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Biomedical subjects

R Kaliszan

Publications and source records attributed to R Kaliszan.

At least 37 records · Page 2Linked to original sources
PubMed1993

Prediction of drug binding to melanin using a melanin-based high-performance liquid chromatographic stationary phase and chemometric analysis of the chromatographic data.

The high-performance liquid chromatographic retention parameters (k) have been determined for a series of 29 phenothiazines and related drugs. The k values were obtained on a hydrocarbon-bound silica stationary phase, an aminopropyl stationary phase and an aminopropyl phase coated with melanin. Polycratic retention data determined on a hydrocarbonaceous column were extrapolated to 0% of organic modifier in binary aqueous eluent yielding the chromatographic hydrophobicity parameter, log k'w. Logarithms of capacity factors determined isocratically on the aminopropyl column were subtracted from analogous values obtained with the same column loaded with melanin. The resulting parameter, log k'm-a, in combination with log k'w produced a regression equation (correlation coefficient r = 0.9531, significance level p = 10(-6)) which could be used to describe drug-melanin binding efficiency, EB. Theoretical EB values were calculated by means of the derived equation for the whole series of 29 drugs chromatographed. The efficiency of binding EB to synthetic melanin was also determined by an ultrafiltration method for fifteen members of the series. No statistically significant differences were observed between the EB values calculated using the chromatographic and ultrafiltration approaches. The results indicate that chemometric analysis of the appropriate chromatographic data is a practical method for the evaluation of melanin binding.

Chemical Phenomena↗
PubMed1993

Pyrazine CH- and NH-acids. Antithrombotic activity and chromatographic behaviour.

1. A series of newly synthesized pyrazine CH- and NH-acids was subjected to analytical and pharmacological studies. 2. The compounds were chromatographed in HPLC systems employing three reversed-phase columns and methanol-buffer solvents of various composition at acidic, neutral and alkaline pH. 3. Chemometrical analysis by the principal component method allowed for ordering of the compounds on a plane determined by the first two principal component axes. 4. Pharmacological tests were done for representatives of the series of compounds. 5. An in vivo antithrombotic assay on mice proved diversified bioactivity within the group of agents. 6. Attempts were undertaken to relate chromatographic behaviour to antithrombotic activity. 7. Based on the results obtained, an approach was proposed to reduce the number of pharmacological tests in selecting the most promising agents.

Adenosine Diphosphate↗
PubMed1993

Deactivated hydrocarbonaceous silica and immobilized artificial membrane stationary phases in high-performance liquid chromatographic determination of hydrophobicities of organic bases: relationship to log P and CLOGP.

Retention parameters for a series of 29 organic base drugs (including 17 phenothiazine derivatives) were measured by reversed-phase high-performance liquid chromatography (HPLC) employing new columns of distinctive partition properties. One column was a deactivated alkyl-bonded silica and two others were packed with lecithin-bonded propylamino-silica, i.e. the immobilized artificial membrane (IAM) columns; one of the IAM stationary phases had the unreacted propylamine moieties additionally end-capped with methylglycolate. The highly deactivated hydrocarbonaceous silica column showed regular rectilinear relationships between logarithms of chromatographic capacity factors and the content of organic modifier in aqueous eluent; it is suitable for generating a chromatographic scale of hydrophobicity. Such a scale (hydrocarbonaceous) is different from that provided by measurement of partitioning of solutes between n-octanol and water (alkanol log P scale). The relative hydrophobicity parameters determined by HPLC on the IAM columns were different from both log P scale and from the hydrocarbonaceous chromatographic hydrophobicity scale. The hydrophobicity parameter, CLOGP, theoretically calculated by the fragmental methods, correlated better than log P with chromatographic hydrophobicity parameters. It has been postulated that each hydrophobicity measuring system reveals some specific aspects of the hydrophobicity phenomenon and that the nature of hydrophobic binding sites on receptors and plasma proteins may require different hydrophobicity models than drug permeation through biological membranes. By means of HPLC, diverse hydrophobicity measures can readily be determined, among which those most suitable for specific QSAR applications can be identified.

Chemistry, Pharmaceutical↗
PubMed1993

Comparative analysis of effects of imidazoline drugs on isolated rat heart atria.

