Prostacyclin Analogue Research Articles

Chronic Thromboembolic Pulmonary Hypertension: Medical Treatment

Chronic thromboembolic pulmonary hypertension (CTEPH) is responsible for significant levels of morbidity and mortality. The estimated cumulative incidence of CTEPH is 2-4% among patients presenting with acute pulmonary thromboembolism. Currently, at the time of CTEPH diagnosis, 37.9% of the patients in an international registry were receiving at least one pulmonary arterial hypertension (PAH)-targeted therapy. Advanced medical therapy is considered in patients with inoperable disease, as a bridge to pulmonary endarterectomy or in those with persistent or recurrent pulmonary hypertension. PAH-specific medical therapies include endothelin receptor antagonists, phosphodiesterase inhibitors, and prostacyclin analogues. The present article will focus on recent developments in the pharmacological treatment of CTEPH.

A Multicenter, Retrospective Study of Patients with Pulmonary Arterial Hypertension Transitioned from Parenteral Prostacyclin Therapy to Inhaled Iloprost

Pulmonary arterial hypertension (PAH) is characterized by progressive increases in pulmonary vascular resistance, leading to right heart failure and death. Guidelines recommend customization of treatment, necessitating the development of effective strategies for transitioning patients among treatments. In this study, we characterized our experience with patient transitions from parenteral prostacyclin to inhaled iloprost. We retrospectively assessed records from 11 centers of 37 consecutive patients with PAH aged ≥ 18 years who were treated with intravenous (IV) or subcutaneous (SC) prostacyclin analogues and transitioned to inhaled iloprost. The transition period began on the first day of inhaled iloprost with the intent of discontinuing parenteral prostacyclin and ended on the first day on inhaled iloprost free of parenteral prostacyclin. Persistence was defined as the absence of (1) parenteral prostacyclin while remaining on inhaled iloprost during post-transition Days 1-90 and (2) no reinitiation of parenteral prostacyclin during post-transition Days 90-365. All patients were clinically stable before transitioning to inhaled iloprost. The mean age was 46.5 years, 70.3% were female, 51.4% had idiopathic PAH, and 43.0% were in New York Heart Association Functional Class III. Among patients with an overlapping transition, the mean transition period was 10.5 days. A transition dosing algorithm was used in 10 patients (27.0%). At one year, 78.4% of the patients remained persistent on inhaled iloprost and 81.1% were free of clinical worsening. In selected patients on background oral PAH therapy, transitioning from parenteral prostacyclin to inhaled iloprost appears safe and feasible and is associated with long-term success. Further study is needed to define the optimal patient selection criteria and transition algorithm.

Platelets of humans with type 2 diabetes (DM2) exhibit fewer prostacyclin receptor (IPR) binding sites as well as decreased iloprost (ILO)‐mediated cAMP accumulation

Humans with DM2 exhibit enhanced platelet aggregation that has been suggested to result from increased synthesis of the proaggregatory prostanoid, thromboxane by platelets, as well as from increased platelet thromboxane receptor sensitivity. The proaggretory effects of thromboxane are opposed by the antiaggregatory prostanoid, prostacyclin, released from the endothelium. Platelets express the prostacyclin receptor (IPR) and it has been suggested that reduced IPR activity may contribute to increased thromboxane sensitivity in DM2. Here we investigated the hypothesis that platelets of humans with DM2 exhibit decreased IPR expression as well as reduced responsiveness to the prostacyclin analog, iloprost (ILO) when compared to healthy humans. Platelets of humans with DM2 and controls were isolated from whole blood. Using 3H‐ILO, we determined that the number of IPR binding sites (Bmax) is reduced in platelets of humans with DM2. Furthermore, when platelets of humans with DM2 were stimulated with ILO, increases in cAMP were significantly reduced. The decreased IPR binding capacity and response to prostacyclin in platelets of humans with DM2 may contribute to the increased tendency for platelet aggregation in humans with DM2. Financial support provided by the American Diabetes Association (BS‐150).

