Biomedical subjects

R Süverkrüp

Publications and source records attributed to R Süverkrüp.

15 recordsLinked to original sources

PubMed2000

Dose uniformity and redispersibility of pharmaceutical suspensions 2: assessment of three commercial erythromycin ethyl succinate oral liquids.

The content of active ingredient of single doses of a suspension depends to a large extent upon the redispersibility of the product. Mathematical and technical aspects of a procedure to test this property have been discussed in a preceding article. Here, the method is applied to three commercial erythromycin ethylsuccinate suspensions obtained from community pharmacies in Germany. Three specimens of each product were tested in parallel. For approximately two weeks, samples were taken t.i.d. at 9 am, 1 pm and 5 pm after shaking the bottles on a prototype testing apparatus with an intensity of 134m(2)/s(3) per cycle corresponding to the 25th percentile of a group of 79 subjects, whose shaking habits had been assessed previously. In order to minimize volumetric errors, 2.5ml samples were drawn using a syringe. They were assayed by HPLC with electrochemical detection using oleandomycin as an internal standard. While one of the products performed satisfactorily and one showed moderate shortcomings, the dose uniformity of two specimens of the third product was clearly deficient. The problem seems to be associated with poor wetting behaviour of the solids.

Administration, Oral↗

PubMed1999

Dry Drops: a new preservative-free drug delivery system.

PURPOSE: We compared the tolerability and safety of a lyophilisate (Dry Drops) with conventional eye drops containing the same polymer and electrolytes. In Dry Drops the active ingredient is incorporated in a drop of hydrophilic polymer solution freeze-dried on the tip of a soft hydrophobic carrier strip. Upon contact with tear film and/or conjunctiva the lyophilisate immediately rehydrates and detaches from the carrier. METHODS: Dry Drops containing HPMC as active ingredient and a preservative-free tear film substitute were applied to 64 eyes of 32 healthy volunteers according to a 22 factorial design in an open-label, cross-over, randomised study. Tolerability and safety were quantified and qualified at 0.5, 2, 5 and 10 min after administration via slit-lamp biomicroscopy, questionnaire and visual analogue scales. RESULTS: The differences between Dry Drops and conventional eye drops were not statistically significant. The initial sensation of Dry Drops was slightly less uncomfortable than that of the conventional ophthalmic solution. None of the eyes showed any clinical findings with safety implications. CONCLUSION: The safety and tolerability of a new application form were demonstrated in this phase I study. The improved chemical stability, exact dosing, reduced risk of lesions to the eye surface and good tolerability suggest that the new application device has promise for treatment in ophthalmology as well as in other medical subspecialties.

Adult↗

PubMed1999

Dose uniformity and redispersibility of pharmaceutical suspensions. I: Quantification and mechanical modelling of human shaking behaviour.

Precision and uniformity of single doses are required for most dosage forms including suspensions for oral and ophthalmic administration. Therefore, solids forming sediments or aggregates must be distributed homogeneously immediately before use. If settling occurs, leading pharmacopoeias require that suspensions be redispersible by shaking, but a standardised testing procedure for this property is not available. Obviously, such a test will have to be based upon observations of human shaking patterns. We report the results of a study in which human shaking acceleration profiles were measured and the shaking intensity characterised by the area under the frequency spectrum obtained by Fourier transform of the autocorrelation function. We also present a prototype of a mechanical redispersibility tester, which is more flexible and simulates human shaking behaviour more closely than its pneumatic forerunner, which was described earlier.

Adolescent↗

PubMed1999

Pharmacokinetic-pharmacodynamic modeling of tolerance to the prolactin-secreting effect of chlorprothixene after different modes of drug administration.

The objective of this study was the construction of a pharmacokinetic-pharmacodynamic model to describe the effects of chlorprothixene on prolactin secretion and the time-dependent alterations in the concentration-effect relationship due to tolerance development. Prolactin and chlorprothixene serum concentrations were determined in eight healthy men for up to 72 h after the intravenous and oral administration of chlorprothixene. An integrated pharmacokinetic model and a physiological indirect pharmacodynamic/tolerance model were applied to describe the prolactin-secreting effect of chlorprothixene. A three-compartment model served as pharmacokinetic model. The pharmacodynamic and tolerance model accounted for the baseline effect, the effect induced by the drug, and the regulatory mechanism that opposes the effect of the drug. This model adequately characterized the prolactin response after intravenous and oral drug administration of each individual by the sensitivity (dissociation constant), the efficacy (maximal prolactin secretion rate), the extent, and the rate of tolerance development. We speculate that this approach improves the quality of neuroendocrine challenge tests to determine the subject's sensitivity to drugs and the time course of adaptation.

Administration, Oral↗

PubMed1997

Production of artificial urinary stones from natural materials and their physical properties. First results.

