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Biomedical subjects

H G Luus

Publications and source records attributed to H G Luus.

At least 37 records · Page 2Linked to original sources
PubMed1993

On population and individual bioequivalence.

In a traditional assessment of the bioequivalence of two formulations of a drug one compares the average bioavailability from the two formulations. Anderson and Hauck argued that in some situations it is not sufficient to demonstrate average bioequivalence, and they proposed a method for the assessment of what they called individual bioequivalence, which essentially is the comparison of the individual responses to the two drug formulations within subjects. In this paper we propose a unified strategy for the assessment of bioequivalence that encompasses new approaches to the assessment of both population bioequivalence, which is the comparison of the marginal or population distributions of bioavailabilities, and individual bioequivalence, which is the comparison of the conditional or within-subject distributions of bioavailabilities. The general idea is to use a comparison of the reference formulation to itself as the basis for the comparison of the test with the reference formulation. The new approaches overcome the main weakness of the current methods for the assessment of bioequivalence by considering the variability of bioavailabilities in addition to their means. The current methods for the assessment of bioequivalence, namely the conventional assessment of average bioequivalence and the proposal by Anderson and Hauck for the assessment of individual bioequivalence, emerge as special cases. One can evaluate the new bioequivalence criteria statistically by use of bootstrap confidence intervals.

Acetaminophen↗
PubMed1993

Assessing the risk of ovulation in interaction studies of drugs and oral contraceptives.

When certain drugs are taken concomitantly with an oral contraceptive, the efficacy of the contraceptive may be obtunded, and pregnancy may ensue. Since the function of oral contraceptives is to suppress ovulation, the risk of ovulation is an important parameter in clinical studies investigating interactions between drugs and oral contraceptives. The purpose of this paper is to compare a crossover design, and a new study design used for assessing a possible interaction between a drug and an oral contraceptive, and to discuss the statistical issues involved in the planning and evaluation of the results of such studies.

Confidence Intervals↗
PubMed1993

Considerable cost savings through the analysis of pooled plasma samples in bioequivalence studies that fail to show bioequivalence.

A major part of the cost of bioequivalence studies is due to the drug assays of the individual plasma samples collected from each volunteer. Considerable savings in manpower, time, and especially costs could be achieved if it could be determined before the individual plasma samples are assayed that bioequivalence can not be shown. Such information can in fact be obtained through the analysis of pooled plasma samples. We propose an approach where pooled plasma samples are assayed and the resulting pooled drug concentration profiles for the test and reference product are compared. If this comparison indicates that one will not be able to show bioequivalence in the statistical analysis of the individual data, the individual plasma samples are not assayed. Thus more than 40% of the cost of a bioequivalence study that fails to show bioequivalence can be saved.

Blood Chemical Analysis↗
PubMed1992

The in vivo effect in humans of pyridoxal-5'-phosphate on platelet function and blood coagulation.

Vitamin B6 has an antithrombotic effect. This, based on the results of in vitro studies, has been attributed to an antiplatelet effect. We assessed the in vivo effect of vitamin B6 by measuring the effect of long-term administration of vitamin B6 on platelet function and blood coagulation. Vitamin B6 (pyridoxine hydrochloride), 100mg twice daily p.o. for fifteen days, was administered to 10 healthy volunteers. The bleeding time was measured before the first dose and 15 days after. A baseline value, the acute effect, chronic effect, and the acute-on-chronic effect of vitamin B6 was estimated by measuring platelet function. The following tests were performed: platelet aggregation induced by collagen, ADP and epinephrine; thromboxane A2 (TxA2)-production and prostacyclin inhibition of ADP-induced aggregation. The effects on the coagulation system were monitored by measuring: the prothrombin time, activated partial thromboplastin time and levels of coagulation factor. Vitamin B6 significantly prolonged the bleeding time from 4.1 +/- 1.1 minutes to 6.8 +/- 1.0 minutes (p = 0.0063). Aggregation of platelets with collagen was slightly but not significantly inhibited. Platelet aggregation induced with the agonists ADP or epinephrine was significantly inhibited by vitamin B6, and the platelets tended to aggregate at a slightly decreased rate. The mean TxA2-production was slightly, but not significantly, decreased. Vitamin B6 had no effect on the sensitivity of platelets to prostacyclin, or on the coagulation system. Our results indicate that the antithrombotic effects of vitamin B6 is limited to inhibition of platelet function; there was no measurable influence on coagulation. The results of this in vivo study are however such that clinical trials are warranted to further assess the efficacy of vitamin B6 as an antiplatelet drug.

Blood Coagulation↗
PubMed1992

Caffeine in sport. Influence of endurance exercise on the urinary caffeine concentration.

