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Background and Purpose: Beraprost is a prostacyclin analogue and IP receptor agonist which is approved to treat pulmonary arterial hypertension (PAH) in Asia. The beraprost-314d isomer (esuberaprost) is one of four stereoisomers contained within the racemic mixture of beraprost. The pharmacological profile of esuberaprost is now evaluated to determine how stereoisomer separation affects its potency and mode of action in functional assays., Experimental Approach: Vascular tone was assessed using wire myography in rat and human distal pulmonary arteries (PAs) pre-contracted with U46619 (100 nM). HEK-293 cells stably expressing the human IP receptor (HEK-293-IP) and pulmonary arterial smooth muscle cells (PASMCs) derived from PAH patients were used to assess cyclic AMP (cAMP) generation and cell proliferation, respectively., Key Results: Esuberaprost relaxed rat PAs with a 5-fold greater potency compared with beraprost, and effects were strongly inhibited by RO3244794 (IP receptor antagonist) or L-NAME (NO synthase inhibitor). Esuberaprost caused EP 3 receptor-dependent vasoconstriction at high concentrations ≥ 1000 nM, but contractions were 50% lower compared to beraprost. In HEK-293-IP cells, esuberaprost was 26-fold more potent (EC 50 0.4 nM) at increasing cAMP than beraprost. In human PASMCs, esuberaprost was 40-fold more potent than beraprost at inhibiting cell proliferation (EC 50 3 nM versus 120 nM), contrasting the 5-fold potency difference for cAMP elevation. Antiproliferative effects of esuberaprost appeared more dependent on NO than on the IP receptor. In PAs from patients with pulmonary hypertension, esuberaprost, caused some relaxation whereas beraprost instead produced a weak contraction., Conclusions and Implications: Stereoisomer separation of beraprost has a significant effect on the pharmacology of the individual isomer, esuberaprost, identified in vitro as a highly potent prostanoid IP receptor agonist., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: This study was conducted to evaluate the safety and efficacy of a new more thermostable Flolan (epoprostenol) solution prepared with the reformulated pH 12.0 diluent in Japanese patients with pulmonary arterial hypertension (PAH) receiving higher doses of Flolan than those typically administered in Western countries., Methods: This open-label, single-arm study was conducted in 10 Japanese PAH patients. During the run-in period, patients were intravenously infused with Flolan (45 ng/kg/min or higher doses) solution prepared with the existing pH 10.5 diluent. The patients were then switched to a new more thermostable Flolan solution prepared with the reformulated pH 12.0 diluent and observed for a 4-week treatment period. As a primary endpoint, safety after switching to the new Flolan solution was evaluated. Secondary endpoints included hemodynamics and the necessity for dose adjustment of Flolan in these patients., Results: All 10 patients completed the study period. Observed adverse events were nausea and hepatic function abnormal in 1 patient each, and both events were mild. No patients required dose adjustment due to the change from baseline in mean pulmonary artery pressure (mPAP) measured 3 hrs after switching to Flolan solution prepared with the reformulated diluent. No major changes from baseline in mPAP, pulmonary vascular resistance, or right atrial pressure were observed at 24 hrs and at 4 weeks after switching to the Flolan solution prepared with pH 12.0 diluent. Although some patients showed increases in cardiac output (CO) from baseline at 24 hrs and 4 weeks, no patients required dose reduction as a result of an increase in CO., Conclusion: Neither safety/efficacy concerns nor any dose adjustments of Flolan after switching to a more thermostable Flolan solution prepared with the reformulated pH 12.0 diluent could be required in Japanese patients with PAH receiving higher doses of Flolan., Trial Registration: ClinicalTrials.gov Identifier: NCT02705807.

