Inhibition of platelet aggregation and antagonism of vasopressin-induced ECG changes in primates by a carboprostacyclin analogue, ZK 36374

Adaikan, P.G.; Karim, Saiful; Lau, Lang Chu; Tai, M.Y.; Kottegoda, S. R.

doi:10.1016/0049-3848(84)90168-3

Cited by 16 publications

(6 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…10 Other treatments for PAH-including the prostacyclin analogs epoprostenol and iloprost-have also been shown to have antiplatelet activity in vitro and in humans. 19,[26][27][28] At the time of writing, there is little or no information on the potential for interaction between aspirin and other treatments for PAH; however, the possibility that some of these drugs inhibit platelet aggregation and thus prolong bleeding means that pharmacodynamic and pharmacokinetic interaction studies for these agents and aspirin would be timely and of interest. The NO-sGC-cGMP pathway regulates platelet aggregation as well as vascular tone.…”

Section: Discussionmentioning

confidence: 99%

Riociguat (BAY 63‐2521) and Aspirin: A Randomized, Pharmacodynamic, and Pharmacokinetic Interaction Study

et al. 2016

View full text Add to dashboard Cite

In preclinical studies, drugs that increase cyclic guanosine monophosphate levels have been shown to influence platelet function/ aggregation; however, the effect of riociguat on human platelets is unclear. Aspirin, a platelet inhibitor, is likely to be given concomitantly in patients receiving riociguat. It is therefore important to establish clinically whether (1) riociguat affects platelet function and (2) aspirin and riociguat interact. This randomized, open-label, crossover study investigated potential pharmacodynamic and pharmacokinetic interactions between these drugs in healthy male volunteers (N = 18). There were 3 treatment regimens: a single morning dose of riociguat 2.5 mg, aspirin 500 mg on 2 consecutive mornings, and both treatments together, with riociguat given on the second morning. Fifteen participants were available for pharmacodynamic/pharmacokinetic analysis. There was no effect of riociguat alone on bleeding time, platelet aggregation, and serum thromboxane B 2 levels. The effects of aspirin on these parameters were not influenced by concomitant administration of riociguat. The pharmacokinetic profile of riociguat showed interindividual variability, which was independent of aspirin coadministration. Six of 17 participants available for safety evaluation reported at least 1 treatment-emergent adverse event. All adverse events were of mild severity, apart from 1 report of moderate headache. No serious adverse events occurred. In conclusion, riociguat demonstrated no clinically relevant pharmacodynamic or pharmacokinetic interactions with aspirin at the doses used in this study in healthy men; coadministration of riociguat and aspirin should therefore not require any dose adjustment for either drug.

show abstract

Section: Discussionmentioning

confidence: 99%

Riociguat (BAY 63‐2521) and Aspirin: A Randomized, Pharmacodynamic, and Pharmacokinetic Interaction Study

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Studies in the baboon also suggest that this compound did not exhibit enhanced metabolic stability as compared with carbacyclin. 33 In a further series of carbocyclic analogues, the 15-hydroxy group was protected by modification of the cotail, e.g., by insertion of a 15-cyclohexyl grouping, while protection against /3-oxidation was afforded by insertion of an m-carboxyphenylene residue.8 Despite such modifications (figure 2, A), these prostacyclin analogues still exhibited only a short duration of action, with the hypotensive effects ranging from 0.25 to 1.2 min. Only with supramaximal doses were any differences between the duration of biological action of the analogues detected, and thus such properties have no real clinical or experimental application.…”

mentioning

confidence: 99%

Platelet actions of stable carbocyclic analogues of prostacyclin.

