Contemporary risk scores predict clinical worsening in pulmonary arterial hypertension - An analysis of FREEDOM-EV.

Background: Risk scores integrate clinical variables emphasizing symptoms, exercise capacity, and measures of cardiac strain to predict clinical outcome better than any single value in pulmonary arterial hypertension (PAH). Risk scores have demonstrated prognostic utility for outcomes in registries, and recent studies have suggested that they are also therapy-responsive in controlled trials.

Methods: FREEDOM-EV, a global, placebo-controlled, event-driven study, randomized 690 PAH participants 1:1 to oral treprostinil (TRE) or placebo.

Real-world dosing characteristics and utilization of parenteral treprostinil in the outpatient setting.

Real-world dosing and titration of parenteral (subcutaneous, SC; intravenous, IV) prostacyclin, a mainstay of pulmonary arterial hypertension (PAH) treatment, is not always consistent with prescribing information or randomized trials and has yet to be adequately characterized. The current study describes real-world outpatient dosing and titration patterns over time, in PAH patients initiated on SC or IV treprostinil. A longitudinal, cross-sectional analysis of medication shipment records from US specialty pharmacy services between 2009 and 2018 was conducted to determine dosing and titration patterns of SC or IV treprostinil in the outpatient setting beginning with the patient's first shipment.

Survival and drug persistence in patients receiving inhaled treprostinil at doses greater than 54 µg (nine breaths) four times daily.

Treprostinil is a prostacyclin approved for the treatment of pulmonary arterial hypertension. Commercial data sets indicate that approximately 20-25% of patients are prescribed a higher dose than the maximum recommended dosage of nine breaths per treatment session (bps) (54 μg), four times a day (QID) and numerous studies have demonstrated the safety of doses >9 bps QID. This phase 4, retrospective analysis of specialty pharmacy records assessed the effects of inhaled treprostinil at doses >9 bps QID.

Development of the Pulmonary Hypertension Functional Classification Self-Report: a patient version adapted from the World Health Organization Functional Classification measure.

Background: Pulmonary arterial hypertension (PAH) is characterized by progressive limitations on physical activity, right heart failure, and premature death. The World Health Organization functional classification (WHO-FC) is a clinician-rated assessment used widely to assess PAH severity and functioning, but no equivalent patient-reported version of PAH symptoms and activity limitations exists. We developed a version of the WHO-FC for self-completion by patients: the Pulmonary Hypertension Functional Classification Self-Report (PH-FC-SR).

Inhaled treprostinil and forced vital capacity in patients with interstitial lung disease and associated pulmonary hypertension: a post-hoc analysis of the INCREASE study.

Background: INCREASE was a randomised, placebo-controlled, phase 3 trial that evaluated inhaled treprostinil in patients with interstitial lung disease (ILD) and associated pulmonary hypertension. Treprostinil improved exercise capacity from baseline to week 16, assessed with the use of a 6-min walk test, compared with placebo. Improvements in forced vital capacity (FVC) were also reported.

Pulmonary hypertension due to interstitial lung disease or chronic obstructive pulmonary disease: a patient experience study of symptoms and their impact on quality of life.

Pulmonary hypertension resulting from chronic lung disease such as chronic obstructive pulmonary disease and interstitial lung disease is categorized by the World Health Organization as Group 3 pulmonary hypertension. To identify the symptoms and impacts of World Health Organization Group 3 pulmonary hypertension and to capture data related to the patient experience of this disease, qualitative research interviews were undertaken with 3 clinical experts and 14 individuals with pulmonary hypertension secondary to chronic obstructive pulmonary disease or interstitial lung disease. Shortness of breath, fatigue, cough, and swelling were the most frequently reported symptoms of pulmonary hypertension due to chronic obstructive pulmonary disease or interstitial lung disease, and shortness of breath was further identified as the single most bothersome symptom for most patients (71.

Combination Therapy in Pulmonary Arterial Hypertension-Targeting the Nitric Oxide and Prostacyclin Pathways.

Pulmonary arterial hypertension (PAH) is a chronic and progressive disorder characterized by vascular remodeling of the small pulmonary arteries, resulting in elevated pulmonary vascular resistance and ultimately, right ventricular failure. Expanded understanding of PAH pathophysiology as it pertains to the nitric oxide (NO), prostacyclin (prostaglandin I) (PGI) and endothelin-1 pathways has led to recent advancements in targeted drug development and substantial improvements in morbidity and mortality. There are currently several classes of drugs available to target these pathways including phosphodiesterase-5 inhibitors (PDE5i), soluble guanylate cyclase (sGC) stimulators, prostacyclin class agents and endothelin receptor antagonists (ERAs).

