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NOVEDADES EN EL TRATAMIENTO DE LAS ENFERMEDADES AUTOINMUNES SISTÉMICAS Antagonistas del Receptor de la ENDOTELINA Terapias BIOLOGICAS Parte 1 Dr. Lucio.

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Presentación del tema: "NOVEDADES EN EL TRATAMIENTO DE LAS ENFERMEDADES AUTOINMUNES SISTÉMICAS Antagonistas del Receptor de la ENDOTELINA Terapias BIOLOGICAS Parte 1 Dr. Lucio."— Transcripción de la presentación:

1 NOVEDADES EN EL TRATAMIENTO DE LAS ENFERMEDADES AUTOINMUNES SISTÉMICAS Antagonistas del Receptor de la ENDOTELINA Terapias BIOLOGICAS Parte 1 Dr. Lucio Pallarés Ferreres Unidad Enfermedades Autoinmunes Sistémicas Servicio de Medicina Interna Hospital Son Dureta

2 NUEVAS TERAPIAS Trasplante de médula ósea Dosis inmunoablativas de CYC Recambio plasmático Ac Monoclonales (CD20, CD25, CD40-D40L) Anti-TNF (Infliximab, Etanercept) LJP 394 CTLA4Ig Antag. Receptor Endotelina (Bosentán) Inmunosupresores (Micofenolato)

3 ENDOTELINA La familia de las endotelinas está constituida por tres isoformas de 21 aminoácidos: endotelina-1 (ET-1), endotelina-2 (ET-2) y endotelina-3 (ET-3). Son agentes presores endógenos, secretadas por diferentes tejidos y células del organismo. La ET-1 es sintetizada predominantemente por el endotelio vascular. La ET-1 induce vasoconstricción, es proinflamatoria, profibrosis y tiene acción potencialmente mitógena. Es un importante factor en la regulación del tono vascular y participa en la remodelación vascular. Estos efectos son mediados a través de dos tipos de receptores, ET A y ET B. Los receptores ET A se localizan en músculo liso vascular y son responsables de inducir proliferación celular y vasoconstricción. Los ET B están presentes en células endoteliales y median la relajación vascular por activación de la producción de óxido nítrico y prostaciclina. Además, intervienen en la depuración de la ET-1.

4 Increasing evidence regarding the role of endothelin (ET)-1 as a mediator of PAH suggests that ET antagonism may be an additional therapeutic approach. Bosentan is an orally active nonpeptide antagonist of both ET receptor subtypes (ET-a and ET-b). By blocking the actions of both receptors, bosentan affects the vasoconstricting, proliferative, and fibrotic effects of ET-1. These beneficial effects of bosentan are entirely derived from preclinical animal experiments. Antagonistas de los Receptores de la Endotelina

5 Bosentan Therapy for Pulmonary Arterial Hypertension Rubin, LJ v olume 346 (12), 21 March 2002, pp In a preliminary study, the orally administered dual endothelin- receptor antagonist bosentan improved exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary arterial hypertension. Methods: Double-blind, placebo-controlled study. We assigned 213 patients with pulmonary arterial hypertension (primary or associated with connective-tissue disease) to receive placebo or to receive 6.25 mg of bosentan twice daily for 4 weeks followed by either of two doses of bosentan (125 or 250 mg twice daily) for a minimum of 12 weeks.

6 Bosentan Therapy for Pulmonary Arterial Hypertension At week 16, patients treated with bosentan had an improved six- minute walking distance; mean difference between the placebo group and the bosentan groups was 44 m (P<0.001).

