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Biomedical subjects

C Cerletti

Publications and source records attributed to C Cerletti.

At least 91 records · Page 5Linked to original sources
PubMed1987

Mouse antithrombotic assay: the effects of Ca++ channel blockers are platelet-independent.

In the Mouse Antithrombotic Assay aspirin (30-300 mg/kg) protected mice from death by 15 and 42%, respectively. Four Ca++ channel blockers (nitrendipine, nicardipine, nifedipine and verapamil) were effective in reducing the mortality. At the dose of 100 mg/kg nitrendipine and nicardipine gave 80 and 85% protection respectively. Whereas aspirin almost suppressed completely thromboxane (Tx)B2 and platelet factor-4 release after collagen-epinephrine infusion, neither nitrendipine nor nicardipine modified TxB2 release and only reduced slightly platelet factor-4 release. The treatment with aspirin, nitrendipine or nicardipine did not counteract the fall in circulating platelets counted 1 min after the aggregation challenge, but at 3 min platelet count was significantly higher in aspirin-treated mice than in animals given either Ca++ channel blocker. Mouse platelet aggregation induced in vitro by the combination of collagen and epinephrine was inhibited in samples obtained from mice pretreated with aspirin but was unaffected by the treatment with nitrendipine or nicardipine. The i.v. injection of a 12.5% suspension of hardened red blood cells resulted in death of about 80% of mice within 1 to 2 min. Neither circulating platelet count nor plasma TxB2 level were modified significantly by red cell injection. Aspirin was ineffective whereas both Ca++ channel blockers lowered mortality to 50%. These data suggest that Ca++ channel blockers reduce the mortality in the Mouse Antithrombotic Assay by influencing factors other than platelet aggregation and/or Tx production. These factors might be important in mediating mortality occurring after infusion of hardened red cells.

Animals↗
PubMed1986

Low dose aspirin does not prevent fibrinolytic response to venous occlusion.

Interest in the antithrombotic potential of low-dose aspirin is based on its ability to inhibit thromboxane (Tx)A2-related platelet function with concomitant sparing of vascular prostacyclin (PGI2) production. The aim of this study was to investigate the effect of low-dose aspirin (20 mg daily for 7 days) on the increase in fibrinolytic activity in healthy volunteers after venous occlusion. We also tested the effect of high-dose aspirin (650 mg X 2), of salicylate (569 mg X 2) and of indobufen (200 mg X 2), a new cyclo-oxygenase inhibitor unrelated to salicylates. Low-dose aspirin reduced serum TxB2 generation by about 90% and suppressed arachidonate-induced platelet aggregation. In contrast, fibrinolytic activity, measured by the euglobulin lysis area and the euglobulin lysis time, was not significantly affected. Both high-dose aspirin and indobufen significantly inhibited TxB2 generation and the rise in fibrinolytic activity induced by venous occlusion, without affecting the pre-occlusion values. Salicylate did not significantly affect any parameter studied. Besides offering a favorable solution to the "aspirin dilemma" related to the TxA2/PGI2 balance, low-dose aspirin might leave intact the fibrinolytic capacity of the vessel wall.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Contribution of ADP to the amplification of primary platelet aggregation by platelet activating factor (PAF): modulatory role of aspirin.

Platelet Activating Factor (PAF)-induced human platelet aggregation in citrated plasma is accompanied by activation of the cyclo-oxygenase pathway and release of intracellular constituents including Adenosine-5'-diphosphate (ADP). Inhibition of the cyclo-oxygenase pathway by aspirin prevented the amplification of primary platelet aggregation induced by threshold concentrations of PAF. Removal of ADP by enzymatic systems had little or no effect on PAF-induced full aggregation, but reversed the aggregating effect of PAF (at 10 times threshold concentrations) on 'aspirinated' platelets. Aspirin also prevented the synergism between PAF and ADP when subthreshold concentrations of both compounds were combined. Similar results were obtained in heparinized platelet-rich plasma. Thus, ADP may amplify the primary response to PAF but its role is modulated by the availability of the cyclo-oxygenase pathway products.

Adenosine Diphosphate↗
PubMed1986

Effects of 1 gram oral or intravenous aspirin on urinary excretion of thromboxane B2 and 6-keto-PGF1 alpha in healthy subjects.

Aspirin inhibits cyclo-oxygenase, thus preventing prostanoids formation. After oral administration aspirin is hydrolysed to inactive salicylate partly within the gastrointestinal tract, partly during first pass in the liver, partly in the circulation by plasma esterases. Intravenous aspirin, in contrast, mainly undergoes plasma esterase-catalysed deacetylation. Six healthy male subjects were given 1 g aspirin orally and intravenously two weeks apart according to a cross-over randomized design. Whereas serum TxB2 generation reflecting platelet cyclo-oxygenase activity was suppressed by aspirin by both routes, urinary excretion of TxB2 and 6-keto-PGF1 alpha was not affected by oral aspirin, but was partially though significantly reduced by the i.v. drug. Drug disposition seems therefore to be essential in determining the "biochemical selectivity" of aspirin as related to platelet and renal prostanoids generation.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Inhibition of platelet thromboxane generation by suloctidil in man.

