Quantification of ambrisentan in human plasma by LC-MS/MS and its pharmacokinetic application / 中国临床药理学与治疗学

AIM: To establish an LC-MS/MS method to determine the concentration of ambrisentan in human plasma and apply it to the study of human pharmacokinetics. METHODS: After extracting ambrisentan and internal standard from human plasma by liquid-liquid extraction, chromatographic separation was performed on a Waters Symmetry C

Uso de treprostinil sistémico en una paciente con hipertensión pulmonar grave, sin respuesta a la máxima terapia disponible / Use of treprostinil in a patient with a severe pulmonary arterial hypertension no responding to the maximal therapy available

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.

Synthesis of (+)-ambrisentan / 中国药科大学学报

A five-step synthetic method of ambrisentan starting from benzophenone was developed.The reaction methods of resolution and substitution were optimized.A stable,facilitating method of detection and efficient resolution reagent,L-phenylglycinamide,was used and helped to obtain highly optical pure intermediates.In the substitution reaction,NaOH was chosen as the base,which is safe and suitable for the industry.This method was mild,easily operated with a total yield up to 31.0％,and may have a good application prospect.

Identification of reIated substances in ambrisentan by LC-MS MS techniques / 中国药科大学学报

An LC-TOF /MS and LC-MS /MS method was established for the identification the related substances in ambrisentan.HPLC separation was carried out on an XBridge C18 column(4.6 mm ×150 mm,3.5 μm)with linear gradient elution using a mobile phase consists of acetonitrile,water and 0.15% formic acid.The structures of the related substances were identified by electrospray positive ESI high resolution TOF /MS and MS /MS spec-tra,and verified further through reference substances.Ambrisentan and its related substances can be separated under the established HPLC conditions.Ten related substances were detected and identified.The established method is useful for the identification of related substances in ambrisentan.The results obtained are valuable for its manufacturing process optimization and quality control.

Determination of Ambrisentan Reference Substance by 1 H-Nuclear Magnetic Resonance Spectroscopy / 中国药师

Objective:To develop a method for the quantitative determination of ambrisentan. Methods: 1 H NMR spectra were obtalned with a Bruker AscendTM 400 superconducting NMR spectrometer. For each sample, DMSO-D6 was used as the solvent, the pulse width was 10. 0 μs, the delay time was 5 s and the scanning time was 16. Results: The proton peaks of ambrisentan at δ6. 16 ppm and maleic acid atδ6. 28 ppm were used as the quantitative peaks. The linear regression equation of peak area and quality ratio was Y=0. 140 7X+0. 034 8 with the correlation coefficient of 0. 999 4. RSD was 0. 2%(n=6)in the repeated experiments. The absolute content of ambrisentan reference substance was 99. 9%. Conclusion: The results showed that 1 H NMR can be used in the quantitative determination of ambrisentan without reference substance. The method is reliable, rapid, accurate and simple.

RP-HPLC assay method for related substances of ambrisentan tablets / 中国药学杂志

OBJECTIVE: To establish an HPLC method for determination of the related substances of ambrisentan tablets. METHODS: Gradient elution was performed on an Agela Venusil MP C18 column (4.6 mm × 250 mm, 5 μm). The mixture of 0.02 mol · L-1 phosphate buffer (pH 3.0) and acetonitrile (62:38) was used as mobile phase A, and acetonitrile as mobile phase B. The flow rate was 1.0 mL · min-1; the detection wavelength was set at 220 nm; and the column temperature was maintained at 35℃. RESULTS: After being treated with acid, base, heat, and oxidation, ambrisentan underwent more or less degradation. The method could effectively detect the degradation products of ambrisentan; the separation of impurities was good; the method had good specificity, linearity, and durability. CONCLUSION: The proposed method can be used to separate and determine the related substances of ambrisentan tablets, and is suitable for the quality control of this drug.

Therapeutic effect and safety of ambrisentan on Eisenmenger syndrome / 心血管康复医学杂志

Objective:To observe therapeutic effect of ambrisentan on Eisenmenger syndrome (ES) .Methods:A total of 79 ES patients ,who hospitalized in Wuhan Asia Heart Hospital from Apr 2011 to Mar 2014 ,were divided into ambrisentan group (n=38 ,received digoxin combined ambrisentan treatment) and routine treatment group (n=41 , received digoxin treatment) ,and both groups were treated for 12 weeks .The 6min walking distance (6MWD) , WHO functional class (WHO FC) of pulmonary hypertension etc .were observed in both groups before and 12-week after treatment .Changes of hemodynamic parameters ,including mean pulmonary artery pressure (mPAP) ,total pulmonary resistance (TPR) and ratio of pulmonary circulating flow to system circulating flow (Qp/Qs) etc .,were observed in ambrisentan group before and after treatment . Results:Compared with before treatment , after 12 weeks ,6MWD significantly rose ,TPR significantly reduced ,Qp/Qs significantly increased and WHO FC signifi-cantly improved in ambrisentan group ,P<0.05 or <0.01. Compared with routine treatment group after 12 weeks , there was significant rise in 6MWD [ (356.8 ± 74.1) m vs .(393.7 ± 69.2) m] ,significant reduction in BNP level [(832.5 ± 422.2) ng/L vs .(646.6 ± 297.1) ng/L] and significant improvement in WHO FC (class I/II ,67.5% vs . 86.8% ) in ambrisentan group ,P<0.05 or <0.01. No patient died ,the adverse reactions were mild in ambrisentan group ;one case died in routine treatment group .Conclusion:Oral ambrisentan can significantly improve heart func-tion and exercise capacity in patients with Eisenmenger syndrome ,and it possesses good safety and tolerance .

