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Biomedical subjects

J Y Jeremy

Publications and source records attributed to J Y Jeremy.

At least 109 records · Page 6Linked to original sources
PubMed1990

Indomethacin and ibuprofen inhibit the uptake of 45Ca2+ by washed human platelets through a thromboxane A2-independent mechanism.

Indomethacin and ibuprofen inhibited adrenaline- and calcium ionophore A23187-stimulated 45Ca2+ uptake by isolated human platelets in a concentration-dependent manner. Mediation of these effects by thromboxane A2 (TXA2) inhibition was discounted since under the same experimental conditions, adrenaline did not stimulate TXA2 synthesis and A23187-stimulated TXA2 synthesis was only marginally inhibited by concentrations of ibuprofen and indomethacin that inhibited 45Ca2+ uptake by 50%. These data indicate that the inhibitory action of non-steroidal anti-inflammatory drugs (NSAIDs) on platelet activity may be due, at least in part, to effects on calcium mobilisation at the plasma membrane level. The present results may also be of relevance to the anti-inflammatory action of NSAIDs.

Blood Platelets↗
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

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

The levels and possible involvement of leukotriene B4 and prostaglandin F2 alpha in the control of interstitial fluid volume in the rat testis.

The possible involvement of two arachidonic acid metabolites, prostaglandin F2 alpha (PGF2 alpha) and leukotriene B4 (LTB4), in the stimulatory effect of human chorionic gonadotrophin (hCG) on the volume of interstitial fluid (IF) in the rat testis has been investigated. Administration of hCG caused a time- and dose-dependent increase in the IF levels of PGF2 alpha while LTB4 showed no clear dose-dependence, but did decrease significantly at 2-8 h after injection of 100 IU hCG. Administration of ethane dimethane sulphonate (EDS), which specifically destroys Leydig cells, decreased the volume of IF but the IF levels of LTB4 and PGF2 alpha were unchanged. This indicates that although the absence of Leydig cells results in significant changes in IF volume, LTB4 and PGF2 alpha are probably not involved in these changes. Furthermore, these findings suggest that Leydig cells are not the only contributors to LTB4 and prostaglandins E2 and F2 alpha in testicular IF. In rats injected peripherally with hCG, intratesticular administration of the cycloxygenase inhibitor, indomethacin, decreased PGF2 alpha levels in IF after 2 and 4 h but not at later times. However, no inhibitory effect of indomethacin on the hCG-stimulated increase in IF volume was detected; indeed, at 2 h after injection of indomethacin + hCG there was a significant increase in IF volume in the indomethacin-injected testis. It is concluded that, although prostaglandins and LTB4 are secreted into IF in the rat testis, these arachidonic acid metabolites are apparently not the primary mediators of the increase in IF volume that follows hCG treatment.

Analysis of Variance↗
PubMed1990

Nonsteroidal anti-inflammatory drug therapy and gastric side effects. Does nabumetone provide a solution?

Nabumetone is a novel nonsteroidal anti-inflammatory drug (NSAID) which, although a weak cyclo-oxygenase inhibitor (COI), is converted in the liver to the active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA), which is a more potent COI. Thus nabumetone may reduce gastric erosion while maintaining its efficacy as an anti-inflammatory drug peripherally. To investigate this novel 'prodrug' further we compared the effects of nabumetone and 6-MNA with those of naproxen and indomethacin on the synthesis of the gastroprotective prostaglandins (PG) epoprostenol (I2) and dinoprostone (E2) by rat and human gastric mucosa in vitro, and ex vivo in the rat. The effect of these NSAIDs on platelet aggregation and thromboxane A2 (TXA2) synthesis was also studied. In human and rat gastric mucosa the synthesis of epoprostenol and dinoprostone was inhibited by indomethacin, naproxen and 6-MNA (indomethacin greater than naproxen greater than 6-MNA) whereas nabumetone had no effect whatsoever. Platelet aggregation and TXA2 synthesis were inhibited in a similar manner. These results indicate that nabumetone does not inhibit gastroprotective prostaglandins, whereas its active metabolite, 6-MNA, is an effective inhibitor of prostanoid synthesis in target tissues.