Effects of cumulative concentrations of 16 known imidazoline and 2 imidazole drugs on amplitude and rate of spontaneously beating isolated rat heart atria were measured and related to the respective effects induced by norepinephrine. In addition, the effects of fixed concentrations of the agents on the responses evoked by cumulative concentrations of norepinephrine were determined. In general, imidazolines classified as alpha 1-adrenoceptor agonist showed positive inotropic activity providing evidence for involvement of the alpha 1-adrenoceptor in mediating cardiac contractility. Negative chronotropic effect was common for the imidazolines studied, including alpha 1-adrenoceptor agonists, alpha 2-adrenoceptor agonists, alpha 1/alpha 2-adrenoceptor antagonists and antazoline--an antihistaminergic imidazoline devoid of adrenoceptor affinity. On the other hand, the imidazole derivative, medetomidine, showed a weak positive chronotropic activity. Negative chronotropic properties appeared to be independent of the alpha-adrenoceptors and may result from the membrane stabilizing action, involving probably the sodium channel blockade.

Animals↗
PubMed1992

Antithrombotic activity of a new pyrazine derivative determined by the mouse antithrombotic assay.

A model of pulmonary microembolization in the mouse induced by infusion of epinephrine and collagen was used to determine antithrombotic activity of indomethacin and acetylsalicylic acid and of two newly synthesized pyrazine derivatives. One of the new agents provided marked protection of mice from thrombotic challenge with epinephrine and collagen. Its effectiveness was higher than acetylsalicylic acid (especially at small doses) but smaller than that of indomethacin. The same compound was similar to acetylsalicyclic acid with respect to the inhibition of in vitro human blood platelet aggregation. The new class of pyrazine derivatives (the so-called pyrazine CH- and NH-acids) appears interesting from the view-point of the studies of platelet aggregation and may yield potential antithrombotic drugs.

Animals↗
PubMed1992

Stereochemical aspects of benzodiazepine binding to human serum albumin. I. Enantioselective high performance liquid affinity chromatographic examination of chiral and achiral binding interactions between 1,4-benzodiazepines and human serum albumin.

The displacement of a series of 1,4-benzodiazepine (BDZ) drugs from a chiral stationary phase, based upon human serum albumin, for high performance liquid chromatography was investigated. The different displacement patterns obtained using various mobile phase additives could not be interpreted in terms of binding of the solutes to a single site. The observations were better described by considering the attachment of the BDZs to several loci on the protein. Two main mechanisms of binding were discerned, a nonstereoselective mode, which affected all solutes and seemed to occur at a large number of locations on the protein, and a highly stereoselective mode, which involved only one enantiomer of chiral BDZs and presumably one conformation of certain achiral solutes. The stereoselective binding mode encompassed at least four different sites, each of which displayed slightly different structural requirements. It is suggested that the nomenclature currently used to describe drug binding to human serum albumin may be misleading. Rather than the use of site I or site II, it may be preferable to adopt the terms type I and type II binding, according to the displacement patterns of the compound concerned. This approach would retain the conceptual simplicity of the current notation, while avoiding misleading implications of the exact molecular locus of binding.

Benzodiazepines↗
PubMed1992

Stereochemical aspects of benzodiazepine binding to human serum albumin. II. Quantitative relationships between structure and enantioselective retention in high performance liquid affinity chromatography.

Previously determined retention data for a series of benzodiazepine (BDZ) derivatives, comprising nine achiral compounds, four single enantiomers, and 18 individual isomers of nine racemates, on a chiral stationary phase based on immobilized human serum albumin (HSA) were analyzed to define quantitative relationships between structure and enantiospecific retention. Structural parametrization of the agents was done by means of hydrophobic fragmental constants and electronic and steric parameters obtained by computational chemistry methods. A structural descriptor was identified, a submolecular measure of polarity about the stereogenic center, that accounted for the stronger electrostatic interactions of the second-eluting enantiomer with the HSA chiral stationary phase. Quantitative structure-enantiospecific retention relationships were derived for both enantiomeric series and for achiral compounds, and structural requirements for binding to HSA were determined. Two types of binding sites were postulated. For BDZs in the P-conformation, binding to HSA involved a hydrophobic region with steric restrictions. For BDZs in the M-conformation, a hydrophobic region was also involved, as well as a cationic region that interacted electrostatically with carbon C(3) of the diazepine system and substituents at that carbon. These differences lead to different binding patterns for BDZ enantiomers and provide a rationalization for the diversified behavior of individual BDZs that was observed in previous displacement studies.

