Antithrombotic potential of dihomo-gamma-linolenic acid in man.

The effects of orally ingested dihomo-gamma-linolenic acid (DHLA), the natural biosynthetic precursor of prostaglandin E1 (PGE1), were assessed in human volunteers. Single doses of DHLA (0.1--2g) increased the proportion of DHLA relative to arachidonic acid in plasma and platelets and also increased the ex-vivo capacity of platelets to produce PGE1 and PGE2. More pronounced effects were observed during sustained treatment (five days to four weeks) when DHLA also accumulated in red cell membranes. These biochemical changes were accompanied by potentially antithrombotic changes in haemostatic function. The most common effect, which was consistently detected after 0.1-g single doses of DHLA or its methyl ester, was a decrease in plasma heparin-neutralising activity. Inhibition of platelet aggregation induced by adenosine diphosphate was also detected, though this was generally less pronounced. Sustained treatment in one subject also produced definite inhibition of ristocetin-induced platelet aggregation. There was only one possible adverse effect--a transient cough in a subject with a history of asthma. DHLA therefore seems to have considerable potential as an agent for preventing and treating human thromboembolic disease.     

Antithrombotic effects of some flavonoids alone and combined with acetylsalicylic acid

In the rat, a selection of two experimental models of "prethrombotic states", one of venostatic thrombosis and one of arterial thrombosis was used to compare the antithrombotic of three flavonoid preparations: O,-(beta-hydroxyethyl)-rutosides (HR), an association of trihydroxyethylrutoside and coumarin (troxerutin) and 7-mono-hydroxyethylrutoside (7-Mono-HR), as well as acetylsalicylic acid (ASA). The flavonoids were very effective "protectors" on the prethrombotic models, but only ASA was active on the model of arterial thrombosis. No compound showed a clear protection on the venostatic model if direct activation by kaolin was used. However, if an indirect activation by vessel wall stimulation was used, 7-Mono-HR possessed a marked protective effect. The most favourable results were obtained with an association of 7-Mono-HR and ASA, which could be considered for investigation in clinical thrombosis prophylaxis.     

Antithrombotic agents

The morbidity and mortality associated with thromboembolic diseases are a worldwide problem. Deep venous thrombosis (DVT) and pulmonary embolism (PE) were estimated, some years ago, to be responsible for between 300,000 and 600,000 hospitalisations annually in the US. Arterial thrombosis is a major cause of myocardial infarction (MI), cerebral infarction and peripheral arterial diseases. Currently available antithrombotic drugs can be divided into three classes: anticoagulants (including vitamin K antagonists, unfractionated heparin and low molecular weight heparins [LMWHs]), antiplatelet agents (platelet aggregation inhibitors such as aspirin, ticlopidine and dipyridamole) and thrombolytics (streptokinase, urokinase and tissue plasminogen activator [t-PA]). All these drugs have demonstrated efficacy in the clinic, but each has its limitations. The risk of haemorrhage persists (though to varying degrees), and efficacy in the prevention, in addition to the treatment, of thromboembolic diseases needs to be improved. In addition, reocclusion following thrombolytic therapy remains a far from negligible risk. Current research goals are focused on identifying more potent and specific inhibitors of targets playing a crucial role in the coagulation pathway, such as thrombin and Factor Xa. Long-term goals are to develop thrombin receptor antagonists or analogues of natural occurring anticoagulants (e.g., tissue factor pathway inhibitor [TFPI] and protein C). The search for more effective anti-aggregating agents has resulted in the ongoing development of clopidogrel (a chemical analogue of ticlopidine), and thromboxane synthase inhibitors and receptor blockers. However, the main efforts have been focused on developing antagonists of the platelet receptor glycoprotein, Gp IIb/IIIa.Much work has been performed to improve the fibrin specificity of thrombolytic agents. In all these areas, new promising chemical structures have been identified, and a number of new antithrombotic agents are in development. The potential development issues remain the risk of bleeding at therapeutic doses, the possible lack of efficacy in sub-groups of treated patients, as well as dose adjustment and treatment duration.The considerable clinical progress in interventional cardiology (e.g., percutaneous transluminal coronary angioplasty [PTCA] and stent implantation) has increased the need for antithrombotic drugs with high local efficacy at the site of arterial injury. Recent progress in the knowledge of plaque rupture-induced disorders, particularly the major role of tissue factor, is suggesting new concepts for antithrombotic therapy. The experience from clinical trials with antithrombotic agents, the validation of biological parameters predictive of a prethrombotic state, and the improvement in non-invasive methods to control drug efficacy are likely to contribute to significant therapeutic progress in the prevention and treatment of venous and arterial thrombosis.     

