequately described the pharmacokinetic profile. The apparent clearance was 9.05 L/h (95% confidence interval [CI] 7.14–11.09) and the apparent volume of distribution was 283 L (95% CI 168–491) for a typical individual of 17.5 kg. The relative bioavailability with high-fat diet was as high as 1.95-fold compared with regular food. Following the intake of regular meals, 4 mg/kg qid was adequate with a PTA ≥ 71.8% for prophylaxis. A dosage of 6 mg/kg qid under a regular diet reached a PTA ≥ 73.4% for treatment. The recommended dosage of posaconazole for prophylaxis and treatment could be predicted by the pharmacokinetic model based on bodyweight and diet type in pediatric patients.

Intraocular pressure and diurnal fluctuation of open-angle glaucoma and ocular hypertension: a baseline report from the LiGHT China trial cohort

AimsTo report the baseline intraocular pressure (IOP) characteristics and its diurnal fluctuation in the Laser in Glaucoma and Ocular Hypertension China cohort.Methods622 primary open-angle glaucoma (POAG) patients and 149 ocular...

Impact of Body Mass Index on Serum Concentrations of Antidepressants and Antipsychotics.

Rates of overweight and obesity are higher in patients suffering from psychiatric disorders than in the general population. Body composition and enzyme functions are affected by overweight, and consequently, the pharmacokinetics of drugs may vary in overweight patients. Thus, overweight and obesity are important factors in psychiatric disorders and their treatment. This analysis aimed to investigate the impact of body mass index (BMI) on serum concentrations of the antidepressant drugs amitriptyline, doxepin, escitalopram, mirtazapine, and venlafaxine, and the antipsychotic drugs clozapine, quetiapine, and risperidone, taking into account the following confounding parameters: age, sex, and smoking habit. Inpatients and outpatients (N = 1657) who took at least one of the target drugs were included in this retrospective analysis. Serum concentrations of the target drugs and their metabolites were determined at the Department of Psychiatry, Psychosomatics, and Psychotherapy of the University Hospital of Würzburg during routine therapeutic drug monitoring (January 2009-December 2010), which was performed in the morning (trough level) at steady state. Dose-corrected serum concentrations (CD) of the active moiety of doxepin and venlafaxine and of O-desmethylvenlafaxine were negatively associated with BMI (partial Pearson correlation, R = -0.267, P = 0.002; R = -0.206, P ≤ 0.001; R = -0.258, P ≤ 0.001), and the CDs were different in normal weight, overweight, and obese patients (analysis of covariance, P = 0.004, P < 0.001, P ≤ 0.001). No association was found between BMI and serum concentrations of amitriptyline, escitalopram, mirtazapine, clozapine, quetiapine, and risperidone. In obese patients, higher doses of doxepin and venlafaxine are necessary to achieve similar serum concentrations as in normal weight patients and to avoid treatment-resistant depression.

Fasting Status and Circadian Variation Must be Considered When Performing AUC-based Therapeutic Drug Monitoring of Tacrolimus in Renal Transplant Recipients.

Therapeutic drug monitoring (TDM) is mandatory for the immunosuppressive drug tacrolimus (Tac). For clinical applicability, TDM is performed using morning trough concentrations. With recent developments making tacrolimus concentration determination possible in capillary microsamples and Bayesian estimator predicted area under the concentration curve (AUC), AUC‐guided TDM may now be clinically applicable. Tac circadian variation has, however, been reported, with lower systemic exposure following the evening dose. The aim of the present study was to investigate tacrolimus pharmacokinetic (PK) after morning and evening administrations of twice‐daily tacrolimus in a real‐life setting without restrictions regarding food and concomitant drug timing. Two 12 hour tacrolimus investigations were performed; after the morning dose and the following evening dose, respectively, in 31 renal transplant recipients early after transplantation both in a fasting‐state and under real‐life nonfasting conditions (14 patients repeated the investigation). We observed circadian variation under fasting‐conditions: 45% higher peak‐concentration and 20% higher AUC following the morning dose. In the real‐life nonfasting setting, the PK‐profiles were flat but comparable after the morning and evening doses, showing slower absorption rate and lower AUC compared with the fasting‐state. Limited sampling strategies using concentrations at 0, 1, and 3 hours predicted AUC after fasting morning administration, and samples obtained at 1, 3, and 6 hours predicted AUC for the other conditions (evening and real‐life nonfasting). In conclusion, circadian variation of tacrolimus is present when performed in patients who are in the fasting‐state, whereas flatter PK‐profiles and no circadian variation was present in a real‐life, nonfasting setting.

