RESUMEN
BACKGROUND: Idiopathic pulmonary arterial hypertension is associated with high morbidity and mortality. In recent years, the use of targeted therapies has led to an improvement in prognosis. Prostacyclin analogues treprostinil and epoprostenol require continuous subcutaneous or intravenous infusion and are generally administered in a stepwise approach. However, there are no clear recommendations for transition in high-risk patients requiring high doses of prostacyclin analogues. CASE SUMMARY: In this report, we describe the case of a 20-year-old woman under combined treatment with sildenafil, macitentan, and treprostinil who required transition from subcutaneous treprostinil therapy to intravenous epoprostenol due to erratic drug absorption and functional class progression. The transition was performed over 48 h in a stepwise approach reducing treprostinil dose 4 ng/kg/min every 3 h while increasing epoprostenol infusion 2 ng/kg/min until achieving a maintenance dose of 32 ng/kg/min. There were no side effects requiring changes in the infusion rate. DISCUSSION: Patients with advanced pulmonary arterial hypertension may necessitate switching from subcutaneous treprostinil to epoprostenol. Although many protocols have been used to date, there are no guidelines to direct this process safely. This 48-h scheme based on the pharmacokinetic properties of each drug was successful and well-tolerated.
RESUMEN
OBJECTIVE: Pulmonary 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. CONCLUSIONS: Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.
Asunto(s)
Epoprostenol/análogos & derivados , Insuficiencia Cardíaca/complicaciones , Hiperglucemia/tratamiento farmacológico , Hipertensión Pulmonar/tratamiento farmacológico , Metformina/uso terapéutico , Volumen Sistólico/fisiología , Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/fisiología , Animales , Antihipertensivos , Dieta Alta en Grasa , Epoprostenol/uso terapéutico , Corazón/efectos de los fármacos , Corazón/fisiopatología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Hipoglucemiantes , Resistencia a la Insulina , Masculino , Síndrome Metabólico , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/fisiopatología , Ratas , Receptores de Leptina/genéticaRESUMEN
PURPOSE: To evaluate the physical and chemical compatibilities of treprostinil sodium and dopamine hydrochloride. METHODS: Treprostinil sodium (4,000, 76,000, and 500,000 ng/mL) were mixed with dopamine hydrochloride (0.6, 3.2, 6, and 40 mg/mL). Samples were obtained at hours 0, 1, 2, and 4 for physical compatibility and chemical stability testing. Physical compatibility was assessed by visual examination and measurements of turbidity and pH. Drug concentrations were assessed using stability-indicating liquid chromatography mass spectrophotometry (LCMS) for treprostinil sodium and stability-indicating high-performance liquid chromatography (HPLC) for dopamine hydrochloride. RESULTS: Treprostinil sodium 4,000 and 76,000 ng/mL, when mixed with dopamine hydrochloride 0.6, 3.2, 6, and 40 mg/mL, were stable for 4 hours. Treprostinil sodium 500,000 ng/mL was stable when mixed with dopamine hydrochloride 0.6 mg/mL for 4 hours, but when mixed with dopamine hydrochloride 3.2, 6, and 40 mg/mL, significant precipitation was seen. CONCLUSION: Treprostinil sodium 4,000 and 76,000 ng/mL were stable for 4 hours during simulated Y-site coadministration with dopamine hydrochloride 0.6, 3.2, 6, and 40 mg/mL. Treprostinil sodium 500,000 ng/mL is stable when mixed with dopamine hydrochloride 0.6 mg/mL.
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Antihipertensivos/química , Dopaminérgicos/química , Dopamina/química , Incompatibilidad de Medicamentos , Epoprostenol/análogos & derivados , Administración Intravenosa , Epoprostenol/química , Concentración de Iones de Hidrógeno , Factores de TiempoRESUMEN
En los pacientes con Hipertensión Arterial Pulmonar (HAP) de alto riesgo, en clase funcional (CF)IV, la terapia específica debe ser combinada y debe incluir una prostaciclina (PGI2) de uso sistémico en espera de trasplante bipulmonar (TBP). En el sistema público la única PGI2 disponible para asociar a Sildenafil y algún inhibidor de endotelina (Ambrisentan o Bosentan) es Iloprost nebulizado, que si bien es efectiva, no logra estabilizar los casos graves con severa disfunción del ventrículo derecho (VD). Se presenta el primer caso en el Instituto del Tórax, centro de referencia nacional de HAP, del uso de treprostinil en una paciente de 24 años con HAP grave e indicación de TBP. Treprostinil es un análogo sintético de PGI2 de uso subcutáneo en dosis desde 1 a 40 ng/kg/min. La paciente presentaba una situación de extrema gravedad: CF IV, distancia recorrida en el test de caminata de 6 min (DRTC 6 min) < 300 m,derrame pericárdico y severa disfunción del VD con TAPSE (índice de disfunción del VD) de 13 cm/s asociado a ProBNP >2.500 pg/ml. Luego de 6 meses de hospitalización en intermedio, terapia triple (Sildenafil, Ambrisentan e Iloprost nebulizado) asociado a O2,diuréticos y milrinona, logró ser dada de alta a las 3 semanas del inicio de treprostinil, regresando al trabajo a los 2 meses y estabilizando su condición en CF III, con DRTC 6 min > 440 m, mejoría de la función del VD(TAPSE 19). El ProBNP persistió elevado, 1.491 pg/ml, indicando que su enfermedad es grave y progresiva; sin embargo, ha logrado un nivel de estabilidad clínica que le permite una adecuada vida de relación familiar y laboral.