This study was conducted to evaluate the influence of excessive sweating during long-distance running on the urinary concentration of caffeine after the intake of a large amount of caffeine. Nine endurance-trained athletes participated in a randomised cross-over study in which 450 mg caffeine were taken with and without exercise. Exercise consisted of running for 30 min on a treadmill at 75% of maximum heart rate, one hour after intake of caffeine. This endurance exercise caused a decrease in the urine flow as well as in the amount of caffeine excreted in urine. The combined effect of both these decreases is that the concentrations of caffeine detected in urine were similar with and without exercise. The maximum caffeine concentration detected in any urine sample was 11.9 micrograms/ml without exercise and 10.4 micrograms/ml with exercise. It can be concluded that excessive sweating during long-distance running did not enhance the urinary caffeine concentration.

Adolescent↗
PubMed1992

Safety, tolerance and pharmacokinetics of cefpirome administered intramuscularly to healthy subjects.

The pharmacokinetics of cefpirome were studied in healthy male subjects following single (0.5, 1.0 and 2.0 g) and multiple (1.0 g every 12 h for 3.5 days) intramuscular injections. High pressure liquid chromatography was used to determine cefpirome concentrations in plasma and urine. Cefpirome was absorbed rapidly, mean peak times were 1.6-2.3 h. Pharmacokinetics were linear over the 0.5 to 2.0 g range with mean total body clearance ranging from 148 to 154 mL/min. The peak plasma concentration and area under the curve increased in a dose proportional manner. The terminal half-life (2 h) was not influenced by dose or duration of dosing. There was no drug accumulation after multiple in administrations. About 70-80% of an administered dose was excreted in the urine as unchanged cefpirome. Cefpirome was well tolerated, slight to moderate pain being reported in less than 30% of the injections.

Adult↗
PubMed1992

Recombinant hirudin, a new anticoagulant, has no effect on faecal blood loss.

Hirudin is a selective thrombin inhibitor with strong anticoagulant properties which could elicit gastro-intestinal bleeding. A double-blind cross-over study of the effects of hirudin on gastro-intestinal bleeding was therefore conducted on 12 healthy, consenting males. After labelling erythrocytes with 51Cr and returning them intravenously, stools were collected for 2 days to measure radioactivity and hence baseline faecal blood loss. After injection of hirudin or placebo stools were collected for 3 days. Partial thromboplastin time was measured sequentially after medication with hirudin or placebo. This procedure was repeated after injection of the alternate medication 1 week later. Hirudin was tolerated well. Mean faecal blood loss associated with hirudin was slightly higher than with placebo (1.63 ml vs 1.15 ml over 3 days; 95% confidence interval for the difference between hirudin and placebo was -0.68 to 1.63) but these differences are clinically irrelevant. After hirudin injection PTT was elevated to about twice the baseline values but returned to baseline within 12 h after the last hirudin injection.

Adolescent↗
PubMed1992

The effects of felodipine on the pharmacokinetics of diazepam.

Twelve consenting, caucasian male volunteers participated in a double-blind, randomized, crossover study of the effects of felodipine, a calcium antagonist, on the pharmacokinetics of diazepam. There were two trial periods of 12 days each with a wash-out period of 9 days between them (total duration: 12 + 12 + 9 = 33 days). During the 12-day periods they received either felodipine or placebo each morning under fasting conditions. On day 6 of each of the two 12-day periods, diazepam, 10 mg was injected i.v. 30 minutes after the felodipine/placebo. Diazepam and desmethyldiazepam concentrations were measured in plasma up to 168 hours after the injection. Diazepam plasma concentrations and pharmacokinetic parameters were not affected by the concomitant medication with felodipine. However, the co-administration of felodipine increased desmethyldiazepam plasma concentrations relative to placebo: mean area under the plasma concentration-time curve of 4,910 vs 5,581 ng.h/ml and mean peak concentrations of 40 vs 47 ng/ml. Felodipine might cause a retarded elimination of desmethyldiazepam, possibly by obtruding the formation of oxazepam. The clinical relevance of these findings remains to be elucidated.

Adult↗
PubMed1992

Comparison of absorption rates in bioequivalence studies of immediate release drug formulations.

For immediate release drug formulations, the maximum concentration (Cmax), the time to the maximum concentration (tmax), the mean residence time (MRT), and recently, the Cmax/AUC ratio have been suggested as absorption rate characteristics. Several authors have used simulation studies to investigate the relative merits of these characteristics. In contrast, we investigate here the "true" relationships between these four characteristics in a more theoretical manner. Specifically, we show that in the one-compartment open model the difference in tmax, and the ratio of the Cmax/AUC ratio of two drug formulations are equivalent characteristics for the comparison of the absorption rate of two drug formulations. In two- or higher compartment models these relationships hold approximately. This provides a powerful argument for the use of the observed Cmax/AUC ratio, rather than tmax, as a measure for the rate of absorption, because it is well-known that Cmax/AUC can be observed with higher precision than tmax. We also show that the difference in MRT for two-drug formulations equals the difference in mean absorption time under very general conditions, and for the one- and the two-compartmental model we prove this explicitly. Thus the difference in MRT emerges as the most direct characteristic of the difference in absorption rates, and in that sense is superior to both the tmax difference and the Cmax/AUC ratio. Based on empirical evidence and the results of simulation studies published in the literature we recommend that for drugs with short elimination half-lives, the difference in MRT is the primary characteristic for the comparison of absorption rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1991

Evaluation of nitrendipine--a new calcium channel blocker.