Deterioration of Nighttime Respiratory Mechanics in COPD: Impact of Bronchodilator Therapy

COPD is associated with nighttime respiratory symptoms, poor sleep quality, and increased risk of nocturnal death. Overnight deterioration of inspiratory capacity (IC) and FEV1 have been documented previously. However, the precise nature of this deterioration and mechanisms by which evening bronchodilation may mitigate this occurrence have not been studied. What is the effect of evening dosing of dual, long-acting bronchodilation on detailed nocturnal respiratory mechanics and inspiratory neural drive (IND)? A double-blind, randomized, placebo-controlled crossover study assessed the effects of evening long-acting bronchodilation (aclidinium bromide/formoterol fumarate dihydrate: 400/12 μg) or placebo on morning trough IC (12h after the dose; primary outcome) and serial overnight measurements of spirometry, dynamic respiratory mechanics, and IND (secondary outcomes). Twenty participants with COPD (moderate/severe airway obstruction and lung hyperinflation) underwent serial measurements of IC, spirometry, breathing pattern, esophageal and transdiaphragmatic pressures, and diaphragm electromyography (diaphragmatic electromyography as a percentage of maximum; IND) at 6 time points from 0 to 12h after the dose and compared with sleeping IND. Compared with placebo, evening bronchodilation was not associated with increased morning trough IC 12h after the dose (P= .48); however, nadir IC (lowest IC, independent of time), peak IC, area under the curve for 12h after the dose, and IC for 10h after the dose were improved (P< .05). During placebo, total airways resistance, lung hyperinflation, IND, and tidal esophageal and transdiaphragmatic pressure swings all increased significantly overnight compared with baseline evening values; however, each of these parameters improved with bronchodilator treatment (P< .05) with no change in ventilation or breathing pattern. Respiratory mechanics significantly deteriorated at night during placebo. Although the morning trough IC was unchanged, evening bronchodilator treatment was associated consistently with sustained overnight improvements in dynamic respiratory mechanics and inspiratory neural drive compared with placebo CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02429765.

Efficacy of tiotropium in treating patients with moderate-to-severe asthma: A meta-analysis and systematic review based on 14 randomized controlled trials.

Background:The goal of the current meta-analysis and systematic review was to explore the efficacy of tiotropium in treating patients with moderate-to-severe asthma on the basis of qualified randomized controlled trials (RCTs).Methods:The following online electronic databases, such as Cochrane, PubMed, and Embase database were screened to identify qualified studies updated to January 2019 through the use of index words. Several literatures that were relevant to the present analysis were also included. To further analyze the main outcomes, we utilized the odds rations (OR), and mean difference (MD) along with its 95% confidence interval (95% CI).Results:A total of 14 RCTs with 4998 patients in the tiotropium group and 5074 patients in the control group were included in the present study. On the basis of the pooled results, tiotropium was significantly associated with improved morning PEF (SMD: 3.29, 95%CI: 2.03–4.55), evening PEF (SMD: 3.36, 95%CI: 2.24–4.48), peak FEV (SMD: 2.67, 95%CI: 1.47–3.88), and trough FEV (SMD: 1.90, 95%CI: 0.87–2.92) vs the control group. Nevertheless, no significant difference was observed in peak FVC (SMD: 0.77, 95%CI: −0.21–1.76), trough FVC (SMD: 0.67, 95%CI: −0.18–1.53), AE (RR: 0.98, 95%CI: 0.94–1.02) and serious AE (RR: 1.08, 95%CI: 0.77–1.52) between the 2 groups.Conclusions:In this review, we summarized the significant effect of tiotropium for the treatment of moderate-to-severe asthma, mainly in increasing morning PEF, evening PEF, peak FEV and trough FEV based on high-quality RCTs. Nevertheless, no significant difference in peak FVC, trough FVC, AE and serious AE was found between the 2 groups. A close comparison of the 2 groups revealed that more high-quality larger-sample RCTs are needed to gather more strong evidence on the therapeutic efficacy and safety of tiotropium for clinical practice.

