Potent Prostacyclin Research Articles

The selective PGI2 receptor agonist selexipag ameliorates Sugen 5416/hypoxia-induced pulmonary arterial hypertension in rats.

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by a progressive increase in pulmonary artery pressure due to an increase in vessel tone and occlusion of vessels. The endogenous vasodilator prostacyclin and its analogs are used as therapeutic agents for PAH. However, their pharmacological effects on occlusive vascular remodeling have not been elucidated yet. Selexipag is a recently approved, orally available and selective prostacyclin receptor agonist with a non-prostanoid structure. In this study, we investigated the pharmacological effects of selexipag on the pathology of chronic severe PAH in Sprague-Dawley and Fischer rat models in which PAH was induced by a combination of injection with the vascular endothelial growth factor receptor antagonist Sugen 5416 and exposure to hypoxia (SuHx). Oral administration of selexipag for three weeks significantly improved right ventricular systolic pressure and right ventricular (RV) hypertrophy in Sprague-Dawley SuHx rats. Selexipag attenuated the proportion of lung vessels with occlusive lesions and the medial wall thickness of lung arteries, corresponding to decreased numbers of Ki-67-positive cells and a reduced expression of collagen type 1 in remodeled vessels. Administration of selexipag to Fischer rats with SuHx-induced PAH reduced RV hypertrophy and mortality caused by RV failure. These effects were probably based on the potent prostacyclin receptor agonistic effect of selexipag on pulmonary vessels. Selexipag has been approved and is used in the clinical treatment of PAH worldwide. It is thought that these beneficial effects of prostacyclin receptor agonists on multiple aspects of PAH pathology contribute to the clinical outcomes in patients with PAH.

Clinical Pharmacokinetic Performance of a Ralinepag Extended-Release Tablet

Purpose Ralinepag is an oral, potent, and selective prostacyclin receptor agonist in development for treating pulmonary arterial hypertension. The study goal was single-dose pharmacokinetic (PK) comparison of ralinepag extended-release (XR) and ralinepag/selexipag immediate-release (IR) formulations and multiple-dose PK performance of ralinepag XR under fasted/fed conditions. Methods Study 1: cohort 1 (n=12) - fasted healthy subjects took single ralinepag doses sequentially over 4 treatment periods: 30 mcg IR capsule, then 60, 120, and 180 mcg doses of an XR tablet. Cohort 2 (n=12) - fasted subjects took single selexipag doses sequentially over 3 treatment periods: 200, 400, and 600 mcg IR tablets. Study 2: fasted (n=19) or fed (n=18) healthy subjects received ralinepag XR tablets in a repeat dose-escalation paradigm over 25 days (starting dose 60 mcg once daily [qd], titrated by additional 60 mcg increments every 5 days up to 300 mcg qd as tolerated). Results Study 1: dose-adjusted peak plasma exposure (Cmax/D) measures were lower for ralinepag XR versus IR (geometric mean ratio [GMR] range up to 41.2%). Dose-adjusted total plasma exposure (AUC/D) measures were similar for XR and IR (GMR range up to 97.9%). Selexipag and MRE-269 plasma PK profiles were consistent with the need for administration at least twice daily. Study 2: dose-dependent plasma exposure measures were observed for ralinepag XR tablet with low steady-state peak-to-trough ratio (≤2) upon qd dosing, approximating the ‘ideal’ continuous IV infusion-like PK profile for agents in this drug class, and minimal food effect. Females had higher mean exposure measures than males, for which such differences were not statistically significant or considered clinically meaningful. Conclusion The ralinepag XR tablet offers improved PK performance over both ralinepag and selexipag IR formulations, with extended exposure and low peak-to-trough ratio with qd dosing, supporting its use in the ADVANCE Phase 3 program.