Oral administration of 100 or 200 mg suloctidil to healthy volunteers resulted in serum thromboxane B2 (TxB2) inhibition. This reached a maximum level between 90 min and 4 h after drug ingestion. TxB2 levels returned to 75% of basal values 6 h after 100 mg and more than 8 h after 200 mg, reaching control values at 24 h. Different experiments were performed to define the metabolic step at which suloctidil acts to inhibit serum TxB2 generation. Suloctidil prevented TxB2 synthesis also when platelet-rich plasma was stimulated by exogenous arachidonic acid or whole blood was clotted in the presence of exogenous arachidonic acid. This rules out the possibility that it inhibits phospholipases. No rediversion of prostaglandin synthesis after suloctidil occurred concomitantly with TxB2 inhibition, suggesting that the drug is not a selective thromboxane synthase inhibitor. In contrast, a significant reduction of serum PGE2 formation was found, suggesting a mechanism of action of suloctidil involving inhibition of cyclo-oxygenase. This was supported by the finding that PGI2 production by rat smooth muscle cells stimulated with arachidonic acid was significantly prevented by suloctidil in vitro. Suloctidil, however, did not prevent aspirin-induced inhibition of serum TxB2 generation. Blockade of platelet cyclo-oxygenase activity by suloctidil is therefore exerted at a level different from that of aspirin. In conclusion, suloctidil is a relatively weak nonselective cyclo-oxygenase inhibitor whose effect on platelet TxA2 production hardly accounts for its reported inhibitory effect on platelet aggregation.

Adult↗
PubMed1986

Biochemical selectivity of oral versus intravenous aspirin in rats. Inhibition by oral aspirin of cyclooxygenase activity in platelets and presystemic but not systemic vessels.

In rats intravenous aspirin was only slightly more effective an inhibitor of platelet thromboxane B2 (TxB2) than of aorta 6-keto-prostaglandin (PGF)1 alpha generation (1.9 versus 2.1 mg/kg). In contrast, oral aspirin was about five times more effective on platelet than on aorta cyclooxygenase activity. The "biochemical selectivity" of aspirin as an inhibitor of platelet and vascular cyclooxygenase thus was not apparent after intravenous administration of the drug. However, this could be achieved by relatively low doses of oral (or intraduodenal) aspirin, on account of "presystemic" acetylation of platelet cyclooxygenase. Even in this condition, though, aspirin selectivity was relative to "systemic" peripheral vessels but not to the vessels of the enterohepatic circulation. Indeed after an oral or intraduodenal dose of 5 mg/kg aspirin, generation of portal vein 6-keto-PGF1 alpha was inhibited to much the same extent as platelet TxB2, while inferior vena cava 6-keto-PGF1 alpha formation was spared.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Current issues in thrombosis prevention with antiplatelet drugs.

In this review, the major current problems related to the pharmacology and clinical use of antiplatelet drugs are discussed in relation to the physiopathology of the platelet-vessel wall interaction and arterial thrombus formation. Although platelet adhesion to injured vessels is a crucial step in thrombogenesis, none of the currently used antiaggregating drugs prevents this phenomenon. Why the normal endothelium does not react with platelets is not known. Thus we are unable to pharmacologically restore endothelial 'non-thrombogenicity' when lost by single or repeated injury. In contrast, more information is available on the mechanisms controlling and amplifying platelet activation by physiological stimuli (such as collagen and thrombin), and on their pharmacological modulation. The 3 main amplification loops involve arachidonic acid metabolism, ADP release and possibly the availability of a phospholipid platelet activating factor. These pathways are in turn activated by the phosphatidylinositol cycle. The most widely used antiaggregating drug is aspirin. It prevents the formation of arachidonic acid metabolites both in platelets and in vascular cells. The use of low-dose aspirin, thromboxane-synthase inhibitors, thromboxane receptor antagonists, epoprostenol (prostacyclin) and its stable analogues, and ticlopidine all appear to be promising pharmacological approaches, but none has so far been tested in clinical trials for thrombosis prevention. On the other hand, aspirin (in relatively large doses of 300 to 1500 mg daily), sulphinpyrazone and dipyridamole have been tested alone or in combination in the secondary prevention of thromboembolic complications. Aspirin has significantly reduced both the occurrence of myocardial infarction and mortality rate in patients with unstable angina and/or previous myocardial infarction; it has also proved beneficial in cerebrovascular disease. The beneficial effect of aspirin was dose-independent. In some of these trials aspirin was combined with either dipyridamole or sulphinpyrazone. When used alone, the latter compound has reduced sudden death or thromboembolic complications in patients with myocardial infarction. It remains to be established whether antiplatelet therapy may prevent or stop the progression of atherosclerosis.

