thromboxane-b2 and dithiadene

On the basis of values corresponding to concentrations exhibiting 50% inhibition of platelet aggregation induced with different stimuli and 50% inhibition of arachidonic acid liberation and thromboxane generation, we compared the antiplatelet effect of two cationic amphiphilic drugs--chloroquine and dithiaden. Compared to chloroquine, dithiaden was much more effective in inhibiting platelet aggregation, A-23187 induced arachidonic acid liberation and thromboxane generation. Chloroquine, on the other hand, was more effective in the inhibition of thrombin-induced arachidonic acid liberation.

Topics: Adult; Arachidonic Acid; Benzothiepins; Blood Platelets; Calcimycin; Chloroquine; Humans; In Vitro Techniques; Male; Middle Aged; Phospholipases A; Platelet Aggregation; Platelet Aggregation Inhibitors; Thrombin; Thromboxane B2

Topics: Adenosine Diphosphate; Benzothiepins; Blood Platelets; Calcimycin; Histamine H1 Antagonists; Humans; Ionophores; Malondialdehyde; Nephelometry and Turbidimetry; Platelet Aggregation Inhibitors; Thrombin; Thromboxane B2

The effects of bromadryl, dithiaden, chloroquine and propranolol on thrombin-stimulated rat platelet aggregation (measured turbidimetrically) and thromboxane B2 generation (detected by an RIA method) were compared with four selected physico-chemical parameters of these drugs. Platelet aggregation was inhibited in the rank order of potency: bromadryl > dithiaden > propranolol > chloroquine, which corresponded with the decrease in the net charge of the terminal methyl-(or ethyl-) groups in the side chain and with the increase of the dipole moment of drug molecules. On the other hand, the rank order of potency in which the drugs tested inhibited thromboxane B2 formation (chloroquine > dithiaden > bromadryl > propranolol) correlated well with the decline in molar refractivity of the drugs. No relationship was found between inhibitory effects of drugs and their partition coefficients. The results presented indicate that inhibition of platelet functions might consist of several types of drug-cell interactions, depend on the structure and physico-chemical properties of the drugs and cannot be estimated simply on the basis of partition coefficients.

Topics: Animals; Benzothiepins; Blood Platelets; Chemical Phenomena; Chemistry, Physical; Chloroquine; Diphenhydramine; Dose-Response Relationship, Drug; Platelet Aggregation Inhibitors; Platelet Function Tests; Propranolol; Radioimmunoassay; Rats; Software; Structure-Activity Relationship; Thrombin; Thromboxane B2

The histamine receptor H1-antagonists of cationic amphiphilic drug (CAD) structure BromadrylR (BRO) and DithiadenR (DIT) were investigated on stimulated functions of blood platelets in vitro. Both drugs dose-dependently decreased platelet aggregation. BRO significantly decreased aggregation in concentrations of 20 and 200 mumol/l in thrombin and ADP stimulated platelets, respectively. DIT was 10 times less active as compared with BRO. A dose-dependent inhibitory effect of BRO and DIT was demonstrated on thrombin stimulated production of malondialdehyde (MDA) and thromboxane (TXB2) generation in platelets. A significant decrease in MDA production and TXB2 generation was measured with BRO and DIT in 10 mumol/l concentration. Results showed that the antihistaminic drugs BRO and DIT inhibited stimulated aggregation in relation to membrane phospholipid peroxidation and arachidonic cascade activation in platelets. These data, along with results from studies on the effect of other CAD on platelets, revealed that antihistaminic drugs interfere with stimulated aggregation by inhibiting phospholipase A2 rather than the intraplatelet histamine receptor.

Topics: Adenosine Diphosphate; Benzothiepins; Blood Platelets; Diphenhydramine; Dose-Response Relationship, Drug; Histamine H1 Antagonists; Humans; Malondialdehyde; Platelet Aggregation; Platelet Aggregation Inhibitors; Thrombin; Thromboxane B2

Topics: Adenosine Diphosphate; Animals; Benzothiepins; Calcimycin; Histamine H1 Antagonists; In Vitro Techniques; Male; Malondialdehyde; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Thrombin; Thromboxane B2