Ralinepag Plasma Levels Correlate with Improvements in Functional and Hemodynamic Parameters in Patients with Pulmonary Arterial Hypertension

Purpose Ralinepag is an oral, selective, and potent prostacyclin receptor agonist in development for the treatment of pulmonary arterial hypertension (PAH) that has shown efficacy in patients with PAH in a randomized, double-blind Phase 2 study. Despite evidence of a dose-effect relationship for some drugs targeting the prostacyclin pathway, the relationship between drug plasma levels and efficacy is unknown, particularly for oral therapies. This post hoc analysis of the Phase 2 study evaluated whether ralinepag plasma levels correlated with improvements in functional and/or hemodynamic parameters, including pulmonary vascular resistance (PVR) and 6-minute walk distance (6MWD). Methods Adults with stable functional class II-IV PAH and 6MWD of 100-500 m, on background approved single or dual oral PAH treatment, were randomized 2:1 to receive ralinepag (n=40) or placebo (n=21) for 9 weeks of titration, then 13 weeks of maintenance. Treatment was initiated at 10 µg twice daily (bid) and titrated weekly to maximum tolerated dose, up to 300 µg bid. Ralinepag plasma levels were measured 4 hours post-dose at Weeks 9, 10, 14, 18, and 22 (maintenance phase: Weeks 9-22), and mean levels were calculated. Right heart catheterization was performed at Baseline and at Week 22. Efficacy was assessed as percent change in functional and hemodynamic parameters from Baseline to Week 22. Correlation coefficients between mean plasma levels of ralinepag and percent change in efficacy parameters were calculated. Results Ralinepag plasma levels correlated with ralinepag dose. Over the 22-week study period, there was a significant correlation between ralinepag plasma levels and improvements in PVR and 6MWD (Table). Conclusion In patients with PAH, ralinepag plasma levels correlated with ralinepag dose and with improvements in PVR and 6MWD, demonstrating a correlation between plasma levels of a prostacyclin pathway oral drug and hemodynamic/functional parameters.

Discovery of a new series of potent prostacyclin receptor agonists with in vivo activity in rat.

The design and synthesis of two closely related series of prostacyclin receptor agonist compounds that showed excellent human IP receptor potency and efficacy is described. Compounds from this series showed in vivo activity after SC dosing in the monocrotaline model of PAH in rat.

Infusion of iloprost without a peristaltic pump: Safety and tolerability

Introduction: Iloprost is a potent prostacyclin (PGI2) analogue that is effective in the treatment of peripheral arterial disease, vasculitis, pulmonary hypertension, and secondary Raynaud’s phenomenon. Intravenous infusions are generally administered with the aid of a peristaltic pump to reduce the risk of adverse reactions caused by unintentional increases in the infusion rate. This increases the cost of care in terms of equipment and personnel and may limit the use of this drug. Materials and methods: We retrospectively analyzed 18,432 iloprost infusions administered between 1999 and 2009 to 272 patients with systemic sclerosis (n = 253) and 19 with peripheral arterial disease (n = 19). All infusions were administered in the day hospital over 6 h with a normal IV set-up with a roller flow regulator. Flow rates were set to deliver iloprost at 1-2 ng/kg/min. Rates were verified by direct drop counts during the first 15-20 minutes of the infusion and at each subsequent check. Results: There were no adverse events that were fatal, life-threatening, or associated with prolongation of hospitalization and very few events requiring intensive care or continuous monitoring. The latter included 4 cases of tachycardia/arrhythmia (extrasystoles in most cases), 3 cases of hypotension (systolic pressure < 80 mmHg), and 2 cases of hypertension (BP > 170/100 mmHg). All other adverse reactions were mild, reversible, and similar to those seen with iloprost infusion with peristaltic pump. Only one patient had to be switched to another prostanoid (due to intolerance). Discussion: Iloprost infusion administered with a normal IV flow regulator appears to be as safe, well tolerated, and effective as traditional infusion with a peristaltic pump.