Prostaglandin I2 (PGI2) and its analogues (such as beraprost sodium, BPS) are beneficial for the treatment of pulmonary arterial hypertension (PAH). The encapsulation of BPS in nanoparticles to provide sustained release and targeting abilities would improve both the therapeutic effect of BPS on PAH and the quality of life of patients treated with this drug. BPS was encapsulated into nanoparticles prepared from a poly(lactic acid) homopolymer and monomethoxy poly(ethyleneglycol)-poly(lactide) block copolymer. The accumulation of nanoparticles in damaged pulmonary arteries was examined using fluorescence-emitting rhodamine S-encapsulated nanoparticles. The monocrotaline-induced PAH rat model and the hypoxia-induced mouse model were used to examine the pharmacological activity of BPS-encapsulated nanoparticles. A nanoparticle, named BPS-NP, was selected among various types of BPS-encapsulated nanoparticles tested; this was based on the sustained release profile in vitro and blood clearance profile in vivo. Fluorescence-emitting rhodamine S-encapsulated nanoparticles were prepared in a similar manner to that of BPS-NP, and showed accumulation and prolonged residence in monocrotaline-damaged pulmonary peripheral arteries. Intravenous administration of BPS-NP (once per week, 20μg/kg) protected against monocrotaline-induced pulmonary arterial remodeling and right ventricular hypertrophy. The extent of this protection was similar to that observed with oral administration (once per day, 100μg/kg) of BPS alone. The once per week intravenous administration of BPS-NP (20μg/kg) also exhibited an ameliorative effect on hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy. The beneficial effects of BPS-NP on PAH animal models seem to be mediated by its sustained release and tissue targeting profiles. BPS-NP may be useful for the treatment of PAH patients due to reduced dosages and frequency of BPS administration., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Treprostinil is a synthetic prostacyclin analogue with antiplatelet and vasodilatory properties. It is the only prostacyclin analogue with different options of delivery, i.e. subcutaneous, intravenous, inhaled or oral. Subcutaneous treprostinil has been shown in short- and long-term studies to improve exercise capacity, functional class, haemodynamics and survival in patients with pulmonary arterial hypertension (PAH). Pain at the infusion site has been a major drawback of subcutaneous treprostinil, hampering dose titration, and ultimately leading to increased discontinuation rates. The additional clinical interest in treprostinil as an alternative intravenous prostacyclin has developed due to its favourable properties, including longer half-life, chemical stability, the possibility of intravenous infusion without the need for ice packs, and easy drug preparation. Intravenous treprostinil improves exercise capacity, functional class and haemodynamics in patients with PAH, over the period of 12 weeks. If patients are switched to intravenous treprostinil, they usually need to double the dose to attain the same efficacy. Whether the effect of intravenous treprostinil remains clinically relevant beyond 12 weeks is not known, and a longer follow-up would be required to investigate this. Inhaled treprostinil is an efficacious treatment in PAH patients who are moderately symptomatic on background oral therapy. Oral treprostinil on top of background therapy did not lead to an improvement in 6-minute walking distance after 16 weeks of treatment.

Background: Recent studies have reported an increase in catheter-related bloodstream infections (BSIs) and gram-negative BSIs among patients with pulmonary arterial hypertension treated with IV treprostinil. One possible explanation is the neutral pH of the treprostinil diluent compared with the basic pH of epoprostenol. We hypothesized that administering IV treprostinil with epoprostenol diluent will lower the rate of gram-negative BSI., Methods: We prospectively enrolled patients treated with IV treprostinil and changed the diluent from native diluent to epoprostenol diluent. We compared the incidence of BSI and gram-negative BSI between those receiving IV treprostinil with epoprostenol diluent (n = 25) and those actively receiving IV epoprostenol (n = 61), as well as with a cohort of patients who received IV treprostinil in native diluent (n = 34). Incidence rates of BSI were expressed as a fraction of 1,000 medicine treatment days., Results: There were similar rates of BSI in those treated with treprostinil with epoprostenol diluent and those treated with epoprostenol (0.32 of 1,000 vs 0.40 of 1,000; P = .79). Also, there were similar rates of gram-negative BSI in these two cohorts (0.08 of 1,000 vs 0.20 of 1,000; P = .46). BSI rates were not statistically different between those treated with treprostinil with epoprostenol diluent and those treated with treprostinil (0.32 of 1,000 vs 0.90 of 1,000; P = .06). However, gram-negative BSIs were significantly lower in patients treated with treprostinil with epoprostenol diluent than in those treated with treprostinil (0.08 of 1,000 vs 0.71 of 1,000, respectively; P = .01)., Conclusions: Patients treated with treprostinil with epoprostenol diluent have a lower incidence of gram-negative BSI than do those treated with treprostinil and a similar rate to those treated with epoprostenol. Changing the diluent of treprostinil to epoprostenol diluent, in combination with the use of water-tight seals throughout the delivery system, appears to be an effective safety measure.

