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Biomedical subjects

D P Mikhailidis

Publications and source records attributed to D P Mikhailidis.

At least 19 recordsLinked to original sources
PubMed1992

Serotonin, histamine and platelets in vascular disease with special reference to peripheral vascular disease.

Cardiovascular disease is a major cause of death. There is evidence that this disease is predicted and its progression influenced by various factors (e.g. hyperlipidaemia). In this review, we consider aspects of platelet structure and function which may explain how this cell type contributes to the pathogenesis of vascular disease. The platelet also contains bioamines (serotonin, 5-HT; histamine) which are potent vasoactive substances. Studies involving patients with peripheral vascular disease (PVD) where abnormalities in platelet function (platelet aggregation and platelet shape change) and in bioamine status (vascular, platelet and plasma bioamine concentrations) are reviewed. We also discuss how platelet activation (in vitro) and plasma lipids influence intraplatelet bioamine status. Finally, we report in vitro evidence of the effect of two drugs prescribed to PVD patients: aspirin and naftidrofuryl. Aspirin is an ineffective inhibitor of 5-HT-induced whole blood platelet aggregation whereas naftidrofuryl is effective in the presence or absence of aspirin. By identifying and altering the factors which contribute to the pathogenesis of atherosclerosis we will be better equipped to prevent, reverse or retard this process.

Animals↗
PubMed1990

Differential inhibitory potencies of non-steroidal antiinflammatory drugs on smooth muscle prostanoid synthesis.

In isolated rat aorta and urinary bladder, indomethacin inhibited the synthesis of the prostaglandins (PG) PGI2, PGE2, PGF2 alpha and TXA2 equipotently when PG synthesis was stimulated with excitatory receptor agonists (noradrenaline and carbachol), fluoride (a G protein activator), phorbol ester (a protein kinase C (PKC) activator) and calcium ionophore A23187 (a creator of artificial calcium channels). However, there was a marked right shift (30 fold) in the indomethacin concentration-inhibition curves when PG synthesis was stimulated by arachidonate (PG substrate) and trauma (freeze fracturing and sonication). Although less potent than indomethacin, the NSAIDs tiaprofenic acid and ibuprofen showed a similar disparity between the IC50s with the same PG stimulators. Since PG synthesis stimulated by receptor agonists, fluoride, phorbol ester and A23187 is dependent on calcium channel activation whereas trauma and arachidonate-stimulated PG synthesis bypass calcium channel activation, these data indicate that NSAIDs inhibit not only cyclooxygenase but also (and more potently) the mobilisation of Ca2+ linked to PG synthesis in these tissues.

Animals↗
PubMed1990

ADPase activity in human maternal and cord blood: possible evidence for a placenta-specific vascular protective mechanism.

ADPase enzyme activity was assessed in maternal and cord plasma by adding radiolabelled ADP and quantitating the degradation products. Cord plasma had sufficiently greater ADPase activity than the corresponding maternal plasma obtained ante- and post-partum. Thus, residual radiolabelled ADP was 30, 32 and 17% of total radioactivity after 30 min incubation (37 degrees C) in maternal ante-partum, maternal post-partum and cord plasmas, respectively. ADPase may act as a platelet aggregation inhibitor in the placental and fetal circulation.

Apyrase↗
PubMed1990

Effect of the antiinflammatory prodrug, nabumetone and its principal active metabolite on rat gastric mucosal, aortic and platelet eicosanoid synthesis, in vitro and ex vivo.