Transitioning from Parenteral Treprostinil to Inhaled Treprostinil in Patients with Pulmonary Arterial Hypertension

Treprostinil is a potent prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH, World Health Organization Group I). Previously, treprostinil was available only in subcutaneous (SC) or intravenous (IV) formulations. Availability of an inhaled formulation of treprostinil has provided clinicians with an alternative to continuous SC or IV treprostinil in appropriate patients. Stable PAH patients whose quality of life has been dramatically impacted by side effects of parenteral therapy or those who have had recurrent, life-threatening bloodstream infections but are otherwise responding well to treatment may be the candidates for continuing prostacyclin therapy with inhaled treprostinil. However, there is little clinical experience with transitioning patients from parenteral to inhaled treprostinil. We present the results of two cases that highlight important considerations in transitioning patients from parenteral to inhaled therapy, including the pharmacologic and clinical equivalence of formulations, dose titration of formulations and suggested criteria for patient selection.

Sicurezza e tollerabilità della somministrazione di iloprost senza pompa peristaltica

Iloprost is a potent prostacyclin (PGI2) analogue that is effective in the treatment of peripheral arterial disease, vasculitis, pulmonary hypertension, and secondary Raynaud's phenomenon. Intravenous infusions are generally administered with the aid of a peristaltic pump to reduce the risk of adverse reactions caused by unintentional increases in the infusion rate. This increases the cost of care in terms of equipment and personnel and may limit the use of this drug. We retrospectively analyzed 18,432 iloprost infusions administered between 1999 and 2009 to 272 patients with systemic sclerosis (n = 253) and 19 with peripheral arterial disease (n = 19). All infusions were administered in the day hospital over 6 h with a normal IV set-up with a roller flow regulator. Flow rates were set to deliver iloprost at 1-2 ng/kg/min. Rates were verified by direct drop counts during the first 15-20 minutes of the infusion and at each subsequent check. There were no adverse events that were fatal, life-threatening, or associated with prolongation of hospitalization and very few events requiring intensive care or continuous monitoring. The latter included 4 cases of tachycardia/arrhythmia (extrasystoles in most cases), 3 cases of hypotension (systolic pressure < 80 mmHg), and 2 cases of hypertension (BP > 170/100 mmHg). All other adverse reactions were mild, reversible, and similar to those seen with iloprost infusion with peristaltic pump. Only one patient had to be switched to another prostanoid (due to intolerance). Iloprost infusion administered with a normal IV flow regulator appears to be as safe, well tolerated, and effective as traditional infusion with a peristaltic pump.

Effects of vasoactive cyclooxygenase products on shunt flow and extravascular lung water in acute lung injuries

Using 50 mongrel dogs with alveolar flooding produced by oleic acid administration, the possible roles of vasoactive cyclooxygenase products on intrapulmonary shunt flow (QS/QT) and extravascular lung water (ETVI) in acutely injured lungs were assessed. Suppressing cyclooxygenase activity with indomethacin administration diminished the concentrations of thromboxane (TX) B2 and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in arterial blood, resulting in a significant reduction in QS/QT. Furthermore, indomethacin completely suppressed the increase in ETVI. Inhibition of TXA2 generation by OKY-046 (thromboxane A2 synthase blocker) diminished the concentration of TXB2 while increasing that of 6-keto-PGF1 alpha in blood. Administration of either OKY-046 or synthetic prostacyclin (PGI2) markedly enhanced QS/QT, in association with an increase in ETVI. In conclusion, the potent vasodilator prostacyclin was considered to enhance shunt flow, leading to the augmentation of edema formation.

