Effects of taprostene, a stable prostacyclin analogue, on haemodynamics, platelet function and arachidonate metabolism in healthy volunteers

Virgolini, Irene; Fitscha, P; Sinzinger, H.; Barth, H.

doi:10.1007/bf00315573

Cited by 11 publications

(10 citation statements)

References 11 publications

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“…6 and 7). Treatment of HUVECs with the selective IP receptor agonist taprostene (Virgolini et al, 1990) at concentrations up to 6.3 μM increased migration (up to 193 ± 44% of control). Migration plateaued at~26 ± 4% of control at higher taprostene concentrations up to 25.1 μM (Fig.…”

Section: Effects Of Prostanoid Receptor Activation Followed By Desensmentioning

confidence: 95%

Prostanoids regulate angiogenesis acting primarily on IP and EP4 receptors

Hoang

Allison

Murray

et al. 2015

Microvascular Research

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Section: Effects Of Prostanoid Receptor Activation Followed By Desensmentioning

confidence: 95%

Prostanoids regulate angiogenesis acting primarily on IP and EP4 receptors

Hoang

Allison

Murray

et al. 2015

Microvascular Research

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“…Vasodilator effects of taprostene were more pronounced in a study reported by Virgolini et al, (59) who infused the drug at a rate of 25 ng/kg/min for 6 h in four healthy volunteers. During infusion of taprostene, systolic blood pressure dropped from 130 f 12 to 1 1 1 k 5 mm Hg (p < 0.05), diastolic blood pressure decreased from 77 k 5 to 69 f 5 mm Hg (p < 0.05), and heart rate increased from 77 k 4 to 84 k 4 beats/min (p < 0.05).…”

Section: Clinical Studies Clinical Pharmacologymentioning

confidence: 87%

Taprostene (CG‐4203)

Lefer

Darius

1989

Cardiovascular Drug Reviews

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The first reports on prostacyclin (PG12), an autocoid released from the vascular endothelium, was published in 1976 (36). Thereafter, major research interest was focused on this interesting substance. The reasons were the unique properties of PG12, being able to relax vascular smooth muscle and to inhibit platelet aggregation at nanomolar concentrations (37). Later on, additional properties of PG12 were discovered, including inhibition of platelet mitogen release (60) and cytoprotective effects (2 1) useful in myocardial ischemia (22). The successful chemical synthesis of PG12 made sufficient quantities of the substance available to allow investigations of its pharmacologic effects in a variety of experimental models and in initial clinical trials.During this early phase of prostacyclin research, its chemical and metabolic instability was recognized as being a major shortcoming in terms of its becoming a clinically important drug (10). The half-life of PG12 at physiologic pH is about 3 min, and chemical stability occurred only at alkaline pH values (i.e., above pH 9). In vivo, the chemical and metabolic instability of the substance led to rapid inactivation by 15-OH-prostaglandin dehydrogenase and other hydrolytic enzymes. Therefore, it became evident very early that only chemically stable PG12 analogs would be useful as clinically relevant drugs (4 1). Chemically stable analogs of PGIz might additionally offer the chance of manipulating some of the pharmacologic properties of the compound to select for certain properties, including platelet inhibition, vasodilation, or inhibition of mitogen release. Additionally, selective chemically stable analogs offer the opportunity of decreasing the incidence of unwanted side effects, which were evident during the first clinical trials with PGIp (i.e., anxiety and headaches).Several chemically stable analogs of PGIz have been synthesized and studied by experimental and clinical pharmacologists. The present review will focus on the pharmacologic properties and clinical effects of taprostene (CG 4203), a compound syn-

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“…Such a rebound phenomenon did not occur during the infusion of taprostene in healthy volunteers where the sensitivity of platelets to the antiaggregatory effects of prostacyclin and prostaglandin E, was even enhanced whereas the response to prostaglandin D, and taprostene itself did not change. There was no satisfactory explanation for these differences in platelet sensitivity (93). Taprostene did not alter plasma or serum levels of thromboxane B,, platelet factor 4, or P-thromboglobulin in healthy volunteers, nor did it alter metabolism of exogenous radiolabeled arachidonic acid (93).…”

Section: Pharmacology In Volunteersmentioning

confidence: 93%

“…There was no satisfactory explanation for these differences in platelet sensitivity (93). Taprostene did not alter plasma or serum levels of thromboxane B,, platelet factor 4, or P-thromboglobulin in healthy volunteers, nor did it alter metabolism of exogenous radiolabeled arachidonic acid (93).…”

Section: Pharmacology In Volunteersmentioning

confidence: 93%

Taprostene Sodium

Schneider

Friderichs

Kögel

et al. 1993

Cardiovascular Drug Reviews

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In 1976 Vane, Moncada, Gryglewski, and Bunting discovered that "an enzyme isolated from arteries transforms prostaglandin peroxides to an unstable substance that inhibits platelet aggregation" (58). This endothelium-derived compound, later named prostacyclin (PGI,), turned out to be the strongest inhibitor of platelet aggregation described to date. It was further characterized as a potent vasorelaxant agent in vitro (14,22) and in vivo (3). The unique pharmacological profile of prostacyclin very soon raised many hopes as to its therapeutic potential. Prostacyclin has been tested clinically in extracorporeal circulation, cardiopulmonary bypass, peripheral arterial disease, ischemic stroke, pulmonary hypertension, congestive heart failure, and coronary artery disease (91). Further clinical development of prostacyclin was hampered, however, by its chemical and metabolic instability.To overcome these shortcomings of natural prostacyclin, many attempts have been made to synthesize analogues with improved stability. Analogues with the common feature of a replacement of C1-C4 of prostacyclin by a carboxyphenylene residue and substitutions at or near C,, to achieve resistance against 15-hydroxyprostaglandin dehydrogenase have been described (25). Out of these series of analogues, [(5Z, 13E, 9a, 1 la, 15S)-2,3,4-trinor-1,5-inter-m-phenylene-6,9-epoxy-11,15-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanor]-prosta-5,13-dienoic acid, sodium salt (CG 4203; taprostene sodium-hereafter referred to as taprostene) (Fig. 1) yielded substantial prostacyclin activity as well as chemical and metabolic stability (10,25,34). PHARMACOLOGY Inhibition of Platelet ActivityIn hemostasis and thrombosis, activated platelets change shape, adhere to the site of the injury on a vessel wall, aggregate, and produce procoagulant activity. Inhibition of

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Effects of taprostene, a stable prostacyclin analogue, on haemodynamics, platelet function and arachidonate metabolism in healthy volunteers

Cited by 11 publications

References 11 publications

Prostanoids regulate angiogenesis acting primarily on IP and EP4 receptors

Prostanoids regulate angiogenesis acting primarily on IP and EP4 receptors

Taprostene (CG‐4203)

Taprostene Sodium

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