Efficacy and safety of AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, in patients with asthma: a phase 2a randomized, double blind, placebo-controlled crossover trial

BackgroundInhaled corticosteroids reduce inflammation in asthma but chronic use may cause adverse effects. AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, has the potential of an improved risk-benefit profile. We investigated the safety and efficacy of AZD7594 in asthma.MethodsThis phase 2a multi-center, randomized, double-blind, placebo-controlled crossover study enrolled adults with asthma aged 18 to 75 years. Patients were treated with budesonide 200 μg twice daily for 2–3 3 weeks (run in part one). If controlled, as demonstrated by an asthma control questionnaire-5 score of < 1.5, patients entered a three-week run-in (part two) where they received a short acting bronchodilator alone. Thereafter, patients with a fractional exhaled nitric oxide (FENO) ≥25 ppb and pre-dose FEV1 40 to 90% predicted were randomized to one of nine treatment sequences. Each patient received placebo and two of three dose levels of AZD7594 (58, 250, 800 μg) once daily via inhalation, in 14-day treatment periods, separated by three-week washout periods. The primary endpoint was the change from baseline in morning trough FEV1 versus placebo on day 15. Secondary endpoints included measures of airway inflammation and asthma control.ResultsFifty-four patients were randomized and received at least 1 dose of treatment, 48 patients completed the study. Overall 52 patients received placebo, 34 received AZD7594 58 μg, 34 received AZD7594 250 μg, and 34 received AZD7594 800 μg. AZD7594 800 μg demonstrated a significant improvement in Day 15 morning trough FEV1versus placebo (LS means difference 0.148 L 95% CI 0.035–0.261, p = 0.011), with a dose-dependent response seen in the 250 μg (0.076 L -0·036–0·188, p = 0.183) and 58 μg (0·027 L -0·086–0·140, p = 0.683). All secondary endpoints showed statistically significant improvement at the 800 μg dose. All doses demonstrated a significant reduction in FENO at day 15 p < 0.01. No statistically significant difference in plasma cortisol level was observed between AZD7594 and placebo at any dose. AZD7594 was considered safe and well tolerated.ConclusionsTwo-week treatment with AZD7594 demonstrated a favorable risk-benefit profile in patients with mild to moderate asthma. Further clinical studies are needed to fully characterize AZD7594.Trial registrationClinicalTrials.gov number NCT02479412.

BECLOMETHASONE DIPROPIONATE DELIVERED VIA BREATH-ACTUATED INHALER IN PERSISTENT ASTHMA: EFFICACY EVALUATION ACCORDING TO PRIOR TREATMENT

Introduction The treatment effect of beclomethasone dipropionate (BDP) delivered via a novel breath-actuated inhaler (BAI) was evaluated overall, and also according to pre-study therapy to see if the latter influenced efficacy. Methods This was a Phase 3, 6-week, double-blind, placebo-controlled study (NCT02513160) in 425 patients ≥12 years with persistent asthma previously treated with non-corticosteroids (NCS), inhaled corticosteroids (ICS), or ICS/long-acting beta-2 agonists. After a washout/inhaler training period, randomized patients received placebo (BAI), placebo metered-dose inhaler (MDI), BAI 320 mcg/day, BAI 640 mcg/day, or BDP MDI 320 mcg/day. Rescue medication (albuterol/salbutamol) MDI or equivalent was permitted throughout the study. Results In 425 patients, BDP BAI 320 and 640 mcg/day significantly improved baseline-adjusted trough morning forced expiratory volume in 1 second area under the effect curve from 0 to 6 weeks (FEV1AUEC0–6wk; p Conclusions Both BDP BAI doses demonstrated significant improvements in lung function overall according to the primary study endpoint; exploratory subanalysis suggests that efficacy is independent of prior asthma therapy. The safety profile of this new BDP BAI device was comparable to the established safety profile of BDP MDI, with no new safety signals.

Ambulatory blood pressure monitoring and diabetes complications: Targeting morning blood pressure surge and nocturnal dipping.

