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R Kaliszan

Publications and source records attributed to R Kaliszan.

At least 19 recordsLinked to original sources
PubMed1998

Effect of separation conditions on chromatographic determination of hydrophobicity of acidic xenobiotics.

Problems encountered in the chromatographic determination of hydrophobicity of acidic xenobiotics are discussed. First, the definition and meaning of hydrophobicity is briefly presented. Next, the methods of determination of the hydrophobicity parameter by reversed-phase high-performance liquid chromatography are described. The methods of determination of the dead volume are analyzed with regard to calculation of the thermodynamically valid retention parameters. Relationships between retention factors and pH of mobile phase which have been reported in the literature are presented. The effects of ionic strength and buffer composition on the apparent retention parameters are discussed. The reversed-phase stationary phase materials presently employed for hydrophobicity determinations are reviewed. Application of micellar electrokinetic chromatography in the determination of hydrophobicity of ionizable analytes is presented. The ability of chromatography to provide the measures of hydrophobicity of xenobiotics best modelling their biological activity is underlined.

Chromatography, High Pressure Liquid↗
PubMed1998

Retention data from affinity high-performance liquid chromatography in view of chemometrics.

A combination of affinity chromatography and chemometrics is demonstrated to provide information on drug analytes and on biomacromolecules forming stationary phases, which is of relevance to molecular pharmacology and to rational drug design. The approach can also be applied to elucidate the molecular mechanism of enantioseparation on natural biopolymer stationary phases. Affinity high-performance liquid chromatographic data, which were determined on silica-based human serum albumin, alpha1-acid glycoprotein, keratin, collagen, melanin and amylose tris(3,5-dimethylphenylcarbamate) stationary phases, are discussed. Quantitative structure-retention relationships (QSRRs) derived for test series of drug analytes are interpreted in terms of structural requirements of specific binding sites on biomacromolecules. A means to quantify the differences in drug-biomacromolecule binding among the members of analyte families is demonstrated based on hydrophobicity and structural descriptors from molecular modeling. Chemometric processing of appropriately designed sets of affinity chromatographic data may increase the speed and efficiency of a search for new drugs, providing at the same time a chance to reduce the number of in vivo screenings. It can also be of help in rational selection of chiral columns for specific analytical separations.

Amylose↗
PubMed1998

Mechanism of separation on cholesterol-silica stationary phase for high-performance liquid chromatography as revealed by analysis of quantitative structure-retention relationships.

The retention characteristics of a newly synthesized stationary phase were determined for reversed-phase high-performance liquid chromatography obtained by chemical immobilization of cholesterol on spherical silica gel. For a designed series of analytes the retention factors, log k, were determined at several compositions of the methanol-water mobile phase. Logarithms of retention factor corresponding to a hypothetical pure water eluent, log k(w), were calculated by extrapolation of the linear relationships of individual log k data versus volume percent of methanol. The series of 24 test analytes were characterized structurally by means of the logarithms of n-octanol-water partition coefficients, log P, by a set of the linear solvation energy relationship (LSER)-based descriptors of the polarity and bulkiness of the analytes and by structural descriptors of analyte size and polarity acquired by molecular modelling. Quantitative structure retention relationships (QSRR) were derived by multiple regression analysis using the three groups of structural descriptors of analytes and the log k(w) data determined on the new stationary phase. For the sake of comparison the corresponding QSRR equations were also derived for retention parameters determined on a standard octadecylsilica and on the so-called immobilized artificial membrane (IAM) stationary phase. The QSRR analysis clearly proved distinctive retention properties of the new cholesterol-silica stationary phase. It has been concluded that the new phase may possess valuable analytical specificity. Its application for modelling penetration of xenobiotics through biological membranes appears rather unlikely.

Cholesterol↗
PubMed1997

Keratin immobilized on silica as a new stationary phase for chromatographic modelling of skin permeation.

