Tratamiento Farmacológico DE: Presente y Futuro Prof. Dr. Edgardo F Becher Div. Urología Hospital de Clínicas José de San Martín Universidad de Buenos.

Presentación del tema: "Tratamiento Farmacológico DE: Presente y Futuro Prof. Dr. Edgardo F Becher Div. Urología Hospital de Clínicas José de San Martín Universidad de Buenos."— Transcripción de la presentación:

1 Tratamiento Farmacológico DE: Presente y Futuro Prof. Dr. Edgardo F Becher Div. Urología Hospital de Clínicas José de San Martín Universidad de Buenos Aires

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3 Silde/Tada/Vardenafil Similar eficacia y seguridad Diferencias farmacocinéticas Eficacia en diversas etiologías DE Sólo 15-20% de pacientes con DE reciben tratamiento

4 Viagra Beyond ED

5 Experimental study investigating the effect of chronic sildenafil on erectile responses and endothelium-dependent corporal relaxations in rats Behr-Roussel D, et al. AUA 2004.

6 Patients with severe ED are Viagra poor responders Chronic treatment can help salvage them to sildenafil therapy? Behr-Roussel D, et al. AUA 2004.

7 Chronic treatment with sildenafil sc 8 weeks Wash-out 33-36 hours Effect of Chronic Sildenafil on Erectile Responses in Rats In vivo evaluation of erectile response (intracavernous pressure elicit by eletric stimulation) Isometric tension studies Acute sildenafil iv

8 Effect of Chronic Sildenafil on Erectile Responses in Rats ICP/MAP 012345 0 10 20 30 40 50 Vehicle Sildenafil Frequency (Hz) ICP/MAP (%) p<0.0001 Two-Way ANOVA *p<0.05 Bonferroni's complementary analysis * * AUC 45 /MAP 012345 0 10 20 30 p<0.001 Two-Way ANOVA Frequency (Hz) AUC 45 /MAP (s) AUC tot /MAP 012345 0 10 20 30 p<0.0001 Two-Way ANOVA *p<0.05 Bonferroni's complementary analysis * * Frequency (Hz) AUC tot /MAP (s) Significant improvement of frequency-dependent erectile responses in rats Vehicle Sildenafil Vehicle Sildenafil

9 Protocol Endothelium-dependent relaxations – via activation of muscarinic receptors concentration-response curves to acetylcholine – via increase Ca 2+ intracellular concentration concentration-response curves to A23 187 Endothelium-independent relaxations response curves to sodium nitroprusside (SNP) Objective To explore the mechanisms by which chronic sildenafil exerts its beneficial effect on erectile function by isometric tension studies on isolated corporal strips Investigation of Endothelial Function: In Vitro

10 Relaxation to ACH -9-8-7-6-5-4 -40 -30 -20 -10 0 CONT CONT+Chronic SIL * *p<0.01 Two-Way ANOVA Log [ACh] (M) Relaxation (% Phe) Effect of Chronic Sildenafil Administration on Relaxations to ACH, A23 187 And SNP In Corporal Strips of Control Rats Relaxation to SNP -9-8-7-6-5-4 -100 -50 0 ns Log [SNP] (M) Relaxation (% Phe) Relaxation to A23 187 -9-8-7-6-5-4 -40 -30 -20 -10 0 ns Log [A23 187] (M) Relaxation (% Phe)

11 Effect of an acute administration of sildenafil on ICP/MAP in control rats treated chronically with vehicle or sildenafil 135 0 20 40 60 80 Chronic or acute sildenafil Acute sildenafil * *p<0.01 two-way ANOVA p<0.05 Bonferroni's complementary analysis Frequency (Hz) ICP/MAP (%) Chronic Treatment with Sildenafil Potentiates Erectile Responses Following Acute Administration Lack of Tachyphylaxis

12 Study Conclusion Upregulation of corporal endothelial function occurred at the level of the transduction pathway between muscarinic receptors and endothelial NOS in animals treated with chronic sildenafil

13 Independen t October 2001

14 Viagra in Pulmonary Arterial Hypertension (PAH) Pulmonary Arterial Hypertension: contraction of pulmonary artery Unknown etiology Right heart failure Bad prognosis Sildenafil can decrease PAH