Impact of inhaled treprostinil on risk stratification with noninvasive parameters: a post hoc analysis of the TRIUMPH and BEAT studies.

The 2015 European Society of Cardiology/European Respiratory Society treatment guidelines recommend frequent risk assessment in pulmonary arterial hypertension utilizing risk variables. Our objectives were: (1) to investigate the impact of inhaled treprostinil on risk stratification using the French noninvasive approach and REVEAL 2.0, and (2) to analyze the prognostic utility of both risk stratification methods in the predominantly New York Heart Association/World Health Organization functional class III/IV cohorts of TRIUMPH and BEAT.

Novel dose-response analyses of treprostinil in pulmonary arterial hypertension and its effects on six-minute walk distance and hospitalizations.

Treprostinil is a prostacyclin analogue approved for the treatment of pulmonary arterial hypertension. Apart from the inhaled formulation, there is neither a target dose nor a ceiling dose to guide clinicians using treprostinil; doses are individualized for each patient based upon tolerability and clinical improvement. Using combined data from the pivotal subcutaneous and oral treprostinil studies, we evaluated the effect of treprostinil dose on hospitalization and exercise capacity to better define the treprostinil dose-response relationship.

Correction to: Medication Adherence and Healthcare Costs Among Patients with Pulmonary Arterial Hypertension Treated with Oral Prostacyclins: A Retrospective Cohort Study.

Changes within text are indicated in bold.

Implantable system for treprostinil: a real-world patient experience study.

Parenteral prostanoids are effective for improving outcomes in patients with pulmonary arterial hypertension. However, subcutaneous or intravenous delivery via an external pump places a significant burden on patients. Consequently, the Implantable System for Remodulin© (treprostinil) was developed and is associated with a low rate of complications (United Therapeutics (Research Triangle Park, NC) in collaboration with Medtronic, Inc.

Medication Adherence and Healthcare Costs Among Patients with Pulmonary Arterial Hypertension Treated with Oral Prostacyclins: A Retrospective Cohort Study.

Background: Given the improved convenience of oral prostacyclins, there is a shift toward their use in treating pulmonary arterial hypertension (PAH).

Objectives: Our objective was to compare patient characteristics, medication adherence, healthcare resource use (HCRU), and costs among patients receiving oral treprostinil or selexipag.

Methods: We used Truven Health MarketScan Commercial and Medicare databases to identify patients with PAH with a diagnosis code for pulmonary hypertension (PH) plus a prescription for oral treprostinil or selexipag from July 2013 to September 2017.

Bronchodilation induced by PGE is impaired in Group III pulmonary hypertension.

Background And Purpose: In patients with pulmonary hypertension (PH) associated with lung disease and/or hypoxia (Group III), decreased pulmonary vascular tone and tissue hypoxia is therapeutically beneficial. PGE and PGI induce potent relaxation of human bronchi from non-PH (control) patients via EP and IP receptors, respectively. However, the effects of PGE /PGI and their mimetics on human bronchi from PH patients are unknown.

Identifying Patients with Pulmonary Arterial Hypertension Using Administrative Claims Algorithms.

Retrospective administrative claims database studies provide real-world evidence about treatment patterns, healthcare resource use, and costs for patients and are increasingly used to inform policy-making, drug formulary, and regulatory decisions. However, there is no standard methodology to identify patients with pulmonary arterial hypertension (PAH) from administrative claims data. Given the number of approved drugs now available for patients with PAH, the cost of PAH treatments, and the significant healthcare resource use associated with the care of patients with PAH, there is a considerable need to develop an evidence-based and systematic approach to accurately identify these patients in claims databases.

Dosing characteristics of oral treprostinil in real-world clinical practice.

Pharmacokinetic studies with oral treprostinil demonstrate that three times daily (TID) dosing reduces peak-to-trough plasma trepostinil fluctuations compared with twice daily (BID) dosing. TID dosing may allow for faster titration, higher total daily doses, and potentially improve the tolerability of oral trepostinil. This analysis, which looks at the real-world dosing of oral treprostinil, supports the utility of TID dosing.

The impact of delayed treatment on 6-minute walk distance test in patients with pulmonary arterial hypertension: A meta-analysis.

Background: The impact of treatment delay in stable patients with pulmonary arterial hypertension (PAH) remains unaddressed.

