Inhibitory effects of sulphated flavonoids isolated from Flaveria bidentis on platelet aggregation

Flaveria bidentis is a plant species that has as major constituents sulphated flavonoids in the highest degree of sulphatation. Among them, quercetin 3,7,3′,4′-tetrasulphate (QTS) and quercetin 3-acetyl-7,3′,4′-trisulphate (ATS) are the most important constituents. Both showed anticoagulant properties. The objective of the present study was to evaluate the effects of these flavonoids on human platelet aggregation in comparison with the well-known inhibitor quercetin (Qc) by using several agonists. Platelet-rich plasma (PRP) or washed human platelets (WP) were incubated with different concentrations of the flavonoids to be tested (1 to 1000 μM, final concentration), and the platelet aggregation was induced by using adenosine 5′-diphosphate (ADP), epinephrine (EP), collagen, arachidonic acid (AA) and ristocetin as agonists. QTS (500 μM) and Qc (250 μM) markedly inhibited platelet aggregation with all the aggregant agents, except ristocetin, whereas ATS (1000 μM) showed only slight antiplatelet effects. In addition, QTS and Qc antagonized the aggregation of PRP or WP induced by U-46619, a mimetic thromboxane A2 (TxA₂) receptor agonist. Challenged with collagen or arachidonic acid, the thromboxane B₂ (TxB₂) formation was also inhibited by the flavonoids, mainly by QTS and Qc, in WP. These results demonstrate that QTS and in minor extension ATS induce a deleterious effect on the production of TxA₂, as judged by TxB₂ formation, in stimulated WP and a marked interference on the TxA₂ receptor according to the profile of inhibition of the agonist-induced platelet aggregation when using ADP, EP, AA and collagen and confirmed with U-46619.     

Anticoagulant effect of sulphated poly/vinyl alcohol-acrylic acid/copolymers

Copolymers of poly/vinyl alcohol-acrylic acid/ with various content of sulphate and carboxyl groups have been synthetized and tested for their in vitro effect on blood coagulation. The results indicate that the sulphated copolymers display an inhibitory effect but there is a requirement in the charged groups of about 20% in the molecule to possess effective anticoagulation. The biochemical mechanism of their actions is complex, i.e. the inhibition of blood clotting is a consequence of both the accelerated inactivation rate of thrombin by antithrombin-III and a direct inhibitory effect on the thrombin-fibrinogen reaction. Moreover, additional effects may occur on other blood coagulation enzymes than thrombin, depending on the chemical composition of the copolymers.     

Anticoagulant effect of cardiotoxins

Variation of the potent thrombin inhibitors derived from Nα-arylsulfonyl-4-amidinophenylalanine was carried out by interposition of an ω-aminoalkylcarboxylic acid between the Nα-arylsulfonyl residue and the 4-amidinophenylalanine part. The use of glycine as spacer renders the compounds tight binding inhibitors of thrombin. The K_i of the most potent inhibitor reaches the nmol/l range. The inhibitory effect is specifically directed against thrombin, the K_i values for inhibition of trypsin, plasmin and factor Xa are some orders of magnitude higher than those for thrombin inhibition.     

Understanding antidepressant mechanism of action and its effect on efficacy and safety

Common side effects of antidepressants, such as weight gain, sexual dysfunction, and fatigue and sleepiness, may be attributable to their mechanisms of action. Antidepressants are neurotransmitter uptake blockers, enzyme inhibitors, and neurotransmitter receptor blockers. Various mechanisms of action can determine how quickly therapeutic benefit becomes apparent and whether certain acute and persistent side effects occur. Understanding mechanism of action can help clinicians select appropriate antidepressants for individual patients and manage adherence problems due to intolerability. Although more research is needed to further elucidate specific antidepressant mechanisms of action, clinicians can use current knowledge to tailor treatment decisions, such as switching patients to a medication with a different mechanism of action when intolerable adverse events are experienced.     

Therapeutic effect of inosine in Tourette syndrome and its possible mechanism of action

We found incidentally 3 years ago that inosine relieved the symptoms in a patient with Tourette syndrome. Since then, 36 patients suffered from Tourette syndrome were exclusively treated with inosine, 50-90 mg/kg daily in divided doses. The vocal and non-vocal tic attacks were counted either by the observation of an examiner or with a video-tape record. The clinical status was scored as the sum of the number of various tic attacks recorded during a period of 60 minutes (video-tape record) or 20 minutes (direct observation). According to the scores obtained from double blind cross-over trial (11 cases) and open trial (25 cases), the tic attacks were well controlled in 75% of patients treated. A follow-up study by the end of one year medication the efficacy of inosine was still impressive in 50% of patients. Since we have observed that inosine potentiated the release of dopamine from rat striatal synaptosomes, mimicked the action of some dopamine antagonists, it is suggested that inosine might behave as a dopamine antagonist and exerts its effect on Tourette syndrome as haloperidol does.     

Studies on the action mechanism of the antihemostatic effect of lodopeptides.

A synthetic iodopeptide having a glutamic acid-diiodotyrosine molar ratio of 1:1 has been shown to be an effective anticoagulant both in vivo and in vitro. Contrasted with heparin the following general conclusions may be made regarding its action. The iodopeptide does not act through the inactivation of thrombin in plasma. Iodopeptide does interact with fibrinogen to form a complex which, in vitro, is not soluble in buffered saline at physiological pH. At pH 8, iodopeptide interacts with fibrinogen to form a soluble complex in the presence of 0.9% NaCl that is not coaguable either by thrombin or Crotalus venom enzymes. All the available evidence indicates that the fibrinogen to fibrin conversion is not inhibited under these conditions, but that fibrin, once formed, is not able to polymerize due to interference by iodopeptide. Similar results were obtained with heparin in vitro with thrombin-fibrinogen mixtures in the absence of NaCl. Studies with Russell's viper venom in native PRP strongly suggest that the iodopeptide also interferes with processes in the early coagulation pathway associated with prothrombin activation.     