Antagonistas de los receptores de la endotelina para la hipertensión arterial pulmonar / Endothelin receptor antagonists for pulmonary arterial hypertension / Antagonistas dos receptores de endotelina para a hipertensão arterial pulmonar

La hipertensión arterial pulmonar (HAP) es consecuencia de una alteración aguda o crónica de la vasculatura pulmonar, que se caracteriza por el aumento de la presión arterial pulmonar como consecuencia del aumento de la resistencia vascular pulmonar. La fisiopatología de la HAP se caracteriza por la vasoconstricción pulmonar vascular, la proliferación de células musculares lisas, y la trombosis. Estos cambios son el resultado de un desequilibrio entre agentes vasodilatadores (prostaciclina, óxido nítrico, péptido intestinal vaso activo) y vasoconstrictores (tromboxano A2, endotelina, serotonina), los inhibidores de factores de crecimiento y mitógenos, y factores antitrombóticos y protrombóticos. Los recientes avances en el tratamiento están dirigidos a restablecer el equilibrio entre estos sistemas. Los antagonistas de los receptores de endotelina (bosentán, ambrisentán), inhibidores de la fosfodiesterasa tipo 5 (sildenafilo, tadalafilo), y prostaciclina (epoprostenol, iloprost, treprostinil, beraprost) representan las diferentes clases de medicamentos que se utilizan actualmente en monoterapia y en combinación para el tratamiento de la HAP. El propósito de esta revisión es proporcionar al lector una actualización del tratamiento de la HAP con antagonistas de los receptores de la endotelina.

Pulmonary arterial hypertension (PAH) is a consequence of acute or chronic disorder of the pulmonary vasculature, which is characterized by increased pulmonary artery pressure as a result of increased pulmonary vascular resistance. The pathophysiology of PAH is characterized by pulmonary vascular vasoconstriction, smooth muscle cell proliferation, and thrombosis. These changes are a result of an imbalance between vasodilators (prostacyclin, nitric oxide, vasoactive intestinal peptide) and vasoconstrictors (thromboxane A2, endothelin, serotonin), growth inhibitors and mitogenic factors, and antithrombotic and prothrombotic factors. Recent advances in treatment are directed at restoring the balance between these systems. Endothelin receptor antagonists (bosentan, ambrisentan), phosphodiesterase type 5 inhibitors (sildenafil, tadalafil), and prostacylin (epoprostenol, iloprost, treprostinil, beraprost) represent the different classes of medications that are currently used in monotherapy and in combination to treat PAH. The purpose of this review is to provide the reader with an update on the treatment of PAH with antagonists of endothelin receptors.

A hipertensão arterial pulmonar (HAP) é uma consequência da doença aguda ou crônica da vasculatura pulmonar, o que é caracterizado pelo aumento da pressão da artéria pulmonar, como um resultado da resistência vascular pulmonar aumentada. A fisiopatologia de HAP é caracterizada pela vasoconstrição pulmonar vascular, proliferação de células de músculo liso, e trombose. Estas alterações são um resultado de um desequilíbrio entre os vasodilatadores (prostaciclina, o óxido nítrico, o péptido intestinal vasoativo) e vasoconstritores (tromboxano A2, endotelina, serotonina), e inibidores de crescimento de fatores miogênicos, e fatores antitrombóticos e pró-trombóticos. Avanços recentes no tratamento são dirigidos para o restabelecimento do equilíbrio entre estes sistemas. Antagonistas do receptor da endotelina (bosentan, ambrisentan), inibidores da fosfodiesterasa tipo 5 (sildenafilo, tadalafilo) e prostaciclina (epoprostenol, iloprost, treprostinil, beraprost) representam as diferentes classes de medicamentos que são usados atualmente em monoterapia e em combinação para tratar HAP. O objetivo desta revisão é fornecer ao leitor uma atualização sobre o tratamento da HAP com os antagonistas dos receptores de endotelina.

Syncope Caused by Portopulmonary Hypertension : A Case Report / General Medicine

Syncope is a common chief complaint in emergency departments, and although causes in most patients with syncope are benign, some patients have a serious disease. Here we report a 50-year-old patient with facial trauma who had past history of alcoholic liver cirrhosis. He fell down by syncope due to portopulmonary hypertension (PPHTN) accompanied by portal hypertension. Oral ambrisentan, a potent ET_A-selective receptor, 2.5 mg once a day was initiated. His ECG and the results of cardiac catheterization showed improvement in hemodynamic abnormality after the treatment. Also, the patient had no significant symptoms, including syncope, for nine months after receiving ambrisentan.