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D Brockmeier

Publications and source records attributed to D Brockmeier.

At least 37 records · Page 2Linked to original sources
PubMed1988

Penbutolol: pharmacokinetics, effect on exercise tachycardia, and in vitro inhibition of radioligand binding.

The pharmacokinetics of penbutolol 40 mg, its reduction in exercise-induced tachycardia, and the in vitro inhibition of radioligand binding to beta-adrenoceptors by plasma have been investigated in 7 healthy volunteers. The peak penbutolol concentration of 285 ng/ml was observed 1.2 h after administration, and the maximum of 4'-OH-penbutolol of 4.76 ng/ml was found after 1.64 h. Penbutolol was detected for up to 48 h, and 4'-OH-penbutolol dropped below the limit of detection after about 10 h. The terminal plasma concentration of penbutolol declined with an average half-life of 19 h. The maximum reduction in exercise-induced tachycardia was 33 beats/min 2.6 h after taking penbutolol. There was still a significant reduction of about 7 beats/min after 48 h. This effect could be adequately explained by the concentration-time course of penbutolol in combination with Clark's model of the concentration-effect relationship. Antagonist activity in plasma caused 91% inhibition of radioligand binding in vitro to beta 2-adrenoceptors on rat reticulocyte membranes 1.6 h after intake of penbutolol. By 48 h after intake, radioligand binding was still significantly inhibited (23%). The in vitro inhibition of radioligand binding by plasma showed a linear correlation with the reduction in exercise-induced tachycardia for all phases of the workload. The time course of the reduction in heart rate was completely explained by the in vitro inhibition of radioligand binding. However, it was not possible to explain the in vitro inhibition of radioligand binding by the concentration-time course of penbutolol using a simple competition model, although both variables were based on the same sampling site. When the in vitro inhibition of radioligand binding was plotted against the penbutolol concentration at the same sampling times (with both variables transformed to multiples of the apparent inhibition constant) the discrepancy became even more apparent as time-related counterclockwise hysteresis. None of the known metabolites of penbutolol can explain the discrepancy between the penbutolol concentration and the inhibition of radioligand binding in vitro. It appears that an other active metabolite is formed, which contributes to the effect in vitro and in vivo and so can explain the observed discrepancy.

Adrenergic beta-Antagonists↗
PubMed1988

A pharmacokinetic study of roxatidine acetate in chronic renal failure.

The pharmacokinetics of a single oral dose of roxatidine acetate 150 mg were studied in 31 patients with varying degrees of chronic renal failure. The patients were divided into 5 groups according to their creatinine clearance (Clcr): controls (Clcr 94.5 +/- 13.9 ml/min; n = 6); mild chronic renal failure (Clcr 47 +/- 6 ml/min; n = 4); moderate chronic renal failure (Clcr 27.3 +/- 3.1 ml/min; n = 4); severe chronic renal failure (Clcr 12.8 +/- 1.4 ml/min; n = 5) and uraemia (Clcr 6.6 +/- 0.6 ml/min; n = 12). Serum and urine samples were analysed with capillary gas chromatography to measure the salt of the desacetyl metabolite of roxatidine acetate (roxatidine). The terminal half-life was 6.02 +/- 0.31 hours in controls and 7.35 +/- 0.57, 9.3 +/- 0.83, 14.6 +/- 3.7 and 18.10 +/- 2.77 hours, respectively, in the 4 other groups, with progressively decreasing creatinine clearance. Maximum serum concentration and time to maximum serum concentration rose from 816 +/- 75 ng/ml and 2.08 +/- 0.22 hours, respectively, in controls to 1364.7 +/- 156 ng/ml and 4.05 +/- 0.47 hours, respectively, in uraemic patients. Relative total clearance progressively decreased with decreasing glomerular filtration rate (GFR) [from 353.6 +/- 26 ml/min in controls to 90.31 +/- 12.2 ml/min in patients with uraemia]. Renal clearance decreased from a control of 243.9 +/- 56 ml/min to 12.32 +/- 0.18 ml/min in uraemic patients. A linear correlation between creatinine clearance and both relative total clearance and renal drug clearance was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Pharmacokinetics of histamine (H2)-receptor antagonists, including roxatidine, in chronic renal failure.