Iloprost suppresses LPS‐induced lung injury and inflammation via Rac1‐dependent mechanism

Prostacyclin exhibits protective effects on vascular endothelium and enhances endothelial barrier, as reflected by rapid increase in transendothelial resistance. This study investigated for the first time protective effects of stable prostacyclin analog iloprost using in vitro and in vivo models of lung injury and inflammation induced by bacterial wall lypopolysacharide (LPS). Iloprost attenuated disruption of endothelial monolayer and suppressed activation of inflammatory signaling, including p38 mitogen activated protein kinase, NFkB pathway, Rho signaling, attenuated ICAM1 expression, cytokine release, neutrophil adhesion and migration after LPS challenge. In vivo, iloprost exhibited potent inhibition of LPS‐induced lung injury and vascular leak, as detected by suppression of protein and neutrophil accumulation in bronchoalveolar lavage fluid and reduced myeloperoxidase activation, ICAM‐1 expression, and Evans blue extravasation in the lungs. Inhibition of Rac1 activity using pharmacologic inhibitors or siRNA‐mediated knockdown abolished barrier‐protective and anti‐inflammatory effects of iloprost in vitro and in vivo. We conclude that iloprost‐induced elevation of intracellular cAMP triggers Rac signaling, which attenuates LPS‐induced inflammatory pathways of vascular permeability.Funding: NHLBI HL87823, HL076259, and HL058064

Open label study of escalating doses of oral treprostinil diethanolamine in patients with systemic sclerosis and digital ischemia: pharmacokinetics and correlation with digital perfusion

IntroductionTreprostinil diethanolamine is an innovative salt form of the prostacyclin analogue, treprostinil sodium, developed as an oral sustained release (SR) osmotic tablet. The availability of a formulation permitting convenient systemic delivery might have applicability to scleroderma vascular complications. We evaluated pharmacokinetics and perfusion in scleroderma patients with digital ischemia following escalating twice-daily doses of treprostinil diethanolamine SR.MethodsScleroderma patients with digital ulcers were enrolled in this dual-center, open-label, phase I pharmacokinetic study. Drug concentrations and perfusion, quantified by laser Doppler imaging, were measured over 12 hours at the 2 mg and 4 mg (or maximally tolerated) doses. Pharmacokinetic parameters were determined from individual plasma concentration versus time profiles using non-compartmental analysis methods. Digital perfusion and skin temperature were modeled as a function of log-transformed drug concentration and other covariates by performing repeated measures analyses using random effects models.ResultsNineteen scleroderma patients (84% female, 53% limited scleroderma) received treprostinil diethanolamine SR with dose titration up to 4 mg twice daily as tolerated. Peak concentrations (mean maximum plasma concentration (Cmax) = 1,176 and 2,107 pg/mL) occurred approximately 3.6 hours after dose administration, and overall exposure (under the plasma concentration-time curve from time 0 to 12 hours post dose (AUC0-12) = 7,187 and 12,992 hr*pg/mL) was linear between the 2 mg and 4 mg doses. Perfusion and digital skin temperature were positively associated with log-transformed plasma concentration at the 4 mg dose (P = 0.015 and P = 0.013, respectively). The most frequent adverse events were similar to those seen with prostacyclin analogues.ConclusionsOral treprostinil diethanolamine was effectively absorbed in patients with scleroderma. Drug administration was temporally associated with improved cutaneous perfusion and temperature. Treprostinil diethanolamine may provide a new therapeutic option for Raynaud's phenomenon and the peripheral vascular disease of scleroderma.Trial RegistrationClinicalTrials.gov NCT00848939.Electronic supplementary materialThe online version of this article (doi:10.1186/ar4216) contains supplementary material, which is available to authorized users.

