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Background and aimsTreprostinil is a prostacyclin analog used to treat pulmonary arterial hypertension. Dosing is empiric and based on tolerability. Adverse effects are common and can affect treatment persistence. Pharmacogenomic variants that may affect treprostinil metabolism and transport have not been well-characterized. We aimed to investigate the pharmacogenomic sources of variability in treatment persistence and dosing.MethodsPatients were prospectively recruited from an IRB approved biobank registry at a single pulmonary hypertension center. A cohort of patients who received oral treprostinil were screened for participation. Pharmacogenomic analysis was for variants in CYP2C8, CYP2C9, and ABCC4. A retrospective review was conducted for demographics, clinical status, dosing, and response. Fisher's exact test was used for categorical data and Kruskal-Wallis test or Wilcoxon rank sum were used for continuous data.ResultsA total of 15 patients received oral treprostinil and were consented. Their median age was 53 years, 73% were female, and 93% were White. The median total daily dose was 22.5 mg (13.5, 41) at last clinical observation. 40% of patients discontinued treatment with a majority due to adverse effects. Approximately 27% of patients had a loss-of-function variant in CYP2C8 (*1/*3 or *1/*4), whereas 47% of patients had a loss-of-function variant in CYP2C9 (*1/*2, *1/*3, or *2/*2). Minor allele frequencies for ABCC4 (rs1751034 and rs3742106) were 0.17 and 0.43, respectively. Survival analysis showed that increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation [hazard ratio (HR): 0.13; 95% confidence interval (CI): 0.02, 0.91; p = 0.04]. Genetic variants were not significantly associated with dosing.ConclusionGenetic variants responsible for the metabolism and transport of oral treprostinil were common. Increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation. However, dosing

Background and aimsTreprostinil is a prostacyclin analog used to treat pulmonary arterial hypertension. Dosing is empiric and based on tolerability. Adverse effects are common and can affect treatment persistence. Pharmacogenomic variants that may affect treprostinil metabolism and transport have not been well-characterized. We aimed to investigate the pharmacogenomic sources of variability in treatment persistence and dosing.MethodsPatients were prospectively recruited from an IRB approved biobank registry at a single pulmonary hypertension center. A cohort of patients who received oral treprostinil were screened for participation. Pharmacogenomic analysis was for variants in CYP2C8, CYP2C9, and ABCC4. A retrospective review was conducted for demographics, clinical status, dosing, and response. Fisher's exact test was used for categorical data and Kruskal-Wallis test or Wilcoxon rank sum were used for continuous data.ResultsA total of 15 patients received oral treprostinil and were consented. Their median age was 53 years, 73% were female, and 93% were White. The median total daily dose was 22.5 mg (13.5, 41) at last clinical observation. 40% of patients discontinued treatment with a majority due to adverse effects. Approximately 27% of patients had a loss-of-function variant in CYP2C8 (*1/*3 or *1/*4), whereas 47% of patients had a loss-of-function variant in CYP2C9 (*1/*2, *1/*3, or *2/*2). Minor allele frequencies for ABCC4 (rs1751034 and rs3742106) were 0.17 and 0.43, respectively. Survival analysis showed that increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation [hazard ratio (HR): 0.13; 95% confidence interval (CI): 0.02, 0.91; p = 0.04]. Genetic variants were not significantly associated with dosing.ConclusionGenetic variants responsible for the metabolism and transport of oral treprostinil were common. Increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation. However, dosing

ObjectivePulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle.ConclusionsOur data suggest a potential u

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.