京尼平对脂多糖诱导小胶质细胞炎症及凋亡的作用及机制研究

目的探讨京尼平(genipin)对脂多糖(LPS)诱导小胶质细胞(BV-2)炎症及凋亡反应的作用及机制。方法采用LPS诱导BV-2小胶质细胞建立中枢神经系统炎症和凋亡反应模型。实验细胞分为4组:空白对照组、京尼平组、LPS组、LPS+京尼平组。通过ELISA、RT-PCR、Western Blot、细胞流式检测细胞的炎症及凋亡反应。结果与空白对照组比较,LPS可以诱导BV-2细胞上清培养基中IL-6、IL-1β和TNF-α释放和细胞内IL-6、IL-1β和TNF-α转录的增加;同时,LPS还可以激活凋亡蛋白Bax并抑制抗凋亡蛋白Bcl-2的表达,导致细胞凋亡率的明显升高。京尼平预处理可以有效抑制小胶质细胞介导的炎症因子(IL-6、IL-1β和TNF-α)激活,并减少LPS诱导的小胶质细胞凋亡。结论 genipin干预可对LPS诱导的小胶质细胞炎症及凋亡反应起到保护作用。     

Electroconvulsive therapy and its mechanism of action

Electroconvulsive therapy (ECT) is known as an effective treatment for some depressive disorders. Nevertheless ECT continues to be a subject of controversy. The absence of a unifying theory for its mechanisms of action explains the mistrust about ECT. The aim of this article is to review the literature about ECT and to propose a synthesis concerning its mechanisms of action. At the present time, the most reliable hypothesis suggests selective activations of central serotonergic and dopaminergic systems on the one hand, and a direct stimulation of the neuroendocrine neurons on the other hand.     

Anticoagulant activity of peptides from the human placenta

A peptide with anticoagulant activity was isolated from a human placenta homogenate. It was found that this peptide prolongs cephalin-kaolin clotting time moderately and thrombin clotting time of human plasma considerably. The peptide was purified by a three-step procedure; 1/ dialysis of the homogenate, 2/ extraction of the peptides from the filterable fraction, 3/ separation of the peptide mixture on a Dowex column.     

The mechanism of action of aspirin

The therapy of rheumatism began thousands of years ago with the use of decoctions or extracts of herbs or plants such as willow bark or leaves, most of which turned out to contain salicylates. Following the advent of synthetic salicylate, Felix Hoffman, working at the Bayer company in Germany, made the acetylated form of salicylic acid in 1897. This drug was named “Aspirin” and became the most widely used medicine of all time. In 1971, Vane discovered the mechanism by which aspirin exerts its anti-inflammatory, analgesic and antipyretic actions. He proved that aspirin and other non-steroid anti-inflammatory drugs (NSAIDs) inhibit the activity of the enzyme now called cyclooxygenase (COX) which leads to the formation of prostaglandins (PGs) that cause inflammation, swelling, pain and fever. However, by inhibiting this key enzyme in PG synthesis, the aspirin-like drugs also prevented the production of physiologically important PGs which protect the stomach mucosa from damage by hydrochloric acid, maintain kidney function and aggregate platelets when required. This conclusion provided a unifying explanation for the therapeutic actions and shared side effects of the aspirin-like drugs. Twenty years later, with the discovery of a second COX gene, it became clear that there are two isoforms of the COX enzyme. The constitutive isoform, COX-1, supports the beneficial homeostatic functions, whereas the inducible isoform, COX-2, becomes upregulated by inflammatory mediators and its products cause many of the symptoms of inflammatory diseases such as rheumatoid and osteoarthritis.     

The mechanism of action of psychotherapy

Colom F. The mechanism of action of psychotherapy. Bipolar Disord 2002: 4(Suppl. 1): 102. © Blackwell Munksgaard, 2002     

Clinical pharmacology and mechanism of action of zonisamide

Antiepileptic drugs (AEDs) suppress seizures by selectively modifying the excitability of neurons and blocking seizure firing with minimal disturbance of nonepileptic activity. All AEDs have been shown to work by at least one of 3 main mechanisms of action: through modulation of voltage-gated ion channels, enhancement of synaptic inhibition, and inhibition of synaptic excitation. Zonisamide is a novel AED that has a broad combination of complementary mechanisms of action, which may offer a clinical advantage over other antiepileptic agents. By altering the fast inactivation threshold of voltage-dependent sodium channels, zonisamide reduces sustained high-frequency repetitive firing of action potentials. Zonisamide also inhibits low-threshold T-type calcium channels in neurons, which may prevent the spread of seizure discharge across cells. In addition, zonisamide is a weak inhibitor of carbonic anhydrase. However, this mechanism is not believed to contribute to the antiepileptic activity of zonisamide. Although zonisamide also seems to alter dopamine, serotonin, and acetylcholine metabolism, it is not clear to what extent these effects on neurotransmitters are involved in the clinical actions of the drug. In addition to these actions, recent evidence suggests that zonisamide may exert neuroprotective actions, independent of its antiepileptic activity. These potential effects may be important in preventing neuronal damage caused by recurrent seizures. Therefore, it seems that the multiple pharmacological actions of zonisamide may contribute to the seizure reductions observed in a wide range of epilepsies and may help to preserve efficacy in individual patients despite possible changes in electrophysiological status.