Biomedical subjects
Publications and source records attributed to G Blaschke.
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A sensitive high-performance liquid chromatographic determination of dimethindene and its metabolite N-demethyldimethindene in urine has been developed. The quantitative analysis was followed by determination of the enantiomeric ratio of dimethindene on an alpha 1-AGP column (EnantioPac). The urinary data for nine volunteers after oral administration of racemic dimethindene are presented. The isolation, identification and synthesis of the metabolite N-demethyldimethindene are reported.
The precondition for the antineoplastic effect of ifosfamide (ifo) is the oxidation of the oxazaphosphorine ring system, which contains a chiral centre at the phosphorous atom. This "ring oxidation" leads to the formation of alkylating mustard via several steps. A second metabolic pathway produces the cytostatically inactive metabolites 2- and 3-dechloroethyl-ifosfamide (2-d- and 3-d-ifo). The urinary excretion of the optical isomers of unmetabolised ifo and of 2- and 3-d-ifo, which represents the amount of ifo that has not been activated, was investigated by capillary gas chromatography for 18 treatment cycles in 14 children on various therapeutic schedules. The total cumulative excretion in 12 completely sampled cycles ranged from 27% to 50% of the ifo dose. Between 14% and 34% of the dose could be detected as ifo; 9% to 29%, as 3-d-ifo; and 2% to 8%, as 2-d-ifo. At 24 h after the end of therapy, excretion was nearly complete. Without exception, slightly more R-ifo (53%-61%) than S-ifo was excreted. S-2-d-ifo (50%-73%) was the main 2-d-metabolite. S-3-d-ifo (deriving from R-ifo) predominated in 6 of 14 children and R-3-d-ifo, in 8. Enantiomer-specific excretion increased after the end of infusion (up to 73% for R-ifo and 27% for S-ifo). We demonstrated stereospecific metabolism of ifo in children, with two different patterns of side-chain oxidation being observed. There was no evidence of important stereospecific ring oxidation in most children. A benefit should not be expected from the therapeutic application of pure enantiomers.
The metabolism of the non-labelled and 14C-labelled anthelmintic drug, praziquantel (PZQ; CAS 55268-74-1) was investigated by means of microsomal oxidation with rat liver homogenates. The metabolites formed were determined with linear thin-layer chromatography (TLC) radioactivity scanner after TLC separation, separated with TLC and analysed with high-pressure liquid chromatography and mass spectrometry method. The amounts and properties of the formed metabolites were described. It was stated that after microsomal oxidation monohydroxylated PZQ derivatives were obtained in greatest amount; the main fraction formed (35%) contained 4-OH-PZQ derivate which consisted of 80% cis-4-OH-PZQ and 20% of trans-4-OH-PZQ.
3H-labelled enantiomers of the cytostatic drug ifosfamide isolated by chromatographic resolution, were intraperitoneally applied to female NMRI mice. The concentrations of ifosfamide and its metabolites in blood and urine were determined. Both enantiomers of ifosfamide are eliminated at almost equal rates. The metabolites with anticancer activity are formed to a greater extent, 4-ketoifosfamide is formed stereoselectively from S(-)-ifosfamide. In vivo the conversion of aldo- to 4-hydroxyifosfamide does not take place.
N-Hydroxythalidomide (1d), a potential metabolite of thalidomide (1a), was synthesized from N-phthalyglutaminic acid anhydride (1b) and O-tetrahydropyraline hydroxylamine, followed by deprotection. The teratogenicity of 1d was studied using the Hen's-Egg-Test model which had been found applicable for 1a. 1d was more teratogenic to chicken embryos compared to 1a. The percentage of teratogenic malformations in the 1d groups was 28-46%, whereas the percentage in the 1a groups was 20-23%. The oxygen protected precursor N-hydroxythalidomide (1c) was less teratogenic (11-15%).