Background: PH (Pulmonary Hypertension) is a low-prevalence disease (15 cases per 1 million inhabitants), but is nevertheless a serious process with high mortality. Treprostinil is a new drug for the PH treatment, it is a prostacyclin with a half-life of 2-3 hours, which permits subcutaneous administration with rapid absorption and 100% bioavailability. The issue with treprostini is the high rate of drop-outs due to pain at the injection site. Aims: to reduce the rate of drop-outs due to pain at the injection site with the use of Treprostinil Methods: we searches in PubMed and Tripdatabase, fore terms, "capsaicin", "qutenza", "treprostinil", and "pulmonary hypertension", finding no related publication. The treatment with capsaicin 8% patch, was performed for one hour, according to the protocol, the peri-umbilical abdominal area (injection site) was delimited and the patch administered for one hour. Results: erythema at the administration site was subsequently observed, albeit with no further incidents. Good treatment tolerance and discharge. In the control after 1 month, the patient reported changing the injection site to the treated area with a very striking reduction in pain (VAS 2-3) that enabled him to lead a normal life. The patient's satisfaction is very high, and he requires no coadjuvant or rescue treatment. At the 3-month control, the patient continues with the same level of analgesia Conclusions: capsaicin 8% patch could be a valid alternative to be considered in the analgesic control of patients on treatment with subcutaneous treprostinil., Introducción: la HP (hipertensión pulmonar) es una enfermedad poco prevalente (15 casos por 1 millón de habitantes), pero se trata de un proceso grave con una mortalidad muy elevada. El tratamiento se hace con treprostinil administrado por vía subcutánea. El principal efecto secundario que presenta es dolor e inflamación en el punto de infusión, obligando en muchos casos a la retirada del tratamiento. Presentamos un caso clínico de un paciente de 46 años diagnosticado de hipertensión pulmonar secundaria a VIH, que acude en tratamiento con treprostinil subcutáneo y que refirió intenso dolor en la zona de punción (zona abdominal periumbilical) los primeros días (4-5) de la infusión, con una intensidad muy severa (VAS 9-10) que le obligó a estar encamado. Planteamos la posibilidad de tratamiento con parche de capsaicina 8% (Qutenza®) de forma experimental, indicando al paciente su uso fuera de ficha técnica (off-label) y firmando el consentimiento informado. Se realiza tratamiento previo durante una hora con crema EMLA, según protocolo, se delimita la zona abdominal periumbilical (lugar de punción) y se administra parche durante una hora. Se observa posteriormente eritema en la zona de administración, sin más incidencia. Buena tolerancia del tratamiento y alta a domicilio. No existen publicaciones actualmente que hayan estudiado el uso de parche de capsaicina para tratar el dolor relacionado con la infusión de treprostinil s.c., por ello consideramos relevante la experiencia de este caso clínico. De este modo, creemos que, aunque pendiente de la validación por ensayos clínicos, el tratamiento con parches de capsaicina 8% (Qutenza®) podría ser una alternativa válida a tener en cuenta en el control analgésico de los pacientes en tratamiento con treprostinil s.c., logrando de este modo la adherencia a dicho tratamiento y que más pacientes puedan beneficiarse de teprsotinil para el tratamiento de la HP.

Background: PH (Pulmonary Hypertension) is a low-prevalence disease (15 cases per 1 million inhabitants), but is nevertheless a serious process with high mortality. Treprostinil is a new drug for the PH treatment, it is a prostacyclin with a half-life of 2-3 hours, which permits subcutaneous administration with rapid absorption and 100% bioavailability. The issue with treprostini is the high rate of drop-outs due to pain at the injection site. Aims: to reduce the rate of drop-outs due to pain at the injection site with the use of Treprostinil Methods: we searches in PubMed and Tripdatabase, fore terms, "capsaicin", "qutenza", "treprostinil", and "pulmonary hypertension", finding no related publication. The treatment with capsaicin 8% patch, was performed for one hour, according to the protocol, the peri-umbilical abdominal area (injection site) was delimited and the patch administered for one hour. Results: erythema at the administration site was subsequently observed, albeit with no further incidents. Good treatment tolerance and discharge. In the control after 1 month, the patient reported changing the injection site to the treated area with a very striking reduction in pain (VAS 2-3) that enabled him to lead a normal life. The patient's satisfaction is very high, and he requires no coadjuvant or rescue treatment. At the 3-month control, the patient continues with the same level of analgesia Conclusions: capsaicin 8% patch could be a valid alternative to be considered in the analgesic control of patients on treatment with subcutaneous treprostinil., Introducción: la HP (hipertensión pulmonar) es una enfermedad poco prevalente (15 casos por 1 millón de habitantes), pero se trata de un proceso grave con una mortalidad muy elevada. El tratamiento se hace con treprostinil administrado por vía subcutánea. El principal efecto secundario que presenta es dolor e inflamación en el punto de infusión, obligando en muchos casos a la retirada del tratamiento. Presentamos un caso clínico de un paciente de 46 años diagnosticado de hipertensión pulmonar secundaria a VIH, que acude en tratamiento con treprostinil subcutáneo y que refirió intenso dolor en la zona de punción (zona abdominal periumbilical) los primeros días (4-5) de la infusión, con una intensidad muy severa (VAS 9-10) que le obligó a estar encamado. Planteamos la posibilidad de tratamiento con parche de capsaicina 8% (Qutenza®) de forma experimental, indicando al paciente su uso fuera de ficha técnica (off-label) y firmando el consentimiento informado. Se realiza tratamiento previo durante una hora con crema EMLA, según protocolo, se delimita la zona abdominal periumbilical (lugar de punción) y se administra parche durante una hora. Se observa posteriormente eritema en la zona de administración, sin más incidencia. Buena tolerancia del tratamiento y alta a domicilio. No existen publicaciones actualmente que hayan estudiado el uso de parche de capsaicina para tratar el dolor relacionado con la infusión de treprostinil s.c., por ello consideramos relevante la experiencia de este caso clínico. De este modo, creemos que, aunque pendiente de la validación por ensayos clínicos, el tratamiento con parches de capsaicina 8% (Qutenza®) podría ser una alternativa válida a tener en cuenta en el control analgésico de los pacientes en tratamiento con treprostinil s.c., logrando de este modo la adherencia a dicho tratamiento y que más pacientes puedan beneficiarse de teprsotinil para el tratamiento de la HP.

