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Abstract. Endogenous creatinine clearance, serum creatinine and urinary creatinine excretion have been determined in 368 patients hospitalized with various medical diseases, and without known renal disease. The patients were divided into 10‐year age groups and the results were analysed for age and sex differences. The average creatinine clearance in males showed a steady decline from 110 to 34 ml/min/1.73 m2 from the age group 20–29 to the age group 90–99 years. The mean serum creatinine values did not show any significant variations with age, but urinary creatinine (mg/kg b.wt./24 h) decreased from 23.8 in the age group 20–29 to 9.4 in the age group 90–99 years. In females creatinine clearance declined from 95 to 39 ml/min/ 1.73 m2, serum creatinine was without significant change and urinary creatinine (mg/kg b.wt./24 h) decreased from 19.7 in the age group 20–29 to 8.4 in the age group 90–99 years. The finding of considerably decreased creatinine clearance values without elevation of serum creatinine values in the elderly is probably explained by a great reduction with age in lean body mass and thereby in creatinine production. In a group of 106 patients with serum creatinine values between 1.4 and 5.0 mg/100 ml the urinary creatinine (mg/kg b.wt./24 h) was not significantly different from that of patients without renal disease. A risk of overestima‐tion of glomerular filtration rate seems to exist if serum creatinine is used as the only parameter of renal function in these patients and might lead to intoxication with drugs which are mainly excreted by the kidney. The authors suggest a nomogram for rapid evaluation of creatinine clearance in ml/min.

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Clearance of phenytoin after i.v. injection of 100 mg was studied in six patients before and after 2 weeks daily treatment with 450 mg rifampicin, and in 14 patients with tuberculosis receiving standard treatment with 450 mg rifampicin, 300 mg isoniazid, and 1200 mg ethambutol daily. Acetylator status was measured by urinary acetylated sulphadimidine. Clearance of phenytoin in patients receiving only rifampicin increased from 46.7 ml min‐1 +/‐ 20.6 ml min‐1 to 97.8 ml min‐1 +/‐ 33.4 ml min‐1 (P less than 0.01), while clearance in patients on three drugs increased from 47.1 +/‐ 23.4 ml min‐1 to 81.3 ml min‐1 +/‐ 41.6 ml min‐1 (P less than 0.01). No significant differences were observed between the six fast acetylators and the eight slow acetylators. Phenytoin kinetics were unchanged after further 3 months of combined treatment. Rifampicin is a strong inducer of the elimination of phenytoin. Combined treatment with isoniazid has no counter‐acting effect in either fast or slow acetylators.

Aims Activated charcoal is now being recommended for patients who have ingested potentially toxic amounts of a poison, where the ingested substance adsorbs to charcoal. Combination therapy with gastric lavage and activated charcoal is widely used, although clinical studies to date have not provided evidence of additional ef®cacy compared with the use of activated charcoal alone. There are also doubts regarding the ef®cacy of activated charcoal, when administered more than 1 h after the overdose. The aim of this study was to examine if there was a difference in the effect of the two interventions 1 h post ingestion, and to determine if activated charcoal was effective in reducing the systemic absorption of a drug, when administered 2 h post ingestion. Methods We performed a four-limbed randomized cross-over study in 12 volunteers, who 1 h after a standard meal ingested paracetamol 50 mg kg x1 in 125 mg tablets to mimic real-life, where several factors, such as food, interfere with gastric emptying and thus treatment. The interventions were activated charcoal after 1 h, combination therapy of gastric lavage followed by activated charcoal after 1 h, or activated charcoal after 2 h. Serum paracetamol concentrations were determined by h.p.l.c. Percentage reductions in the area under the curve (AUC) were used to estimate the ef®cacy of each intervention (paired observations). Results There was a signi®cant (P<0.005) reduction in the paracetamol AUC with activated charcoal at 1 h (median reduction 66%, 95% con®dence intervals 49, 76) compared with controls, and a signi®cant (P<0.01) reduction for gastric lavage followed by activated charcoal at 1 h (median reduction 48.2%, 95% con®dence interval 32.4, 63.7) compared with controls. There was no signi®-cant difference between the two interventions (95% con®dence interval for the difference x3.8, 34.0). Furthermore, we found a signi®cant (P<0.01) reduction in the paracetamol AUC when activated charcoal was administered 2 h after tablet ingestion when compared with controls (median 22.7%, 95% con®dence intervals 13.6±34.4). Conclusions These results suggest that combination treatment may be no better than activated charcoal alone in patients presenting early after large overdoses. The effect of activated charcoal given 2 h post ingestion is substantially less than at 1 h, emphasizing the importance of early intervention.

In September 1997, an international consensus conference on standardization of studies of neuromuscular blocking agents was held in Copenhagen, Denmark. Based on the conference, a set of guidelines for good clinical research practice (GCRP) in pharmacokinetic studies of neuromuscular blocking agents is presented. Guidelines include: design of the study; relevant patient groups to investigate; test drug administration, sampling and analysis; pharmacokinetic analysis; pharmacokinetic/pharmacodynamic modeling; population pharmacokinetics; statistics; and presentation of pharmacokinetic data. The guidelines are intended to aid those working in this research area; it is hoped that they will assist researchers, editors of scientific papers, and pharmaceutical companies in improving the quality of pharmacokinetic studies.

It is universally stated that antithyroid drugs are concentrated in human milk and are thus contraindicated during breast-feeding. We recently showed, however, that propylthiouracil (PTU) was not concentrated in milk and a study has now been made of the excretion of another widely used antithyroid drug carbimazole (CMI) in human milk. Methimazole (MMI) in blood and milk from five lactating women was measured after oral administration of CMI 40 mg, which is rapidly and completely transformed to the active antithyroid compound MMI. One hour after CMI, the mean serum-MMI reached 253 microgram/I and the mean concentration of MMI in milk reached 182 microgram/I. MMI was found to be unionized and not to be protein bound in serum, and it occurred in milk in the same concentration as the serum; the mean milk/serum ratio was 0.98. The mean total amount of MMI excreted in milk over 8 h was 34 microgram (SEM +/- 5, n = 5), i.e. 0.14% of the dose administered.

This study examines blood pressure (BP) and independent factors related to BP in the acute phase of stroke. The study is part of the community-based Copenhagen Stroke Study. In a multivariate regression model we analyzed the impact of clinical and medical factors on admission BP. BP declined with increasing time from stroke onset with a total of 8/4 mm Hg. Independent factors related to diastolic BP were ischemic heart disease (–3.9 mm Hg), male gender (2.2 mm Hg), known hypertension prior to stroke (8.6 mm Hg), and primary hemorrhage (9.7 mm Hg). Independent factors related to systolic BP were age (3.6 mm Hg/10-year increase), atrial fibrillation (–7.2 mm Hg), ischemic heart disease (–6.0 mm Hg), intracerebral hemorrhage (13.3 mm Hg), and known hypertension prior to stroke (16.3 mm Hg). No independent relations were seen between BP and diabetes, claudication, previous stroke, smoking, daily alcohol consumption, initial stroke severity and lesion size. The increase in BP in the acute phase of stroke is a uniform response to the ischemic event per se. BP is not related to stroke severity. Several factors are independently related to the BP level in acute stroke. The clinical significance of this is yet to be tested, but these factors may contribute to the seemingly complex relation between BP and outcome.