In this paper the effects of chronic renal failure on the pharmacokinetics of H2-antagonists are reviewed and the results obtained with roxatidine presented. In normal renal function renal clearance is around 60-80% of total plasma clearance of all H2-antagonists. Consequently, prolongation of serum half-life, mainly due to a decrease in urinary excretion, is noted in patients with decreasing glomerular filtration rate. In chronic renal failure, a dose reduction is therefore necessary with all H2-antagonists, including roxatidine. It appears that neither haemodialysis nor peritoneal dialysis substantially influences the pharmacokinetics of these drugs. Therefore, the same dosage schedule as in uraemia may be applied in patients with dialysis. Finally, in the elderly the dosage of all H2-antagonists should be adapted to the expected decrease in renal function.

Anti-Ulcer Agents↗
PubMed1986

The absorption of piretanide from the gastro-intestinal tract is site-dependent.

The absorption of piretanide was investigated after placing the drug in the stomach, duodenum and ascending colon under visual control. The relative amounts absorbed and the rates of absorption were estimated from the area under the curve and the total mean time, respectively. Similar amounts of piretanide were absorbed and at almost the same rate after placement in the stomach and duodenum; the area under the curve for the stomach was 250 ng h/ml and for the duodenum 243 ng h/ml, the mean absorption times being 1.97 h and 1.51 h respectively. A marked difference was observed in the rate of from the ascending colon; the area amounted to 66 ng h/ml and the mean time to 3.99 h. Although area values for the colon were significantly different from those observed with the stomach and duodenum, it must be emphasised that the amount absorbed depends on the time the drug is in contact with the absorbing surface. There is discussion of whether the differences in absorption between the duodenum and colon can be explained by the physico-chemical properties of the drug alone, or whether the results reflect a saturable transport mechanism.

Adult↗
PubMed1986

Mean residence time.

The definition of mean residence time in the strict sense of mathematical statistics is deduced. It is demonstrated that the area-normalized concentration time curve is an estimate of the probability density function for residence times of drug molecules in the pharmacokinetic system, provided that the area under the concentration-time profile is proportional to the total amount eliminated from the system. Criticisms (8) on the determination of the mean residence time are refuted. The linearity of pharmacokinetic systems is defined, based on the statistical interpretation of these systems.

Humans↗
PubMed1986

Model-free evaluation and mean-time concept in pharmacokinetics.

Pharmacokinetic characteristics may be separated into three classes: firstly, those which are truly independent of pharmacokinetic modelling - curve characteristics for instance, such as Cmax or tmax, but also organic clearance values; secondly, those which can be evaluated without an explicit pharmacokinetic model but under basic assumptions - characteristics such as total clearance, mean and variance of residence times or total volume of distribution; and thirdly, those which are bound to elaborate pharmacokinetic models, such as hybrid constants, micro-constants or partial volumes of distribution. It can be demonstrated that the second class - the model-independent evaluated characteristic - and the third are mutually transferrable; examples of this transcription are given. However, these purely theoretical considerations can only demonstrate that the second class is consistent with classic pharmacokinetic modelling. The usefulness of the model-independent evaluated characteristic is underlined by results of clinical pharmacological investigations in which this technique was applied. The topics addressed by these studies cover the problems of deep compartments, differences in absorption, influence of disease, drug interaction, and first-pass metabolization. Since the mean-time concept in particular is still controversial in the literature, some general theoretical explanations seem to be necessary.

Humans↗
PubMed1986

Kinetics of piretanide absorption from the gastrointestinal tract.

In a recent report, it was shown that the loop diuretic piretanide is rapidly absorbed after placement of a piretanide solution in the duodenum, while the rate of absorption is definitely slower when the drug is instilled into the ascending colon (5). When piretanide is instilled into the stomach, the absorption process does not differ significantly from that after placement in the duodenum, neither with respect to amount nor rate (5). However, it was not clear from this study whether piretanide is directly absorbed from the stomach or rapidly released into the duodenum. In a study with five volunteers piretanide was instilled into the stomach via a gastroscope. The volunteers took part in two trial phases in a randomized cross-over design: in one phase the administration of 6 mg piretanide was preceded by intravenous administration of 40 mg hyoscine-N-butylbromide (HNB) to immobilize the stomach while in the alternative phase this coadministration of HNB was omitted. Furthermore, the volunteers were lying on their left side to avoid the gastric fluid leaking out into the intestine by gravity. From the concentration-time-curves monitored it can be concluded that piretanide is absorbed directly from the stomach for almost all subjects but with different rates. The rate of absorption increases clearly when the immobilizing effect of HNB disappears. It is most probable that returning peristaltic waves and succeeding gastric emptying results in enhanced absorption from the upper intestinal tract. Furthermore, a pharmacokinetic model which takes into account the differences in the rate of absorption along the gastrointestinal tract was adjusted to the data.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

In vitro--in vivo correlation of dissolution, a time scaling problem? Transformation of in vitro results to the in vivo situation, using theophylline as a practical example.