In high risk Pulmonary Arterial Hypertension (PAH) patients with functional class (FC) IV, specific therapy must be combined and must include systemic prostacyclin (PGI2), meanwhile they are enlisted for double lung transplant (DLT). In Chilean Public Health System, nebulized Iloprost is the only PGI2 available to combine with Sildenafil and either Ambrisentan or Bosentan as endothelin receptor antagonist. This association is not enough for severe cases with right ventricular (RV) dysfunction. The first case from the National Institute of Thorax as a referral center is presented now in a 24 years-old lady treated with treprostinil. She has severe PAH with DLT indication. Treprostinil is a PGI2 analog, for subcutaneous use in a dose from 1 to 40 ng/kg/min. She was extremely sick, with FC IV, she walked < 300 m at 6 min walking test (6 MWT), presented pericardial effusion and severe RV dysfunction, with TAPSE (echocardiography index for RV dysfunction)=13 cm/s, ProBNP > 2,500 pg/ml. Six months after being at intensive care unit with triple therapy (Sildenafil, ambrisentan and nebulized Iloprost) plus oxygen, diuretics and milrinone, she was finally discharged after receiving a 3 weeks treprostinil course. She came back to work two months later and her condition was more stable: FC III, she walked > 440 m at 6MWT, with a significant improvement in RV function with TAPSE = 19. Although ProBNP decreased to 1,491pg/ml, it was still high, pointing out the progressive nature of her disease. However, she met a better clinical condition which allows her to reach a much better quality of life from a personal, familial and social point of view.
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Humanos , Femenino , Adulto Joven , Epoprostenol/análogos & derivados , Hipertensión Pulmonar/tratamiento farmacológico , Antihipertensivos/uso terapéutico , Fenilpropionatos/uso terapéutico , Piridazinas/uso terapéutico , Radiografía Torácica , Epoprostenol/uso terapéutico , Combinación de Medicamentos , Citrato de Sildenafil/uso terapéutico , Angiografía por Tomografía Computarizada , Hipertensión Pulmonar/diagnóstico por imagenRESUMEN
La hipertensión pulmonar es una complicación frecuente de la displasia broncopulmonar. A pesar de su alta incidencia, existen pocos tratamientos disponibles. El epoprostenol y el treprostinil son análogos de las prostaglandinas I2, que activan la adenilato ciclasa e incrementan el adenosín monofosfato cíclico en las células de la musculatura lisa de la arteria pulmonar y pueden resultar eficaces en el tratamiento de estos pacientes. Se presenta el caso de un prematuro de extremado bajo peso con hipertensión pulmonar secundaria a displasia broncopulmonar grave, no respondedora a óxido nítrico inhalado y sildenafilo, que fue tratado con análogos de prostaglandinas I2. En nuestro paciente, este tratamiento evidenció mejoría clínica y ecocardiográfica significativa tras varias semanas de tratamiento.
Pulmonary hypertension is a common complication of bronchopulmonary dysplasia, with a high mortality rate. Despite the high incidence of pulmonary hypertension, there are few available treatments. Epoprostenol and treprostinil are prostaglandin I2 analogs that activate adenylate cyclase and increase cyclic adenosine monophosphate in the pulmonary arterial smooth muscle cells. Therefore, they may be an effective treatment for these patients. We report the use of prostaglandin I2 analogs in an extremely low birth weight preterm baby with severe bronchopulmonary dysplasia associated with pulmonary hypertension non-responding to inhaled nitric oxide and sildenafil. In our patient this treatment resulted in remarkable clinical and echocardiographic improvement, evident after a few weeks of treatment.
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Humanos , Masculino , Recién Nacido , Displasia Broncopulmonar/complicaciones , Hipertensión Pulmonar/diagnóstico , Traqueostomía , Epoprostenol/uso terapéutico , Recien Nacido Extremadamente Prematuro , Hipertensión Pulmonar/tratamiento farmacológicoRESUMEN
Pulmonary hypertension is a common complication of bronchopulmonary dysplasia, with a high mortality rate. Despite the high incidence of pulmonary hypertension, there are few available treatments. Epoprostenol and treprostinil are prostaglandin I2 analogs that activate adenylate cyclase and increase cyclic adenosine monophosphate in the pulmonary arterial smooth muscle cells. Therefore, they may be an effective treatment for these patients. We report the use of prostaglandin I2 analogs in an extremely low birth weight preterm baby with severe bronchopulmonary dysplasia associated with pulmonary hypertension non-responding to inhaled nitric oxide and sildenafil. In our patient this treatment resulted in remarkable clinical and echocardiographic improvement, evident after a few weeks of treatment.
