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BackgroundMedication non-adherence has an important impact on treatment efficacy and healthcare burden across a range of conditions and therapeutic areas. The aim of this analysis was to determine predictors of non-adherence and impact of non-adherence on treatment response in adults with attention-deficit/hyperactivity disorder (ADHD).MethodsPost-hoc analysis of a 13-week randomized, double-blind placebo-controlled study of OROS methylphenidate (MPH) 54 and 72 mg/day. Primary efficacy variable was the Conners’ Adult ADHD Rating Scale – Screening Version (CAARS:O-SV). Daily adherence was calculated as average daily adherence (100 × capsules taken/2), with overall adherence calculated as the average daily adherence. Predictors of adherence were assessed using mixed-effects logistic regression. Descriptive statistics were generated for change in CAARS:O-SV score for adherent (> 95% adherence) and non-adherent subjects. Predictors of change were analyzed using a mixed model.ResultsSubjects were allocated to OROS MPH (54 mg, n = 87; 72 mg, n = 92) or placebo (n = 97). Mean adherence was 92.6% and 93.3% (OROS MPH 54 and 72 mg/day, respectively), versus 97.5% (placebo). Adherence was higher and less variable in completers. Factors significantly associated with non-adherence included female sex, shorter time since ADHD diagnosis, higher education level (completion of university) and score on the Drug Use Screening Inventory psychiatric disorders subscale. Improvements from baseline in CAARS:O-SV score were numerically greater in subjects defined as adherent than in those who were non-adherent. Significant predictors of CAARS:O-SV change in patients who completed the study included percentage adherence up to the point of assessment (p < 0.0001), baseline score (p < 0.0001) and family history of ADHD (p = 0.0003).ConclusionThe results of this analysis suggest that newly diagnosed patients, those with a high score on the DUSI-R psychiatric disorder scale, women, and subjects with high educational degrees may be at increased risk of non-adherence. Clinicians and policymakers should therefore pay special attention to these individuals, as non-adherence is a significant predictor of reduced response to treatment.Trial registrationEudraCT #: 2007-002111-82

Background Reduced kidney function is common among patients with heart failure. In patients with heart failure and/or kidney disease, iron deficiency is an independent predictor of adverse outcomes. In the AFFIRM-AHF trial, acute heart failure patients with iron deficiency treated with intravenous ferric carboxymaltose demonstrated reduced risk of heart failure hospitalization, with improved quality of life. We aimed to further characterize the impact of ferric carboxymaltose among patients with coexisting kidney impairment. Methods The double-blind, placebo-controlled AFFIRM-AHF trial randomized 1132 stabilized adults with acute heart failure (left ventricular ejection fraction <50%) and iron deficiency. Patients on dialysis were excluded. The primary endpoint was a composite of total heart failure hospitalizations and cardiovascular death during the 52-week follow-up period. Additional endpoints included cardiovascular hospitalizations, total heart failure hospitalizations, and days lost to heart failure hospitalizations or cardiovascular death. For this subgroup analysis, patients were stratified according to baseline estimated glomerular filtration rate (eGFR). Results Overall, 60% of patients had an eGFR <60 ml/min/1.73 m2 (the lower eGFR subgroup). These patients were significantly older, more likely to be female and to have ischemic heart failure, and had higher baseline serum phosphate levels and higher rates of anemia. For all endpoints, event rates were higher in the lower eGFR group. In the lower eGFR group, the annualized event rates for the primary composite outcome were 68.96 and 86.30 per 100 patient-years in the ferric carboxymaltose and placebo arms, respectively (rate ratio, 0.76; 95% confidence interval, 0.54–1.06). The treatment effect was similar in the higher eGFR subgroup (rate ratio, 0.65; 95% confidence interval, 0.42–1.02; P interaction=0.60). A similar pattern was observed for all endpoints (P interaction>0.05). Conclusions In a cohort of patients with acute heart failure, left ventricular ejection fraction <50%, and iron deficiency, the safety and efficacy of ferric carboxymaltose were consistent across a range of eGFR values.

Butyrobetaine transport into the liver was studied using isolated rat hepatocyte plasma membrane vesicles. In the presence of a sodium chloride gradient, an overshoot could be observed, indicating active sodium-dependent transport. A similar overshoot was recorded in the presence of lithium, but not of potassium, cesium, or choline chloride. Investigation of several sodium salts revealed that an overshoot could only be observed in the presence of chloride, but not of nitrate, thiocyanate, sulfate, or gluconate. An osmolarity plot in the presence of sodium chloride revealed a slope different from zero and a positive intercept, indicating active transport and nonspecific binding, respectively. In agreement with the osmolarity plot, the kinetic characterization of butyrobetaine transport revealed a binding and a saturable component. The saturable compo- Mammals maintain their carnitine body stores by ingesting carnitine in the diet and by carnitine biosynthesis. 1 Carnitine biosynthesis starts with methylation of protein-linked lysine at the 6-amino position, with subsequent release of trimethyllysine by proteolysis. 2 Because availability of trimethyllysine limits carnitine biosynthesis, 3 and most of the trimethyllysine body stores are located in skeletal muscle, 4 skeletal muscle protein turnover is considered to be the rate-limiting step in carnitine biosynthesis. 2 Free trimethyllysine is subsequently hydroxylated in the 3-position, 5 and converted to butyrobetaine by glycine cleavage and oxidation of the resulting trimethyl-4-amino-butyraldehyde. 2,5,6 While most tissues can convert trimethyllysine to butyrobetaine, in the rat, 3-hydroxylation of butyrobetaine to carnitine is almost entirely confined to the liver. 6,7 To reach the cytoplasm of the hepatocytes, butyrobetaine must be transported across the basolateral plasma membrane.Because the plasma concentration of butyrobetaine is two to three times lower than the concentration in the liver, 8,9 this transport must be an active, energy-consuming process. To the best of our knowledge, so far only one study investigating the transport of butyrobetaine into the liver has been published. 10 In this study, butyrobetaine transport into isolated hepatocytes was found to be saturable and active, with a K m value of 0.5 mmol/L, which is approximately 100 times higher than the butyrobetaine plasma concentration. Because the driving force of butyrobetaine transport was not identified in this study, and the kinetic analysis did not include butyrobetaine concentrations in the range of its plasma concentration, we decided to study butyrobetaine transport into isolated rat liver plasma membrane vesicles and to express this transport in Xenopus laevis oocytes.