Ambulatory blood pressure monitoring (ABPM) correlates more closely to organ damages than clinic blood pressure (BP). In the current study we aimed to investigate the association between micro- and macrovascular complications of diabetes and both diurnal and nocturnal variability in BP.A total of 192 patients with type 2 diabetes (T2DM) who had complete data on ABPM were selected. BP categories were defined based on 2017 ACC/American Heart Association BP guideline. The cross-sectional association between different BP phenotypes and diabetes complications including cardiovascular disease (CVD), nephropathy, retinopathy, and neuropathy was assessed using multiple logistic regression models adjusted for age, sex, body mass index, hypertension (HTN), hemoglobin A1c, fasting blood glucose (FBG), triglyceride (TG), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol.Approximately 48.9% of participants with T2DM had 24-hour HTN. The prevalence of daytime, nighttime, and clinic HTN were 35.9%, 96.3%, and 53.1%, respectively. Approximately 54.2% of participants had nondipping nocturnal pattern and 28.6% were risers. Nondipping nocturnal BP was associated with CVD, neuropathy, and retinopathy (P = .05, .05, and .014, respectively). Sleep trough morning blood pressure surge (MBPS) was associated with neuropathy (P = .023). Neuropathy was also associated with other components of MBPS (P < .05).We demonstrated that diabetic neuropathy was associated with all the components of MBPS and abnormal dipping status. Our results indicated loss of nocturnal BP dipping but not MBPS as a risk factor for CVD and retinopathy in patients with T2DM. Our findings once again highlighted the importance of ambulatory BP monitoring and targeted antihypertensive therapy directed toward to restore normal circadian BP in patients with T2DM.

Interaction between ABCG2 421C>A polymorphism and valproate in their effects on steady-state disposition of lamotrigine in adults with epilepsy.

To investigate the impact of glucuronidation enzyme (UGT1A4*3 142T>G, UGT1A4*2 70C>A, UGT2B7 -161C>T) and transporter (MDR1/ABCB1 1236C>T, ABCG2 421C>A) polymorphisms on steady-state disposition of lamotrigine and on the lamotrigine-valproate interaction. Adults with epilepsy on lamotrigine monotherapy (n=131) or lamotrigine + valproate treatment (n=74) were genotyped and steady-state lamotrigine and valproate morning troughs were determined as a part of routine therapeutic drug monitoring. No effect of UGT and MDR1/ABCB1 polymorphisms was observed. In the entire cohort, ABCG2 421A allele had no effect however an interaction between the variant allele and valproate was observed: (i) in lamotrigine-only patients, variant allele (vs. wild type homozygosity) was independently (adjustments: age, sex, body mass index, lamotrigine dose, other polymorphisms) associated with mildly lower lamotrigine troughs [geometric means ratio (GMR)=0.76, 95% confidence interval (CI) 0.59-0.98], whereas in lamotrigine + valproate patients it was associated with higher troughs (GMR=1.72, 95%CI 1.14-2.62); (ii) valproate cotreatment was overall associated with markedly higher troughs vs. lamotrigine monotherapy (GMR=3.49, 95%CI 2.73-4.44), but more so in variant allele carriers (GMR=5.24, 95%CI 3.38-8.15) than in wild type homozygotes (GMR=2.32, 95%CI 1.89-2.83); (iii) variant allele effects in two treatment subsets and valproate effects in two genotype subsets differed by 2.36-fold (95%CI 1.39-3.67); (iv) increase in lamotrigine troughs associated with increasing valproate troughs was greater in variant allele carriers than in wild type homozygotes, i.e. variant allele effect increased with increasing valproate troughs. This study is first to indicate a potentially relevant interaction between ABCG2 421C>A polymorphism and valproate in their effects on lamotrigine disposition.

Novel UHPLC-MS/MS method for the determination of rotigotine in the plasma of patients with Parkinson's disease.

A novel ultra-high-pressure liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of the dopamine receptor agonist rotigotine in human plasma. Following liquid-liquid extraction with tert-butyl methyl ether from 500 μL plasma, the chromatographic analysis was performed on a Gemini NX3 column using 5 mm pH 5.0 ammonium acetate-5 mm ammonium acetate in methanol as binary gradient mobile phase, at a flow rate of 0.3 mL/min. The MS/MS ion transitions were 316.00 → 147.00 for rotigotine and 256.10 → 211.00 for the internal standard (lamotrigine). The lower limit of quantitation was 50 pg/mL and the linearity was determined from 50 to 2500 pg/mL. The mean recovery was 96.9%. Both intra- and interassay imprecision and inaccuracy were ≤15% at all quality control concentrations. The method was successfully applied to measure morning trough plasma rotigotine concentrations in a series of patients with Parkinson's disease on chronic treatment. The present study describes the first fully validated method for rotigotine determination in human plasma.

