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Aims/hypothesis: Vascular complications observed in diabetes are often related to altered platelet functions. The most widely used hypoglycaemic drugs for treating Type II (non-insulin-dependent) diabetes mellitus are sulphonylurea derivatives. The purposes of this study were to evaluate the inhibitory effects of hypoglycaemic agents on platelet aggregation, to measure their lipophilicity and identify their structural parameters which assess their antiaggregatory activity., Methods: An antiaggregatory test in vitro was carried out for 13 sulphonylurea derivatives. Aggregation of platelets, incubated with the agents at concentrations varying from 7.5 to 480 micromol/l, was induced by 10 micromol/l ADP. Drug lipophilicity parameter, log k(w), was measured by gradient HPLC and the agents were subjected to molecular modelling., Results: The most pronounced inhibition of platelet aggregation was by glimepiride, gliclazide, gliquidone, glibenclamide and compound 2A. The IC(25) values were 15.9, 18.6, 20.4, 28.5 and 34.7 micromol/l, respectively. Quantitative structure-activity relationships indicate that antiaggregatory activity is mainly affected by electronic and not by lipophilic properties of the agents., Conclusion/interpretation: Glimepiride appeared to be a more potent ADP-induced platelet aggregation inhibitor in vitro than gliclazide. Antiaggregatory activity was shown for gliquidone and confirmed for glibenclamide. The QSAR analysis supports the hypothesis of a free radical mechanism of action of sulphonylurea derivatives previously suggested for gliclazide.

The action of acetylsalicylic acid, ticlopidine and a new pyrazine derivative HF90 selected in preliminary screenings (11, 18, 19) was studied by using the mouse antithrombotic assay according to DiMinno and Silver (22) and in vitro blood platelet aggregation method according to Born (23). Acute pulmonary thromboembolism was induced by injection of a mixture of collagen and epinephrine into the mouse tail vein. The effect of HF90, an acidic pyrazine derivative possessing active methylene moiety, administered at doses of 50 and 100 mg/kg, was compared to the action of the well established antithrombotic agents: ticlopidine (100 mg/kg) and acetylsalicylic acid (20 mg/kg). The compounds were administered i.p. in single doses 1 h and 24 h before the thrombotic challenge or once a day per three consecutive days before the thrombotic challenge. Ticlopidine appeared to provide the better protection against microembolism than acetylsalicylic acid although its effect has not manifested itself immediately after administration. The pyrazine derivative examined has a lower but significant antithrombotic activity. The chemical class of pyrazine derivatives with active methylene moiety (the so called pyrazine CH/NH-acids) (16) provides a new original antiinflammatory pharmacophore and HF90 may serve as the "lead compound" in the search for new agents of pharmacological interest.

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.

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.

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.

The effect of seven commonly used in therapy imidazoline derivatives on human blood platelet aggregation was studied. Three of the agents, i.e. clonidine, antazoline and tetryzoline were classified as partial agonists of the receptor responsible for aggregation. Two other drugs, i.e. phentolamine and tolazoline act as competitive antagonists of relatively high receptor affinity. The remaining imidazolines: xylometazoline and naphazoline effectively inhibit the platelet receptor in a non-competitive manner. The last two compounds seem to be selective alpha 2-adrenoceptor antagonists.

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.