European Journal of Clinical Pharmacology

A comparative pharmacokinetic study was performed with two types of suppository each containing 20 mg piroxicam. The bioavailability of piroxicam was studied in 24 healthy volunteers in a double blind, randomised, cross over study. No significant difference was found in the pharmacokinetic parameters [AUC(0–72 h), AUC, Cmax, t1/2β calculated from plasma concentration time curves, indicating that the two preparations were bioequivalent.

Four patients with a biliary fistula received 0.5 mg3H-methylproscillaridin as a single oral dose. 55% of the dose was excreted in bile, 16% in urine and 3% in faeces. More than 60% of the radioactivity excreted in bile and urine appeared within the first 24 hours. 78% of the radioactivity in bile consisted of CHCl3-insoluble metabolites of methylproscillaridin, incubation of which with β-glucuronidase led to splitting off glucuronic acid from almost 80%. Methylproscillaridin can be regarded as the principal conjugated compound. TLC-separation of CHCl3-soluble compounds from bile showed identical running of radioactivity with methylproscillaridin, proscillaridin and scillarenin and three unknown metabolites P1, P2, and P3. In urine the CHCl3-soluble fraction averaged 16% to 34% of the total amount and was identified as methylproscillaridin, proscillaridin, scillarenin, P2 and P3. The relative composition of the total radioactivity in faeces amounted to 77% methyl-proscillardidin, 4% scillarenin and 12% polar metabolites.

The number of marketed non-steroidal anti-inflammatory agents varies widely from one European country to another, partly as a consequence of differing regulatory policies. During a four-year period, nine of 18 applications to market such drugs in the Netherlands failed; the remaining nine compounds were all licenced; in all, 22 single drug entities of this type are currently on sale. In Norway during the same period none of the 15 applications received was granted, though five cases are still pending; only seven such drugs are currently licenced for sale. The reasons for the national decisions and for the discrepancies between them are analyzed. A study of the prescribing practice of rheumatologists in the two countries suggests that some 10 to 15 products of this type are in fact needed in order to provide a reasonable choice. Current registration trends could markedly discourage further research investment in this field unless in the near future a basis is found for developing non-steroidal anti-inflammatory drugs with distinct advantages as compared with all those so far known.

Objective/methods: The pharmacokinetics of the plasma substitute oxypolygelatine (OPG) were studied in 12 healthy volunteers after single-dose administration of 27 ml · kg−1 body weight, with a maximum of 2000 ml. OPG was determined in plasma and urine over 48 h after the infusion. Peak plasma OPG concentrations at the end of the infusion were determined to 4.600 (623) μg · ml−1, the area under the plasma concentration/time curve (AUC0∞) was calculated to 70.135 (15.861) μg · h · ml−1. Results: The model-independently calculated volume of distribution came to 23.1 (4.8) l with a clearance total is (Cltot) of 24.6 (6.8) ml · min−1. The initial half-life according to a three-compartment model came to 0.3 (0.2) h, followed by a distribution half-life of 3.1 (2.6) h and a terminal elimination half-life of 13.4 (2.2) h. Cumulative urinary excretion of OPG was 64% after 48 h. Conclusion: This low recovery rate may be explained by the distribution of OPG into the extravascular space and subsequent degradation in tissue sites.

To investigate whether the CYP3A4/5 and ABC transporter genetic polymorphisms could affect the pharmacokinetics of lenvatinib in Chinese healthy subjects. Thirty-two healthy Chinese volunteers were enrolled and took oral administration of 8 mg lenvatinib. Plasma concentration of lenvatinib was determined by UPLC-MS/MS, the CYP3A4*1G, CYP3A5*3, ABCB1 (3435 C>T, 1236 C>T, 2677 G>T/A), ABCG2 (421 C>A, 34 G>A), and ABCC2-24 C>T genotypes were determined by SnapShot Technique. In ABCB1 3435T carriers (n = 19), AUC0–120h (815.7 (701.9–923.9) ng·h/mL) and AUC0-∞ (843.3 (722.2–977.7) ng·h/mL) were significantly higher than ABCB1 3435CC homozygous subjects (n = 13, 575.3 (513.7–756.9) ng·h/mL and 590.0 (540.5–782.0) ng·h/mL, respectively); on the contrary, the clearance (CL/F) of ABCB1 3435T carriers was significantly lower (9.5 (8.2–11.1) L/h vs. 13.6 (10.4–14.8) L/h). And the Cmax in CYP3A4*1G/*1G allele carrier subjects was higher than *1 carrier (73.4 ng/mL vs. 53.5 (46.1–60.6) ng/mL), but did not reach the level of significantly statistical difference. Genetic polymorphisms of ABCC2, ABCG2, and CYP3A5 could not influence pharmacokinetic parameters of lenvatinib. This work presented an evidence that the ABCB1 3435 C>T polymorphism could significantly affect the exposure and clearance of lenvatinib. These findings may explain the reasons for the huge inter-individual differences in lenvatinib, and should contribute to clinical individualized treatment.