Assessment of the efficacy and safety of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler versus a multi-dose inhaler in patients with chronic obstructive pulmonary disease

BackgroundThis study tested the clinical non-inferiority of the fluticasone propionate/salmeterol combination 50/250 μg (FSC) Rotacaps®/Rotahaler® system, a single unit dose inhaler, with the multi-dose FSC Diskus® inhaler in adults with chronic obstructive pulmonary disease (COPD). MethodsThis multi-centre, randomised, double-blind, double-dummy, two-way cross-over study compared 12 weeks' treatment of FSC administered twice daily using Rotacaps/Rotahaler or Diskus. The primary endpoint was change from baseline in trough morning forced expiratory volume in 1 s (FEV1) at Day 85, and the pre-defined non-inferiority criteria was: the lower limit of the confidence interval (CI) for the treatment difference (Rotacaps/Rotahaler-Diskus) in least squares (LS) mean change from baseline, being greater than −45 mL. Secondary endpoints included change in breathlessness (as measured by transition dyspnoea index (TDI)) and COPD-specific health status measures. ResultsThe LS mean increase from baseline in trough FEV1 at Day 85 was 116 mL in the Rotacaps/Rotahaler group and 91 mL in the Diskus group (difference in model-adjusted LS mean change: 25 mL (95% CI 2 mL, 47 mL)), the lower limit of the CI for the treatment difference being greater than the protocol-defined criterion for non-inferiority i.e. −45 mL. Data for breathlessness, COPD-specific health status and safety parameters were similar following FSC treatment via either inhaler. ConclusionsThis study demonstrated the clinical non-inferiority of FSC 50/250 μg when administered using Rotacaps/Rotahaler compared with Diskus in patients with COPD. The risk:benefit profile for the two inhalers was comparable.

Assessment of the efficacy and safety of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler and a multi-dose inhaler in patients with asthma

BackgroundIn developing countries, there is a need for access to affordable inhaled respiratory medicines. This study tested the clinical non-inferiority of fluticasone propionate/salmeterol combination (FSC) 50/250 μg Rotacaps®/Rotahaler® compared with FSC 50/250 μg Diskus®. MethodsA multi-centre, randomised, double-blind, double-dummy study evaluated 12 weeks, twice daily treatment of FSC 50/250 μg administered using Rotacaps/Rotahaler or Diskus inhaler in a crossover design in patients with asthma (pre-bronchodilator forced expiratory volume in 1 s (FEV1) 40%–85% of predicted, FEV1 reversibility ≥12%, prior stable dose with inhaled corticosteroid (ICS) or ICS/long acting beta-agonist). The primary efficacy endpoint, change from baseline in trough morning FEV1 at Day 85, was analysed using a model for repeated measures analysis. The pre-defined criterion for non-inferiority was the lower limit of the CI (0.025, one-sided significance level) for the treatment difference (Rotacaps/Rotahaler-Diskus) in least squares (LS) mean change from baseline, being greater than −125 mL. Secondary endpoints included serial FEV1 measurements, morning peak expiratory flow (PEF), rescue medication use, day- and night-time asthma symptoms, Asthma Control Test (ACT) scores, and serial cortisol measured over 12 h (area under the curve (AUC0-12)). ResultsTreatment with FSC 50/250 μg via Rotacaps/Rotahaler or Diskus resulted in a similar LS mean increase from baseline in trough FEV1 at Day 85 (231 mL and 203 mL respectively). The difference in the model-adjusted LS mean change was 28 mL (95% CI -24 mL, 80 mL), fulfilling the criterion for non-inferiority. Data for all secondary endpoints were similar for the two treatments, supporting the primary endpoint findings. Both treatments were well tolerated and demonstrated similar safety profiles. ConclusionThis study demonstrated the clinical non-inferiority of FSC 50/250 μg when administered using Rotacaps/Rotahaler compared with administration using Diskus in patients with asthma, and suggests there is no difference in the risk:benefit profile between the two FSC inhalers.