Methods: This meta-analysis included six datasets of PAH therapies with randomized-controlled trials (RCT) and corresponding open-label extension (OLE) studies. We evaluated the change in 6MWD at 1year in the OLE studies by active treatment versus ex-placebo group.

A Comprehensive Review of Treprostinil Pharmacokinetics via Four Routes of Administration.

Treprostinil is available in three different formulations and four different routes of administration: Remodulin (treprostinil sodium, intravenous and subcutaneous administration), Tyvaso (treprostinil sodium, inhaled administration), and Orenitram (treprostinil diolamine, oral administration) for the treatment of pulmonary arterial hypertension (PAH). Pharmacokinetic studies have been performed in healthy volunteers and patients with PAH. The intent of this review is to outline pharmacokinetic considerations of the three treprostinil formulations and provide clinicians with a resource that may support clinical decisions in treating patients with PAH.

Consistency of return to normal function, productivity, and satisfaction following migraine attacks treated with sumatriptan/naproxen sodium combination.

Objectives: To assess the consistency of improved functioning, productivity, and medication satisfaction in migraines treated with a single tablet of sumatriptan 85 mg/naproxen sodium 500 mg (S/NS) using an early intervention approach.

Methods: Two randomized, double-blind, placebo-controlled, 4-period crossover, multi-attack, multi-center, outpatient studies of moderate to severe adult migraineurs were conducted to compare S/NS with placebo. Participants recorded outcome assessments in a diary during the 24 hours following study medication.

Treatment satisfaction is associated with improved quality of life in patients treated with inhaled treprostinil for pulmonary arterial hypertension.

Background: Patient treatment satisfaction is likely to be a highly relevant outcome measure in pulmonary arterial hypertension (PAH), a condition for which the benefits of treatment must be weighed against frequent, undesirable side effects, inconvenience, and complications associated with therapy. In this study, we sought to evaluate the psychometric properties of a patient-reported treatment satisfaction measure and its relationship to quality of life (QoL) among patients transitioning from inhaled iloprost (iILO) to inhaled treprostinil (iTRE).

Methods: We studied treatment satisfaction among 66 subjects with PAH in a single-arm, open-label, multi-center trial of iTRE following transition from iILO.

Rapid transition from inhaled iloprost to inhaled treprostinil in patients with pulmonary arterial hypertension.

Background: Inhaled 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.

Aims: In 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.

High-resolution HLA genotyping and severe cutaneous adverse reactions in lamotrigine-treated patients.

Background: Severe cutaneous adverse reactions (SCARs) are associated with over 200 medicines including lamotrigine, an antiepileptic drug. Previous studies have suggested the involvement of immune mechanisms in the development of drug-induced SCARs.

Methods: High-resolution HLA genotyping was performed for 65 patients of European ancestry treated with lamotrigine (22 cases with lamotrigine-induced SCARs and 43 controls on lamotrigine without SCAR-related symptoms).

Medullary pain facilitating neurons mediate allodynia in headache-related pain.

Objective: To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia.

Methods: Inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas, and sensory thresholds of the face and hind-paws were characterized.

The influence of CYP3A5 genotype on dexamethasone induction of CYP3A activity in African Americans.

The CYP3A5(*)1 allele has been associated with differences in the metabolism of some CYP3A substrates. CYP3A5 polymorphism may also influence susceptibility for certain drug interactions. We have previously noted a correlation between basal CYP3A activity and the inductive effects of dexamethasone using the erythromycin breath test (ERBT).

Gastric stasis occurs in spontaneous, visually induced, and interictal migraine.

Objective: To evaluate and compare gastric motility and emptying during spontaneous migraine to previous observations from induced migraine.

Background: We have previously demonstrated a delay in gastric emptying both during the interictal period and during an induced migraine. A limitation noted in these studies was whether there are differences gastrointestinally during a visually induced migraine compared to spontaneous migraines.

Enhanced aqueous dissolution of a poorly water soluble drug by novel particle engineering technology: spray-freezing into liquid with atmospheric freeze-drying.

Purpose: The purpose of this work was to investigate spray-freezing into liquid (SFL) and atmospheric freeze-drying (ATMFD) as industrial processes for producing micronized SFL powders with enhanced aqueous dissolution. Micronized SFL powders dried by ATMFD were compared with vacuum freeze-dried SFL powders.

Method: Danazol was formulated with polyvinyl alcohol (MW 22,000), polyvinylpyrrolidone K-15, and poloxamer 407 to produce micronized SFL powders that were freeze-dried under vacuum or dried by ATMFD.