Skin permeability of organic compounds depends on their lipophilicity but can also be affected by compounds interactions with specific skin components. A good chromatographic model of percutaneous penetration determined solely by lipophilicity is provided by the immobilized artificial membrane (IAM) columns. To complete the model a new high-performance liquid chromatographic (HPLC) stationary phase was prepared by physical immobilization of keratin on silica support. The keratin immobilized on silica has properties typical for the reversed-phase materials but it retains specifically acidic solutes. The keratin column can be used to conveniently compare keratolytic properties of xenobiotics. It was demonstrated that retention parameters determined on a keratin column can be combined with the retention parameters determined on the IAM column to predict differences in skin permeability within a class of drugs. It has been postulated that HPLC can model skin permeation thus reducing research time and costs as well as the use of laboratory animals.

Chromatography, High Pressure Liquid↗
PubMed1996

Quantitative structure-retention relationships in the examination of the topography of the binding site of antihistamine drugs on alpha 1-acid glycoprotein.

Quantitative relationships between the structure of antihistamine drugs (AHD) and their retention on an alpha 1-acid glycoprotein (AGP) HPLC column (QSRR) were studied in order to identify characteristic structural features of the binding site for AHD on AGP. The hydrophobicity of AHD was determined by HPLC on an immobilized artificial membrane (IAM) column. A highly significant QSRR equation was obtained which describes the retention of AHD on AGP in terms of the chromatographically determined hydrophobicity parameter, electron excess charge on the aliphatic nitrogen and a molecular size descriptor. The topography of the AHD-binding site on AGP was suggested to be a conical pocket with lipophilic regions at the mouth of the receptor and an anionic region close to the spike of the cone. Protonated aliphatic nitrogen is supposed to guide a drug molecule towards the anionic region of the binding site. Hydrophobic aryl moieties provide anchoring of the molecule in the lipophilic regions of the binding site. Steric hindrance prevents the molecule from plunging into the binding site.

Binding Sites↗
PubMed1995

Mydriasis elicited by imidazol(in)e alpha 2-adrenomimetics in comparison with other adrenoceptor-mediated effects and hydrophobicity.

alpha 2-Adrenoceptor agonists cause both mydriasis and platelet aggregation. This work is aimed at identifying the factors accompanying and affecting mydriatic activity. For eight imidazol(in)e drugs mydriatic, hypotensive and bradycardic activities were determined in rats. The lipophilicity of the agents was determined chromatographically and calculated theoretically. A correlation was found between the hypotensive and the bradycardic potency and between the mydriatic activity and both the hypotensive and bradycardic activity. Mydriatic activity depended on the lipophilicity of the agents studied. The human platelet antiaggregatory activity of the drugs did not correlate with either the mydriatic or cardiovascular activity and it was independent of lipophilicity. The dependence of the centrally induced effects on lipophilicity and the lack of such a dependence in the case of the in vitro alpha 2-adrenoceptor-mediated platelet aggregation may be interpreted as resulting from heterogeneity of the rat cerebral and the human platelet alpha 2-adrenoceptors. The alpha 2-adrenergic activity of drugs in the model of mydriasis in rats cannot be predicted from their activity in causing human platelet aggregation in vitro.

1-Octanol↗
PubMed1995

Comparative studies of antiplatelet activity of nonsteroidal antiinflammatory drugs and new pyrazine CH- and NH-acids.

Nine known nonsteroidal antiinflammatory drugs (NSAID) and three new pyrazine derivatives possessing an active methylene moiety (pyrazine CH/NH-acids) were tested with regards to their in vitro and in vivo antiplatelet activity. Concentrations of the agents were determined which caused 25% and 50% inhibition of aggregation of human blood platelets induced by fixed concentrations of ADP, collagen and epinephrine. The in vivo test consisted in determination of percent protection of mice from pulmonary microembolism caused by injection of a mixture of collagen and epinephrine. The in vitro antiaggregatory activity of the agents studied was rather low, excepting the inhibition of the collagen-induced aggregation by ketoprofen. Several NSAID and two new pyrazine CH/NH-acids appeared highly potent antithrombotic agents in vivo. Activity of NSAID expressed as percent protection against lung thromboembolism in the mouse was demonstrated to depend quantitatively on acid properties of the agents. The new chemical class of pharmacologically active agents, pyrazine CH/NH-acids, offers an original pharmacophore which is distinctive from the carboxylic or enolic functionalities typical for the established NSAID, and as such, may be devoid of some disadvantages of known antiplatelet drugs.

Adenosine Diphosphate↗
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↗