PROSPECT Patient Subgroups and Etiologies: Predictors of Outcomes

Purpose The PROSPECT Registry is a multicenter, observational, US registry evaluating the use of epoprostenol for injection with arginine (Veletri®, Epo-A), offering expanded storage capacity and prolonged room temperature stability in patients (pts) with pulmonary arterial hypertension (PAH). PROSPECT includes pts currently receiving, being initiated on, or transitioning from other prostacyclin (PGI2) analog therapy to Epo-A with follow-up at 1 year from enrollment. Here, we examine predictors of increased mortality. Methods and Materials Data lock was 17 Sept 2012. We conducted univariate and multivariate analyses of candidate predictors with 331 PROSPECT pts who were either “naive” or “transitioned” according to use of synthetic PGI2 or PGI2 analog within 30 days prior to Epo-A initiation. Results Mean (± SD) time from diagnosis to study entry for naive (n = 139) and transitioned (n = 192) pts was 35.7 ± 54.9 and 70.5 ± 56.3 mos, respectively. Mean follow-up was 8 and 9 mos for surviving naive and transitioned pts, respectively; 33% of naive and 37% of transitioned pts completed 1 yr of follow-up. Patients had the following characteristics at Epo-A initiation: age (mean ± SD), 50 ± 15 years; female, 77%; functional class (FC) III, 51%, FC IV, 11%; renal insufficiency, 8%; PAH associated with connective tissue disease (CTD-APAH), 26%. Deaths occurred in 14 naive and 24 transitioned pts. Independent predictors of mortality (multivariate HR [95% CI]) were FC IV (3.51 [1.73, 7.09]; P Conclusions Renal insufficiency, male sex, and FC IV are significant independent predictors of mortality in PAH pts who are either prostacyclin naive or transitioned to Epo-A. Future analyses from the ongoing PROSPECT registry may provide further insight into this cohort.

A slow-releasing form of prostacyclin agonist (ONO1301SR) enhances endogenous secretion of multiple cardiotherapeutic cytokines and improves cardiac function in a rapid-pacing–induced model of canine heart failure

Cardiac functional deterioration in dilated cardiomyopathy (DCM) is known to be reversed by intramyocardial up-regulation of multiple cardioprotective factors, whereas a prostacyclin analog, ONO1301, has been shown to paracrinally activate interstitial cells to release a variety of protective factors. We here hypothesized that intramyocardial delivery of a slow-releasing form of ONO1301 (ONO1301SR) might activate regional myocardium to up-regulate cardiotherapeutic factors, leading to regional and global functional recovery in DCM. ONO1301 elevated messenger RNA and protein level of hepatocyte growth factor, vascular endothelial growth factor, and stromal-derived factor-1 of normal human dermal fibroblasts in a dose-dependent manner in vitro. Intramyocardial delivery of ONO1301SR, which is ONO1301 mixed with polylactic and glycolic acid polymer (PLGA), but not that of PLGA only, yielded significant global functional recovery in a canine rapid pacing-induced DCM model, assessed by echocardiography and cardiac catheterization (n = 5 each). Importantly, speckle-tracking echocardiography unveiled significant regional functional recovery in the ONO1301-delivered territory, consistent to significantly increased vascular density, reduced interstitial collagen accumulation, attenuated myocyte hypertrophy, and reversed mitochondrial structure in the corresponding area. Intramyocardial delivery of ONO1301SR, which is a PLGA-coated slow-releasing form of ONO1301, up-regulated multiple cardiotherapeutic factors in the injected territory, leading to region-specific reverse left ventricular remodeling and consequently a global functional recovery in a rapid-pacing-induced canine DCM model, warranting a further preclinical study to optimize this novel drug-delivery system to treat DCM.

Parenteral iloprost in the symptomatic treatment of hip osteoarthritis

Background: Iloprost is a prostacyclin analogue that has been used in the treatment of symptomatic bone marrow edema of different aetiology. Objective: To present a case of bilateral hip osteoarthritis treated with intravenous iloprost. Case: A 32-year old Filipino female presented with pain in the lower back and bilateral hip of two years duration, precipitated by weight-bearing activities such as prolonged standing and walking long-distances, and temporarily relieved by rest. She had no known co-morbid conditions, denied intake of any herbal or over-the-counter medications, but had a history of practicing mixed-martial arts for eight years. Complete blood count, blood chemistries and inflammatory markers were all normal. Radiographs of the hips showed sclerosis on the superior portion of the left acetabulum consistent with osteodegenerative changes. Magnetic resonance imaging of the hips revealed subtle heterogenous marrow signals within both acetabulum and femoral heads with minimal effusion. Bone marrow edema, probably of osteoarthritic etiology was diagnosed. Beginning avascular necrosis was also considered. The patient was given Iloprost 20 ug daily intravenous infusions for six doses. No untoward event was noted. Hip pain decreased by 50% after the second dose (from VAS 7/10 to VAS 3/10), and completely resolved after the fifth dose. The patient was subsequently advised off-loading for 3 to 4 weeks and was prescribed physical therapy for gait training. Conclusion: Iloprost is a prostacyclin analogue that may be used in the symptomatic treatment of bone marrow edema of different causes, including osteoarthritis.