Synthesis of 2‐[4‐(Imidazolin‐2‐Ylideneamino)Benzyl]‐Indan‐1‐Ones as Novel Potent Prostacyclin Antagonists

AbstractProstacyclin is involved in many pathological conditions, such as sensitization of inflammation induced pain and isovolumetic distention. Therefore, antagonism of prostacyclin action may be useful in the alleviation of these conditions. In this study, novel potent prostacyclin antagonists, 2‐[4‐(imidazolin‐2‐ylideneamino)benzyl]‐indan‐1‐ones were synthesized from their respective substituted indanones in three steps. The construction of the amino‐imidazole moiety of these derivatives is achieved by using in situ generation of chloro‐imidazole and reaction with their respective anilines. Thus, these N‐substituted 2‐imidazolines can be prepared safely and efficiently. Moreover, these compounds show potent prostacyclin antagonistic activity by inhibition of prostacyclin agonist induced ERK1/2 phosphorylation in human erythroleukemia cells. Moreover, we observed an increase in activity with the increase in electro‐donating property of the substitution on the indanone aromatic ring. Prostacyclin antagonists with increased potency may be designed based on these findings. These compounds may also be invaluable tools for the study of the physiological functions of prostacyclin.

A new method of iloprost administration without a peristaltic pump

ObjectiveThe purpose of this study was to assess the efficacy of administering iloprost therapy via a flow-regulator system compared with the traditional peristaltic pump infusion system. BackgroundIloprost is a potent prostacyclin (PGI2) analogue that is effective in the treatment of thromboangiitis obliterans, peripheral arterial occlusive disease, scleroderma, Raynaud's phenomenon, and primary pulmonary hypertension. Due to its rapid clearance from the central compartment, iloprost is usually administered intravenously with a peristaltic pump infusion system, which limits its use to hospitalized patients. MethodsIn this open-label, randomized clinical trial, we used a simple plastic tube with a flow regulator (calibrated in milliliters per minute), instead of a peristaltic pump, to administer iloprost 0.5 to 2.0 ng/kg per minute. ResultsBetween January 1995 and December 1999, 82 patients were enrolled in the study. They received iloprost by infusion for a combined total of 4056 days. Iloprost was well tolerated; no patient withdrew from the study as a result of adverse events. Preliminary results showed that the flow-regulator system had clinical effects comparable to those obtained with the peristaltic pump infusion system. ConclusionsUse of a flow regulator could provide advantages in administering PGI2 analogue therapy for various ischemic diseases.

A Prostacyclin Analogue Crosses the in Vitro Perfused Human Placenta and Improves Transfer in Some Pathologic States

Placental blood flow is reduced in pregnancies complicated by hypertension, intrauterine growth retardation, maternal smoking, or diabetes. Umbilical-placental production of the potent vasodilator prostacyclin is also reduced in these pathologic states and this deficiency may contribute to an associated increase in the incidence of low infant birthweight by affecting a reduction in placental nutrient transfer. We have studied the effects of the prostacyclin analogue carbacyclin on diffusional transfer in the human placenta perfused in vitro. We have found that carbacyclin crosses the human placenta and can significantly increase diffusional transfer in placenta from pregnancies complicated by hypertension or maternal smoking and in the normal term placenta in which prostacyclin production has first been reduced through the administration of ibuprofen. Carbacyclin had no effect, however, in untreated placenta from normal pregnancies or in placenta from diabetic pregnancies. These results suggest that the prostacyclin-deficient perfused placenta may serve as a model for several placental insufficiency syndromes and that the possibility that prostacyclin analogues may improve deficient nutrient transfer in some pathologic pregnancies warrants further investigation.

Failure of vasodilator infusion to alter pulmonary diffusing capacity in systemic sclerosis

Patients with systemic sclerosis (SSc) do not exhibit a normal increase in the diffusing capacity for carbon monoxide (DLCO) on assuming the supine position. We sought to determine whether a potent prostacyclin derivative and vasodilator, iloprost, would reverse this defect. Fourteen patients with SSc were enrolled in a randomized, double-blind, placebo-controlled study of iloprost. Patients were tested before and during 3 days of iloprost or placebo infusion with both upright and supine pulmonary function studies. The results of baseline pulmonary function studies including DLCO were not significantly altered by iloprost. Furthermore, iloprost did not alter the abnormal postural DLCO response. These results suggest that the pulmonary vascular defects seen in this group of patients are not a consequence of reversible pulmonary vasospasm.

