Dopamine D2R Agonist-Induced Cardiovascular Effects in Healthy Male Subjects: Potential Implications in Clinical Settings.

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 ß -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 ß -1 blocking agent might mitigate the risk of cardiovascular morbidity among patients receiving long-term D2 receptor agonists.

Serial CSF sampling over a period of 30 h via an indwelling spinal catheter in healthy volunteers: headache, back pain, tolerability and measured acetylcholine profile.

BACKGROUND/AIM: Timed interval cerebrospinal fluid (CSF) sampling by indwelling catheterization can be a valuable corroborative tool for the pharmacokinetic and pharmacodynamic assessment of drugs. CSF sampling in studies on drug candidates for Alzheimer's disease have been conducted in evaluations of the biomarkers acetylcholine (ACh), tau proteins, amyloid precursor protein and beta-amyloid fragments. The primary aim of this study was to study the feasibility and the burden on the healthy volunteers of serial CSF sampling within the contract research organization environment in order to establish a standardized research tool for future drug development studies. MATERIALS AND METHODS: This study is a validation study in healthy subjects: eight healthy male subjects aged 55-75 years were enrolled. After eligibility had been confirmed, the subjects were admitted to the clinical pharmacology unit 2 days before starting the CSF sampling procedure. Hydration by drip infusion of 2 L saline was performed for 24 h before starting the CSF sampling procedure, and for antithrombotic purposes, Fraxiparine (nadroparine calcium) was given 12 and 36 h after intradural catheterization. CSF catheterization was performed by board-certified anesthesiologists with experience in inserting indwelling intrathecal catheters. Subjects only required to remain in a horizontal position for the first 24 h after removal of the catheter. CSF and blood samples were collected by interval sampling over a 30-h period. RESULTS: The study was completed by seven of the eight subjects. Six subjects who completed the study reported adverse effects (AEs) which were all mild and from which they recovered during their stay in the clinic. A total of 25 AEs were reported of which 13 were considered to be procedure-related. The procedure was well tolerated by all participating subjects, and the VAS scale scores for headache and back pain were low. CSF samples were analyzed for ACh. All values were above the lowest limit of quantification. On average, the ACh concentration started at a low level but rose between 1 and 2 h after insertion of the catheter and then remained high during the whole sampling period up to 30 h. CONCLUSION: Serial sampling of CSF in seven healthy volunteers up to 30 h occurred without serious complications and was well tolerated. The CSF collected was of good quality and facilitated the assessment of an Alzheimer's disease-sensitive biomarker. We conclude that this validation study can form the basis for future patient studies aimed at elucidating disease mechanisms and the pharmacodynamics of drugs in the developmental stage.

The impact of cytochrome P450-2D6 genotype on the use and interpretation of therapeutic drug monitoring in long-stay patients treated with antidepressant and antipsychotic drugs in daily psychiatric practice.

PURPOSE: This retrospective follow-up study investigates whether cytochrome P450-2D6 (CYP2D6) genotype explains variability in plasma concentrations of psychotropic drugs in daily psychiatric practice. METHODS: The study population consisted of 62 hospitalised psychiatric patients genotyped for CYP2D6. Primary endpoint was the normalised plasma concentration ratio which was defined as the [measured concentration]/[mean therapeutic concentration] allowing comparison of plasma concentrations of different substrates. Secondary endpoint was a plasma concentration above the therapeutic range. The determinant was CYP2D6 genotype classified as ultrarapid metaboliser (UM), extensive metaboliser (EM), intermediate metaboliser (IM), or poor metaboliser (PM). The relation between CYP2D6 genotype and the normalised plasma concentration ratio was assessed with a linear mixed-effects model after adjustment for the Prescribed Daily Dose (PDD). The risk of having a plasma concentration above the therapeutic range was assessed with a logistic mixed-effects model. RESULTS: For antidepressants, CYP2D6 genotype PM (1.68 (95%CI: 1.01-2.28)) and IM (1.09 (95%CI: 0.77-1.29)) were associated with higher normalised plasma concentration ratios of antidepressants compared to EMs (0.56 (95%CI: 0.26-0.74)). In addition, the risk of a plasma concentration above the therapeutic range was increased for PMs (OR 33.1 (95%CI: 2.0-544.6)) and IMs (OR 8.2 (95%CI: 1.1-60.3)) relative to EMs using antidepressants. CYP2D6 genotype could not clearly explain variability in plasma concentrations of antipsychotics possibly due to a low frequency of therapeutic drug monitoring (TDM) in antipsychotics primarily metabolised by CYP2D6 in daily psychiatric practice. CONCLUSIONS: CYP2D6 genotype contributes to clinically relevant variability in plasma concentrations of antidepressants but probably not antipsychotics in daily clinical practice.

Polymorphic drug metabolism (CYP2D6) and utilisation of psychotropic drugs in hospitalised psychiatric patients: a retrospective study.

AIM: The aim of the current retrospective study was to assess the influence of polymorphic drug metabolism as assessed by genotyping, on the on the utilisation of psychotropic drugs in hospitalised psychiatric patients. The utilisation of psychotropic drugs was assessed using pharmacy records with emphasis on the number of prescriptions and prescriptions for possible side effects. METHODS: CYP2D6 genotype was assessed in 241 psychiatric patients by investigation for the five most common allelic variants ( CYP2D6*3, *4, *6, *7, *8) and the presence of gene duplication using allele-specific polymerase chain reaction. Data concerning the pharmacotherapy of the patients were retrieved from the pharmacy information system. Data was analysed on differences observed in pharmacy records concerning the different metabolic classes: ultra rapid metabolisers (UMs), extensive metabolisers (EMs) and poor metabolisers (PMs). RESULTS: For CYP2D6, 2.5% was UM (95% CI: 0.5-4.5%, n=6) and 8.3% was PM (95% CI: 4.8-11.8%, n=20). Drugs metabolised by CYP2D6 were less frequently prescribed in PMs than EMs (21.1% vs 33.6%, P=0.023). The average duration of prescriptions was significantly lower in PMs than EMs (54 days vs 106 days, P=0.010). Between UMs and EMs, no significant differences were found, although a similar tendency was observed. With regard to dose, no consistent differences were observed between the CYP2D6 genotype classes. Drugs against Parkinsonian-like side effects were given twice as frequently in PMs as EMs (6.9% vs 3.4%, P=0.045). CONCLUSIONS: Patients with impaired CYP2D6 metabolism received fewer CYP2D6 drugs. PMs were more prone to Parkinsonian-like side effects as evidenced by more prescriptions for drugs combating these side effects. Dose titrations were not often used to compensate for genetic polymorphisms. Pharmacy records might be a useful tool to detect differences related to polymorphic metabolism.