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Endogenous formation of gamma-hydroxybutyric acid (GHB) has been described in humans. It is considered to be a neurotransmitter and/or neuromodulator although its precise physiological role remains unclear. This molecule is used in the treatment of alcoholism and alcohol withdrawal. GHB, at least in central nervous system, has ethanol-like activities and it is well-known that ethanol decreases platelet function. However, there are no information regarding the GHB and its effect on platelet function. Therefore, the goal of the study was to investigate the most notable GHB effects on human platelet aggregation in vitro.

Several 2,7-di(N-cycloamino)-3-phenyl-1,8-naphthyridine derivatives were synthesized and tested for their ability to inhibit human platelet aggregation in vitro induced by arachidonic acid, collagen and ADP. Only five compounds showed any appreciable activity, and the results of all the active derivatives were similar to those of papaverine in the test with arachidonic acid and collagen. Moreover, the most active compounds were investigated in the test with ADP and again showed a significant activity. The tested compounds that possessed the best activity were also shown to increase the c-AMP level significantly without involving the adenylyl cyclase system.

In the present study the effect of N-methyl-D-aspartate (NMDA) on thromboxane B2 synthesis and on [Ca2+]i was studied in human platelets. NMDA (10−7M) completely inhibited the synthesis of thromboxane B2 from exogenous arachidonic acid (AA), while it did not interfere with the aggregating effect of the thromboxane A2 receptor agonist U-46619. NMDA (0.1 μM–10 μM) dose-dependently increased intracellular calcium in washed platelets pre-loaded with fura 2 AM, and this effect was not additive with that of AA. NMDA shifted the dose-response curve of AA to the right. At the highest AA concentrations platelet aggregation was not inhibited. The antiaggregating effect of NMDA was not antagonized by NG-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase (NOS) inhibitor. Finally, NMDA (0.01 nM–100 nM) associated with either aspirin or indomethacin significantly potentiated the antiaggregating activity of both cyclo-oxygenase inhibitors. It was concluded that NMDA is a potent inhibitor of platelet aggregation and thromboxane B2 synthesis in human platelet rich plasma (PRP).

Several 1,8-naphthyridine derivatives have been diazotizated to obtain the corresponding hydroxy derivatives or mixture of hydroxy and hydroxy nitro derivatives. The respective amounts of hydroxy and hydroxy nitro derivatives depends on the nature of the substituents, on their position on the naphthyridine nucleus, on the amount of sodium nitrite and on the reaction temperature. A study of the electronic density of some molecules suggests a possible explanation of the effects induced by the nature of the substituents and of their position. Some of the compounds were tested for their ability to inhibit human platelet aggregation in vitro induced by arachidonic acid. Only compound 26 showed interesting antiplatelet activity.

Several 2,7-di(N-cycloamino)-3-phenyl-1,8-naphthyridine derivatives were synthesized and tested for their ability to inhibit human platelet aggregation in vitro induced by arachidonic acid, collagen and ADP. Only five compounds showed any appreciable activity, and the results of all the active derivatives were similar to those of papaverine in the test with arachidonic acid and collagen. Moreover, the most active compounds were investigated in the test with ADP and again showed a significant activity. The tested compounds that possessed the best activity were also shown to increase the c-AMP level significantly without involving the adenylyl cyclase system.

Recent studies indicate that taurine levels are reduced both in plasma3 and platelets obtained from patients with insulin-dependent diabetes mellitus (IDDM) in the absence of any complications of disease3. We have demonstrated that between plasma taurine levels and glycosylated hemoglobin levels (HbAlc) there is an inverse linear correlation indicating that taurine levels could be of some relevance in the control of metabolic state3. Moreover, when taurine levels are increased by taurine supplementation, the sensitivity of platelets obtained from IDDM patients to arachidonic acid is decreased3.

In human volunteers it has been shown that taurine supplementation decreases collagen-induced thromboxane release and platelet aggregation (6). In addition, we found that, while in vitro taurine did not modify platelet aggregation per se, it potentiated the effect of anti-aggregating agents such as aspirin, papaverine, or sodium nitroprusside (13). These observations seem to indicate a possible role for taurine in the modulation of platelet function.

In plasma, the physiological levels of taurine have been reported to be 0.05–0.22 mM depending on the species1 while platelet levels are a hundred times higher than the plasma2. These cellular fragments possess active transport sites2. However, the physiological significance of taurine in the platelets is still obscure although it has been shown that taurine stabilizes platelets against platelet activating factor (PAF) in guinea-pigs and ADP in man3,4

Several 4-nitro- and 4-amino-5-acyl-6-aryl-3(2 H )pyridazinones were prepared and their in vitro and ex vivo antiaggregatory properties were evaluated. 4-Nitro derivatives 3 generally showed good activity in vitro towards arachidonic acid (AA)-induced human blood platelet aggregation. The 4-amino compound 4a , which has weak in vitro activity, exhibited antiplatelet activity, particularly on adenosine dephosphate (ADP)-induced aggregation ex vivo in rabbit. Moreover, the same compound was shown to be active in platelet-activating factors (PAF)- induced rat paw hyperalgesia and to be endowed with low acute oral toxicity. The 4-amino derivatives 4a – m and the other pyridazinones 5–9 administered orally to rats were also found to be more potent antiinflammatory agents than acetyl salicylic acid (ASA). Compounds 3a and 4a , tested in vitro on lipopolysaccharide (LPS)-stimulated rat peritoneal macrophages, were seen to be active in the inhibition of prostaglandin E 2 (PGE 2 ) production and interleukin-1 activity. Structure–activity relationship studies in the series of antiaggregating pyridazinones 3 have shown the primary importance of the nitro and acetyl substituents at positions 4 and 5, respectively. Hydrophobic substituents at position 2 were also required for better activity.