Effect of Oral Administration of A Prostacyclin Analog (Op-41483) On Pulmonary Function and Bronchial Responsiveness in Stable Asthmatic Subjects

To examine whether prostacyclin has an attenuating effect on nonspecific bronchial responsiveness in asthma, we measured provocative concentration of methacholine producing a 20% fall in forced expiratory volume in 1 second (PC20-FEV1) before and after oral administration of a chemically stable prostacyclin analog (OP-41483) (200 micrograms 4 times a day for 4 days) in 8 patients with stable asthma. Neither baseline pulmonary function nor PC20-FEV1 significantly improved after the treatment. These results suggest that prostacyclin may have no direct effect on bronchial responsiveness in asthmatics. Further studies using more potent and long-lasting prostacyclin mimetic will be needed to confirm the conclusion.

Failure of vasodilator infusion to alter pulmonary diffusing capacity in systemic sclerosis

purpose: Patients with systemic sclerosis (SSc) do not exhibit a normal increase in the diffusing capacity for carbon monoxide (DL co) on assuming the supine position. We sought to determine whether a potent prostacyclin derivative and vasodilator, iloprost, would reverse this defect. patients and methods: Fourteen patients with SSc were enrolled in a randomized, doubleblind, placebo-controlled study of iloprost. Patients were tested before and during 3 days of iloprost or placebo infusion with both upright and supine pulmonary function studies. results: The results of baseline pulmonary function studies including DL co were not significantly altered by iloprost. Furthermore, iloprost did not alter the abnormal postural DL co response. conclusion: These results suggest that the pulmonary vascular defects seen in this group of patients are not a consequence of reversible pulmonary vasospasm.

The post‐occlusive hyperemic response in patients with systemic sclerosis

We investigated post-ischemic hyperreactive cutaneous blood flow in patients with primary Raynaud's phenomenon and Raynaud's phenomenon secondary to systemic sclerosis (SSc). Reactive hyperemia was measured over a locally warmed area of skin, using a laser Doppler flowmeter, following 5 minutes of suprasystolic occlusion of blood flow. We found that patients with primary Raynaud's phenomenon had normal post-ischemic blood flow compared with normal controls. In contrast, patients with SSc had reduced levels of baseline and peak blood flow compared with either the primary Raynaud's phenomenon patients or the normal subjects. Infusion of carbaprostacyclin, a potent prostacyclin analog vasodilator, did not increase blood flow in the SSc patients, nor did it restore the reactive hyperemic response. These findings are consistent with the hypothesis that patients with the nonvasoconstricted condition of SSc have fixed structural defects that limit cutaneous microvascular blood flow.

Preservation of Canine Platelets with Iloprost (ZK 36374) during Extracorporeal Circulation

(J. Extra-Corpor. Technol. 19[3] p. 258-264 Fall 1987, 23 ref.) Contact between blood and synthetic/air interfaces during extracorporeal circulation (ECC) results in adverse platelet alterations. We tested the efficacy of a new reversible potent prostacyclin analogue, iloprost (ZK 36374), in preventing these untoward conseguences in fifteen mongrel dogs undergoing extracorporeal circulation using either a membrane or bubble oxygenator. In treated groups, infusion of iloprost was incrementally increased to 150 ng/kg/min at least 15 minutes prior to incision. Equal infusion volumes of saline were administered to the control group. Platelet counts in control dogs (n = 6, membrane/control) decreased to 57 ± 10% (mean ± standard error of the mean) of initial levels by 30 minutes of ECC; in contrast, dogs infused with iloprost demonstrated consistently stable platelet counts despite perfusion with either membrane (1 07 ± 1 0%, n = 6) or bubble (81 ± 13%, n = 3) oxygenators. At 30 minutes of ECC, the iloprost infusion was discontinued. Although the platelet counts in the membrane iloprost-treated group continued to remain stable (99 ± 7%), platelet counts in the bubble iloprost-treated group droppped precipitously to 49 ± 1 0% within 60 minutesof discontinuance of infusion. Furthermore, by 90 minutes of ECC, platelets continued to demonstrate reduced sensitivity to ADP as measured by percent light transmission in both control (53 ± 15%) and bubble iloprost-treated (20 ± 16%) groups. In contrast, the membrane iloprost-treated group regained normal reactivity (80 ± 15%). We conclude that iloprost effectively prevents adverse platelet alterations during ECC. Furthermore, its salutary effects in membrane oxygenator systems persist long after platelet functional inhibition is reversed.