Intravenous prostacyclin analogue iloprost (Ilomedin®) in the treatment of a patient with Buerger’s disease

Buerger’s disease, or thromboangiitis obliterans, is a severe disabling systemic disease of vessels. The paper describes a case of thromboangiitis obliterans in a patient with three extremities amputated during vascular therapy. The course intravenous administration of the stable prostacyclin analogue iloprost (Ilomedin®) allows the only extremity to be preserved.

Beraprost enhances production of antigen-specific IgG isotypes without modulating germinal center B cell generation and the affinity maturation

Immune regulating functions of lipid mediators are being recognized. Prostaglandins (PGs) are derived from phospholipid by cyclooxygenase-2 (COX-2) in inflammatory tissues. Based upon our previous data that imply an immune modulating activity of prostacyclin, we hypothesized that PGs promote the humoral immune responses in vivo. To test this hypothesis, we examined the effect of a prostacyclin analog beraprost and PGE2 on the antibody responses that were induced by immunizing mice with keyhole limpet hemocyanin (KLH). Beraprost was used due to the extremely unstable property of prostacyclin. Our results showed that beraprost indeed promoted the production of anti-KLH antibodies, which was dose-dependent and specific to beraprost because PGE2 did not modulate the antibody response compared with controls. The enhancing effect of beraprost was reproduced in the secondary responses, suggesting that memory B cell generation during the primary response was significantly affected by beraprost. Analysis of the isotypes of anti-KLH antibodies revealed that beraprost stimulated the production of IgA and IgG subisotypes but not IgM. However, germinal center B cell generation and the affinity of anti-KLH antibodies were not affected by beraprost administration. To confirm these results we immunized COX-2 knockout mice with KLH and analyzed whether the results with wild-type mice were reflected in the absence of PGs. The primary and secondary antibody responses were significantly impaired in the KO animals. The levels of anti-KLH IgG subisotypes and IgA were severely reduced in KO mice whereas those of IgM were comparable to controls. These results reveal an unrecognized function of PG in the humoral immune responses.

GRP-002 A Case Report: Management of Pain After Subcutaneous Injection of Treprostinil

BackgroundTreprostinil is a prostacyclin analogue indicated for the treatment of Pulmonary Arterial Hypertension (PAH) for patients with functional NYHA class III. The administration is a continuous subcutaneous infusion. It is...

A sustained-release prostacyclin analog ONO-1301 attenuates pancreatic fibrosis in experimental chronic pancreatitis

A sustained-release prostacyclin analog ONO-1301 attenuates pancreatic fibrosis in experimental chronic pancreatitis

Central pancreatic resection: Still an uncommon (but safe) surgical option

s / Pancreatology 13 (2013) e1–e94 e61 Ono Pharmaceutical Co., Ltd., Research Headquarters, Osaka, Japan Background: Chronic pancreatitis (CP) is an intractable disease with destruction of acinar and duct cells, interstitial fibrosis, and infiltration of inflammatory cells. ONO-1301, a novel sustained release prostacyclin analog, has an anti-fibrotic effect to lung, heart, kidney and liver, partly associated with induction of hepatocyte growth factor (HGF). However, its effect on CP is not clear. Aim: The aim of our study was to examine the effect of ONO-1301 on CP. Methods: CP was induced by dibutyltin dichloride (DBTC) (7mg/kg) in rats. Seven days after DBTC injection (day7), a slow release form of ONO1301(10mg/kg) or vehicle (control) was injected. At day 14 and 28, we evaluated histopathological CP score (edema, fatty change, inflammatory cells infiltration and fibrosis), and the expression of HGF, cytokines and collagen type1 in pancreas by realtime PCR. Results: Histopathological CP score was improved in the ONO-1301 treated group (1301 group) compared to control; especially, inflammatory cells infiltration at day 14 and interstitial fibrosis at day 28. HGF mRNA increased significantly after administration of ONO-1301, whereas IL-1b, IL-6, TNF-a, TGF-b, MCP-1 and collagen mRNA decreased significantly at day 14, and collagen, MCP-1 and TGF-b tended to decrease at day 28. Decreased inflammatory cytokines production and inflammatory cells infiltration could attenuate the following fibrosis in 1301 group. These findings might suggest that ONO-1301 suppressed local inflammation at early stage of CP with induction of HGF. Conclusion: ONO-1301 suppressed pancreatic fibrosis in the DBTCinduced CP model through inhibition of inflammatory cells infiltration in the early stage of CP. Similar to other organs, this effect of ONO-1301 might be associated with induction of HGF.