Two principal approaches to demonstrating the continuous in vivo relevance of an in vitro dissolution test are outlined. The first uses the convolution technique to predict the concentration-time course in vivo; the second uses deconvolution as a mathematical tool to estimate the in vivo dissolution profile. The weighting function must be known to utilise either technique. Defined by the aim of the analysis the dose-normalized response to the oral solution is regarded as the weighting function (Impulse Response). In both cases the essential step is continuous comparison of the predicted time dependent data with actual readings of the same class. To permit the prediction of concentration-time data from in vitro dissolution data the basic equations for the transformation of the time base from in vitro to in vivo conditions are developed. The transformation is essential, since one cannot assume that the time scales for the in vitro and the in vivo experiment are definitely the same. The estimated in vivo dissolution profile using the deconvolution technique gives a hypothetical image of the true in vivo dissolution curve. Comparison with in vitro dissolution test results, using one of the equivalence testing procedures, reveals how closely and for how long the in vitro dissolution test simulates the in vivo dissolution process. For the formulation of theophylline studied, equivalence of the in vitro and the estimated in vivo dissolution profiles was not confirmed for the entire period of observation, but it was demonstrated for approximately the first 5 h. The later inequivalence is not due to possible non-linear or time-dependent kinetics of theophylline. There is a discussion of whether a change in pH, agitation of the formulation, diffusion conditions or the absorption rate constant along the gastrointestinal tract might explain the biphasic linear correlation of the in vitro and in vivo data observed.

Adult↗
PubMed1985

Pharmacokinetics of an extended-release dosage form of molsidomine in patients with coronary heart disease.

Molsidomine (N-carboxy-3-morpholino-sydnonimine-ethylester; Cassella-Riedel Pharma GmbH, Frankfurt/M. FRG) has an antianginal effect for up to 3-5 h after oral administration of 2 mg Corvaton [1]. Plasma levels of the parent drug can be measured during this interval. A new galenic formulation (Corvaton retard) has been developed to prolong the duration of the therapeutic action and to improve patient compliance. The present study was carried out to establish whether the in vitro dissolution profile of the tablet was reflected in vivo, thus permitting prediction of plasma molsidomine levels in patients with coronary heart disease.

Aged↗
PubMed1985

Mean time and first-pass metabolism.

The theoretical principles are outlined for estimating the fraction of a drug undergoing first-pass metabolism using only the plasma levels found after a single oral dose. Data for 3 drugs are used to illustrate the method. It involves analysis of the parent drug and the metabolite formed during the first passage through the gut wall and liver and evaluation of their total mean times. The mean time characteristics of molsidomine, nortriptyline and propranolol are considered and they confirm the theoretically deduced dependency of the mean time of the parent drug and the metabolite. Whether the results are more precise than those obtained from comparison of areas after oral and intravenous administration is discussed. From the data presented it is clear that the mean time method depends on the scatter inherent in the data. In order to estimate the true first-pass effect, greater scatter requires an increased number of data pairs, i.e. subjects. If intravenous data are not available, however, the method described provides a rough but worthwhile estimate of the first pass effect.

Humans↗
PubMed1985

Absorption of glibenclamide from different sites of the gastro-intestinal tract.