La hipertensión pulmonar es una complicación frecuente de la displasia broncopulmonar. A pesar de su alta incidencia, existen pocos tratamientos disponibles. El epoprostenol y el treprostinil son análogos de las prostaglandinas I2, que activan la adenilato ciclasa e incrementan el adenosín monofosfato cíclico en las células de la musculatura lisa de la arteria pulmonar y pueden resultar eficaces en el tratamiento de estos pacientes. Se presenta el caso de un prematuro de extremado bajo peso con hipertensión pulmonar secundaria a displasia broncopulmonar grave, no respondedora a óxido nítrico inhalado y sildenafilo, que fue tratado con análogos de prostaglandinas I2. En nuestro paciente, este tratamiento evidenció mejoría clínica y ecocardiográfica significativa tras varias semanas de tratamiento.
Asunto(s)
Antihipertensivos/uso terapéutico , Displasia Broncopulmonar/complicaciones , Epoprostenol/análogos & derivados , Epoprostenol/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiología , Humanos , Recien Nacido con Peso al Nacer Extremadamente Bajo , Recién Nacido , MasculinoRESUMEN
Introducción: La reducción en la variabilidad de la frecuencia cardiaca ha sido identificada como factor de riesgo en enfermedad cardiovascular, pero su descripción en hipertensión arterial pulmonar severa se desconoce. Material y métodos: Se estudiaron pacientes con hipertensión arterial pulmonar grave, 32 con hipertensión pulmonar primaria, 34 con hipertensión pulmonar secundaria a cardiopatía congénita (Eisenmenger) y 44 sujetos control sin evidencia de enfermedad. La evaluación del registro ambulatorio de la frecuencia cardiaca se realizó por métodos convencionales. El análisis espectral y la relación a baja y alta frecuencia se realizó utilizando el método de Fourier. Comparaciones entre día y noche se realizó entre los grupos. Después de conocer el perfil circadiano, 15 pacientes con hipertensión pulmonar fueron seleccionados para recibir tratamiento al azar con Treprostinil (Prostaglandina) o placebo por vía subcutánea. Posteriormente (3 meses) se analizaron nuevamente los parámetros de variabilidad de frecuencia cardiaca y de hemodinámica para conocer el impacto de dicha terapéutica. Resultados: Se detectó un estado franco de hipertonía simpática en el grupo de hipertensión pulmonar, sobre todo en los pacientes con hipertensión pulmonar primaria. El efecto de Treprostinil fue claramente asociado con disminución del tono simpático y un aumento de la capacidad física. Conclusiones: Los pacientes con hipertensión arterial pulmonar, cursan con equilibrio simpático-vagal alterado sobre todo durante el día. Hay pérdida del ritmo circadiano. Dichos trastornos pueden ser reversibles con la aplicación de treprostinil. El equilibrio simpáticovagal de la frecuencia cardiaca es un instrumento no invasivo que permite estratificar mejor al paciente con hipertensión arterial pulmonar grave.
BACKGROUND: A reduction of heart rate variability (HRV) is currently considered an independent risk factor for morbidity, mortality and severity of severalcardiac disease, however, the dynamic sympathovagal modulation on HRV during 24 hr in primary pulmonary hypertension (PPH) had not been described. METHODS: 24 hr Holter monitoring (HA) were recorded in 32 patients (mean age 34, +/-12, 90% female) with severe primary pulmonary hypertension (mean pulmonary pressure, 90:t:12 mm Hg), and in 34 patients (mean age 36 +/-14, 60% female) with Eisenmenger syndrome (ES) secondary to septal ventricular defect or atent ductus arteriosus. A control group (n=44) paired for age, gender and arterial pulmonary pressure was included. HRV time and spectral parameters (mean, SDNN, SDANN, rMSSD, PNN50, LF, HF and LF/HF ratio) were analyzed during three periods: 24 hr; day (8-22:00), night (23-07:00) and also every hour of recording at 5 min-intervals). After detection of sympatho-vagal balance 15 patients were randomized, Treprostinil (prostaglandin) was administered to 6 patients and subcutaneous placebo to 9. RESULTS: HRV frequency parameters during 24 hr HM were significantly different among groups. LF/HF (day) 5.9:1:12.5:1:1P.001 and LF/HF night) 2.8:tlvs.1.5:l:.8.034. Sympathovagal modulation on 24 hr HRV showed that heart rate circadian rhythm is clearly altered in both PPH and ES, but the sympathetic tone in PPH is higher at l 24 hr. (p < .05), after administering treprostinil a recovery of sympathovagal balance was observed CONCLUSIONS: Autonomic cardiac disturbance is clearly present in PPH and ES. The circadian rhythm of HRV is first lost due to an increase of sympathetic tone. These changes may be markers of autonomic disbalance that favor the development of arrhythmias and sudden death. The sympathovagal balance in PPH could be considered an important risk marker.