Biomedical subjects

L P Balant

Publications and source records attributed to L P Balant.

At least 19 recordsLinked to original sources

PubMed1996

Investigation of xenobiotic metabolism by CYP2D6 and CYP2C19: importance of enantioselective analytical methods.

Investigations into the genetic polymorphism of drug metabolism have involved specific models to screen poor and extensive metabolisers of xenobiotics. Debrisoquine, sparteine, S-mephenytoin and dextromethorphan are particularly well known. They have been extensively described in the literature and are used to phenotype human subjects before performing investigations with new drugs which are believed to be under the control of a genetic polymorphism. Dextromethorphan, debrisoquine and sparteine are good substrates for CYP2D6, whereas the S-enantiomer of mephenytoin is a good substrate for CYP2C19, both being two isozymes of cytochrome P-450. In many drugs, the hepatic microsomal oxidative metabolism involving stereogenic centres congregates either with CYP2D6 or with CYP2C19 or, in certain cases, with both of them. The availability of both CYP2D6 from poor and extensive metabolisers and an enantioselective assay would allow genetic polymorphism in drug biotransformation to be investigated in vitro ex vivo at an early stage of drug development before the IND (investigational new drug). Single-dose investigations in vivo can also be performed when only minimal pre-clinical toxicological data are available and produce more reliable results than in vitro studies. This paper focuses on the problem of genetic polymorphism in drug development and specifically discusses some relevant knowledge gained in the last two decades on enantioselective bioassays. Specific examples are given.

Aryl Hydrocarbon Hydroxylases↗

PubMed1996

New alterations of serum glycoproteins in alcoholic and cirrhotic patients revealed by high resolution two-dimensional gel electrophoresis.

Plasma protein are synthesized and secreted by the liver. Several reports have shown that excessive consumption of ethanol interferes with the hepatic protein synthesis and/or secretion. This study was undertaken to identify the plasma/serum proteins altered in two groups of patients with different alcohol-related diseases: actively drinking alcoholic patients group without liver disease and alcohol cirrhotic patients group. Two-dimensional gel electrophoresis was used to separate proteins with high resolution. Proteins were detected by silver staining and glycoproteins were specifically visualized and analyzed after lectin blotting followed by chemiluminescence detection. Different protein alterations were identified in each group of patients. In the alcoholic group, two new glycosylation modifications of serum proteins were identified. An abnormal microheterogeneity of haptoglobin and alpha1-antitrypsin was detected in the serum of all alcoholic patients. We also characterized by two-dimensional gel electrophoresis the carbohydrate deficient transferrin. The modifications of haptoglobin, alpha1-antitrypsin and transferrin present a similar change of charge and molecular weight in the two-dimensional gel electrophoresis pattern. These qualitative estimations support the hypothesis of a general mechanism of liver glycosylation alteration of serum proteins induced by excessive alcohol consumption. The immunoglobulin alterations were easily visualized and identified for the cirrhotic and the alcoholic patients. And finally, the decrease of haptoglobin and albumin spots for cirrhotic patients was confirmed.

Alcoholism↗

PubMed1996

Practical experience and issues in designing and performing population pharmacokinetic/pharmacodynamic studies.

An expert meeting to discuss issues relating to the design of population pharmacokinetic/pharmacodynamic (PK/PD) studies was held in Brussels in March 1995, under the auspices of the European Co-operation in Science and Technology (COST), Medicine (B1) programme. The purpose of the meeting was to discuss the experts' experience in designing and performing population PK/PD studies. The topics discussed were current practice, logistical issues, ensuring the accuracy of data, covariate assessment, communication, and protocol design.

Belgium↗

PubMed1996

Metabolic interaction between fluoxetine and clomipramine: a case report.

An 83-year-old patient suffering from a depressive episode was treated with a combination of clomipramine and fluoxetine. As no marked improvement was observed and cardiac side-effects were observed, a blood sample was taken for therapeutic drug monitoring. The result showed that the concentrations of clomipramine and desmethylclomipramine were very high (i.e. in the subtoxic range). A metabolic interaction was suspected and both antidepressants were immediately discontinued. Over time, concentrations of clomipramine and its metabolite decreased slowly and, simultaneously, the mood improved and side-effects disappeared. When clomipramine and desmethylclomipramine concentrations reached the lower limit of the optimal therapeutic range, monotherapy was restarted with clomipramine, and the patient improved enough to be discharged from the hospital.

Aged↗

PubMed1996

Antidepressants and drug-metabolizing enzymes--expert group report.

