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Biomedical subjects

I Klebovich

Publications and source records attributed to I Klebovich.

At least 37 records · Page 2Linked to original sources
PubMed1997

Human bioequivalence study of a new nifedipine containing retard filmtablet after single and repeated administration.

A clinical pharmacokinetic bioequivalence study with two retard filmtablet preparations, both containing 20 mg of nifedipine (CAS 219829-25-4) was carried out. The investigated test preparation was Cordaflex 20 mg retard filmtablet. The pharmacokinetic parameters were determined after single and repeated administration in 15 and 16 healthy male volunteers, respectively, in open, randomised studies of cross-over design. Plasma levels of nifedipine were determined by HPLC with electrochemical detection using a robotic sample preparation technique. Statistical comparison of the pharmacokinetic parameters (AUC0-infinity, AUCss, tau tmax, Cmax, Css,min, Css,av, MRT, etc.) calculated from plasma concentration-time curves by ANOVAlog, confidence interval, Schuirman's, Westlake's, Anderson's and Wilcoxon's tests, furthermore the comparison of the clinical results did not show any significant difference between the two preparations. It is concluded that the two preparations are bioequivalent after repeated administration.

Adult↗
PubMed1997

[Bioanalytic examination and pharmacokinetics of captopril. Bioequivalence studies of different captopril-containing Tensiomin preparations].

The authors of the present report reviewed the literature of various bioanalytical methods for the pharmacokinetics and metabolism of captopril and present their own results obtained in bioanalytical and pharmacokinetic studies. The authors performed a detailed comparative clinical, pharmacokinetic and bioequivalence study, in Hungary, with 3 different captopril tablets, 50 mg each, namely with Tensiomin (EGIS Pharmaceuticals Ltd.), as test preparation and Capoten (E.R. Squibb & Sons, Inc.) and Lopirin (Squibb Pharma GmbH) as reference preparations. Bioequivalence study of Tensiomin and Capoten preparations both containing 100 mg of captopril was carried out in the United States. Relative bioavailability and comparative pharmacokinetic parameters were determined in 24 and 25 healthy volunteers, respectively, in single-dose, randomised studies of three-way (50 mg) or two-way (100 mg) cross-over design. The individual pharmacokinetic parameters determined for the test and reference preparations with different active principle content were tmax, Cmax, AUCOo-t, AUCo-infinity t beta 1/2, Cmax/AUCo-infinity. Statistical evaluation of the results of bioequivalence studies was made using confidence interval calculation and the Test/Reference ratio (50 and 100 mg), and by Schuirmann's, Hauck-Anderson's, Westlake's, Wilcoxon's methods (50 mg) and power test (100 mg). All the above tests indicated statistical equivalence between the test and reference preparations. The test and reference preparations of different strengths had identical relative bioavailability. Accordingly, the clinical and biological equivalence of 50 mg and 100 mg Tensiomin tablets with 50 mg and 100 mg Capoten tablets and 50 mg Lopirin tablet have been demonstrated in two independent comparative bioequivalence studies.

Administration, Oral↗
PubMed1997

Pharmacokinetic and bioequivalence study of two gemfibrozil preparations.

A comparative pharmacokinetic study has been performed in 19 healthy male volunteers in a single-dose, randomized, two way cross-over design with two preparations of gemfibrozil (CAS 25812-30-0) capsules each of them containing 300 mg active ingredient. The test preparation was Innogem 300 mg capsule. The plasma concentration of gemfibrozil was determined by a validated HPLC-UV analytical method. The statistical comparison of individual pharmacokinetic parameters (AUC0-16, AUC0-oc Cmax, tmax) of the two capsule preparations was performed by three-way analysis of variance (ANOVA), Wilcoxon's, Westlake's, Schuirmann's and Hanck-Anderson's method as well as by the calculation of confidence intervals on the ratio of test/reference. The relative bioavailability of the test preparation with respect to the reference preparation in terms of the AUC0-oc was 104.06 +/- 21.61%. No statistically significant difference was found between the pharmacokinetic parameters, calculated from plasma concentration-time curves, indicating that the two preparations were bioequivalent.