Benzodiazepines↗
PubMed1992

Synthesis, structure and biological activity of 1,2,4-triazolo-1,3-thiazine derivatives.

A group of condensed triazole-thiazine derivatives (2a-i, 3b, 3j) was obtained in reaction of the corresponding 5-substituted 1,2,4-triazole-3-thiones (1a-j) with epichlorohydrin in alkaline medium. The structure of the compounds synthesized was confirmed by spectral and roentgenographic methods. Tuberculostatic and circulatory activities of the compounds were also studied.

Animals↗
PubMed1991

Chromatographic data for pharmacological classification of imidazol(in)e drugs.

A set of eighteen imidazol(in)e derivative drugs of various pharmacological activity were analysed under different high-performance liquid chromatographic (HPLC) conditions. Capacity factors were determined employing methanol-buffer eluents at seven volume ratios and at pH 10.9, 7.0 and 2.9. The use of an alkaline buffer was possible owing to the application of poly(butadiene)-coated alumina (PBCA) as the stationary phase. Two systems employing octadecylsilica (ODS) columns were applied, one operated at pH 7.0 and the other at pH 2.9. Capacity factors of the test solute drugs were determined in 21 chromatographic systems. All the data were subjected to chemometric analysis despite the fact that, except for the PBCA systems, only a limited range of linearity of the logarithm of capacity factor versus volume fraction of methanol in mobile phase was observed. The matrix of 21 x 18 capacity factors was statistically analysed by the principal component method. The first two principal components accounted for 80% of the variance in the capacity factors studied. The principal component object scores clearly separated the agents into groups in accordance with their pharmacological classification. It was concluded that diverse retention data can provide more information relevant to the bioactivity of solutes than just a one-dimensional hydrophobicity scale.

Chromatography, High Pressure Liquid↗
PubMed1991

Imidazo[4,5-b]pyridine derivatives of potential tuberculostatic activity. Part 1: Synthesis and quantitative structure-activity relationships.

New derivatives of imidazo[4,5-b]pyridine and 9H-dipyrido-[1,2-a:3',2'-d]imidazole were synthesized. Antibacterial activity against Mycobacterium tuberculosis of selected compounds was determined. These data were combined with the corresponding bioactivity data previously generated for two other series of imidazo[4,5-b]pyridines. Analysis of Quantitative Structure-Activity Relationships [QSAR] was carried out using nonempirical structural descriptors. Hydrophobicity of the agents studied was found decisive for their activity. A QSAR equation was derived allowing rational design of active derivatives.

Antitubercular Agents↗
PubMed1991

Imidazo[4,5-b]pyridine derivatives of potential tuberculostatic activity, II: Synthesis and bioactivity of designed and some other 2-cyanomethylimidazo[4,5-b]pyridine derivatives.

Based on the analysis of Quantitative Structure--Activity Relationships (QSAR) three representatives of imidazo[4,5-b]pyridine derivatives of predicted high antibacterial activity against Mycobacterium tuberculosis were synthetized and tested bacteriologically. Excellent agreement of the predicted and experimentally observed bioactivity was noted. Additional new derivatives of 4-methyl-4H-2-cyanomethylimidazo[4,5-b]pyridine (7) and 2-(alpha-methylcyanomethyl)imidazo[4,5-b]pyridine (22) were also synthesized and some of them were tested for tuberculostatic activity. The compounds synthesized according to a standard "trial and error" approach appeared generally inactive.

Acetonitriles↗
PubMed1991

Human blood platelet alpha adrenoceptor in view of the effects of various imidazol(in)e drugs on aggregation.

1. Sixteen imidazol(in)e derivative drugs were tested with regards to their aggregatory and antiaggregatory effects on human blood platelets. 2. Platelet aggregation in response to fixed concentrations of the agents was quantified by the turbidimetric method of Born. 3. Inhibitory effects of the imidazol(in)es against the epinephrine (10(-5) M) induced aggregation was related to concentration of the agents. Of the compounds studied, UK 14,304 elicited an aggregatory effect of a magnitude similar to epinephrine. 4. A strong aggregatory agent appeared also moxonidine. 5. Small aggregation was observed in response to clonidine, antazoline and tetryzoline. 6. For all the group of imidazol(in)e drugs, excepting UK 14,304 and moxonidine, a significant inhibition of the epinephrine induced aggregation was noted. 7. Analysing inhibitory activity of imidazol(in)es one notes the drugs commonly assumed to interact with alpha 2 adrenoceptor among the most potent inhibitors, and those classified as alpha 1 adrenoceptor agonists among the less active agents. 8. The results here obtained suggest some similarity between the platelet adrenoceptor and the alpha 2 subtype of adrenoceptor identified in human circulatory system. 9. Differences appear between the two types of receptors and the existence of a separate alpha 3 class of adrenoceptors in human blood platelets should be considered.