In a study of eight volunteers and six patients, glibenclamide was placed at different sites of the gastro-intestinal tract under visual control. The dose was instilled once into the stomach and once into the duodenum of the eight volunteers in a randomized crossover design. The six patients underwent diagnostic colonoscopy, and the dose was placed into the ascending colon if pathological findings were not present. The area under the concentration-time curve, completed by extrapolation, and the mean residence time of the drug in the body were calculated. These pharmacokinetic characteristics were examined using a Jonckheere test for ordered alternatives and a Wilcoxon signed rank pair test. The means of the areas under the curve were 477 +/- 131 ng . h ml-1 for the stomach, 475 +/- 142 ng . h ml-1 for the duodenum and 486 +/- 301 ng . h ml-1 for the colon. The mean residence time changed from 2.67 +/- 0.35 h for the stomach to 2.42 +/- 0.48 h for the duodenum and 3.55 +/- 0.68 h for the colon. These results indicate that although glibenclamide is absorbed from all three sites of the gastro-intestinal tract to the same extent, the rates of absorption are different. It is discussed whether these findings really confirm the pH-partition hypothesis in drug absorption. Since glibenclamide--a weak acid--has a pK-value of about 6.5, these data seem to confirm the pH-partition hypothesis of drug absorption.

Adolescent↗
PubMed1984

In vitro-in vivo correlation, a time scaling problem? Evaluation of mean times.

A new algorithm for the calculation of the mean time and further statistical moments is presented by means of a mathematical deduction which is outlined in brief. The graphical interpretation of the mathematical results demonstrates that the calculation is easy to perform. Furthermore the method is illustrated in detail with data from a sustained release formulation of theophylline. These data were obtained from a clinical study and from an in vitro dissolution test with the same formulation. Statistical analysis revealed that the rate of release in vivo was slower than in vitro by a factor of 0.7, using a commercial dissolution model. Implications of this approach with respect to in vitro - in vivo correlations are discussed.

Kinetics↗
PubMed1983

[Pharmacokinetic aspects of excretory urography in children].

Contrast media able to pass through the kidney were a major advance in the field of radiodiagnostics. Excretory urography is usually performed using metabolically-inactive substances which accumulate in the kidney and kidney-pelvis. A two-compartment model has always been used so far for pharmacokinetic evaluation of this. However, in doing so, the kidney pelvis was not taken in account. A further compartment was therefore added to this model which enables all the physiological processes demonstrated by excretory urography to be included in the evaluation. With this model, blood and urine levels can be used at the same time to calculate pharmacokinetic variables, as shown in 6 pediatric patients. In addition to the cumulative excretion of urine and blood levels of the contrast medium, the concentrations of the latter in the renal pelvis are shown. Particular attention is paid to the effects of two important factors in investigations using contrast medium--diuresis and total body fluid volume.

Adolescent↗
PubMed1982

In vitro--in vivo correlation, a time scaling problem? Basic considerations on in vitro dissolution testing.

The profile of cumulative amount released from a solid dosage form, observed in an in vitro liberation apparatus, represents the cumulative frequency of the residence times of drug molecules in the galenic formulation. The profile of release over time is usually affected by the dissolution models as well as by the experimental conditions. Such differing dissolution curves may become superimposable by a simple linear transformation of the time base. This is clearly demonstrated by two completely different retard formulations, film coated pellets and an erosible matrix tablet, which were tested in two dissolution apparatus, the Sartorius dissolution model and the USP-Paddle model. The parameters used in the transformation of the time base can be evaluated from the statistical moments of the residence times; the moments themselves are calculated from the cumulative frequency functions. The term "equivalence" of dissolution profiles is defined and discussed. The outlined considerations and methods are immediately transferable to the comparison of in vitro and in vivo liberation conditions.

Biopharmaceutics↗
PubMed1981

[Reconstruction of dissolution profiles of microcapsulated formulations by the mean and variance of dissolution times (author's transl)].

The influence of drug bioavailability on therapeutic regimens has increased the interest in in vitro dissolution testing and the quantitative interpretation of dissolution profiles. The mean and variance of in vitro dissolution times are appropriate parameters for discriminating different dissolution profiles. This article demonstrates that both parameters can easily and immediately be derived from dissolution data. Moreover, it is shown that the mean and variance of in vitro dissolution times define the parameters which appear in the model equation of a linear transport process. This model equation is proved to be valid for five formulations of N-carboxy-3-morpholinosydnone imine ethyl ester (molsidomine, Corvaton). It is applicable to dissolution data from a great variety of pharmaceutical formulations, provided that the dissolution process consists of a sequence of independent events. The model parameters are found by two different methods: by direct computation from the mean and variance of the dissolution times and by non-linear least-square parameter estimation. Both methods are compared on the basis of their resulting sum of squares (F-Test). The new pragmatic, statistical approach of data examination proves to be as effective as established routines.

Biological Availability↗