Background: The aim of this study was to evaluate the stability and microbiological properties of a formulation of epoprostenol sodium with L-arginine and sucrose excipients (epoprostenol AS)., Methods: The stability of the reconstituted solutions after storage at 5°C and 25°C, diluted solutions (3000-60,000 ng/mL) at controlled room temperature, and diluted solutions (3000-60,000 ng/mL) stored at 5°C and then at room temperature were evaluated. Solutions were prepared using sterile water for injection or sterile saline (sodium chloride 0.9%) for injection. Shelf-life was assessed by determining potency over time relative to initial potency. In this context, potency is synonymous with content. The antimicrobial activity of reconstituted (100,000 ng/mL for 0.5 mg vial, 300,000 ng/mL for 1.5 mg vial) and diluted (3000 ng/mL) epoprostenol AS was measured using an antimicrobial effectiveness test after inoculation with six species of bacteria, yeast, and mold., Results: Reconstituted epoprostenol AS was stable for up to one day's storage at 25°C or 7 days' storage at 5°C. Epoprostenol AS was stable for up to 72 hours when diluted, depending on temperature and concentration. The maximum shelf-life of the diluted solution if the reconstituted solution had been stored for up to one day at room temperature or up to 7 days at 5°C, was between 24 and 72 hours, depending on concentration. Following storage of diluted solutions at 5°C for up to 8 days, maximum shelf-life was between one and 2 days, depending on temperature and concentration. Potency was not dependent on diluents. Preservative testing confirmed no microbial growth for any of six organisms tested for at least 14 days at 5°C or 25°C for the reconstituted solution and for at least 16 days at 5°C followed by one day at 25°C for the diluted solutions., Conclusion: Epoprostenol AS has favorable thermal stability and does not support the growth of any micro-organism tested for up to 17 days. This extended stability under ambient conditions has the potential to improve convenience further for patients.

Treprostinil is a stable, long-acting prostacyclin analogue which can be administered as a continuous subcutaneous infusion using a portable miniature delivery system. Subcutaneous treprostinil has been shown in a large multicenter randomized controlled trial to improve exercise capacity, clinical state, functional class, pulmonary hemodynamics, and quality of life in patients with pulmonary arterial hypertension, an uncommon disease of poor prognosis. Side effects include facial flush, headache, jaw pain, abdominal cramping, and diarrhea, all typical of prostacyclin, and manageable by symptom-directed dose adjustments, and infusion site pain which may make further treatment impossible in 7%-10% of the patients. Long-term survival in pulmonary arterial hypertension patients treated with subcutaneous treprostinil is similar to that reported with intravenous epoprostenol. There are uncontrolled data suggesting efficacy of subcutaneous treprostinil in chronic thromboembolic pulmonary hypertension. Treprostinil can also be administered intravenously, although increased doses, up to 2-3 times those given subcutaneously, appear to be needed to obtain the same efficacy. Preliminary results of a randomized controlled trial of inhaled treprostinil on top of bosentan and sildenafil therapies have shown significance on the primary endpoint, which was exercise capacity as assessed by the distance walked in 6 minutes. Trials of oral formulations of treprostinil have been initiated.

Background: Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary vascular resistance which leads to right ventricular failure. Serotonin and the serotonin transporter play an important role in animal and human studies of PAH. We therefore hypothesized that PAH patients treated with high-affinity selective serotonin reuptake inhibitors (SSRIs) would have a reduced risk of death compared to PAH patients not treated with SSRIs., Methods: We performed a retrospective cohort study of 84 consecutive adult PAH patients who underwent initial evaluation from January 1994 to June 2002 at the Pulmonary Hypertension Center of the New York Presbyterian Hospital. Patient-time while receiving high-affinity SSRIs (K(d)<1nmol) (paroxetine, sertraline, or fluoxetine) was considered "exposed". Patient-time while receiving tricyclic, atypical, or no antidepressants was considered "unexposed"., Results: Thirteen of the 84 patients (15%) used high-affinity SSRIs during the study period. Five patients were taking high-affinity SSRIs at baseline and 8 initiated high-affinity SSRIs during the follow-up period. The median time from baseline evaluation until initiation of high-affinity SSRIs was 125 (0-1227) days. The median duration of high-affinity SSRI use was 482 (110-1624) days and the total at-risk time on high-affinity SSRIs was 18.1 person-years. Seventy-nine (94%) patients were treated with warfarin; 38 (45%) received continuous intravenous epoprostenol; 12 (14%) received continuous subcutaneous treprostinil, and 23 (27%) were treated with oral bosentan. The median follow-up was 764 days. Twenty-four patients died and one underwent lung transplantation during the study period. There were no differences in age, gender, diagnosis, hemodynamics, or incidence of acute vasoreactivity between SSRI users and non-users. The risk of death for high-affinity SSRI users was lower but not statistically significantly different from that of non-users (hazard ratio=0.53, 95% CI 0.07 to 3.9, p=0.53). Adjustment for demographics, diagnosis, hemodynamics, or other therapies did not significantly change this result., Conclusions: SSRI use was associated with a 50% reduction in the risk of death in a cohort of PAH patients which was not statistically significant. Larger cohort studies may better define this relationship; an adequately powered trial of high-affinity SSRIs in PAH patients may be warranted.

