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Antiaggregatory Activity of Hypoglycaemic Sulphonylureas

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Antiaggregatory Activity of Hypoglycaemic Sulphonylureas Diabetologia (2002) 45:1034–1037 DOI 10.1007/s00125-002-0855-0 Short communication Antiaggregatory activity of hypoglycaemic sulphonylureas D. Siluk1, R. Kaliszan1, P. Haber1, J. Petrusewicz2, Z. Brzozowski3, G. Sut4 1 Department of Biopharmaceutics and Pharmacodynamics, 2 Department of Pharmacology, Medical University of Gdan´sk, Poland 3 Department of Chemical Technology of Drugs, Medical University of Gdan´sk, Poland 4 Navy Hospital, Hospital Dispensary, Gdan´sk, Poland Abstract Results. The most pronounced inhibition of platelet aggregation was by glimepiride, gliclazide, gliquidone, Aims/hypothesis. Vascular complications observed in glibenclamide and compound 2A. The IC25 values were diabetes are often related to altered platelet functions. 15.9, 18.6, 20.4, 28.5 and 34.7 µmol/l, respectively. The most widely used hypoglycaemic drugs for treat- Quantitative structure-activity relationships indicate that ing Type II (non-insulin-dependent) diabetes mellitus antiaggregatory activity is mainly affected by electronic are sulphonylurea derivatives. The purposes of this and not by lipophilic properties of the agents. study were to evaluate the inhibitory effects of hypo- Conclusion/interpretation. Glimepiride appeared to glycaemic agents on platelet aggregation, to measure be a more potent ADP-induced platelet aggregation their lipophilicity and identify their structural parame- inhibitor in vitro than gliclazide. Antiaggregatory ac- ters which assess their antiaggregatory activity. tivity was shown for gliquidone and confirmed for Methods. An antiaggregatory test in vitro was carried glibenclamide. The QSAR analysis supports the hy- out for 13 sulphonylurea derivatives. Aggregation of pothesis of a free radical mechanism of action of platelets, incubated with the agents at concentrations sulphonylurea derivatives previously suggested for varying from 7.5 to 480 µmol/l, was induced by gliclazide. [Diabetologia (2002) 45:1034–1037] 10 µmol/l ADP. Drug lipophilicity parameter, log kw, was measured by gradient HPLC and the agents were Keywords Hypoglycaemic sulphonylureas, lipophili- subjected to molecular modelling. city, platelet aggregation, QSAR. In diabetes secondary vascular complications are often in altered membrane lipid dynamics and fluidity, dis- observed and the disease is an independent risk factor turbed intermediary metabolism, including arachido- for cardiovascular disorders. It has been suggested nate and prostaglandin pathways, as well as in in- that one of the factors in the progression of diabetic creased production of free radicals and decreased con- complications is platelet dysfunction. Platelet malfor- tent of antioxidants [1]. In several investigations, in- mations concern their structure and function and result creased platelet adhesiveness, aggregability and TxA2 release were documented [2]. Moreover, increased Received: 24 October 2001 / Revised: 21 March 2002 platelet sensitivity was reported towards von Wille- Published online: 12 June 2002 brand factor (vWF), fibrinogen, immune complexes © Springer-Verlag 2002 and glycated low-density lipoproteins as well as en- hanced platelet release of intracellular material, like Corresponding author: R. Kaliszan, PhD, Department of Bio- β-thromboglobulin, platelet factor 4 and platelet- pharmaceutics and Pharmacodynamics, Medical University of derived growth factor, whereas platelet survival and Gdan´sk, Gen. Hallera 107, 80-416 Gdan´sk, Poland, E-mail: [email protected] platelet nitric oxide synthase activity decreased [3]. Abbreviations: ASA, Acetylsalicylic acid; PPP, platelet-poor- One of the most widely used group of anti- plasma; PRP, platelet-rich-plasma; QSAR, quantitative struc- hyperglycaemic drugs for treating Type II (non-insu- ture-activity relationships; TxA2, thromboxane A2. lin-dependent) diabetes mellitus are sulphonylurea de- D. Siluk et al.: Antiaggregatory activity of hypoglycaemic sulphonylureas 1035 rivatives. Their auxiliary antiplatelet activity could be 450 µl of platelet suspension resulting in a final concentration useful. An influence of several sulphonylurea deriva- of ADP equal to 10 µmol/l. Percent aggregation was calculated tives on platelet functions and metabolism in vitro and 6 min after adding the aggregating agent and was standardised by assuming that PPP represented 100% and PRP 0% light in vivo has been reported [4, 5] but there has been a transmission. The drugs were dissolved in DMSO, which at the lack of a systematic comparison of antiplatelet action concentration used did not alter platelet aggregation. PRP was of a representative series of sulphonylureas widely incubated with solutions of individual agents of fixed