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

Efficacy and Safety of Oral Treprostinil Monotherapy for the Treatment of Pulmonary Arterial Hypertension

Background— Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with no cure. Parenteral and inhaled prostacyclin analogue therapies are effective for the treatment of PAH, but complicated administration requirements can limit the use of these therapies in patients with less severe disease. This study was designed to evaluate the safety and efficacy of the oral prostacyclin analogue treprostinil diolamine as initial treatment for de novo PAH. Methods and Results— Three hundred forty-nine patients (intent-to-treat population) not receiving endothelin receptor antagonist or phosphodiesterase type-5 inhibitor background therapy were randomized (treprostinil, n=233; placebo, n=116). The primary analysis population (modified intent-to-treat) included 228 patients (treprostinil, n=151; placebo, n=77) with access to 0.25-mg treprostinil tablets at randomization. The primary end point was change from baseline in 6-minute walk distance at week 12. Secondary end points included Borg dyspnea index, clinical worsening, and symptoms of PAH. The week 12 treatment effect for 6-minute walk distance (modified intent-to-treat population) was 23.0 m ( P =0.0125). For the intent-to-treat population, 6-minute walk distance improvements were observed at peak (26.0 m; P =0.0001) and trough (17.0 m; P =0.0025) plasma study drug concentrations. Other than an improvement in the combined 6-minute walk distance/Borg dyspnea score, there were no significant changes in secondary end points. Oral treprostinil therapy was generally well tolerated; the most common adverse events (intent-to-treat) were headache (69%), nausea (39%), diarrhea (37%), and pain in jaw (25%). Conclusions— Oral treprostinil improves exercise capacity in PAH patients not receiving other treatment. Oral treprostinil could provide a convenient, first-line prostacyclin treatment option for PAH patients not requiring more intensive therapy. Clinical Trial Registration:— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00325403 .

Successful management of an acute subdural hematoma in a patient dependent on continuous treprostinil infusion therapy

Treprostinil is a synthetic analog of prostacyclin, which is used for treatment of pulmonary arterial hypertension (PAH). Continuous subcutaneous administration of treprostinil has been proven in randomized controlled trials to improve quality of life, hemodynamics, and 5-year survival in patients with PAH. The efficacy of treprostinil has been attributed to its vasodilatory and antiplatelet effects. Unfortunately, the efficacy of treprostinil in the treatment of PAH is rapidly reversed upon cessation of the continuous infusion. Furthermore, cases of patients rapidly declining or succumbing to disease progression upon cessation of treprostinil have raised significant concern regarding discontinuation of this medication. To date, there are no reports of emergency craniotomies performed in the setting of continuous subcutaneous infusion of treprostinil. The authors report a case of a patient with PAH, treated with continuous administration of subcutaneous treprostinil as well as warfarin, who developed an acute subdural hematoma (SDH). Despite adequate INR (international normalized ratio) correction, the patient eventually underwent an emergency craniotomy for evacuation of the SDH while on continuous treprostinil administration. This case highlights the neurosurgical dilemma regarding the appropriate management of acute SDHs in patients receiving continuous treprostinil infusion.

Treprostinil therapy for PAH

Oral treprostinil—a prostacyclin analogue—is a potential initial therapy for patients with class II or III symptoms of pulmonary arterial hypertension (PAH). This finding comes from the international, double-blind, placebo-controlled FREEDOM-M trial, which was designed to assess the safety and efficacy of oral treprostinil therapy in patients with de novo PAH, who were not being treated with any other approved PAH therapy.