The rational prescribing of drugs is an essential skill of medical doctors. Clinical pharmacologists play an important role in the development of these skills by teaching clinical pharmacology and therapeutics (CP&T) to undergraduate medical students. Although the approaches to teaching CP&T have undergone many changes over the last decennia, it is essential that the actual teaching of CP&T continues to be a major part of the undergraduate medical curriculum. The learning objectives of CP&T teaching in terms of developing the therapeutic competencies of undergraduate medical students are described, with an emphasis on therapeutic decision-making. On the basis of current theories of cognitive psychology and medical education, context-learning is presented as an effective approach by which to achieve therapeutic competencies. An example of a CP&T curriculum is presented.

To evaluate the relationship among supraventricular and ventricular arrhythmias with blood pressure and heart rate (HR) values, we studied 2 groups of 20 hypertensive men with (group I) and without (group II) left ventricular hypertrophy. Ambulatory electrocardiographic tracings were recorded continuously, together with ambulatory arterial pressure. Systolic (SBP) and diastolic (DBP) blood pressure values measured over 24 h showed no difference between the two groups, but we found greater variability in SBP in group I. The incidence of ventricular and supraventricular arrhythmias was significantly higher in patients of group I; moreover, we found a strong correlation between the incidence of ventricular extrasystoles (VPCs) and SBP, DBP, and HR values in group I, whereas in group II the incidence of supraventricular extrasystoles (APCs) was higher during peaks of SBP and HR values. The relationship between APCs and SBP observed in group II may be attributable to the pressure stimulus on a normal atrium, and the significant correlation between VPCs and SBP, DBP, and HR values may be due to episodes of subendocardial ischemia or to the influence of adrenergic stimulation on previously compromised myocardial tissue.

Objective: The pharmacokinetics of ketoprofen following intramuscular injection or oral tablet was determined in children aged 10–69 months. Methods: Ten children received a single intramuscular injection of 1 mg kg–1 ketoprofen. Six children, weight 12–17 kg, received a 12.5-mg ketoprofen tablet and four children, weight 18–23 kg, received a 25-mg tablet. Venous blood samples were collected at 15 min and 30 min and 1, 2, 4, 6 and 8 h following drug dosing. Plasma ketoprofen levels were measured using a validated high-performance liquid chromatography method. Results: The maximal plasma concentration of ketoprofen ranged between 3.6 µg ml–1 and 7.4 µg ml–1 in the intramuscular group and, following a dose normalisation, between 2.8 µg ml–1 and 8.2 µg ml–1 in the tablet group (dose normalised for 1 mg kg–1). The rate and extent of absorption of ketoprofen were comparable after intramuscular and oral administration. The relative bioavailability of oral ketoprofen was about 100% of the intramuscular administration. The extrapolated area under the plasma concentration–time curve (AUC0– ∞) ranged between 8.8 µg ml–1 h and 14.6 µg ml–1 h in the intramuscular group and between 8.7 µg ml–1 h and 14.1 µg ml–1 h in the tablet group (dose-normalised AUC0– ∞). The terminal half-life was comparable in both study groups, ranging between 0.8 h and 2.2 h in the intramuscular group and between 0.9 h and 2.1 h in the tablet group. Conclusion: According to the pharmacokinetic properties determined in this study, there is no justification for using intramuscular administration in awake children.