Animals↗
PubMed1990

Effects of fish oil supplements in NIDDM subjects. Controlled study.

The aim of this study was to evaluate the effects of a fish oil preparation (MaxEPA) on hemostatic function and fasting lipid and glucose levels in non-insulin-dependent diabetic (NIDDM) subjects. Eighty NIDDM outpatients aged 55.9 yr (mean SD 11.5 yr) participated in a prospective double-blind placebo-controlled study of MaxEPA capsules (10 g/day) or olive oil (control) treatment over 6 wk. Patients received either MaxEPA or olive oil in addition to preexisting therapy. Metabolic and hemostatic variables were measured before treatment and after 3 and 6 wk. Platelet membrane eicosapentaenoic acid (EPA) content increased in the treatment group (P less than 0.001). MaxEPA supplementation was associated with a significant fall in total triglycerides (P less than 0.001) but did not affect total cholesterol (P = 0.7) compared with control treatment. Fasting plasma glucose increased after 3 wk (P = 0.01) but not after 6 wk (P = 0.17) treatment with MaxEPA. Spontaneous platelet aggregation in whole blood fell in the MaxEPA group (P less than 0.02) after 6 wk, but there were no changes in agonist-induced platelet aggregation, thromboxane generation in platelet-rich plasma, or plasma beta-thromboglobulin and platelet factor IV levels. An increase in clotting factor VII (P = 0.02), without changes in fibrinogen or factor X levels, occurred in the MaxEPA group. Similar reductions in blood pressure were observed in both groups. Dietary supplementation with MaxEPA capsules (10 g/day) in NIDDM subjects is associated with improvement in hypertriglyceridemia but with deleterious effects in factor VII and blood glucose levels. Most indices of platelet function are unaffected by this therapy.

Blood Glucose↗
PubMed1989

Iron chelators inhibit human platelet aggregation, thromboxane A2 synthesis and lipoxygenase activity.

The iron chelators desferrioxamine and 1,2-dimethyl-3-hydroxypyrid-4-one (L1) inhibited human platelet aggregation in vitro as well as thromboxane A2 synthesis and conversion of arachidonate to lipoxygenase-derived products. Non-chelating compounds related to L1 were without effect on cyclooxygenase or lipoxygenase activity. Since both cyclooxygenase and lipoxygenase are iron-containing enzymes, it is suggested that the inhibition of platelet function by these iron chelators may be related to the removal or binding of iron associated with these enzymes. These iron chelators may therefore be of potential therapeutic value as platelet antiaggregatory agents and of possible use in the treatment of atherosclerotic and inflammatory joint diseases.

Adenosine Diphosphate↗
PubMed1989

Muscarinic stimulation of prostanoid synthesis by the isolated rat trachea: calcium dependency and effect of cortisol and cigarette smoke.

Tracheal prostanoid synthesis was stimulated by parasympathomimetics: arecoline greater than carbachol = methacholine greater than acetylcholine much greater than arecaidine. McNA343, dimethyl phenyl piperazinium (DMPP), nicotine, potassium and isoprenaline were without effect. Prostanoid synthesis was also stimulated by Ca2+ ionophore A23187 and arachidonic acid (AA). Carbachol-stimulated prostanoid synthesis was inhibited by cholinergic antagonists (atropine greater than ipratropium bromide much greater than gallamine greater than pirenzepine); adrenaline and isoprenaline were without effect. Carbachol-stimulated prostanoid synthesis was also inhibited by the Ca2+-channel blockers, nifedipine, diethylstilboestrol and TMB-8. Hydrocortisone and betamethasone inhibited carbachol- and A23187-stimulated, but not AA-stimulated, prostanoid synthesis following an 18 h tissue culture. Cigarette smoke extracts had a biphasic effect on carbachol-, A23187- and AA-stimulated prostanoid synthesis (potentiation at low concentrations, inhibition at high concentrations of extracts). These data demonstrate (1) that rat tracheal prostanoid synthesis is stimulable by activation of muscarine receptor-linked Ca2+ mobilisation, and (2) that tracheal prostanoid synthesis may be involved in secretion of mucus, the disruption of which by cigarette smoking may be related to the pathophysiology of airway disease.

Acetylcholine↗