Iloprost

Iloprost (ZK 36374) is a synthetic analogue of prostacyclin PGI2. Target: Iloprost is a stable prostacyclin analog commonly employed in the treatment of peripheral vascular disease and also indicated in the treatment of patients affected by systemic sclerosis (SSc) in the presence of severe Raynaud's phenomenon (RP). [1] Iloprost dilates systemic and pulmonary arterial vascularbeds. Iloprost also affects platelet aggregation but the relevance of this effect to the treatment of pulmonary hypertension is unknown. The two diastereoisomers of iloprost differ in their potency in dilating blood vessels, with the 4S isomer substantially more potent than the 4R isomer.[2] Iloprost is a stable carbacyclin derivative of prostacyclin, was studied during electrically-induced coronary artery thrombosis in the open chest anesthetized pig. Infusion of ZK 36374 (100 ng/kg/min, n = 6) had no effect on heart rate and cardiac output, but caused a 20% reduction in mean arterial blood pressure by peripheral vasodilation. In animals receiving solvent or no drug prior to thrombosis induction, the time to occlusive coronary artery thrombosis (TOT) was 30 +/- 2 minutes (mean +/- SEM, n = 17). Pretreatment with an i.v. infusion of ZK 36374 (100 ng/kg/min) prolonged TOT by 50% to 47 +/- 7 minutes (p less than 0.005, n = 6). This prolongation of TOT was not due to the lower blood pressure in the ZK 36374 group, as dihydralazine in a dose that lowered arterial blood pressure to the same extent had no effect on TOT (32 +/- 4 minutes, n = 4). The results indicate that ZK 36374 may be useful in delaying (or preventing) occlusive coronary artery thrombi. [3]

References:
[1]. Della Bella S, et al. Novel mode of action of iloprost: in vitro down-regulation of endothelial cell adhesion molecules. Prostaglandins Other Lipid Mediat. 2001 Jun;65(2-3):73-83. [2]. van der Giessen WJ, et al. The effect of the stable prostacyclin analogue ZK 36374 on experimental coronary thrombosis in the pig. Thromb Res. 1984 Oct 1;36(1):45-51. [3]. Addonizio VP Jr, et al. Prevention of heparin-induced thrombocytopenia during open heart surgery with iloprost (ZK36374). Surgery. 1987 Nov;102(5):796-807.

Potential new treatment for non-freezing cold injury: is Iloprost the way forward?[Pubmed:28341787]

J R Army Med Corps. 2017 Oct;163(5):361-363.

INTRODUCTION: Non-freezing cold injury (NFCI) remains largely under-reported, and is of particular importance in the armed forces where its prevalence is greatest. Iloprost, a synthetic prostaglandin I2 analogue, has previously been used with some success in the treatment of vasospastic and freezing cold injuries, although its role in NFCI remains unclear. CASE REPORT: An Iloprost infusion was used to treat the long-term sequelae of an ex-soldier suffering with ongoing pedal pain and loss of function 20 years after the initial NFCI insult sustained on military exercise. Following 5 days of Iloprost infusion, he reported 4 weeks of markedly reduced pain and increased mobility before symptom relapse. A second infusion was thus given 3 months later, which resulted in increased pain and analgesic requirements. DISCUSSION: The use of Iloprost in the treatment of NFCI is discussed and its use in a condition which physicians consistently struggle to treat effectively is considered. Careful counselling is recommended as symptoms may be worsened.

Iloprost, Prostaglandin E1, and Papaverine Relax Human Mesenteric Arteries With Similar Potency.[Pubmed:28362714]

Shock. 2017 Sep;48(3):333-339.

OBJECTIVE: Nonocclusive mesenteric ischemia (NOMI) is accompanied by mesenteric artery spasms that are at least in part due to endothelin system activation. Acute treatment includes intra-arterial infusion of vasodilators such as Iloprost, prostaglandin E1 (PGE1), and papaverine. Their effectiveness is not well characterized in human mesenteric arteries. We directly compared their potency to relax isolated human mesenteric arteries. To explore the potential of Rock inhibition to treat mesenteric artery spasms, we tested if endothelin-1 (ET-1)-induced mesenteric artery constrictions depend on rho kinase (Rock). METHODS: Mesenteric artery segments were obtained from patients who underwent elective abdominal surgery. Vasodilator concentration-response curves were recorded from ET-1-preconstricted vessels by small vessel myography. Rock expression was investigated by Western blot and the potency of Rock inhibition to blunt ET-1-induced mesenteric artery constriction was tested. RESULTS: Iloprost, PGE1, and papaverine similarly reduced vascular tone to 20% to 30% of ET-1-induced wall tension. In human mesenteric arteries, logEC50 was significantly less for Iloprost than for PGE1 or papaverine. Respective logEC50 values were -7.72 +/- 0.08 mol/L, -6.58 +/- 0.17 mol/L, and -6.73 +/- 0.19 mol/L in 150 mum to 300 mum lumen diameter arteries. These vessels were also more sensitive to Iloprost than 500 mum to 1,000 mum lumen diameter arteries (logEC50 -7.29 +/- 0.07 mol/L). Rock1 and Rock2 were expressed in human mesenteric arteries but Rock inhibition did not significantly affect ET-1-induced vasoconstrictions. CONCLUSIONS: Iloprost, PGE1, and papaverine have a similar potency to relax mesenteric arteries. Our data suggest that Iloprost but not Rock inhibition may be particularly useful to treat ET-1-induced spasms of distal mesenteric arteries.