Icare ONE Home Tonometry in Children With and Without Known Glaucoma.

The Icare ONE (Finland Oy) rebound tonometer may have promise for home tonometry in children with glaucoma. The purpose of this study was: (1) to assess the feasibility of Icare ONE home tonometry in a small number of children with and without glaucoma and (2) to characterize diurnal intraocular pressure (IOP) variations in children with and without glaucoma. Patients were recruited from Duke pediatric ophthalmology clinic. Parents underwent in-clinic training for Icare ONE tonometry. Parents were instructed to record the subject's IOP using Icare ONE at 6 time intervals daily for 10 sequential days. Eight normal subjects (16 eyes) and 10 subjects (10 eyes) with glaucoma were included. All parents successfully performed Icare ONE home tonometry. In-clinic Icare ONE IOP exceeded Goldmann applanation in both groups. Normal subjects (mean age, 11.8 y) had a mean daily IOP range of 4.8 ± 4.6 mm Hg for right eyes and 5.2 ± 1.7 mm Hg for left eyes, and demonstrated relative peaks in the morning and relative troughs in the evening. Subjects with glaucoma (mean age, 12.4 y) had a mean daily IOP range of 8.6 ± 8.2 mm Hg, and demonstrated an even distribution of relative peaks and troughs throughout the day. Icare ONE home tonometry seems feasible in a small number of children. Normal eyes demonstrated smaller daily IOP ranges than glaucomatous eyes. Normal eyes were also more likely to show a relative early morning IOP peak and a late evening IOP trough. It is likely that the limited sampling in this study limits its generalizability to all children with glaucoma or to normal children.

A model-based longitudinal meta-analysis of FEV1 in randomized COPD trials.

A model-based, longitudinal meta-analysis of the efficacy on morning trough forced expiratory volume in 1 second (FEV1 ) in chronic obstructive pulmonary disease (COPD) is presented. Literature data from 142 randomized maintenance trials were included, comprising 106,422 patients who received 19 compounds. 1982 morning trough FEV1 observations were available, each representing the mean FEV1 for a study arm at a specific timepoint. The final model for absolute FEV1 included baseline, disease progression, placebo effect, and drug effect estimates for all compounds, with interstudy variability on all model components and additional interarm variability on baseline. A dose-response relationship was identifiable for 10 of the 19 compounds. Drug-drug interactions among direct bronchodilators and the effect of concomitant background COPD treatment were included. Covariates were identified on baseline. Disease progression was proportional to the baseline FEV1 , and a mean baseline of <1.2 L resulted in a lower efficacy, in particular for antiinflammatory treatments.

Treatment non-adherence as a trigger for status epilepticus: An observational, retrospective study based on therapeutic drug monitoring

To investigate the role of non-adherence to antiepileptic drug treatment as a trigger for status epilepticus (SE). 124 consecutive admissions for SE in patients with established epilepsy were studied. Those who had had therapeutic drug monitoring at admission were identified. Non-adherence was defined as a serum concentration/dose ratio at admission of <75% of the patient's own trough control value. In 64 cases serum concentration/dose ratios at admission were available for comparison with morning trough values. Treatment non-adherence was identified in a total of 24 (38%), 50% in children, 32% in patients 16-59 years and in 44% above 60. Missed medication had been reported in only two of these patients. No cases with confirmed non-adherence had a fatal outcome (p=0.05). No significant differences between non-adherent and adherent admissions concerning demographic factors or epilepsy and SE characteristics were found. Antiepileptic drug non-adherence is a common cause of SE across all ages, but is not always identified due to the first history-based information often being elusive. Prompt and reliable recognition of non-adherence is imperative for correct management. This is the first study to demonstrate the extent of non-adherence by therapeutic drug monitoring in SE.