The PRAISE study: A prospective, multi-center, randomized, double blinded, placebo-controlled study for the evaluation of iloprost in the early postoperative period after liver transplantation (ISRCTN12622749)

BackgroundLiver graft dysfunction can deteriorate to complete organ failure and increases perioperative morbidity and mortality after liver transplantation. Therapeutic strategies reducing the rate of graft dysfunction are of current clinical relevance. One approach is the systemic application of prostaglandins, which were demonstrated to be beneficial in reducing ischemia-reperfusion injury. Preliminary data indicate a positive effect of prostacyclin analogue iloprost on allograft viability after liver transplantation. The objective of the study is to evaluate the impact of iloprost in a multi-center trial.Methods/DesignA prospective, double-blinded, randomized, placebo-controlled multicenter study in a total of 365 liver transplant recipients was designed to assess the effect of intravenous iloprost after liver transplantation. Primary endpoint will be the primary graft dysfunction characterized as presentation of one or more of the following criteria: ALAT or ASAT level > 2000 IU/ml within the first 7 postoperative days, bilirubine ≥ 10 mg/dl on postoperative day 7; INR ≥ 1.6 on postoperative day 7 or initial non-function. Secondary endpoints are parameters of post-transplant morbidity, like rates of infections, biliary complications, need of clotting factors or renal replacement therapy and the graft and patient survival.DiscussionA well-established treatment concept to avoid graft dysfunction after liver transplantation does not exist at the moment. If the data of this research project confirm prior findings, iloprost would improve the general outcome after liver transplantation.Trial RegistrationGerman Clinical Trials Register: DRKS00003514. Current Controlled Trials Register: ISRCTN12622749.

Chryseomonas luteola bloodstream infection in a pediatric patient with pulmonary arterial hypertension receiving intravenous treprostinil therapy

Treprostinil is a prostacyclin analogue approved for the treatment of pulmonary arterial hypertension (PAH). It is commonly administered through a central venous catheter (CVC). Treprostinil is associated with the incidence of Gram-negative bacterial bloodstream infections (BSI), a susceptibility that has been associated with a diluent used for treprostinil. We report the case of a 14-year-old boy with idiopathic PAH on continuous intravenous treprostinil therapy who presented with fever and fatigue. A blood culture drawn from his CVC was positive for the rare Gram-negative organism Chryseomonas luteola. The patient made a complete recovery with antibacterial treatment. This is the only documented case of a C. luteola BSI in a PAH patient receiving continuous intravenous treprostinil. We recommend maintaining a high index of suspicion for both common and rare Gram-negative pathogens and the early administration of appropriate antibiotic therapy in this population. The use of an alternate diluent solution, such as Sterile Diluent for Flolan, further decreases the infection risk.

Rapid Transition from Inhaled Iloprost to Inhaled Treprostinil in Patients with Pulmonary Arterial Hypertension

BackgroundInhaled treprostinil is a prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH) that may provide a more convenient treatment option for patients receiving inhaled iloprost while maintaining the clinical benefit of inhaled prostacyclin therapy.AimsIn this open-label safety study, 73 PAH patients were enrolled with primarily World Health Organization Class II (56%) or III (42%) symptoms. At baseline, most patients (93%) were receiving 5 μg of iloprost per dose but 38% of patients reported a dosing frequency below the labeled rate of 6–9 times daily. Patients initiated inhaled treprostinil at 3 breaths four times daily (qid) at the immediate next scheduled iloprost dose. The primary objective was to assess the safety of rapid transition from iloprost to inhaled treprostinil; clinical status and quality of life were also assessed.ResultsMost patients (84%) achieved the target treprostinil dose of 9 breaths qid and remained on study until transition to commercial therapy (89%). The most frequent adverse events (AEs) were cough (74%), headache (44%), and nausea (30%), and five patients prematurely discontinued study drug due to AE (n = 3), disease progression (n = 1), or death (n = 1). At week 12, the time spent on daily treatment activities was reduced compared to baseline, with a mean total savings of 1.4 h per day. Improvements were also observed at week 12 for 6-min walk distance (+16.0; P < 0.001), N-terminal pro-B-type natriuretic peptide (−74 pg/mL; P = 0.001), and the Cambridge Pulmonary Hypertension Outcome Review (all domains P < 0.001).ConclusionsPulmonary arterial hypertension patients can be safely transitioned from inhaled iloprost to inhaled treprostinil while maintaining clinical status.