Iloprost Use in Patients with Persistent Intestinal Ischemia Unsuitable for Revascularization.[Pubmed:28323233]

Ann Vasc Surg. 2017 Jul;42:128-135.

BACKGROUND: Persistent or chronic intestinal ischemic injury (i3) can lead to severe malnutrition and acute mesenteric ischemia. Although recommended, revascularization of splanchnic arteries is sometimes unrealizable. METHODS: We report a case series of Iloprost use in consecutive stable patients with persistent i3 unsuitable for revascularization followed in a tertiary care center. The feasibility of revascularization was discussed and ruled out by a multidisciplinary team, and informed consent was obtained prior to consideration of a vasoactive therapy. Therapeutic response was defined at 6 months by a decrease in the use of analgesic and parenteral nutrition, and no need for intestinal resection. RESULTS: Between 2006 and 2015, 6 patients (mean age: 51) were included. Splanchnic vascular insufficiency was due to superior mesenteric artery (SMA) thrombosis (n = 4), dissection of the celiac trunk and SMA (n = 1), or repeated vasospasm resulting in chronic nonocclusive mesenteric ischemia (n = 1). Iloprost was delivered via continuous intravenous perfusion at a maximum dosage of 2 ng/kg/min for 6 hours/day on 4 consecutive days, without severe adverse events. Therapeutic response was observed in 4 patients, 3 of which completely stopped parenteral nutrition and analgesic with no need for intestinal resection. CONCLUSIONS: Our results are consistent with findings of a favorable effect of Iloprost in patients with persistent splanchnic ischemia that should be confirmed in prospective trials.

Decreased vasorelaxation induced by iloprost during acute inflammation in human internal mammary artery.[Pubmed:28373136]

Eur J Pharmacol. 2017 Jun 5;804:31-37.

Cyclooxygenase-2 (COX-2) induction in human internal mammary arteries (IMA) under inflammatory conditions has been associated with attenuated norepinephrine (NE)-induced vasoconstriction. This effect was associated with increased prostaglandin (PG) E2 and prostacyclin (PGI2) releases. The present study was designed to assess the role of these PG and their receptors (EP and IP, respectively) on the vascular reactivity during acute inflammation. Isolated IMA were cultured in the absence (Control conditions) or presence (Inflammatory conditions) of both interleukin-1 beta (IL-1beta) and lipopolysaccharide (LPS). The vasorelaxation and the increased content of cyclic adenosine monophosphate (cAMP) induced by Iloprost, a PGI2 analogue, were significantly reduced under inflammatory conditions and restored in preparations cultured with the IP antagonist (CAY10441). Decreased cAMP levels under inflammatory conditions are due to at least increased phosphodiesterase (PDE) 4B expression. On the other hand, PGE2, thromboxane analogues and EP agonists-induced vasoconstrictions were not affected under inflammatory conditions. No vasorelaxation was observed with PGD2, PGE2 or the EP2/4 agonists in pre-contracted IMA. Finally, using RT-qPCR and immunohistochemistry, the COX-2, IP receptor and PGI2 synthase (PGIS) were detected. A significant increase of COX-2 and moderate increase of IP mRNA expression was observed under inflammatory conditions, whereas PGIS mRNA level was not affected. This study demonstrates that PGI2/IP receptor signalling and PGI2-induced relaxation are impaired in human IMA during acute inflammation, whereas the responses induced by other prostanoids are not affected. These results could explain some of the mechanisms of vascular dysfunction reported in inflammatory conditions.

Novel mode of action of iloprost: in vitro down-regulation of endothelial cell adhesion molecules.[Pubmed:11403500]

Prostaglandins Other Lipid Mediat. 2001 Jun;65(2-3):73-83.

Iloprost is a stable prostacyclin analog commonly employed in the treatment of peripheral vascular disease and also indicated in the treatment of patients affected by systemic sclerosis (SSc) in the presence of severe Raynaud's phenomenon (RP). Several mechanisms of action of the drug other than vasodilation and antiplatelet effect have been demonstrated that may be involved in the exertion of its clinical efficacy. Aim of the present study was to investigate whether Iloprost down-regulated lymphocyte adhesion to endothelium through a modulation of adhesion molecule expression on the surface of endothelial cells. In the presence of Iloprost, both lymphocyte adhesion and IL-1 stimulated expression of ICAM-1 and ELAM-1 exhibited a significant reduction, while unstimulated adhesion molecule expression was not significantly affected. Our results confirm that Iloprost is able to down-regulate lymphocyte adhesion to endothelial cells and indicate that endothelium itself could be target of Iloprost administration. Attenuation of the inflammatory response through modulation of cellular interactions could be suggested as a potential mechanism of action of Iloprost, when used in the treatment of pathological conditions characterized by endothelial activation.

The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs.[Pubmed:10634944]

Biochim Biophys Acta. 2000 Jan 17;1483(2):285-93.

Stable cell lines that individually express the eight known human prostanoid receptors (EP(1), EP(2), EP(3), EP(4), DP, FP, IP and TP) have been established using human embryonic kidney (HEK) 293(EBNA) cells. These recombinant cell lines have been employed in radioligand binding assays to determine the equilibrium inhibitor constants of known prostanoid receptor ligands at these eight receptors. This has allowed, for the first time, an assessment of the affinity and selectivity of several novel compounds at the individual human prostanoid receptors. This information should facilitate interpretation of pharmacological studies that employ these ligands as tools to study human tissues and cell lines and should, therefore, result in a greater understanding of prostanoid receptor biology.