Antidepressant drugs are extensively metabolized. Consequently, the biotransformation pattern of antidepressants has an important influence on their clinical properties, i.e., pharmacokinetics, toxicity, drug-drug interactions, side-effect profile and last but not least therapeutic efficacy. It was against this background that a multidisciplinary group of experts discussed the clinical relevance of the rapidly increasing body of knowledge of antidepressant-metabolizing enzymes. The variability of the response of a given individual to an antidepressant is determined genetically and by the environment. Genetic polymorphism of drug-metabolizing enzymes and inhibition by other substrates may affect the enzymatic biotransformation of antidepressants. In vitro assay techniques allow an estimation of the potential variability in clinical response to antidepressants and a reasonable prediction of the drug-drug interaction patterns. The results of in vitro tests should therefore be considered early in the development of an antidepressant as a background for designing clinical studies (treatment schedules and dosing). Physicians should have an understanding of the relevance of genetic polymorphism for clinical practice. Education is needed in order to fill the existing gaps in knowledge about antidepressant-enzyme interactions and their application in daily treatment practice. The information on potential drug interactions determined by genetic polymorphism and based on studies with enzymes should be increasingly contained in drug compendia.

Antidepressive Agents↗

PubMed1996

The use of population pharmacokinetics in drug development.

Currently, there is an increasing focus on the implementation of pharmacokinetic-pharmacodynamic (PK-PD) studies and modelling as essential tools for drug development. Strategies involving specifically the population approach, which are based on relatively recent statistical methodology (e.g. nonlinear mixed effects modelling, NONMEM) have been advocated for investigating pharmacokinetic and pharmacodynamic variability as well as dose-concentration-effect relationships. The present article outlines this approach, and discusses how it can be implemented within the framework of the studies currently performed as part of the clinical phases of new drug development. It also considers study design and performance, based on real-life experiences. Population approaches, if designed carefully and early, as part of the planning of the drug development programme, are expected to play a significant role at every phase of the programme and to contribute to providing information that is valuable for registration purposes. Statistical methodology and software are now widely available. However, practical issues such as integration of the population approach within existing protocols, quality control of the data, timing of laboratory and statistical analyses, as well as resource allocation, remain legitimate concerns to be considered in prospective studies.

Clinical Trials, Phase I as Topic↗

PubMed1995

Human blood platelet protein map established by two-dimensional polyacrylamide gel electrophoresis.

Two-dimensional (2-D) maps of cytosol and enriched-membrane platelet proteins has allowed the identification of more than 25 spots by three different methods: matching of the platelet gels with other 2-D reference maps, immunoblotting with chemiluminescence detection, and N-terminal sequencing. Different G protein (guanosine triphosphate-binding protein) subunits, cytoskeletal proteins, and proteins common to the human liver, red blood cells and plasma were identified. The two platelet protein maps presented here contribute to the project of identification of human cell and body fluid proteins. They may serve as working tools since platelets are popular models for the study of central nervous system neurotransmitter systems and stimulus-response coupling mechanisms.

Blood Platelets↗

PubMed1995

Ocular availability of gentamicin in small animals after topical administration of a conventional eye drop solution and a novel long acting bioadhesive ophthalmic drug insert.

PURPOSE: Gentamicin eye drop solutions have a short precorneal residence time. The present study investigates the effect of gentamicin using a new long acting delivery Bioadhesive Ophthalmic Insert (BODI) in healthy dogs and rabbits and compares the results with a conventional regimen using an eye drop solution. METHODS: In vivo assays were performed on animals after deposition of one BODI and instillations of an eye drop solution. Tear samples were collected over 72 hours and 60 minutes, in the case of inserts and eye drop solution respectively. The gentamicin concentration profiles in tear fluid (determined by a fluorescent polarization immunoassay technique) was individually analyzed, in each animal, in relation with the minimum inhibitory concentration observed in vitro against some bacteria. A non classical pharmacokinetic approach was used for the analysis of the topically applied drug substance, involving two parameters: the efficacy area under the curve (AUCeff) and the efficacy time (teff). RESULTS: In the case of the eye drop solution, the AUCeff were higher in dogs (2.80 10(3) - 3.64 10(3) [micrograms ml-1 h]) than in rabbits (0.64 x 10(3) - 0.95 x 10(3) [micrograms ml-1 h]); the teff had a similar behavior: 6-15 [h] in dogs and 2-6 [h] in rabbits. In the case of BODIs, the AUCeff and the teff were quite similar between dogs and rabbits: 190 10(3) - 205 10(3) [micrograms ml-1 h] and 70-76 [h], respectively. The AUCeff and the teff were always much higher in the case of BODIs than for the eye drop solution both in dogs and rabbits. CONCLUSIONS: This study shows that topical administration of gentamicin using BODIs can improve treatment due to the decreasing number of applications while ensuring an effective level of antibiotic in tears controlled by the device.