Abyssomicins, inhibitors of the para-aminobenzoic acid pathway produced by the marine Verrucosispora strain AB-18-032

A screening method was established to detect inhibitors of the biosynthetic pathways of aromatic amino acids and para-aminobenzoic acid, the precursor of folic acid, using an agar plate diffusion assay modified as an antagonism test. By this screening method, a family of three novel polycyclic polyketides named as abyssomicins was isolated from a marine strain of Verrucosispora. The main component abyssomicin C inhibits the pathway between chorismate and para-aminobenzoic acid and is strongly active against gram-positive bacteria, including multi-resistant clinical isolates of Staphylococcus aureus.     

Promotion of thyroid carcinogenesis by para-aminobenzoic acid in rats initiated with N-bis(2-hydroxypropyl)nitrosamine.

Sulfonamide analogues of para-aminobenzoic acid (PABA), a precursor of folate synthesis, have beneficial effects as antifolate, but thyroid peroxidase inhibition has been reported as a side effect that results in promotion of rat thyroid carcinogenesis. In the present study, effects of PABA itself on F344 rat thyroid carcinogenesis after initiation with N-bis(2-hydroxypropyl)nitrosamine (DHPN) were evaluated. In experiment 1, rats in groups 1-4 received a single subcutaneous injection of DHPN at 2800 mg/kg, and groups 5 and 6 received vehicle saline alone. From 1 week after DHPN initiation, rats in groups 2, 3, 4, and 6 were fed basal diet containing 0.25%, 0.5%, 1.0%, and 1.0% PABA, respectively, for 40 weeks. Rats in groups 1 and 5 received basal diet alone throughout the experiment. The final incidence of thyroid follicular cell adenomas and adenocarcinomas was significantly (p < 0.05 or 0.01) increased in groups 3 and 4 as compared to group 1. No thyroid tumors were found in groups 5 and 6. In experiment 2, animals in group 1 were fed basal diet alone, while groups 2 and 3 were given 0.5% and 1.0% PABA in the diet, respectively, for 2 weeks. Thyroid weights in group 3, and serum thyroid stimulating hormone level and proliferative activity of follicular cells in groups 2 and 3 were significantly (p < 0.05 or 0.01) elevated. In addition, the serum thyroxine level in group 3 was significantly (p < 0.05) depressed. These results clearly indicate that PABA exerts promotion/progression effects on rat thyroid carcinogenesis as a result of hypothyroidism followed by negative-feedback via the thyroid-pituitary axis.     

荭草苷的抗血栓作用研究

目的:研究荭草苷的抗血栓作用。方法:观察预防给予荭草苷后对小鼠体外凝血时间、小鼠全血凝块溶解作用、家兔血浆凝血酶原时间(PT)、家兔血浆白陶土部分凝血活酶时间(KPTT)、家兔血浆凝血酶时间(TT)、二磷酸腺苷二钠(ADP)诱导的家兔血小板聚集作用、家兔优球蛋白溶解时间(ELT)的影响。结果:与生理盐水组比较,荭草苷(1、2、4mg/kg)组能显著延长小鼠体外凝血时间,对小鼠全血凝块溶解作用无明显影响;荭草苷(0·625、1·25、2·5mg/kg)组能明显延长家兔PT、KPTT及TT,并能显著抑制ADP引起的血小板聚集,对家兔ELT无明显影响。结论:荭草苷具有明显的抗血栓形成作用。     