Blood Platelets↗
PubMed1991

Synthesis and pharmacological activity of 5-substituted-s-triazole-3-thiols.

Two subgroups of 5-substituted triazoles were synthesized: derivatives of 3(3-substituted-amino-2-hydroxypropylthio)-5-substituted-4H-1,2,4- triazole and derivatives of N-substituted amides of 5-substituted-s-(1,2,4-triazole-3)thioglycolic acid. Selected members of the two subseries were tested pharmacologically. The blood pressure lowering effect in anaesthetized normotensive rats was weak to moderate. More pronounced was the inhibitory effect against adrenaline induced human blood platelet aggregation. In experiments on isolated rat heart atria and on isolated rat tail artery the activity of the agents was much weaker than in the case of known beta or alpha adrenoceptor antagonists. Generally, the chance to find a potential antihypertensive agent within the group studied seems to be low. Antiaggregatory activity of the compounds deserves further studies.

Animals↗
PubMed1988

Antiaggregatory activity of imidazoline drugs and chemicals as a function of their structure.

The concentration-response curves were constructed for 18 azole derivatives (including seven imidazoline drugs) as the inhibitors of the adrenaline-induced human blood platelet aggregation. It was demonstrated by the quantitative structure-activity relationships analysis that the less hydrophobic agents started to act as effective inhibitors at lower concentrations but that stronger effects could be obtained with the more hydrophobic derivatives. The conclusion was drawn that the inhibitory activity observed was the result of nonspecific hydrophobic interactions of the agents with both an andrenergic platelet receptor and a site of loss on serum albumin.

Dose-Response Relationship, Drug↗
PubMed1986

Quantitative retention relationships as a function of mobile and C18 stationary phase composition for non-cogeneric solutes.

Twelve non-homologous solutes with a wide range of functional groups were chromatographed on a series of well-characterized stationary phases with a range of methanol-water mobile phases. Retention correlations were found for quantum mechanically calculated molecular parameters. These parameters, the total molecular energy, and the maximal excess electronic charge difference, were found to be better descriptors of retention than the dipole moment or fragmental constants. The implication of these results in terms of retention mechanisms on reversed-phase materials are discussed.

Chemical Phenomena↗
PubMed1986

Surface electric charge of the active and inactive polymorphs of chloramphenicol palmitate.

Higher zeta-potential values were found for the crystalline particles of polymorph A when compared with polymorph B of chloramphenicol palmitate when measured at identical conditions. In the case of the thermomicroscopically prepared crystal sample being a mixture of the polymorphs, the resulting zeta potential was higher than that measured for pure form B and lower than that found for form A. It has been assumed that the zeta potential reflects differences in the surface properties of the polymorphs. These differences are briefly discussed from the point of view of the adsorption of the charge-generating ions as well as of the marked differences in bioactivity reported for the polymorphs.

Chloramphenicol↗
PubMed1986

Blood platelet adrenoceptor: aggregatory and antiaggregatory activity of imidazoline drugs.

The effects of seven commonly used imidazoline drugs on human blood platelet aggregation and their inhibitory activity against the adrenaline-induced process were studied. The alpha-adrenoceptor reacting drugs, prazosin and yohimbine, were used as the standards. Low agonistic properties were found in the case of antazoline, clonidine and tetryzoline, whereas those three drugs along with naphazoline, phentolamine, tolazoline and xylometazoline exhibited marked antagonistic activity against the adrenaline-induced aggregation. The results are discussed from the point of view of the existing classification of the alpha-receptors. The conclusion is that the human blood platelet alpha-adrenoceptors, although resembling the properties of the alpha 2-subtype, form either a separate subclass of the receptors or a heterogeneous population of the alpha 2-subtype and an adrenergic receptor different from both alpha 1- and alpha 2-subclasses.

Adult↗