concen- used. We therefore examined the antiaggregatory ac- trations (7.5–480 µmol/l) for 10 min before challenge with an tivity of nine commonly used hypoglycaemic drugs aggregating agent in a dual channel optical aggregometer (gliclazide, glimepiride, glibenclamide, tolbutamide, (Model 490, Chrono-Log, Haverton, Pa., USA) at 37°C under gliquidone, glipolamide, glibornuride, chlopropamide, continuous stirring (1000 rpm). Antiaggregatory properties of each compound were studied using blood from at least five do- glipizide) and of four synthesised sulphonylurea de- nors. rivatives of pronounced hypoglycaemic activity in animal tests [6]. We also included torasemide, a loop Computer modelling and calculation of physico-chemical diuretic with sulphonylurea structure and activity re- properties. As the molecular structure descriptors of the sul- phonylureas the net positive charge on the sulphur atom, δ , ported as a weak TxA2 receptor antagonist [7]. Ace- S tylsalicylic acid served as a reference antiaggregatory and the energy of the lowest unoccupied molecular orbital, ELUMO, were used in QSAR analysis. The descriptors were cal- drug. Quantitative structure-activity relationship (QSAR) culated by standard CAChe MOPAC 2000 program (Fujitsu studies were carried out to identify structural des- FQS, Kraków, Poland). The logarithms of n-octanol/water par- criptors of the agents contributing to their antiag- tition coefficients were calculated with the use of ClogP soft- gregatory activity and hence clarify the molecular ware (BioByte, Claremont, Calif., USA). QSAR models were mechanism of their action. derived using Statgraphic Plus 4.0 software (Manugistics, Rockville, Md., USA). Assessment of lipophilicity parameter log kw by gradient elu- Materials and methods tion. A newly elaborated gradient chromatographic method of lipophilicity assessment [9] was applied. Specificity of the pro- The procedures related to the study were approved by cedure for sulphonylureas consisted in applying a so-called im- the Medical University of Gdan´sk Bioethics Committee mobilised artificial membrane column IAM.PC.DD 30 mm× (NKEBN/694/2000). Blood samples were donated at the Blood 4.6 mm i.d. (Regis, Morton Grove, Ill., USA). Donation Centre in Gdan´sk by healthy men who gave their in- formed consent. The donors were 22 to 60 years old, of normal Statistics. The data are expressed as means ± SEM. Differ- glucose tolerance status, with a BMI in the normal range, with ences between control and test were assessed by Student’s different smoking habits, and they had not taken drugs known t test; p value of less than 0.05 was considered statistically sig- to interfere with platelet function for at least 1 week before the nificant. venipuncture. Materials. ADP was purchased from Sigma Chemicals Results (St Louis Mo., USA); DMSO and sodium citrate from Fluka Chemie (Buchs, Germany). Compounds 2A: N-{4-[2-(pyr- azole-1-carbonamide)-ethyl]-benzenesulphonyl}-N′-cyclohexyl- Effects of sulphonylurea derivatives on platelet aggre- urea, 5A: N-{4-[2-(4-ethylpyrazole-1-carbonamide)-ethyl]ben- gation in vitro. Effects of drugs on platelet aggrega- zenesulphonyl}-N′-cyclohexylurea, 6A: N-{4-[2-(3,5-dimeth- tion in vitro are shown (Fig. 1). The compounds ap- ylpyrazole-1carbonamide)-ethyl]-benzenesulphonyl}-N′-cyclo- peared to be relatively weak inhibitors of aggregation. hexylurea, 14A: N-{4-[2-(4-chloro-3,5-dimethyl-pyrazole-1-car- Therefore only the concentrations causing 25% inhibi- bonamide)-ethyl]-benzenesulphonyl}-N′-cyclohexylurea and glipolamide were synthesised according to a procedure report- tion of aggregation (IC25±SEM, n=8–10) could be as- ed elsewhere [6]. Glibenclamide, chlorpropamide, tolbutamide sessed for seven of them. The IC25 values for 7 out of and acetylsalicylic acid were gifts from Polpharma (Starogard 14 agents studied are given in Table 1. The IC25 Gdan´sk, Poland), gliclazide from Jelfa (Jelenia Góra, Poland), for five most potent sulphonylureas: glimepiride, gli- glimepiride from Hoechst Marion Roussel (Frankfurt, Ger- clazide, gliquidone, glibenclamide and compound 2A many), gliquidone from Boehringer Ingelheim (Biberach, were 15.9, 18.6, 20.4, 28.5, 34.7 µmol/l, respectively. Germany), glibornuride from Grünenthal (Aachen, Germany) For ASA IC was 21.9 mol/l. The IC values glipizide from Pfizer (Groton, Conn., USA) and torasemide 25 µ 25 from Roche Diagnostics (Mannheim, Germany). for glibornuride and torasemide were higher than 100 µmol/l and amounted to 123.0 and 316.2 µmol/l, In vitro platelet aggregation. Platelet aggregation was mea- respectively. Chlorpropamide, glipizide, glipolamide, sured by the Born method [8]. Blood was collected by veni- tolbutamide and compounds 5A, 6A and 14A did not puncture into 3.8% sodium citrate solution (volume ratio 9:1) show measurable antiplatelet activity at the concentra-
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