Antithrombotic Activity of a New Pyrazine Derivative Determined by the Mouse Antithrombotic Assay

Abstract: A model of pulmonary microembolization in the mouse induced by infusion of epinephrine and collagen was used to determine antithrombotic activity of indomethacin and acetylsalicylic acid and of two newly synthesized pyrazine derivatives. One of the new agents provided marked protection of mice from thrombotic challenge with epinephrine and collagen. Its effectiveness was higher than acetylsalicylic acid (especially at small doses) but smaller than that of indomethacin. The same compound was similar to acetylsalicylic acid with respect to the inhibition of in vitro human blood platelet aggregation. The new class of pyrazine derivatives (the so-called pyrazine CH- and NH-acids) appears interesting from the view-point of the studies of platelet aggregation and may yield potential antithrombotic drugs.     

抗血栓药物的研究进展

血栓栓塞性疾病是引起人类疾病死亡的主要原因之一．随着人们对其发病机制研究与认识的不断深入以及药物设计和筛选技术的日臻成熟,针对各种靶点的新型抗血栓药物不断涌现,如二磷酸腺苷受体阻滞剂、Xa因子抑制剂、凝血酶抑制剂等,我国药学研究者也在这些靶向抗血栓药物研究领域取得一定进展。综述我国学者近些年在国内外学术期刊上发表的相关研究论文中所涉及的各类新型抗血小板药物、抗凝血药物和血栓溶解剂的结构、活性和构效关系。     

A prospective,comparative study of the para-aminobenzoic acid test and faecal elastase 1 in the assessment of exocrine pancreatic function

BACKGROUND: The assessment of exocrine pancreatic insufficiency is part of the routine work-up of patients with persistent diarrhoea or suspected steatorrhoea. Direct and indirect tests for the diagnosis of exocrine pancreatic insufficiency have their drawbacks. Measurement of faecal elastase 1 by enzyme-linked immunoabsorbent assay is a simple, non-invasive, robust test for exocrine pancreatic insufficiency. METHODS: We performed a prospective comparison of the para-aminobenzoic acid test and faecal elastase 1 test in 45 patients being investigated for diarrhoea or suspected steatorrhoea. Details of clinical suspicion, imaging and response to treatment were recorded. RESULTS: Exocrine pancreatic function was normal in 20 patients with normal para-aminobenzoic acid and faecal elastase 1 levels. Eight patients had exocrine pancreatic insufficiency with low para-aminobenzoic acid and faecal elastase 1 levels, which improved with enzyme supplementation. In 14 of the 15 patients with low or borderline low para-aminobenzoic acid and normal faecal elastase 1 levels, a non-pancreatic cause was found; one patient had a false positive para-aminobenzoic acid test. Two had normal para-aminobenzoic acid but low faecal elastase 1 levels. One improved with pancreatic supplementation, and imaging revealed chronic pancreatitis. The other had a false positive faecal elastase 1 test related to profuse diarrhoea. CONCLUSIONS: Faecal elastase 1 estimation is a simple, non-invasive, robust test of exocrine pancreatic insufficiency, performed on an out-patient stool sample. Its diagnostic performance is superior to that of the para-aminobenzoic acid test in investigating patients with diarrhoea or suspected steatorrhoea.     

Antithrombotic activities of saponins fromIlex pubescens

Methanol extract ofIlex pubescens roots prolonged bleeding time threefold, and inhibitied the generation of malondialdehyde released during platelet aggregation induced by thrombin. Through several purification procedures, its saponin, named ilexoside, was proved to be responsible for the antithrombotic activities of the plant. Ilexosides A,-D and-J, and 24-carboxypomolic acid showed strong inhibitory activities on platelet aggregation induced by thrombin.