Abstract. Verhave JC, Baljé-Volkers CP, Hillege HL,

Aim: To assess the impact of comorbidities on chronic heart failure (CHF) therapy. Methods: The IMPROVEMENT-HF survey included 11,062 patients from 100 primary care practices in 14 European countries. The influence of patient characteristics on drug regimes was assessed with multinomial logistical regression. Results: Combined drug regimes were given to 48% of CHF patients, consisting of 2.2 drugs on average. Patient characteristics accounted for 35%, 42% and 10% of the variance in one-, two-and three-drug regimes, respectively. Myocardial infarction (MI), atrial fibrillation (AF), diabetes, hypertension, and lung disease influenced prescribing most. AF made all combinations containing h-blockers more likely. Thus for single drug regimes, MI increased the likelihood for non-recommended h-blocker monotherapy (OR 1.3; 95% CI 1.2 -1.4), while for combination therapy recommended regimes were most likely. For both hypertension and diabetes, ACE-inhibitors were the most likely single drug, while the most likely second drugs were h-blockers in hypertension and digoxin in diabetes. Conclusions: Patient characteristics have a clear impact on prescribing in European primary care. Up to 56% of drug regimes were rational taking patient characteristics into account. Situations of insufficient prescribing, such as patients post MI, need to be addressed specifically.

Metabotropic Glutamate Receptor 5 (mGluR5) negative allosteric modulators (NAMs) may play a role in some psychiatric disorders such as anxiety and depression. The pharmacokinetic profile and pharmacodynamics effects of mGluR5-NAMs have been previously reported. We performed a post hoc analysis of pharmacological and clinical data obtained from 18 young healthy female subjects who received a mGluR5-NAM in the context of a phase I drug-drug interaction study between a mGluR5 NAM and a monophasic oral contraceptive. mGluR5-NAM was administered in an escalating bidaily dose level design. There was no interaction between the OC and mGluR5-NAM. Higher morning mGluR5-NAM plasma concentrations were found compared to evening concentrations. Most of the observed clinically significant neuropsychiatric adverse reactions occurred nocturnally and included visual (pseudo) hallucinations, insomnia accompanied by secondary behavioural disorders, and cognitive dysfunction symptoms of sufficient severity to interfere with daily functioning. Circadian rhythm-related physiological variations in drug absorption and disposition may explain this pharmacokinetics-pharmacodynamics apparently disproportionate relationship. We suggest that clinical trials evaluating basic pharmacokinetic properties of psychiatric medications consider potential drug's chronopharmacokinetics. This may assist with dose optimization and minimize serious neuropsychiatric adverse reactions in the vulnerable psychiatric patient.

Dopamine D2 receptor agonists represent a first line treatment option in young patients with signs and symptoms of idiopathic Parkinson's disease. An association between the use of D2 receptor agonists in Parkinson's disease patients and heart failure has been reported. The identification of the underlying mechanism is needed to minimize the resultant cardiovascular morbidity. In a phase I clinical trial, a D2 receptor agonist (pramipexole) was administered to 52 healthy male subjects following a dose escalation scheme. Serial measurements of resting blood pressure, heart rate, and derived parameters including pulse pressure, pulsatile stress, and rate pressure product were analysed. Statistically significant and clinically relevant increases in most of the assessed parameters were found. Ten subjects were removed prematurely from the trial because of clinically significant increases in blood pressure and/or heart rate requiring immediate intervention with IV rescue medications including a selective β-1 blocker. The observed drug-related changes in vital signs were of clinical relevance and might explain some of the cardiovascular morbidity reported in patients receiving D2 receptor agonist in clinical settings. We suggest that the additional use of a β-1 blocking agent might mitigate the risk of cardiovascular morbidity among patients receiving long-term D2 receptor agonists.

Similarity in bioassays means that the test preparation behaves as a dilution of the standard preparation with respect to their biological effect. Thus, similarity must be investigated to confirm this biological property. Historically, this was typically conducted with traditional hypothesis testing, but this has received substantial criticism. Failing to reject similarity does not imply that the 2 preparations are similar. Also, rejecting similarity when bioassay variability is small might simply demonstrate a nonrelevant deviation in similarity. To remedy these concerns, equivalence testing has been proposed as an alternative to traditional hypothesis testing, and it has found its way in the official guidelines.However, similarity has been discussed mainly in terms of the parameters in the dose-response curves of the standard and test preparations, but the consequences of nonsimilarity on the relative bioactivity have never been investigated.This article provides a general equivalence approach to evaluate similarity that is directly related to bioequivalence on the relative bioactivity of the standard and test preparations. Bioequivalence on the relative bioactivity can only be guaranteed for positive (only nonblanks) and finite dose intervals. The approach is demonstrated on 4 case studies in which we also show how to calculate a sample size and how to investigate the power of equivalence on similarity.