Whittle¹,

Moncada²

1985

Circulation

View full text Add to dashboard Cite

SINCE THE TIME of the discovery of prostacyclin' and the elucidation of its chemical structure as prostaglandin (PG) (5Z)-9 deoxy-6, 9 a-epoxy-&APGF,,2 many synthetic prostacyclin analogues have been pre- Many structural variants of prostacyclin have been synthesized, including 5,6-dihydro analogues, exemplified by 6f3-PGI,,3-5 thia prostacyclins such as (5Z)-6,9-thia prostacyclin,6 nitrogen-containing analogues such as 9-deoxy-9a-6-nitrilo-PGF ,7 ring-expanded 5,9-epoxy derivatives such as 9-deoxy-5, 9a-epoxy-PGFI,7 and interphenylene analogues.' However, the synthesis and biological actions of stable carbocyclic analogues of prostacyclin, in which the enol-ether oxygen atom is replaced by a methylene group, has attracted much attention and has been described by several groups.9'6 Carbacyclin analogues. Carbacyclin, or (5E)-6a carbaprostaglandin '2 (figure 1, A), inhibits human platelet aggregation induced by a variety of agents including ADP, collagen, and arachidonic acid, while also inhibiting aggregation in platelet-rich plasma (PRP) obtained from several species, including the rabbit, rat, and dog.12 16 In our studies with carbacyclin,'3 this stable analogue was 0.03 times as potent as prostacyclin as an inhibitor of aggregation induced by ADP (table 1), collagen, and arachidonic acid. As with prostacyclin, the antiaggregating activity of carbacyclin was enhanced by preincubation of platelets with theophylline, the phosphodiesterase inhibitor,'3' 1 ' indicating stimulation of cyclic AMP as its mechanism of inhibitory action. Indeed, other studies have shown an elevation of platelet cyclic AMP after incubation with the analogue. 14 Carbacyclin has been shown to be a potent inhibitor of platelet aggregation ex vivo when infused intravenously in the dog and rabbit, being 0.1 times as active as the parent, prostacyclin.'3 Likewise, this analogue was effective in vivo in reducing formation of thrombi in canine coronary arteries'6 when infused intravenously. Studies with carbacyclin in anesthetized baboons have likewise shown inhibition of platelet aggregation determined ex vivo after intravenous or intragastric administration. 17In our studies in human PRP with analogues synthesized and supplied by the Upjohn Company, (5Z)-carbacyclin was less active than the (5E)-analogue, the latter being isosteric'2 with naturally occurring prostacyclin (5Z-PGI2). As expected, the (15R)-epimer had mimimal activity, as did the 2-nor derivative (table 1). Substitution in the 9 position'5 can also alter antiaggregating potency, with (5Z)-9,8-ethynyl and 9-cyano groupings enhancing activity and 9,3-methyl, 9-pentyl-1-ynyl, and 9-ethyl groupings decreasing activity compared with that induced by carbacyclin itself (table 1).Studies in human PRP with 9,f-methyl-carbacyclin (ciprostene; figure 2, B) have shown it to have comparable potency as an antiaggregating agent against several aggregating agents (table 2). This compound is equiactive in vitro in human PRP and whole blood, and elevates platelet cyclic AMP levels.'9Studies using...

show abstract

“…In the experimental animal, Iloprost (ZK 36 374), a chemically stable carboprostacyclin derivative, was shown to be more potent than PGI2 with respect to antiplatelet properties, and it in duced less vasodilation [8,9]. Also, studies in which human platelets were incubated with ZK 36 374 de monstrated that the drug may be an even more power ful antiaggregating agent than PGI2 [8,10,11]. Fur ther, in human whole blood aggregation studies, ZK 36 374 caused disaggregation of preformed platelet aggregates [12].…”

Section: Discussionmentioning

confidence: 99%

Effect of Iloprost (ZK 36 374), a Novel Prostacyclin Analogue, on ADP-induced Platelet Aggregation

Wadenvik¹,

Kutti²

1985

Acta Haematol

View full text Add to dashboard Cite

The effect of Iloprost (ZK 36 374), a chemically stable carboprostacyclin derivative, on ADP-induced platelet aggregation was investigated using platelet-rich plasma obtained from healthy male volunteers. It was shown that Iloprost in a dose-dependent fashion powerfully inhibits both the primary and secondary wave of ADP-induced platelet aggregation. Similarly, Iloprost immediately and most effectively disaggregates preformed platelet aggregates.

show abstract

Inhibition of platelet aggregation and antagonism of vasopressin-induced ECG changes in primates by a carboprostacyclin analogue, ZK 36374

Cited by 16 publications

References 8 publications

Riociguat (BAY 63‐2521) and Aspirin: A Randomized, Pharmacodynamic, and Pharmacokinetic Interaction Study

Riociguat (BAY 63‐2521) and Aspirin: A Randomized, Pharmacodynamic, and Pharmacokinetic Interaction Study

Platelet actions of stable carbocyclic analogues of prostacyclin.

Effect of Iloprost (ZK 36 374), a Novel Prostacyclin Analogue, on ADP-induced Platelet Aggregation

Contact Info

Product

Resources

About