Racial impact of diurnal variations in blood pressure on cardiovascular events in chronic kidney disease

Ambulatory blood pressure parameters, nocturnal dipping and morning surge, are associated with cardiovascular outcomes in several populations. While significant variation exists between racial groups in ambulatory blood pressure measurements and the incidence of cardiovascular disease, the effect of race on the associations of dipping and morning surge with cardiovascular outcomes is unknown. In a prospective analysis of 197 African American and 197 Japanese individuals with non–diabetic chronic kidney disease matched by age and renal function, we analyzed the associations of dipping and morning surge with cardiovascular events for both races and assessed whether these relations differed by race. Higher sleep–trough morning surge was independently associated with cardiovascular events in Japanese (hazard ratio, 1.93 per 10 mm Hg; 95% confidence interval, 1.20–3.10) but not in African American participants, with race an effect modifier (P–value <.01). Dipping was not associated with cardiovascular events in either racial group. In individuals with chronic kidney disease, the association between morning surge and cardiovascular events appears to be dependent upon race, with higher morning surge a risk factors in Japanese but not in African Americans.

P227 Efficacy And Safety Of Budesonide-formoterol (bf) Spiromax(R) In Adults And Adolescents With Asthma: Randomised Comparison With Bf Turbuhaler(R)

Background DuoResp Spiromax ® (Teva Pharmaceuticals) is a dry-powder inhaler designed to deliver budesonide and formoterol fumarate (BF Spiromax ® ) with maximum ease of use. Pharmacokinetic studies have shown bioequivalence of BF Turbuhaler ® . This study compared the efficacy and safety of these devices in patients with asthma. Methods This was a 12-week, multicentre, double-blind, randomised, controlled trial (N=605). Eligible patients (≥12 years old) had persistent asthma with FEV 1 40–85% predicted, had used a SABA and ICS for ≥8 weeks before screening and were maintained on stable-dose ICS for 4 weeks. The primary objective was to demonstrate non-inferiority of twice-daily BF Spiromax ® 160/4.5mcg to BF Turbuhaler ® 200/6mcg, with respect to change from baseline in weekly average of daily trough morning PEF. Results This analysis was based on the per protocol population (N=290 and N=284 for BF Spiromax ® and BF Turbuhaler ® groups, respectively). The least squares mean change from baseline to Week 12 in morning PEF was 18.8 L/min with BF Spiromax ® and 21.796 L/min with BF Turbuhaler ® . Non-inferiority of BF Spiromax ® vs BF Turbuhaler ® was demonstrated, as the lower limit of the 95% two-sided CI (–9.02 L/min) is greater than –15 L/min. Similarly, no significant between-group differences were observed in secondary efficacy endpoints. Both devices were well tolerated, with no significant differences in the incidence of adverse events or asthma exacerbations. Conclusions This study has demonstrated the non-inferiority of BF Spiromax ® vs BF Turbuhaler ® in adults and adolescents with asthma. Further data are required to confirm whether BF Spiromax ® can be used as an alternative to BF Turbuhaler ® in other indications. Sponsor: Teva Pharmaceuticals.

Interaction between brivaracetam (100 mg/day) and a combination oral contraceptive: A randomized, double‐blind, placebo‐controlled study

This randomized, double-blind, placebo-controlled, two-way crossover study aimed to assess the pharmacokinetic interactions between brivaracetam 100 mg/day and a combination oral contraceptive (OC) containing 30 μg ethinylestradiol and 150 μg levonorgestrel. The study was performed in 28 healthy women over five 28-day menstrual cycles: baseline (OC only), two treatment cycles with brivaracetam (50 mg b.i.d.) or placebo coadministered with OC separated by a wash-out cycle (OC only), and a follow-up cycle (OC only). The OC was administered on days 1-21 of each cycle, and brivaracetam or placebo on days 1-28 of the treatment cycles. Pharmacokinetics of ethinylestradiol and levonorgestrel were determined on day 20; brivaracetam morning trough levels on days 20 (with OC) and 29 (without OC) were compared. Cmax (maximum plasma concentration) and AUC (area under the plasma concentration versus time curve) ratios for brivaracetam versus placebo (90% confidence interval [CI]) were 0.96 (0.88-1.04) and 0.90 (0.86-0.95) for ethinylestradiol, and 0.95 (0.91-0.99) and 0.92 (0.88-0.97) for levonorgestrel, within predefined bioequivalence limits (0.80-1.25). Brivaracetam trough levels were similar on days 20 and 29 (ratio 1.08; 90% CI 0.98-1.18). No differences in breakthrough bleeding were seen across the five cycles. It was concluded that there were no interactions between brivaracetam 100 mg/day and the OC.