Considered from a clinical point of view, all artificial stones known so far are inappropriate for experimental investigations, because they do not correspond to natural urinary stones in shape, physical properties and chemical composition. A special technique has now been developed for the production of biometric artificial stone models. Standard artificial carbonate apatite stones were produced by a coating technique where several layers of a suspension consisting of pure substance were applied around a core. Density and crushing strength of these ball-shaped artificial stones corresponded to natural apatite stones. Experimental chemolitholysis investigations showed comparable results in respect to the dissolution of artificial apatite stones and of natural stones of the same chemical composition. The disintegration behaviour was studied in ESWL tests which revealed a correlation between generator voltage and number of shock waves necessary for complete disintegration. For the first time, an artificial urinary stone has now been produced which is comparable to a natural stone of the same chemical composition not only in shape but also in its physical properties and lysis behaviour. These stones are suitable for use in systemic scientific investigations on disintegration and chemolitholysis.

Apatites↗

PubMed1996

Mean input times of three oral chlorprothixene formulations assessed by an enhanced least-squares deconvolution method.

The efficacy and quality of drug formulations are determined mainly by their bioavailability, which is defined by the rate and extent of drug absorption. The zero and first moments of the serum concentration time profile provide relevant information on the bioavailability. On the basis of the body residence time distributions, mean input times may be used as drug absorption rate parameters, but due to computational errors the statistical moments procedure is in some instances of limited value. To circumvent these problems we have developed a procedure to calculate mean input times from input profiles obtained by least-squares deconvolution. We enhanced the performance of the deconvolution method by directly generating initial estimates of one input rate for each sampling interval and compared the statistical properties of various input rate characteristics using data from a bioavailability study on four chlorprothixene preparations. The analysis of variance revealed that estimates of mean input times depended on the calculation procedure. Mean input times estimated by the least-squares deconvolution method were more reliable and less variable than those computed as differences of mean body residence times.

Administration, Oral↗

PubMed1996

Pharmacokinetics of chlorprothixene after single intravenous and oral administration of three galenic preparations.

The absolute and relative bioavailability of chlorprothixene (CAS 113-59-7, Truxal) was studied in eight healthy male volunteers with three different formulations: solution, suspension and coated tablet. An intravenous infusion and an oral aqueous solution served as references. Single doses of 100 mg were administered in a randomized complete-block design with washout periods of two weeks. Serum concentrations of chlorprothixene were assayed using a high-performance liquid chromatographic method with electrochemical detection. After a 1-h infusion period the maximum serum concentration (Cmax) of chlorprothixene was 430 +/- 81 ng/ml (mean +/- S.D.) and subsequently decreased with a terminal elimination half-life (t1/2) of 25.8 +/- 13.6 h. The total serum clearance (Cl) and the apparent volume of distribution at steady state (Vss) were 867 +/- 167 ml/min and 1035 +/- 356 l, respectively. The profiles of the chlorprothixene serum concentration vs. time and the resulting pharmacokinetic parameters were similar for all orally administered formulations. The absolute oral bioavailability of 17% of the solution indicated a marked presystemic metabolism. The bioavailability of chlorprothixene relative to the oral solution was 56.4% with the coated tablet and 67.7% with the suspension. All pharmacokinetic parameters showed wide inter-subject variations, partly attributable to the respective formulation.

Administration, Oral↗

PubMed1994

The extension grade: a model-unspecific rate characteristic derived from steady-state plasma level fluctuations.

The rate aspect of bioavailability for pharmaceutical dosage forms in general and sustained-release preparations in particular can be quantified by an extension grade (EG), which is readily computed from steady-state data after administration of a test product and a suitable reference. Although the EG is unrelated to specific pharmacokinetic models or statistical moment analysis, interindividual differences of disposition kinetics are properly accounted for. It characterizes drug input in its entirety (i.e., the combination of drug release and absorption kinetics) and assumes values in the interval [0, 1]. Its properties resemble in several respects those of the area under the concentration versus time curve quotient F, which indicates the extent of bioavailability. The EG can be calculated from steady-state plasma levels and urinary excretion rates and from corresponding profiles observed after administration of single doses. It is easy to implement specific experimental designs for the determination of the EG.

Biological Availability↗

PubMed1990

[Bioequivalence of theophylline retard capsules in children and relation of metabolism to administration route].

The bio-availability of two slow-release theophylline capsules employing different sustained-release principles, was investigated in 12 children suffering from bronchial asthma, on this basis of the renal excretion of the unchanged active substance. With the aid of a model-bound convolution procedure, the completeness and the variability of absorption on multiple dosaging under non-steady-state conditions were established. Depending upon the retardation principle, both the mean bioavailability and its scatter differed from one preparation to the other, one of them being, on average, more completely absorbed than the other, while, at the same time, showing an appreciably more variable bio-availability. In consequence of the first pass metabolisation, the percentage of theophylline that was excreted unchanged in the urine, was greater with the intravenous route of administration than with peroral application. In the case of the secondary metabolite 3-methylxynthine, the situation was reversed.

Adolescent↗

PubMed1989

Numerical stability of pharmacokinetic deconvolution algorithms.

The sensitivity of pharmacokinetic deconvolution algorithms with respect to simulated experimental error has been studied. Approximations of cumulative absorption profiles reconstructed from simulated data sets with normally distributed random error were compared with corresponding known input functions. The coincidence of both functions was assessed in 600 numerical experiments by the nonparametric Kolmogorov-Smirnov test. A constrained iterative nonlinear regression procedure based on the analytical convolution of multiphasic zero-order input functions with linear disposition models was found to perform well under conditions where the results of direct numerical deconvolution and model-based mass balance methods were unsatisfactory.