Adult↗
PubMed1996

Sensitive high-performance liquid chromatographic determination of nifedipine in dog plasma using an automated sample preparation system with laboratory robot.

Nifedipine, a calcium-channel blocking drug was analysed in dog plasma after oral dosing with two different formulations. Sample preparation was automated with a laboratory robot. Quantitative determination of the drug was performed on a reversed-phase HPLC system with electrochemical detection (ED) using an internal standard. Validation of the analytical method showed that the system is well suited for pharmacokinetic studies on dogs. The assay was linear in the range 1-50 ng/ml. Inter-day and intra-day variability were between 6.43-18.15% C.V. and 1.57-5.53% C.V., respectively.

Animals↗
PubMed1996

Determination of alpha-methyldopa in human plasma by validated high-performance liquid chromatography with fluorescence detection.

A sensitive reversed-phase gradient elution high-performance liquid chromatographic method with fluorescence detection has been developed for the determination of alpha-methyldopa (AMD) in human plasma. Separation of the investigated compound and the 3,4-dihydroxyphenylalanine (DOPA) internal standard was achieved on a Nucleosil 7 C18 column with a 5 mM heptanesulphonic acid sodium salt containing 0.05 M potassium dihydrogenphosphate (pH 3.2)-acetonitrile mobile phase. The composition of the mobile phase was changed according to a linear gradient time program. Detection was performed at 270 nm fluorimetric excitation and 320 nm emission. The compounds were isolated from plasma by Bond-Elut C18 solid-phase extraction. The limit of quantitation was found to be 10 ng/ml plasma. The assay was validated with respect to accuracy, precision and system suitability. All validated parameters were found to be within the 20% required limits. On the basis of the sensitivity, linearity and validation parameters the developed analytical method was found to be suitable for application in a bioequivalency study.

Chromatography, High Pressure Liquid↗
PubMed1996

Simultaneous determination of nerisopam, a novel anxiolytic agent showing polymorphic metabolism, and its N-acetyl metabolite from human plasma by a validated high performance liquid chromatographic method.

A sensitive reversed-phase high-performance liquid chromatographic method with ultraviolet absorbance detection has been developed to simultaneously determine the concentrations of nerisopam (EGIS-6775) and its N-acetyl metabolite (EGIS-7649) from human plasma. The separation of the investigated compounds and internal standard was achieved on a Nucleosil 7 C(18) column with 2 mM heptanesulphonic acid containing 0.04 M phosphoric acid-acetonitrile-methanol (70:25:5, v/v), pH 2.7 mobile phase. The detection was performed at 385 nm. The compounds were isolated from plasma by Bakerbond C(18) solid-phase extraction. The limit of quantitation was 10 ng/ml plasma for each compound investigated. The assay has been validated with respect to accuracy, precision and system suitability. All validated parameters were found to be within the necessary limits. On the basis of the sensitivity, linearity and validation parameters, the developed analytical method was found to be suitable for the determination of nerisopam and its N-acetyl metabolite from human plasma and for application in pharmacokinetic studies and human drug monitoring. The pharmacokinetic parameters obtained from twelve human volunteers are reported. It was found that nerisopam acetylation is polymorphic: the volunteers with fast or slow acetylator phenotypes produced significantly different plasma concentrations. In slow acetylator phenotypes the concentration of nerisopam was considerably higher in plasma, while the level of its acetyl metabolite was higher in plasma of fast acetylators.

Anti-Anxiety Agents↗
PubMed1996

[Comparative human pharmacokinetic studies of 20 mg nifedipine-containing Cordaflex and Adalat film coated retared tablets].

