Platelet Function Studies during and after Infusions of ZK 36374, a Stable Prostacyclin Analogue, to Healthy Volunteers

Yardumian, D. A.; Mackie, Ian; Brennan, Ewan; Bull, Helen A.; Machin, S.J.

doi:10.1159/000215265

Cited by 7 publications

(6 citation statements)

References 14 publications

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“…These concentrations are below the in vitro IC 50 levels required to induce inhibition of platelet aggregation, which may readily explain the observed lack of a relevant effect of selexipag on platelet aggregation in this study. In contrast, the PGI 2 analogues iloprost, beraprost, and treprostinil inhibit platelet aggregation [25,26,27]. The relevance of this observation, if any, needs to be further explored.…”

Section: Discussionmentioning

confidence: 99%

Multiple-Dose Up-Titration Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Selexipag, an Orally Available Selective Prostacyclin Receptor Agonist, in Healthy Subjects

et al. 2014

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Objective: The objective of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in development for pulmonary arterial hypertension in healthy subjects. Methods: This was a double-blind, placebo-controlled, randomised, multiple-ascending-dose, up-titration study. Male subjects received increasing oral doses of selexipag (400-1,800 µg; n = 12) or placebo (n = 4) twice daily for 3 days each, using incremental steps of 200 µg between each dose level. Standard safety and tolerability data were collected. Blood samples were taken to assess the pharmacokinetics of selexipag and its active metabolite ACT-333679 and possible effects on platelet aggregation. Results: Dose levels of selexipag up to 1,600 μg were well tolerated and this dose was identified as the maximum tolerated dose. Plasma exposure to ACT-333679 was approximately 4 times higher than that to selexipag. Steady-state conditions for both compounds were reached on day 3 of each dose level, and no accumulation of selexipag or ACT-333679 was observed. Based on the area under the curve and the maximum plasma concentration, the pharmacokinetics of selexipag and ACT-333679 were dose proportional. At the highest dose level, the geometric mean terminal half-life of selexipag and ACT-333679 was 1.4 and 8.7 h, respectively. The observed effects on platelet aggregation were variable without obvious drug- or dose-dependent pattern. Conclusions: Oral administration of increasing doses of selexipag was well tolerated. The present results support the conduct of future clinical trials.

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Section: Discussionmentioning

confidence: 99%

Multiple-Dose Up-Titration Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Selexipag, an Orally Available Selective Prostacyclin Receptor Agonist, in Healthy Subjects

et al. 2014

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“…These results could not be explained only by the immediate short-lived vasodilatory action of iloprost. It is therefore generally thought that the additional positive effects of iloprost on platelets, endothelial cells and phagocytes [6][7][8][9][10][11][12], as well as on the cytokine production [14], may induce a sort of healing of the microvascular lesion responsible for Raynaud's phenomenon, and of its consequences in SSc.…”

Section: Discussionmentioning

confidence: 99%

“…The drug is a chemically stable derivative of prostacyclin, with a longer half-life and similar biological properties [5], including vasodilatation, inhibition of platelet aggregation [6], inhibition of leukocyte chemotaxis and adhesion to the endothelium [7,8], downregulation of adhesion molecules on phagocytes and endothelial cells [9,10], and enhanced fibrinolytic activity [11]. These actions can influence the pathophysiological mechanisms responsible for Raynaud's phenomenon in SSc, which include vasospasm, increased platelet activation, vascular endothelial damage, fibrotic intimal hyperplasia and luminal narrowing in the digital arteries [12].…”

Section: Introductionmentioning

confidence: 99%

Systemic Sclerosis Therapy with Iloprost: A Prospective Observational Study of 30 Patients Treated for a Median of 3 Years

Bettoni¹,

Geri²,

Airò³

et al. 2002

Clin Rheumatol

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Iloprost is useful in the short-term treatment of severe Raynaud's phenomenon and ischaemic ulcers in patients with systemic sclerosis (SSc), but its long-term effects are largely unknown. The aim of this study was to report long-term outcome (median follow-up 36 months) in a prospective observational study of a cohort of 30 consecutive patients with SSc who received iloprost therapy with maintenance infusions every 3 weeks after an initial cycle of 5 consecutive days. At the end of the observation, compared to the pretreatment point, we observed complete healing of digital ulcers in 19/21 patients (90%), a decrease of the Raynaud's phenomenon visual analogue score from 10/10 (25th-75th percentile 7-10) to 5/10 (4-6.75) ( P <0.001) and, in patients with diffuse cutaneous involvement, of the modified Rodnan skin thickness score from 25.5 (16.5-31.5) to 16 (13.5-20) ( P = 0.02), minimal improvement of the Health Assessment Questionnaire from 0.87 (0.68-1.37) to 0.75 (0.62-1.25), which was neither statistically nor clinically significant. The forced vital capacity was not significantly changed, but the diffusion capacity corrected for the alveolar volume decreased from 71% (54-76.7) of the expected value to 62% (51.5-71) ( P = 0.02). In one patient with limited SSc a positive effect on pulmonary hypertension was observed. Six patients, after a median of 25 months of treatment and healing of digital ulcers, discontinued the therapy; after a median of 10 months ulcers did not recur in five of these six. Other reasons for discontinuation were: tolerability (1), disease progression (normotensive renal crisis: 1), and death due to intracranial haemorrhage (1). This same patient had previously suffered a central retinal vein thrombosis. In conclusion, long-term therapy with iloprost in patients with SSc has a durable effectiveness on ischaemic ulcers and Raynaud's phenomenon, but it is not possible to conclude that the natural history of the disease was modified.

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“…This desensitization of platelets did not result in adverse clinical sequelae (95). Studies investigating this phenomenon in atherosclerotic patients showed that progressive loss of antiplatelet activity of iloprost can be avoided by using a 6-h daily infusion regimen (53).…”

Section: Effects On Plateletsmentioning

confidence: 92%

Iloprost in Peripheral Vascular Disease

Krais¹,

Müller²

1991

Cardiovascular Drug Reviews

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Platelet Function Studies during and after Infusions of ZK 36374, a Stable Prostacyclin Analogue, to Healthy Volunteers

Cited by 7 publications

References 14 publications

Multiple-Dose Up-Titration Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Selexipag, an Orally Available Selective Prostacyclin Receptor Agonist, in Healthy Subjects

Multiple-Dose Up-Titration Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Selexipag, an Orally Available Selective Prostacyclin Receptor Agonist, in Healthy Subjects

Systemic Sclerosis Therapy with Iloprost: A Prospective Observational Study of 30 Patients Treated for a Median of 3 Years

Iloprost in Peripheral Vascular Disease

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