Absorption↗

PubMed1989

Renal clearance of theophylline and its major metabolites: age and urine flow dependency in paediatric patients.

The renal clearance of theophylline (TH) and its metabolites 1,3-dimethyluric acid (1,3-DMU), 3-methylxanthine (3-MX), and 1-methyluric acid (1-MU) has been studied in 10 children aged 8 months to 14 years. Individual renal clearances were calculated from serum levels and amounts excreted in urine after i.v. administration of the parent drug. The clearance of 1,3-DMU was found to depend both upon urine flow rate and age, which are interrelated. An effect of urinary pH was expected, but was not studied. Consistent age-dependent changes in the relative quantities of metabolites excreted were not observed.

Adolescent↗

PubMed1987

Total theophylline clearance in childhood: the influence of age-dependent changes in metabolism and elimination.

Theophylline metabolism and elimination during childhood are age-dependent. The total clearance, which is the sum of metabolic and renal clearances is highest in infants and young children. To differentiate between the two pathways, theophylline concentrations were measured in both serum and urine in 16 children aged 2 weeks-16 years using the fluorescence polarization immunoassay. It was found that both partial clearances assume maximal values at about the same age, but the fraction of total clearance attributable to the renal route decreases continuously.

Adolescent↗

PubMed1985

Segmentally continuous input functions in linear multicompartment systems.

The convolutions of segmentally continuous zero- and first-order input functions with the general form of pharmacokinetic multicompartmental disposition functions can be used to analyze and simulate the time course of drug invasion into the central compartment of mammillary models and certain physiologically relevant recirculating systems. The generalized model equations may be used to assess the reliability and intercorrelations of parameter estimates directly, since partial derivatives with respect to all model constants can be computed explicitly. In combination with curve-fitting algorithms, input functions identical to those of the point-area deconvolution can be obtained, although at the expense of significantly longer computing times. On the other hand, the range of potential applications goes far beyond the reconstruction of the time course of drug absorption.

Bile↗

PubMed1979

Discontinuous absorption processes in pharmacokinetic models.

The limited contact time of absorbable drug with absorbing surfaces is, in some cases, a significant factor determining the fraction of the dose absorbed. A simple modification of customary linear compartmental models is presented to account for this situation, and a general input function in the Laplace domain for truncated first-order absorption is derived. An extension to series of truncated absorption processes is discussed.

Absorption↗

PubMedDate not supplied

[Dosage problems in suspension eyedrops].

PURPOSE: In opthalmic suspensions, the mean dose and the uniformity of amounts administered in single drops depend upon the redispersibility of drug particles by shaking. The present article is a contribution to the development of the experimental and theoretical basis for a reproducible test, by which the dose uniformity of suspension eyedrops can be assessed under therapeutically relevant conditions. The requirement that suspension eyedrops and similar dosage forms should be redispersable after sedimentation upon storage is stated in the monographs on eyedrops of the German Pharmacopoeia and can be found in similar contexts in other pharmacopoeias. Until now, however, no corresponding test method has been specified. METHODS: Shaking profiles were recorded in 31 subjects and 27 patients using an acceleration sensor. They were compared with the acceleration profile of a computer-controlled pneumatic shaker and sampler. Both frequency and intensity of the shaking action were quantified by Fourier analysis of the acceleration profiles. The drug content of single drops of Isopto-dex (0.1% dexamethasone), Chibro-Amuno 3 (1% indomethacin), and Inflanefran-forte (1% prednisolone acetate) was assessed exhaustively in four 5-ml specimens of each ophthalmic suspension using the apparatus. The dose uniformity of single drops of suspension eyedrops was measured by UV-spectrophotometry for the entire contents of bottles. Four samples per day were drawn after six shaking cycles for approximately 4 weeks with three intervals of 4 h during daytime and 1 interval of 12 h during the night. RESULTS: The shaking intensity of patients was lower than that of healthy subjects, while the frequency was similar for both groups. The intensity of the apparatus corresponds to the 67th percentile of the patients and to the 18th percentile of the healthy subjects. It was sufficiently close to the central values of both distributions to allow comparisons. for Isopto-dex, the mean drug content of 9.5 microns per drop amounted to only 25% of the value expected after complete redispersion, with a coefficient of variation (CV) of 23%. The mean value for Chibro-Amuno 3 was 93% of the expected quantity of indomethacin with a CV of 34%, while the mean content of Inflanefran-forte drops was 95% of the labelled dose with a CV as low as 9%. CONCLUSION: The drug content of single drops of ophthalmic suspensions can be studied under well-defined and reproducible conditions by means of a computer-controlled pneumatic shaking and sampling apparatus. Under the conditions prevailing in this study, the solidified sediment of Isopto-dex was incompletely redispersed, so that doses were significantly too low. A variable dosing pattern with acceptable mean was observed for Chibro-Amuno 3, while the results for Inflanefran-forte were fully satisfactory.

Adult↗