Comparative pharmacokinetic studies have been carried out with two 20 mg nifedipine active substance-containing retard film coated tablets, Cordaflex produced by EGIS Pharmaceuticals Co., Ltd. and Adalat of Bayer AG. The pharmacokinetic parameters and the relative bioavailability were determined in 15 and 16 healthy male volunteers, respectively after single and repeated administration in open, randomized cross over study. The plasma concentration of nifedipine was determined by HPLC-ED method, using laboratory robot for automated sample preparation. On the basis of graphical and statistical comparison of the pharmacokinetic parameters (AUC0-infinity, AUCss,0-tau, tmax, Cmax, Css,min, Css,av, MRT, etc.) calculated from the time-plasma concentration curve, moreover on the basis of clinical results, there was no significant difference between the two preparations. In conclusion, the relative bioavailability of Cordaflex and Adalat 20 mg retard tablets did not show significant difference after single and repeated administration.

Administration, Oral↗
PubMed1996

[Bioanalysis of gemfibrozil. Comparative human pharmacokinetics of 300 mg of gemfibrozil-containing Innogem and Lopid capsules].

Comparative pharmacokinetic study was performed in 19 healthy male volunteers in a single-dose, randomized, two way cross-over trial on two preparations of gemfibrozil (Innogem and Lopid capsules) each of them containing 300 mg active ingredient. After administration either the test preparation (Innogem, EGIS Pharmaceuticals Ltd.,) or the reference preparation (Lopid, Parke-Davis) in human, the plasma concentration of gemfibrozil was determined by validated HPLC-UV (225 nm) bioanalytical method. After the relatively simple liquid-liquid extraction of the plasma samples the separation was carried out under isocratic condition on Nucleosil 10, C-18 column. On the basis of the validation process the limit of quantitation (LOQ), of the HPLC method was 250 ng/0.5 ml. All the validation parameters fell within the internationally accepted range. The comparison of individual pharmacokinetic parameters (AUC0-16, AUC0-infinity Cmax, tmax) of the two capsule preparations was accomplished by three-way analysis of variance (ANOVA), Wilcoxon's, Westlake's, Schuirmann's and Hauck-Anderson's method as well as by the calculation of confidence intervals on the ratio of test/reference values. The relative bioavailability of Innogem with respect to Lopid 300 mg capsule for AUC0-infinity was 104.06 +/- 21.61%. No statistically significant difference was found in the clinical results and between the pharmacokinetic parameters calculated from plasma concentration-time curves indicating that the two gemfibrozil preparations were bioequivalent after single administration.

Analysis of Variance↗
PubMed1995

Antipyrine, coumarin and glipizide affect n-acetylation measured by caffeine test.

The effect of various treatments on acetylation status measured by caffeine metabolites was investigated in 17 subjects with non-insulin dependent diabetes mellitus (NIDDM). The test drugs, caffeine (200 mg), antipyrine (20 mg/kg) and coumarin (5 mg), were given simultaneously, and urinary 5-acetylamino-6-formyl-amino-3-methyluracil/1-methylxanthine (AFMU/1X) molar ratio was measured before and after 8 weeks of therapy. The urinary AFMU/1X molar ratio decreased (p < 0.05) after 8 weeks of therapy with glipizide (2.5 mg), but remained unaltered in those treated with placebo or those who self-monitored blood glucose (SMBG) by glucometer. Antipyrine and coumarin decreased (p < 0.05) the AFMU/1X molar ratio both in diabetics and healthy volunteers. Our data demonstrate that glipizide, antipyrine and coumarin may interfere with the classification of acetylator status measured by caffeine metabolites.

Acetylation↗
PubMed1994

Determination of panomifene in human plasma by high-performance liquid chromatography.

An ion-pair HPLC method was developed for the determination of the antiestrogenic drug panomifene, (E)-1,2-diphenyl-1-(4-[2-(2-hydroxyethylamino)ethoxy]phenyl)-3,3,3 - trifluoropropene, in human plasma. Tamoxifen, 20 ng in 1 ml of plasma, was used as an internal standard. The compounds were isolated from plasma by liquid-solid extraction. Fluorescence detection was achieved by on-line photochemical conversion of the compounds into highly fluorescent phenanthrene derivatives. The sensitivity of the method was 1 ng/ml. The within-day and between-day precision, linearity, extraction recovery and stability of panomifene in plasma and in deproteinized plasma were determined for validation of the method. The method is suitable for measuring plasma levels of panomifene and tamoxifen and for pharmacokinetic studies.

