European Journal of Clinical Pharmacology

The pharmacokinetics of zileuton, a novel selective 5-lipoxygenase inhibitor, were studied in 37 patients with rheumatoid arthritis after administration of 200 mg, 400 mg, and 600 mg zileuton for 4 weeks. Patients had 6-h pharmacokinetic evaluation of zileuton on day 14. Plasma zileuton concentrations were quantitated using HPLC. Zileuton pharmacokinetic parameters were estimated using standard noncompartmental methods. A population analysis of zileuton pharmacokinetics was also performed with the NONMEM computer program. The pharmacokinetics of zileuton in patients with rheumatoid arthritis were similar to those previously estimated in normal healthy humans. The peak concentrations and the areas under the curves during the dosing interval were dose proportional. The noncompartmental means of the CL/f, terminal-phase half-life, and V/f of zileuton were approximately 545 ml min−1, 1.4 h, and 64.3 1, respectively. The estimate of population typical values of the CL/f for a 70-kg person (540 ml min−1) and V/f for a 70-kg person (64.8 1) from the NONMEM analysis were in agreement with the noncompartmental estimates. Differences in body weight, but not age or gender, helped explain some of the variability in the pharmacokinetics of zileuton in patients. Therefore, there is no pharmacokinetic basis for alteration of the zileuton dose size or the dosing schedule in patients with rheumatoid arthritis.

Objective: The fade in train-of-four (TOF) monitoring is considered to be due to blocking of the prejunctional nicotinic acetylcholine receptors (AchRs). During onset of the neuromuscular block (NMB) tubocurarine (TC) causes more fade in the TOF responses than vecuronium (VEC). Therefore we wanted to investigate whether onset or duration of action of VEC or TC would be improved with a priming dose of an agent with different prejunctional activity. Methods: The rates of NMB were measured following priming doses of 0.15 mg · kg−1 of TC and 0.015 mg ·  kg−1 of VEC with 6 min priming time. The individual time course of action of 0.6 mg · kg−1 of TC (1.13 × ED 95) and 0.1−0.2 mg · kg−1 of VEC (1.75–3.5 × ED95) were examined with a priming dose of the same agent or the other agent, by measurement of changes in the evoked compound EMG from the hypothenar muscle. Results: Priming doses of TC decreased mean TOF ratio to 67% [95% confidence interval (CI) = 56–78] during priming time, which was significantly lower than after priming with VEC 87% (76–97; P < 0.001). Despite the higher TOF ratio, the priming dose of VEC accelerated the onset time of intubation dose of TC more than the priming dose of TC (P = 0.0018). Priming with TC prolonged the duration of VEC-induced NMB by 35–70 min compared with priming with VEC, which means that a small priming dose of TC changes VEC from a muscle relaxant with intermediate action to a long-acting agent. Conclusion: Priming with TC caused a lower TOF ratio; however, priming with TC did not accelerate the onset time of either agent as much as priming with VEC. It appears that potentiation of NMB after combination of VEC and TC is not dependent on “fade” receptors.

The dose-response relationship of the new bronchodilator Clenbuterol (NAB 365, Boehringer Ingelheim) was tested in 12 patients with chronic obstructive lung disease. Clenbuterol is a beta-2-sympathicomimetic, from a series of substituted phenylethanolamines, and it is characterised by good absorption and prolonged action after systemic administration. The action of four different doses of Clenbuterol inhalation solution (6, 12, 24 and 48 µg corresponding to 2, 4, 8 and 16 drops of a 0.006% solution) was assessed after a single inhalation on 4 successive days. The parameters monitored were bronchial resistance and FEV1. The effect of all four doses was the same, both in respect of improvement in FEV1 and of decrease in bronchial resistance. The increase in expiratory volume and the decrease in bronchial resistance lasted for 6 h. The results show that for inhalation therapy Clenbuterol is a potent, selective bronchodilator, which is largely free of sideeffects. It has still to be determined whether a maximal effect could be achieved with a lower dose 6 µg.

The aims of this study were to describe combinations of beta-blockers (BB), renin-angiotensin system (RAS) blockers, and mineralocorticoid receptor antagonist (MRA) prescriptions and their trajectories in heart failure with preserved ejection fraction (HFpEF) patients, and to assess their effect on the three-year all-cause and cardiovascular (CV)-mortality. We used data from the EPICAL2 cohort of 689 hospitalized HFpEF patients. Medication prescriptions were collected at hospital discharge and at 6, 12, and 24 months after discharge. A multi-trajectory approach was used to conjointly model groups of individuals following similar trajectories over medications prescriptions. We used Cox and Fine‐Gray models, to evaluate respectively the associations between 3-year all‐cause mortality and CV-mortality and the trajectory groups. Multi-trajectory modelling revealed five distinct trajectory groups: group1 (N = 232, 33.6%) stable ACEI/ARB and BB prescriptions, group 2 (N = 199, 28.8%) stable ACEI/ARB prescription, group 3 (N = 133, 19.3%) stable BB prescriptions, group 4 (N = 78, 11.3%) stable prescriptions of none of the medications, and group 5 (N = 47, 6.8%) stable ACEI/ARB, BB, and MRA prescriptions. As compared to the group 4 of patients receiving none of the three medications, patients receiving a stable prescription of one or a combination of two or the three medications over 2 years) had a lower overall mortality over 3-year follow-up, i.e., group 1 (HR = 0.5, 95% CI 0.4–0.8), group 2 (HR = 0.6, 95% CI:0.4–0.8), group 3 (HR = 0.5, 95% CI:0.4–0.7), and group 5 (HR = 0.5, 95% CI:0.3–0.9). However, none of these trajectory groups was associated with a lower CV-mortality over 3 years. In an unselected population-based sample of HFpEF patients, the long-term stable use of the combination ACEI/ARB and BB, BB exclusively, ACEI/ARB exclusively, or the combination ACEI/ARB and BB and MRAs was associated with reduced three-year all-cause mortality.

The aim of this study was to examine the effect of carbamazepine on the pharmacokinetics of orally administered simvastatin in healthy volunteers. In a randomised, two-phase crossover study and a wash out of 2 weeks, 12 healthy volunteers took carbamazepine for 14 days (600 mg daily except 200 mg daily for the first 2 days) or no drug. On day 15, each subject ingested 80 mg simvastatin. Serum concentrations of simvastatin and its active metabolite simvastatin acid were measured up to 24 h. Carbamazepine decreased the mean total area under the serum concentration–time curve of simvastatin and simvastatin acid by 75% (P<0.001) and 82% (P<0.001), respectively. The mean peak concentrations of both simvastatin and simvastatin acid were reduced by 68% (P<0.01), and half-life of simvastatin acid was shortened from 5.9±0.3 h to 3.7±0.5 h (P<0.01) by carbamazepine. Carbamazepine greatly reduces the serum concentrations of simvastatin and simvastatin acid, probably by inducing their metabolism. Concomitant administration of carbamazepine and simvastatin should be avoided or the dose of simvastatin should be considerably increased.