Binding of antiarrhythmics to phospholipids has been quantified by measuring the drug-induced fluorescence increase in 8-anilino-1-napthalenesulfonate (ANS)-treated phosphatidylcholine membranes. The ability of test compounds to increase fluorescence intensity to 50% varies between 1.3 and 88 X 10(-6) M, exhibiting a potency ratio of 1.8 log units. The antiarrythmics tested in this study exhibited a wide spectrum of lipophilicity ranging between sigma f = 6.66 for the most lipophilic compound asocainol, to sigma f = 1.21 for the most hydrophilic compound procainamide. The pKa values ranged from 10.80 for quinacainol to 6.26 for ethmozine. Consequently, the test compounds are 99.9 to 6.8% protonated at physiological pH. Binding of antiarrythmics to phosphatidylcholine membranes appears to be determined mainly by their lipophilicity (r = 0.91), irrespective of the pKa, as demonstrated for ethmozine and lidocaine which showed an excellent fit to the regression line. Binding of a variety of antiarrhythmics (n = 8) to phosphatidylcholine appeared to correlate significantly with the mean daily dosage for these drugs (r = 0.97).
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Ifosfamide, a chiral anticancer drug with phosphorus as chiral centre, was resolved into its enantiomers by chromatography on polyamides with bonded optically active substituents. Both enantiomers were isolated and characterized, the enantiomeric purity being at least 95% (31P nuclear magnetic resonance in the presence of an optically active shift reagent) and 99% (analytical chromatography), respectively. Experiments on the resolution of other oxazaphosphorines including the therapeutic drugs cyclophosphamide and trofosfamide are described.
The chiral benzodiazepines camazepam (1) and ketazolam (2) were resolved into the enantiomers by chromatography on the optically active adsorbent poly[(S)-N-(1-cyclohexylethyl)-methacrylamide] and fractional crystallisation or repeated chromatography, respectively. The IC50 values of the isomers and of the racemates of both compounds were determined by displacement of radioactively labelled 3H-flunitrazepam and 3H-propyl-beta-carboline-carboxylate from their specific binding sites. (+)-Camazepam exhibits 14fold higher affinity compared to the (-)-enantiomer. In contrast only slight differences in the receptor affinity are observed with the ketazolam enantiomers.
The enantiomers of ifosfamide were isolated chromatographically by the use of an optically active adsorbent. The biological activities of the racemic product and of the enantiomers (+)- and (-)-ifosfamide were compared as to the acute toxicity after single intraperitoneal administration on mice. Futhermore, the antitumor activity has been compared with regard to the rat leukemia L 5222 and the haematotoxicological effect. Under the conditions given, no biological differences between these 3 ifosfamide preparations were observed.
A number of racemic benzothiadiazine diuretics and two carbonyl analogue drugs were resolved into their optical isomers by liquid chromatography on chiral polyacrylamides 1. Enantiomeric resolution, which was, in some cases, almost complete, depended considerably on the substitution of the heterocyclic moiety of the drug molecules. Synthesis of the new adsorbent lb is described. The enantiomers of the benzothiadiazines penflutizide (2a) and bendroflumethiazide (2b) in high optical purity, as well as enriched (+)-buthiazide (2j) were obtained by repeated chromatography on a semipreparative scale. Chiroptical data, optical purity employing the chromatographic method, and first-order racemization kinetics as a function of pH in aqueous solutions were determined.
Optically pure d- and l-Chloroquine Diphosphate were examined for their efficacy against Plasmodium berghei in mice. The d-enantiomer is significantly more effective than the corresponding l-enantiomer, and in subcurative doses the d-enantiomer is also signficantly more active than the racemate. This increased activity has however no influence upon Chloroquine-resistant strains of P. berghei. The LD50 in non-infected mice is higher for the d-enantiomer than for either the racemate or the l-enantiomer when mice were treated orally one and 4 times. These differences in efficacy and toxicity between the d- and l-enantiomer of Chloroquine are however not as pronounced as those found for the enantiomers of many other drugs and furthermore these differences are limited to subcurative doses.
Racemic thalidomide is chromatographically separated on optically active polyamide giving both enantiomers. After i.p. administration only the S-(-)-enantiomer is teratogenic on SWS mice and Natal rats.
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