The effect of some epsilon-aminocaproic acid derivatives on platelet responses

epsilon-Aminocaproic acid (EACA) is a synthetic low molecular drug with antifibrinolytic activity. However, treatment with this drug can be incidentally associated with an increased thrombotic tendency. The aim of the present work was to test synthetic EACA derivatives for their antiplatelet activities. We investigated the effect of three EACA derivatives with antifibrinolytic activity: I. epsilon-aminocaproyl-L-leucine hydrochloride (HClH-EACA-L-Leu-OH), II. epsilon-aminocaproyl-L-(S-benzyl)-cysteine hydrochloride (HClH-EACA-L-Cys(S-Bzl)-OH) and III. epsilon-aminocaproyl-L-norleucine (H-EACA-L-Nle-OH) on platelet responses (aggregation and adhesion) and on their integrity. It was found that: 1. as judged by LDH release test, none of the tested compounds, up to 20 mM, was toxic to platelets, 2. in comparison with EACA, all the synthetic derivatives inhibited much stronger the ADP- and collagen-induced aggregation of platelets suspended in plasma (platelet rich plasma) and aggregation of these cells in whole blood, 3. EACA and its derivatives exerted a similar inhibitory effect on the thrombin-induced adhesion of platelets to fibrinogen-coated surfaces. Since platelet activation and blood coagulation are tightly associated processes, the antiplatelet properties of EACA derivatives are expected to indicate reduced thrombotic properties of these derivatives compared to EACA.     

Effects of in vivo administration of kainic acid on the extracellular amino acid pool in the rabbit hippocampus

The effect of local administration of kainic acid in the rabbit hippocampus was studied; the hippocampus was perfused continuously in the freely moving animal with an implanted 0.3-mm dialysis fiber. The pattern of endogenous amino acids in the perfusate, reflecting extracellular amino acids, was monitored with liquid chromatography separation and fluorimetric detection of amino acid derivatives. Kainic acid was included in the perfusion medium for up to 70 min at 0.1-1.0 mM and, with time, induced epileptiform activity. Endogenous glutamic acid, taurine, and phosphoethanolamine levels were increased selectively at the lower perfusion concentrations of kainic acid. Long perfusion periods with higher concentrations increased the levels of virtually all amino acids. Perfusion of the hippocampus with depolarizing concentrations of potassium gave an amino acid response partly similar to that seen with kainic acid treatment. However, one notable difference between the two responses was that the extracellular concentration of glutamine, although not influenced by kainic acid, was significantly decreased after high potassium concentrations. These results confirm previous notions that kainic acid has a primarily excitatory effect, one manifestation of this effect being the release of glutamic acid.     

Effects of altering dietary fatty acid composition on prostaglandin synthesis and fertility

Several studies over the past 20 years have demonstrated that subjects on diets composed of substances with high levels of n-3 polyunsaturated fatty acids (PUFAs) (e.g. fish) have a decreased incidence of heart disease. On this basis, a recent report from the Department of Health has advised UK consumers to decrease the proportion of saturated as opposed to unsaturated fats in their diet and to increase the ratio of n-3 to n-6 PUFAs. This could be achieved by altering the amounts of these constituents in milk and meat. n-3 Fatty acids can most easily be added to animal feed as either fish oil or linseed oil and can be increased in the blood and milk of ruminants following protection to avoid hydrogenation in the rumen. In western countries the ratio of consumption of n-6 to n-3 PUFAs is greater than 10 and current evidence tends to suggest that a ratio nearer 5 would be more desirable and compatible with cardiovascular well being. As fertility in the UK dairy herd is already poor, it is important to establish whether alterations in dietary n-3 and n-6 PUFAs affects herd fertility before widespread changes in animal diets are recommended. Therefore, this review considers the role played by PUFAs and eicosanoids in fertility, with particular reference to the implications for farm livestock production. The evidence reviewed shows that alteration of the concentration and ratio of n-6 and n-3 PUFAs in feeds can influence prostaglandin synthesis/metabolism in a number of mammalian systems. The changed patterns of prostaglandin synthesis can as a consequence, affect the diverse functions (e.g. hormone secretion) that are normally mediated via prostaglandins. Similarly, changes in prostaglandin synthesis effected through manipulation of PUFAs has a major bearing on fertility (as PGs affect many reproductive parameters, e.g. ovulation). Several studies in cattle and other mammals, show that feeding or infusing different types of fat with varying PUFA content to females can alter: the number and size of ovarian follicles, the ovulation rate, progesterone production by the corpus luteum, the timing of luteolysis and gestational length. In the male most recent work has focussed on sperm production and experiments in fowl have demonstrated clear effects of dietary PUFAs on both the sperm membrane phospholipid composition and on fertilizing ability.     

Experimental study of the prophylactic anti-influenza and interferon-inducing activity of epsilon-aminocaproic acid

Epsilon-aminocaproic acid, an original antifibrinolytic had a rapid and prolonged protective effect, thus lowering the death rate of experimental mice contaminated with virulent strains of the influenza virus. The protective effect of the acid was observed after its intraperitoneal administration in a dose of 20 mg/mouse 24 hours before contamination by the strain with the H3N2 antigenic formula and after intranasal application of 15 mg of epsilon-aminocaproic acid divided into 2 doses 2 days before contamination by the strain with the H1N1 antigenic formula. In the animals contaminated by the H1N1 influenza virus 5 days after subcutaneous administration of the drug in a dose of 30 mg there was detected in the lungs a much lower number of the infectious viruses 3 days after the contamination. It was shown that 3 and 6 weeks after initiation of the 5-day treatment course with subcutaneous administration of epsilon-aminocaproic acid in a daily dose of 90 mg/mouse the animal resistance to the H1N1 influenza virus increased. No interferonogenic activity after administration of epsilon-aminocaproic acid was observed in the mice.     

Synergistic antifibrinolytic action of the potato protease inhibitor and epsilon-aminocaproic acid.

Fibrinolysis inhibition by a mixture of potato inhibitor and E-aminocaproic acid was greater than might be expected from the sum of the antifibrinolytic effects of these inhibitors investigated separately. This inhibition was observed in studies on the plasma euglobulin fraction and in a system containing isolated elements of the fibrinolytic system. The synergistic antifibrinolytic action of the potato protease in hibitor and E-aminocaproic acid is probably due to the fact that these inhibitors have different mechanisms of action and thus there is no competition between them for the effectors in the enzyme molecule.