Chromatography, High Pressure Liquid↗
PubMed1993

Simple and rapid determination of clomiphene cis and trans isomers in human plasma by high-performance liquid chromatography using on-line post-column photochemical derivatization and fluorescence detection.

A validated, sensitive and rapid high-performance high-performance liquid chromatographic method has been developed for the analysis of both cis and trans isomers of clomiphene in human plasma. The method involves a new off-line pre-column solid-phase extraction for sample preparation of clomiphene from human plasma in the presence of an internal standard. Analysis was performed by isocratic elution on a LiChrospher 100 RP-18 5-microns column using on-line post-column photochemical derivatization, with fluorescence detection at 247 nm (excitation) and 378 nm (emission). The limit of quantitation was 0.75 ng/ml for the cis isomer and 1.25 ng/ml for the trans isomer. The precision and accuracy of method were between good laboratory practice (GLP) required limits.

Chromatography, High Pressure Liquid↗
PubMed1993

HPLC method for rapid determination of acetylator phenotype by measuring urinary caffeine metabolites.

A validated reversed-phase high-performance liquid chromatographic (RP-HPLC) method is developed for the selective and rapid determination of two major metabolites of caffeine, namely 5-acetylamino-6-formylamino-3-methyluracil (AFMU) and 1-methylxanthine (MX) from human urine. HPLC separation is achieved by means of a Supersphere-60 RP-Select B (4 microns) analytical column using a non-linear gradient elution programme of 70-95% solvent B (2.5% acetic acid-methanol, 60:40, v/v) in solvent A (water-acetonitrile, 80:20, v/v). A selective UV detection method is used for determination of AFMU, MX and internal standard with readings at 284, 268 and 248 nm, respectively. Urine samples are prepared for measurement by a simple chloroform-diethyl ether (80:20, v/v) extraction. The assay is validated with respect to linearity, sensitivity, accuracy, precision and system suitability. All validation parameters are found to be within the required limits. The limit of detection of AFMU and MX is found to be 50 ng/200 microliters urine. Calibration curves show good linearity between 0.1 and 5 micrograms/200 microliters urine concentration range for both metabolites. The assay is sufficiently sensitive and rapid (4.5 min chromatographic run) to be applied for routine monitoring of change in AFMU/MX molar ratio, indicating acetylation phenotype and change of caffeine metabolism in clinical cocktail studies.

Caffeine↗
PubMed1993

[Pharmacokinetics and metabolism of tofizopam (Grandaxin)].

Present publication summarizes the pharmacokinetics and metabolism investigations of anxiolytic tofizopam (Grandaxin) carried out in Hungary and in other countries. The pharmacokinetics and metabolism of tofizopam were studied in animals (mice, rat, rabbit, dog, monkey) and humans. The pharmacokinetics profile of the compound can be described by a two-compartment open model, where the absorption and distribution phase were found to be rapid (tmax 0.5-1.0 hour in rats and 1.0-1.5 hours in humans). The unchanged tofizopam and 14C-total radioactivity were eliminated from human plasma with a biological half-life (t beta 1/2) of 2.7-3.5 hours and 15-21 hours, respectively, which show a slower elimination of the metabolites. The main route of elimination was the excretion of the mainly conjugated metabolites after the intensive first-pass metabolism in urine and/or faeces, depends on the species. The major route of biotransformation was mono-, di-, tri- and tetra-o-demethylation in the various degree and positions of aromatic ring(s).

Animals↗
PubMed1992

Comparative bioavailability of two different rectal preparations of piroxicam in man.

