Suloctidil: Relationship between pharmacokinetics and antithrombotic effect

Roba, J.; Cavalier, R.; Hérin, Michel; Lambelin, G

doi:10.1016/0049-3848(83)90366-3

Cited by 8 publications

(5 citation statements)

References 6 publications

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“…TxB2 production returned to approx imately 75% of the basal levels 6 h after 100 mg and more than 8 h after 200 mg, reaching control levels at 24 h. There was a good correlation between the time course of TxB2 inhibition measured in this study and the plasma levels of the drug reported by Roba et al [1983b], The high individual variability of the drug's effect can be related to differences in its pharmacokinetics which give rise to a large number of metabolites whose activities are not yet known [Roba et al. 1983b], Different experiments were made to de fine the metabolic step at which suloctidil inhibits serum TxB2 generation.…”

Section: Discussionsupporting

confidence: 72%

Inhibition of Platelet Thromboxane Generation by Suloctidil in Man

Bucchi

Cerletti

Gaetano

1986

Pathophysiol Haemos Thromb

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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.

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Section: Discussionsupporting

confidence: 72%

Inhibition of Platelet Thromboxane Generation by Suloctidil in Man

Bucchi

Cerletti

Gaetano

1986

Pathophysiol Haemos Thromb

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“…These effects have been attributed to membrane changes (25,26), cellular metabolic alterations (26,27) or competitive inhibition of stimuli (3). In this regard, plasma drug concentrations following oral administration in amounts sufficient to inhibit platelet aggregation ex vivo are inactive on platelet aggregation in vitro (28). Since the antispasmodic activities of suloctidil are observed in vitro at concentrations comparable to those achieved in plasma after repeated oral administration, it has been proposed that the parent drug is responsible for both the vasodilatory and anti thrombotic effects.…”

Section: Studies With Suloctidilmentioning

confidence: 99%

Studies of Suloctidil in Experimental Thrombosis in Baboons

Hanson

Harker

1985

Thromb Haemost

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SummarySuloctidil has been evaluated in the baboon for its antithrombotic efficacy using models of both acute and chronic arterial thrombogenesis. Acute thrombus formation was initiated by Dacron vascular grafts inserted as extension segments into chronic arteriovenous shunts. 111In-platelet deposition was measured by scintillation camera imaging for one hour. The results after oral administration of suloctidil (100 mg/kg/d in two divided doses) were not different from control studies. Moreover, concurrent heparin anticoagulation did not affect 111In-platelet deposition compared with control data. In contrast, ticlopidine (20 mg/ kg/d) significantly decreased platelet deposition that was reduced further by the addition of heparin.Chronic arterial-thromboembolism was initiated by segments of polyurethane (Biomer) cannula introduced into chronic arteriovenous shunts. Thrombus formation by the polyurethane cannula was measured as 111In-platelet turnover (corrected for removal of senescent platelets). Cannula platelet consumption was unaffected by suloctidil (20 mg/kg/d given in two divided doses for two days preceding and throughout the period of platelet survival measurement). In contrast, dipyridamole (10 mg/ kg/d) and sulfinpyrazone (100 mg/kg/d) completely interrupted cannula platelet consumption.We conclude that suloctidil probably has little or no effect on platelet-dependent thrombus formation.

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“…In the present study, the concentration of suloctidil tested in highly efficacious combinations in liquid (16 μM) was twice as concentrated as previously reported maximal plasma concentrations and equal to reported cytotoxic levels in RAW264.7 mouse macrophage cells and C32 human melanoma cells, warranting further testing of lower concentrations of suloctidil in combination with other hits. 30 , 32 , 33 , 42 − 45 While suloctidil’s hepatotoxic effects caused its removal from the market from its original indication of vasodilation to treat arterial diseases, its potential to treat a dangerously lethal infection such as anthrax and its possibility of efficacy at lower concentrations than previously indicated suggest a potential future against B. anthracis .…”

Section: Resultsmentioning

confidence: 99%

Repurposing Clinically Approved Drugs for the Treatment of Bacillus cereus, a Surrogate for Bacillus anthracis

et al. 2020

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Of the numerous infectious diseases afflicting humans, anthrax disease, caused by Bacillus anthracis , poses a major threat in its virulence and lack of effective treatment. The currently lacking standards of care, as well as the lengthy drug approval process, demonstrate the pressing demand for treatment for B. anthracis infections. The present study screened 1586 clinically approved drugs in an attempt to identify repurposable compounds against B. cereus , a relative strain that shares many physical and genetic characteristics with B. anthracis . Our study yielded five drugs that successfully inhibited B. cereus growth: dichlorophen, oxiconazole, suloctidil, bithionol, and hexestrol. These drugs exhibited varying levels of efficacy in broad-spectrum experiments against several Gram-positive and Gram-negative bacterial strains, with hexestrol showing the greatest inhibition across all tested strains. Through tests for the efficacy of each drug on B. cereus , bithionol was the single most potent compound on both solid and liquid media and exhibited even greater eradication of B. cereus in combination with suloctidil on solid agar. This multifaceted in vitro study of approved drugs demonstrates the potential to repurpose these drugs as treatments for anthrax disease in a time-efficient manner to address a global health need.

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Suloctidil: Relationship between pharmacokinetics and antithrombotic effect

Cited by 8 publications

References 6 publications

Inhibition of Platelet Thromboxane Generation by Suloctidil in Man

Inhibition of Platelet Thromboxane Generation by Suloctidil in Man

Studies of Suloctidil in Experimental Thrombosis in Baboons

Repurposing Clinically Approved Drugs for the Treatment of Bacillus cereus, a Surrogate for Bacillus anthracis

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