The stability of treprostinil sodium after dilution in three common i.v. infusion vehicles was assessed. The chemical stability of treprostinil sodium was tested over a 48-hour period at 40 degrees C and 75% relative humidity after dilution in each of three diluents: sterile water for injection, 0.9% sodium chloride injection, and 5% dextrose injection, and after passage through an i.v. delivery system. Chemical analysis was conducted by using a validated stability-indicating high-performance liquid chromatographic assay, visually inspecting the solutions, and measuring the pH of each solution. The preservative effectiveness of the solutions was tested by the recovery of inoculations of compendial microorganisms after 48 hours in dilute solutions of treprostinil sodium. All assay results for treprostinil were within 90.0% to 110.0% of the prepared solutions diluted at 0.004 and 0.13 mg/mL treprostinil sodium in sterile water for injection and 0.9% sodium chloride injection. The assay results were the same for dilute treprostinil solutions in 5% dextrose injection at concentrations of 0.02 and 0.13 mg/mL. The pH values for these solutions remained within acceptable values of 6.0 to 7.2 for the stability study. No change in physical appearance or any visible particulate matter was observed. Approximately 70% of metacresol, the preservative, in the dilute treprostinil sodium solutions was removed before reaching the terminal end of the tubing. None of the dilute treprostinil sodium solutions supported microbial growth in the cassette reservoirs for the organisms considered. Treprostinil sodium 0.13 mg/mL solution in sterile water for injection, 0.9% sodium chloride for injection, and 5% dextrose for injection appeared to be stable after storage in controlled ambulatory drug-delivery systems for 48 hours at 40 degrees C and 75% relative humidity. Treprostinil sodium 0.004 mg/mL in sterile water and 0.9% sodium chloride for injection and 0.02 mg/mL in 5% dextrose injection was also stable under the same conditions. None of the solutions showed signs of microbial growth.

Intravenous epoprostenol is currently FDA approved for management of primary pulmonary hypertension, but it requires intravenous infusion and is associated with adverse effects. The objective of this study was to evaluate the effects of an epoprostenol analog, treprostinil, for management of pulmonary hypertension. Ten tertiary care academic institutions with pulmonary hypertension programs participated in these pilot trials. In the first trial, intravenous epoprostenol and intravenous treprostinil were compared. In the second trial, intravenous treprostinil and subcutaneous treprostinil were compared. In the third trial, subcutaneous treprostinil was compared with placebo infusion during an 8-week period. Intravenous epoprostenol and intravenous treprostinil resulted in a similar reduction in pulmonary vascular resistance acutely (22% and 20%, respectively). Intravenous treprostinil and subcutaneous treprostinil also demonstrated comparable short-term decrease in pulmonary vascular resistance (23% and 28%, respectively). The placebo-controlled 8-week trial demonstrated a mean improvement of 37 +/- 17 m as measured by the 6-minute walk distance in patients receiving treprostinil compared with a 6 +/- 28 m reduction in those receiving placebo. There were trends toward an improvement in cardiac index and pulmonary vascular resistance index in the treprostinil group. Subcutaneous treprostinil has favorable hemodynamic effects when given acutely and in the short term. Treprostinil can be given safely to an ambulatory patient with a novel subcutaneous delivery pump system.