A comparative pharmacokinetic study was performed with two types of suppository each containing 20 mg piroxicam. The bioavailability of piroxicam was studied in 24 healthy volunteers in a double blind, randomised, cross over study. No significant difference was found in the pharmacokinetic parameters [AUC(0-72 h), AUC, Cmax, t1/2 beta] calculated from plasma concentration time curves, indicating that the two preparations were bioequivalent.

Administration, Rectal↗
PubMed1988

Mass spectrometric characterization of some human metabolites of flumecinol.

The mass spectrometric behaviour of six human metabolites formed by hydroxylation in various positions of the alpha-ethyl group or/and on the phenyl ring of 3-trifluoromethyl-alpha-ethyl-benzyhydrol (flumecinol) and seven related compounds has been studied. The electron impact mass (EI) spectra of these compounds show significant and characteristic effects of substituents, but many of them suffer from weakness or even from absence of the M+. peak owing to the very facile primary loss of the alpha-aliphatic chain, i.e. no direct information can be obtained about the size of the molecule and that of this chain. It is demonstrated for derivatives possessing a hydroxylated alpha-ethyl group that the difficulties in structural characterization due to the lack or weakness of M+. and [M + H]+ peaks in their EI and chemical ionization mass spectra, respectively, can be overcome by studying their silyated or boronated derivatives. Furthermore, silyation enables us to obtain a clear base for distinction of the primary and secondary alcohols of this type.

Benzhydryl Compounds↗
PubMed1987

Metabolism of flumecinol in humans.

1. The metabolism of 14C-flumecinol (3-trifluoromethyl-alpha-ethyl-benzhydrol) was studied in volunteers after a single oral dose of 100 mg (11.1 MBq; 300 microCi). Radioactivity excreted in urine was 78.8 +/- 6.0% of dose and in faeces was 12.0 +/- 5.3% dose in 120 h. 2. Unchanged flumecinol was not excreted in urine, but was present in faeces unconjugated (1.2% dose) and as conjugates of glucuronic and sulphuric acids (10.8% dose). 3. Enzymic hydrolysis showed that all urinary metabolites were conjugated with glucuronic and/or sulphuric acids (77.8% dose). Unconjugated urinary metabolites were not found. 4. The major route of flumecinol metabolism was hydroxylation of the alkyl side chain and/or the phenyl group followed by conjugation. 5. Both the CF3-group and the skeleton of the original compound remained intact during metabolism.

Adult↗
PubMed1987

Pharmacokinetic studies of [14C]-flumecinol in humans.

The pharmacokinetics of 14C-labelled 3-trifluoro-methyl-alpha-ethylbenzhydrol (flumecinol, RGH-3332, Zixoryn), a hepatic enzyme inducer, has been studied in 6 male healthy volunteers after a single oral dose of 100 mg (11.1 Mbq; 300 microCi). Flumecinol concentration in plasma was determined (0-96 h) by capillary gas-liquid chromatography. Total radioactivity was assayed by liquid scintillation counting. The peak concentration of unchanged flumecinol in the plasma (130.2 +/- 37.7 ng/ml S.D.) was detected 2.1 h after dosing. The maximum total radioactivity concentration (1414.4 +/- 158.9 ng eq./ml) was found at 2.3 h. The ratio of the plasma radioactivity level to unchanged flumecinol indicated a rapid metabolic transformation and a marked first-pass effect in man. A two-compartment open model was constructed to describe the pharmacokinetics of the drug. The unchanged drug was eliminated from plasma with a biological half-life of 20.7 +/- 1.8 h giving a total body clearance value of 100.9 +/- 33.8 l/h. The volume of distribution of flumecinol was found to be 41.4 +/- 18.4 l/kg. However, the biological half-life of total radioactivity was much longer (35.2 +/- 11.9 h) than that of the decrease of unchanged drug. The value of total body clearance (4.1 +/- 0.6 l/h) and volume of distribution (3.2 +/- 1.6 l/kg) were found to be much lower than that of unchanged flumecinol. Radioactivity excreted with urine was 78.8 +/- 5.9% and with faeces 12.0 +/- 5.3% during 120 h.

Adult↗