Animals↗

PubMed1995

Potential of concentration monitoring data for a short half-life drug: analysis of pharmacokinetic variability for moclobemide.

The pharmacokinetic variability of moclobemide, a new short half-life reversible selective inhibitor of monoamine oxidase (MAO) was investigated through analysis of concentrations measured during early open clinical use. Eighty-nine depressed patients, aged 21-96 years, were included in the present study. Doses ranged from 200 to 900 mg/day, and the time interval between blood sampling and last drug intake on the previous day was between 8 and 23 h. Intraindividual variability was generally moderate, with a few patients displaying consistently high concentrations despite moderate doses. Interindividual variability for measured concentrations was approximately 300-fold. After concentration decrease with time was taken into account (average half-life estimate of 4.6 h), age was identified as a major factor responsible for between-patient variability. Average concentration increase per decade of age was 38%. Neither gender, weight, height, smoking, nor alcohol intake explained a significant additional part of the variance. Analysis of residuals also suggested that phenytoin co-medication may induce moclobemide metabolism. The present study indicates that concentration monitoring of a newly marketed drug can contribute to gaining insight into its pharmacokinetic behavior and to enhancing its rational use in clinical practice.

Adult↗

PubMed1995

Bioequivalence. An updated reappraisal addressed to applications of interchangeable multi-source pharmaceutical products.

This paper reviews study procedures for bioequivalence trials, mainly addressed to the New Drug Application (NDA) of generic drugs, strictly referring to EU and USA guidelines on this matter. Specific attention is devoted to the most appropriate experimental designs, the size of the volunteer sample, the ethical issues involved, statistics to assess bioequivalence and the accepted standard format for final research reports. Some aspects which create serious problems in bioequivalence trials, most of which not fully covered by the EU and USA specific guidelines, are comprehensively discussed. These include a) drugs with elevated variability; b) endogeneous substances and the management of baseline value; c) modified release formulations; d) prodrugs; e) restrictions to be contained in forthcoming guidelines on chiral medicinal products; f) superbioavailability; g) drugs with elevated half-life and h) cases in which bioequivalence trials should not be needed. As generic drugs cost less than the innovator product, agencies have facilitated their NDA procedures by requiring a dossier on chemistry and pharmacy and a pivotal bioequivalence study to demonstrate that the generic formulation is fully interchangeable with the innovator product. Bioequivalence is thus the key requirement for an NDA of a generic drug, and trials should be planned, conducted and reported in the most appropriate way. With this in mind, this review is an up-to-date reappraisal that should stimulate the attention of scientists and regulatory authorities on some open questions on bioequivalence.

Dosage Forms↗

PubMed1994

Analysis of glycoproteins separated by two-dimensional gel electrophoresis using lectin blotting revealed by chemiluminescence.

The carbohydrate structures of blotted glycoproteins can be analyzed by probing with lectins. The objective of the present work was to optimize the lectin blotting of human plasma glycoproteins separated by two-dimensional gel electrophoresis and the detection by the sensitive chemiluminescence method. The proposed detection method was found to be ten times more sensitive than a standard colorimetric reaction. Furthermore, the generated signals are detected on a X-ray film and provide a permanent record. The method is also very reliable when compared to the colorimetric detection. The present procedure for glycoprotein analysis is particularly well suited for screening changes in glycosylation of proteins in biological samples.

Adamantane↗

PubMed1994

Population approaches in drug development. Report on an expert meeting to discuss population pharmacokinetic/pharmacodynamic software.

An expert meeting to discuss population pharmacokinetic/pharmacodynamic software was held in Brussels in November 1993 under the auspices of the European Co-operation in Science and Technology (COST), Medicine (B1) programme. Recently developed statistical methods offer the possibility of gaining integrated information on pharmacokinetics and response from relatively sparse observational data obtained directly in patients who are being treated with the drug under development. These methods can minimize the need to exclude patient groups and also allow analysis of a variety of unbalanced designs that frequently arise in the evaluation of the relationships between dose or concentration on the one hand and efficacy or safety on the other relationships that do not readily lend themselves to other forms of statistical analysis. The purpose of the Brussels meeting was to evaluate the state of both existing software and software under development, and to specify the needs and wishes of potential users of such software. It was apparent from the meeting that software development for population data analysis is currently a very active area of investigation and that several very good packages are already available, with more in development. The general consensus of the meeting was that well validated, easy to use software was essential to the implementation of the population approach to drug development.

Humans↗

PubMed1994