Pulmonary arterial hypertension (PAH) is a rare but serious condition, which if untreated, is associated with a 2-3-year median survival time. A number of treatment options are available for PAH, leading to improvements in exercise capacity, symptoms, and hemodynamics. However, the disease remains incurable and most patients will ultimately progress to right heart failure and death. Three classes of drugs are currently available to improve PAH outcomes, although this review will focus solely on a class of potent vasodilators known as prostacyclins. Currently, four prostacyclin analogs are licensed for the treatment of PAH: epoprostenol, treprostinil, and iloprost in the USA and some European countries, and beraprost in Japan and Korea. Prostacyclins have become the treatment of choice in patients with severe PAH, but there is also evidence to suggest that their earlier use may also benefit patients with mild-to-moderate disease. This review discusses the advantages of prostacyclins in terms of their usefulness in patients whose condition has deteriorated following monotherapy with other agents, and their integral role in combination therapy. The latter appears to offer the potential for pulmonary vasculature remodeling and could be regarded as an emerging paradigm to treat and prevent the progression of PAH., Journal Article, Research Support, Non-U.S. Gov't, Review, SCOPUS: re.j, info:eu-repo/semantics/published

Pulmonary arterial hypertension (PAH) is a rare but serious condition, which if untreated, is associated with a 2-3-year median survival time. A number of treatment options are available for PAH, leading to improvements in exercise capacity, symptoms, and hemodynamics. However, the disease remains incurable and most patients will ultimately progress to right heart failure and death. Three classes of drugs are currently available to improve PAH outcomes, although this review will focus solely on a class of potent vasodilators known as prostacyclins. Currently, four prostacyclin analogs are licensed for the treatment of PAH: epoprostenol, treprostinil, and iloprost in the USA and some European countries, and beraprost in Japan and Korea. Prostacyclins have become the treatment of choice in patients with severe PAH, but there is also evidence to suggest that their earlier use may also benefit patients with mild-to-moderate disease. This review discusses the advantages of prostacyclins in terms of their usefulness in patients whose condition has deteriorated following monotherapy with other agents, and their integral role in combination therapy. The latter appears to offer the potential for pulmonary vasculature remodeling and could be regarded as an emerging paradigm to treat and prevent the progression of PAH., Journal Article, Research Support, Non-U.S. Gov't, Review, SCOPUS: re.j, info:eu-repo/semantics/published

SCOPUS: re.j, info:eu-repo/semantics/published

SCOPUS: re.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

Treprostinil (Remodulin, United Therapeutics) is a stable, long-acting prostacyclin analog, which has been shown to improve clinical state, functional class, exercise capacity and quality of life in patients with pulmonary arterial hypertension, an uncommon disease with poor prognosis. The drug is administered as a continuous subcutaneous infusion using a portable miniature delivery system. Side effects include facial flush, headache, jaw pain, abdominal cramping and diarrhea. These are all typical of prostacyclin impregnation and manageable by symptom-directed dose adjustments. Infusion site pain, a more serious side effect, may limit the treatment in 10% of patients. Otherwise, treprostinil has an excellent safety profile and compares favorably with reference continuous intravenous epoprostenol (Flolan, GlaxoSmithKline) therapy. Treprostinil has a place in currently proposed treatment algorithms of pulmonary arterial hypertension., SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published