Nitrendipine (Baypress; Bayer-Miles), a new calcium channel blocker, was administered to 38 hypertensive patients in an oral dose of 20 mg once or twice daily. Both systolic and diastolic blood pressures were reduced to a clinically relevant extent within 2 hours of taking the medication. There was no loss of effect during the 57 days of the trial. No significant changes in heart rate were noted. On the whole, side-effects were mild and transient and consisted mainly of dizziness, headache, joint pains and oedema.

Adult↗
PubMed1990

The pharmacology of recombinant hirudin, a new anticoagulant.

A new anticoagulant, recombinant hirudin, was given to healthy volunteers (5 per test dose) in single intravenous doses of 0.01, 0.02, 0.04, 0.07 and 0.1 mg/kg to study its anticoagulant effects, how it was tolerated and its pharmacokinetics. Hirudin proved to be a potent anticoagulant with important effects on thrombin (increase in thrombin time and partial thromboplastin time). The maximum pharmacodynamic effect was achieved with the 0.07 mg/kg dose, and upwards. All doses of the compound were tolerated without side-effects. The mean elimination half-life is about 1 hour. Mean total clearance and volume of distribution are approximately 190 ml/min and 14 l, respectively. Hirudin obeys first-order pharmacokinetics.

Dose-Response Relationship, Drug↗
PubMed1989

Statistical significance versus clinical relevance. Part III. Methods for calculating confidence intervals.

Formulae for calculating confidence intervals for different types of studies and conditions are presented. These include means, proportions, difference in means and proportions for paired and unpaired data, more complicated analyses of variance, medians, quantiles, relative risks (odd ratios), standardised ratios and rates, intercepts, slopes and correlation coefficients in regression and correlation analyses, as well as survival proportions calculated in survival analysis. For less frequently used formulae, examples are included.

Clinical Trials as Topic↗
PubMed1989

Statistical significance versus clinical relevance. Part II. The use and interpretation of confidence intervals.

Most clinical studies are carried out to estimate some quantity, such as a difference in means or proportions. However, significance testing without controlling the power of the test is not an appropriate tool for this purpose, since practical conclusions are difficult (or even impossible) to formulate. The use of confidence intervals, which provide effective information in this regard, is recommended and illustrated by means of an example. With confidence intervals, it can clearly be stated in what range the population value (difference, proportion, or any other point estimate) is likely to lie. A clinically relevant interpretation can then be made without difficulty.

Clinical Trials as Topic↗
PubMed1989

Statistical significance versus clinical relevance. Part I. The essential role of the power of a statistical test.

When comparing two treatment groups, hypothesis testing is widely used. However, clinical trialists should be more interested in statistical methods which elicit the magnitude of the differences between treatment groups, rather than a simple indication of whether or not the differences are statistically significant. Statistical significance does not necessarily imply clinical relevance. If the true difference between two treatment groups is so small that it is clinically irrelevant, a sample size can be found for which this difference is statistically significant. On the other hand, if the difference between treatment groups is statistically non-significant, it may still be clinically important. The limitations of conventional hypothesis testing of equal true means as such are highlighted. The need to control the power of the test--which takes into account the difference in treatment means which is considered important (clinically relevant) by the researcher--is discussed.

Clinical Trials as Topic↗
PubMed1989

Bio-availability of three formulations of glibenclamide.

Eighteen healthy men participated in a double-blind, randomised, crossover study to compare the bio-availability of three 5 mg formulations of glibenclamide. The products compared were Daonil (Hoechst), Glycomin (Lennon) and Melix (Lagamed). Volunteers received a continuous intravenous infusion of glucose at a rate of 0.25 g/kg/h for 10 hours. Two hours after commencement of this infusion medication was given orally with 200 ml of a 10% (m/v) glucose solution. The subjects also drank 200 ml of the glucose solution hourly for 5 hours after medication. Blood samples were taken up to 22 hours after medication for radio-immunoassay of glibenclamide as well as for measurement of glucose concentrations. The following kinetic variables were calculated; maximum concentration, time to maximum concentration, terminal half-life, areas under the serum concentration-time curves, relative total clearance, total mean time and relative volume of distribution. Daonil and Glycomin were bio-equivalent, but important differences were demonstrated between these two formulations and Melix. This study method necessitates close surveillance of volunteers in order to detect and treat hypoglycaemia.

Adolescent↗