7 Bosentan Therapy for Pulmonary Arterial Hypertension

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10 Conclusions: The endothelin-receptor antagonist bosentan is beneficial in patients with pulmonary arterial hypertension and is well tolerated at a dose of 125 mg twice daily. Endothelin-receptor antagonism with oral bosentan is an effective approach to therapy for pulmonary arterial hypertension. Bosentan Therapy for Pulmonary Arterial Hypertension Rubin, LJ v olume 346 (12), 21 March 2002, pp

11 The present study was an open-label extension to the preceding double-blind, placebo controlled study of 32 patients with PAH (primary or associated with scleroderma) Twenty-nine patients received bosentan for a year (62.5 mg bid for 4 weeks and then 125 mg bid). Long-term treatment with bosentan is safe and has sustained benefits on exercise

12 PVR and CI for 11 patients completing hemodynamic evaluation at 15 months

13 Modified NYHA functional class of PH as a function of bosentan treatment time (n = 29)

14 Sustained Symptomatic, Functional, and Hemodynamic Benefit With the Selective Endothelin-A Receptor Antagonist, Sitaxsentan, in Patients With Pulmonary Arterial Hypertension. A 1-Year Follow- up Study Langleben D. (CHEST 2004; 126:1377– 1381)

15 To describe the effect of bosentan and its dual inhibition of endothelin-1 ETA and ETB receptors on digital ulcers in patients with systemic sclerosis (SSc). Methods Patients receiving bosentan for SSc-related digital ulcers were identified in eight centers, and their characteristics and follow-up were recorded. Results Nine (six with diffuse and three with limited cutaneous forms of SSc) patients had received bosentan for digital ulcers. Complete healing occurred in seven. Another experienced a significant decrease in the number of ulcers. Only one recurrence was observed. La Presse Médicale Vol 35 - N° 4-C1 - Avril 2006 p Bosentan for treatment of active digital ulcers in patients with systemic sclerosis D Launay, E Diot, E Pasquier, L Mouthon, N Boullanger, O Fain

16 La Presse Médicale Vol 35 - N° 4-C1 - Avril 2006 p

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18 La Presse Médicale Vol 35 - N° 4-C1 - Avril 2006 p

19 CONCLUSION: Bosentan can be effective in the treatment of digital ulcers in some SSc patients with SSc, probably especially those involving substantial ischemia. Bosentan is not a first-line drug in this indication yet and must be carefully used by specialists in SSc. Forthcoming results from the international RAPIDS-2 study should clarify the indications for bosentan in the treatment of SSc-related digital ulcers. La Presse Médicale Vol 35 - N° 4-C1 - Avril 2006 p Bosentan for treatment of active digital ulcers in patients with systemic sclerosis D Launay, E Diot, E Pasquier, L Mouthon, N Boullanger, O Fain

20 What is already known Bosentan, an inhibitor of the ETA and ETB receptors of endothelin 1, is efficacious in pulmonary hypertension associated with systemic scleroderma. Bosentan prevents the onset of new digital ulcers in patients with systemic scleroderma. Bosentan can be efficacious in treating severe active digital ulcers in patients with systemic scleroderma. Bosentan appears to act rapidly, within approximately 4 weeks

21 J Rheumatol Sep;19(9): Intravenous iloprost treatment of Raynaud's phenomenon and ischemic ulcers secondary to systemic sclerosis. Wigley FM, Seibold JR, Wise RA, McCloskey DA, Dole WP. Department of Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ. Iloprost appears useful for the treatment of digital ulcers in systemic sclerosis and is associated with evidence of prolonged physiologic improvement although the mechanism of this effect remains unclear.

22 Existen en el mercado diferentes análogos sintéticos de la prostaciclina (PGI2), como el Alprostadilo (Surgirán®) y el Iloprost (Ilomedín®). En el momento actual, el que posee la indicación aceptada de tratamiento en el Fenómeno de Raynaud es el Iloprost, si bien tanto éste como el anterior Alprostadilo, poseen los mismos efectos vasodilatadores y de antiagregación plaquetaria. En diferentes ensayos realizados todos ellos se han mostrado efectivos en esta patología. DERIVADOS ANÁLOGOS DE LA PROSTACICLINA

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24 Iloprost (Ilomedin ), ampollas de 0,5 ml con 50 g. Se diluye 1 ampolla en 250 ml de salino o glucosado 5%, y se administra en perfusión durante 6 horas. Se inicia en dosis de 0,5 ng/Kg/min y se aumenta de forma progresiva cada 30 minutos hasta obtener la dosis y respuesta óptima, sin efectos secundarios. Dosis inicial: 0,5 ng/Kg/min.Dosis máxima: 2,0 ng/Kg/min.

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