Nabumetone is a novel non-steroidal antiinflammatory drug which although a weak cyclooxygenase inhibitor is converted by the liver to metabolites that are more potent inhibitors of cyclooxygenase. Nabumetone may thus avoid the occurrence of prostanoid-mediated gastropathy while maintaining its efficacy as an antiinflammatory agent. We compared the effect of nabumetone and 6-methoxy-2-naphthylacetic acid (6-MNA; the principal active metabolite of nabumetone) with that of naproxen and indomethacin on the synthesis of rat gastric prostaglandins I2 and E2, in vitro and ex vivo. Ex vivo platelet TXA2 and aortic PGI2 synthesis was also investigated in order to assess peripheral activity of nabumetone metabolites. In vitro, nabumetone was completely without effect on gastric mucosal prostanoid synthesis, whereas indomethacin, naproxen and 6-MNA (in this order of potency) inhibited prostanoid synthesis. Ex vivo, low dose naproxen and indomethacin (less than 5mg.kg-1) markedly inhibited gastric mucosal prostanoid synthesis at 30 min and 2 h post gavage, whereas nabumetone was without significant effect. Nabumetone administration also resulted in the inhibition of platelet TXA2 synthesis, whereas aortic PGI2 synthesis was unaltered. These data indicate that the administration of nabumetone may avoid NSAID gastropathy by leaving gastric mucosal prostanoid synthesis intact and also that the active metabolite(s) of nabumetone are effective inhibitors of cyclooxygenase in an NSAID-target tissue (platelet). The lack of effect of nabumetone administration on vascular PGI2 synthesis may confer an additional advantage over other NSAIDs, since the inhibition of peripheral PGI2 has been implicated in hypertensive and nephrotoxic side effects of NSAIDs.

Animals↗
PubMed1990

The effect of nabumetone and its principal active metabolite on in vitro human gastric mucosal prostanoid synthesis and platelet function.

Nabumetone is a novel non-steroidal anti-inflammatory drug (NSAID) which although a weak cyclooxygenase inhibitor is converted by the liver to metabolites which are more potent inhibitors of cyclooxygenase. Nabumetone may thus avoid the occurrence of gastric erosion while maintaining its efficacy as an anti-inflammatory drug. We compared the effects of nabumetone and 6-methoxy-2-naphthylacetic acid (6MNA; the principal metabolite of nabumetone) with naproxen and indomethacin on in vitro synthesis of the gastroprotective prostaglandins I2 and E2 by human gastric mucosa. To study the effects of 6MNA on peripheral target tissues the effects of the above NSAIDs on human platelet aggregation and thromboxane A2 synthesis were also studied. Prostanoid synthesis by the human gastric mucosa was inhibited by indomethacin, naproxen and 6MNA (in this order of potency) whereas nabumetone was completely without effect. Platelet aggregation and thromboxane A2 synthesis were similarly inhibited by the NSAIDS (viz. indomethacin greater than naproxen greater than 6MNA greater than nabumetone). These results support the view that nabumetone does not inhibit gastroprotective prostanoid synthesis, whereas its active metabolite 6MNA is an effective inhibitor of prostanoid synthesis in target tissues.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Bezafibrate retard in type II diabetic patients: effects on hemostasis and glucose homeostasis.

A double-blind, placebo-controlled trial assessed the effect of a slow-release formulation of bezafibrate (Bezalip Mono, 400 mg daily for 3 months) on lipid profile, glucose homeostasis, platelet function, and plasma fibrinogen concentration in non-insulin-dependent (type II) diabetics. Twenty-four patients completed the trial. There was a significant improvement in the cholesterol (p less than 0.02), triglyceride (p less than 0.01), and nonesterified fatty acid (p less than 0.05) concentrations and in the fasting blood glucose (p less than 0.03) and glycosylated hemoglobin (p less than 0.01) levels of those (n = 11) who received the active preparation but not in those (n = 13) who received placebo. Treatment, but not placebo, also resulted in a significant (p less than 0.01) fall in plasma fibrinogen concentration and a trend towards inhibition of platelet aggregation. Bezafibrate was well tolerated; only one patient (not included in the analysis of results) withdrew from the trial possibly because of side effects of the drug. A larger study is needed to establish whether bezafibrate can reduce nonlipid risk factors (e.g., plasma fibrinogen concentration, glucose intolerance, and hyperinsulinemia) in normo- and hyperlipidemic subjects.

Adult↗