Aspirin↗
PubMed1986

Slow intravenous administration of low dose aspirin inhibits both vascular and platelet cyclooxygenase activity: an experimental study in the rat.

Aspirin irreversibly inhibits cyclooxygenase, thus preventing thromboxane (Tx)A2 production in platelets and prostacyclin in vascular cells. While it is generally accepted that the inhibitory effect of low dose aspirin is cumulative on platelet cyclooxygenase, it is still a matter of debate whether a similar phenomenon also occurs on vascular cyclooxygenase. We have measured in anesthetized rats the inhibitory effect of two doses of aspirin (2.5 and 5.0 mg/kg), given intravenously either as a bolus or as a continuous infusion (for 30 min), on platelet TxB2 and 6-ketoprostaglandin F1 alpha generation by different vascular segments. Aspirin significantly inhibited both platelet and vascular cyclooxygenase independently of the rate of drug administration. The aspirin peak plasma levels at the end of bolus injection was about 170 times higher than the average level measured during the slow infusion (1.21 +/- 0.15 micrograms/ml). At this concentration aspirin did not affect in vitro either platelet or vascular cyclooxygenase activity. Thus the inhibitory effect of aspirin on both platelet and vascular cyclooxygenase seems to be related to total exposure of the enzyme to the drug rather than to the maximal drug concentration attainable in the systemic circulation. These findings may be relevant to the current debate on optimal conditions for the biochemical selectivity of aspirin as an antithrombotic drug.

Animals↗
PubMed1986

Synthesis of guanylhydrazones derived from 3-pyridinol and evaluation of their effect on serum thromboxane B2 and prostaglandin E2 production.

3-Pyridyloxyacetaldehyde guanylhydrazone and the guanylhydrazones of pyridine-2- and -4-aldehydes substituted at the 3-position with the omega-carboxypentyloxy chain were synthesized in order to evaluate their activity as thromboxane synthase inhibitors in vitro. The tested compounds inhibit thromboxane B2 biosynthesis in human serum. The first appears to be a selective inhibitor of thromboxane synthase, since there was a concomitant rise in Prostaglandin E2 (PGE2) level. The derivative of 4-pyridinealdehyde was the more active one of the other two compounds but it also markedly lowered PGE2 biosynthesis proving to be an inhibitor of cyclooxygenase.

Chemical Phenomena↗
PubMed1986

Comparative bioavailability of aspirin from buffered, enteric-coated and plain preparations.

The bioavailability and pharmacokinetics of acetylsalicylic acid were studied in 6 volunteers, under a cross-over design, using plain compressed aspirin, two buffered preparations and an enteric-coated tablet. Absorption, calculated from urinary excretion, was complete for all the formulations. The buffered forms gave higher peak concentrations and AUC for acetylsalicylic acid than the other forms. Absorption from the enteric-coated tablet was the slowest. Acetylsalicylic acid was not measurable in plasma (less than 0.1 micrograms/ml) at any time in 3 subjects after plain and in 2 after enteric-coated aspirin. Acetylsalicylic acid was no longer measurable in plasma after 4 hours, irrespective of the preparation given.

Administration, Oral↗
PubMed1985

Aspirin kinetics and inhibition of platelet thromboxane generation-relevance for a solution of the "aspirin dilemma".

Six healthy male volunteers received aspirin (ASA) in a compressed (320 mg) and an enteric-coated (800 mg) formulation as single oral doses ten days apart. Ten plasma samples were obtained from each volunteer between 5 and 120 min after compressed ASA, and seven between 10 and 240 min after enteric-coated ASA. ASA was undetectable (less than 100 ng/ml) in plasma from three subjects receiving compressed ASA and two receiving the enteric-coated preparation. Plasma levels and kinetic parameters of salicylate were the same in subjects with undetectable and detectable ASA plasma levels. More than 98% inhibition of pre-drug serum TXB2 was noted in all samples collected one and four hours after either ASA preparation. TXB2 generation recovered on average by 3.5% at 24 hr with both preparations. Thus inhibition of platelet TXB2 generation occurred independently of the amount of ASA reaching the peripheral circulation. If this is due to inhibition of platelet function in the enterohepatic circulation followed by extensive first-pass deacetylation of ASA, vascular PGI2 synthesis could be spared. A better knowledge of the kinetic parameters of ASA for each of the formulations used in thrombosis prevention trials might help in solving the "aspirin dilemma".

Adult↗