Potent prostacyclin analogs based on the bicyclo[4.2.0]octane ring system

Potent prostacyclin analogs based on the bicyclo[4.2.0]octane ring system

Heparin-induced platelet activation in sixteen surgical patients: Diagnosis and management

Heparin-induced platelet activation (HIPA) is a syndrome associated with thrombocytopenia, intravascular thrombosis, and arterial emboli. We have evaluated 16 patients for presumed HIPA because of the occurrence of thrombocytopenia or a new thrombotic complication during heparin therapy. In this group, 16 thrombotic events occurred in 10 patients with a mortality rate of 18.8%. Diagnosis was confirmed in vitro by the demonstration of at least 20% platelet aggregation and/or 6% 14C-serotonin release after heparin (0.1 to 3 U/ml) was added to a mixture of patient platelet-poor plasma (PPP, two parts) and aspirin-free donor platelet-rich plasma (PRP, three parts). After heparin was discontinued, seven patients continued to have HIPA in their own PRP although it could no longer be observed in donor PRP. Iloprost, a potent prostacyclin analog that reversibly inhibits platelet activation, completely prevented HIPA and release in all of nine patients. Aspirin, an irreversible cyclooxygenase inhibitor, failed to prevent HIPA in four of these nine patients. In conclusion, HIPA is associated with an extremely high morbidity and mortality rate. Evaluation of the patients' PRP in response to heparin may improve the diagnostic sensitivity of this assay. Aspirin does not reliably prevent HIPA, which suggests participation of thromboxane-independent pathways. Thus, if further exposure to heparin is unavoidable, a more effective platelet inhibitor such as iloprost is required to reliably prevent in vivo HIPA.

Heparin-induced platelet activation in sixteen surgical patients: Diagnosis and management

Heparin-induced platelet activation (HIPA) is a syndrome associated with thrombocytopenia, intravascular thrombosis, and arterial emboli. We have evaluated 16 patients for presumed HIPA because of the occurrence of thrombocytopenia or a new thrombotic complication during heparin therapy. In this group, 16 thrombotic events occurred in 10 patients with a mortality rate of 18.8%. Diagnosis was confirmed in vitro by the demonstration of at least 20% platelet aggregation and/or 6% 14C-serotonin release after heparin (0.1 to 3 U/ml) was added to a mixture of patient platelet-poor plasma (PPP, two parts) and aspirin-free donor platelet-rich plasma (PRP, three parts). After heparin was discontinued, seven patients continued to have HIPA in their own PRP although it could no longer be observed in donor PRP. Iloprost, a potent prostacyclin analog that reversibly inhibits platelet activation, completely prevented HIPA and release in all of nine patients. Aspirin, an irreversible cyclooxygenase inhibitor, failed to prevent HIPA in four of these nine patients. In conclusion, HIPA is associated with an extremely high morbidity and mortality rate. Evaluation of the patients' PRP in response to heparin may improve the diagnostic sensitivity of this assay. Aspirin does not reliably prevent HIPA, which suggests participation of thromboxane-independent pathways. Thus, if further exposure to heparin is unavoidable, a more effective platelet inhibitor such as iloprost is required to reliably prevent in vivo HIPA.

SYNTHESIS OF (Z)-4,5,13,14-TETRADEHYDRO-9(O)-METHANO-Δ6(9α)-PGI1

Abstract A stereoselective synthesis of (Z)-4,5,13,14,-tetradehydro-9(O)-methano-Δ6(9α)-PGI1, a potent prostacyclin analog, has been accomplished.