15 Viagra in Pulmonary Arterial Hypertension (PAH) Mikhail et al – Eur Heart J 2004 PAH patients treated Viagra 50 mg 3x/day PAH cardiac outpu Walk capacity: 112 m

16 Viagra Relieves Pulmonary Hypertension Ghofrani HA & cols.(Germany). The Lancet. 2002;360:895-900, 886-887 Sildenafil es promisorio para el tratamiento a largo plazo de la hipertensión pulmonar crónica debida a fibrosis 16 pacientes con CPH randomizados con sildenafil oral o epoprostenol IV. Grupo sildenafil: menor tasa de resistencia vascular pulmonar al igual que el óxido nítrico mantuvo el coeficiente ventilación perfusión, elevando la presión parcial de óxigeno arterial (14.3 mm Hg, 95% con intervalo de confianza, -1.7 to 31.3). No se registraron efectos adversos.

17 Sildenafil (Viagra) Induces Neurogenesis an Promotes Functional Recovery After Stroke in Rats Zhang R & cols. Stroke (2002), 23:2675-80 Se administró 2 a 5 mg/kg/día 2 a 24 horas post stroke inducido en ratas Wistar durante 7 días vs placebo El sildenafil mejoró el número de células inmunoreactivas a la bromodeoxiuridina (P<0.05) y el número de neuronas inmaduras marcadas con tubulina-j1. Elevados niveles de cGMP, PDE5 y mRNA se encontraban presentes en áreas isquémicas y no isquémicas del cerebro. El sildenafil podría ser útil administrado en ACV en humanos

18 Sildenafil Enhances Flow-mediated Dilation in CHF Patients S 50 S 25 S 12.5 Placebo Katz. JACC. 2000;36:845. Brachial Artery 1 2 5 Minutes Change in FMD (%) 6 4 2 0 -2 p<.05

19 Acute Effect of Sildenafil on Flow-mediated Dilation in Diabetic Patients 0 5 10 15 20 PretreatmentPlaceboSildenafil Brachial artery flow-mediated dilation (% increase) 8% 15% p=1.0 p=0.006 Patients with type 2 diabetes DeSouza et al. Diabetes Care. 2002;25:1336. ®

20 Chronic Effect of Sildenafil on Flow-mediated Dilation in Diabetic Patients 0 5 10 15 20 PretreatmentPlaceboSildenafil Brachial artery flow-mediated dilation (% increase) 8% 9% 14% p=0.4 p=0.003 Patients with type 2 diabetes DeSouza et al. Diabetes Care. 2002;25:1336. ®

21 Sildenafil and Cardioprotection Sildenafil has preconditioning-like powerful cardioprotective effect in the animal models of ischemia-reperfusion injury Future demonstration of the cardioprotective effect in patients with sildenafil could have an enormous impact on bringing the long-studied phenomena of ischemic and pharmacologic preconditioning to the clinical forefront – Kukreja RC, 2004 Salloum F, et al. Circ Res. 2003;92(6):595-597. Kukreja RC, et al. Cardiovasc Res. 2003;60(3):700-701. Das A, et al. Am J Physiol Heart Circ Physiol. 2004;286(4):H1455-H1460. Kukreja RC, et al. J Mol Cell Cardiol. 2004;36(2):165-173.

22 Lichtenstein JR. Arthritis Rheum. 2003; 48:282-3 Use of sildenafil citrate in Raynaud's phenomenon.

23 Sher G, Fisch JD. Hum Reprod. 2000 Apr;15(4):806-9. Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF. Sher G, Fisch JD. Fertil Steril. 2002 Nov;78(5):1073-6. Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development.

24 Du Plessis SS, De Jongh PS, Franken DR. Fertil Steril. 2004 Apr;81(4):1026-33. Effect of acute in vivo sildenafil citrate and in vitro 8- bromo-cGMP treatments on semen parameters and sperm function.

25 Protein Structure of PDE5 3D X ray crystal structure of recombinant PDE5 construct comprising the catalytic domain Surface representation of atomic structure with cGMP bound Globular structure and deep active site cleft Very specific structural requirements required for inhibitors P cGMP-binding sitesCatalytic domain

26 Sildenafil Bound to PDE5 Catalytic Domain Very specific structural requirements required access to catalytic domain

27 Conclusions Aspects of the pharmacology of Viagra appear to be unique and may translate into clinical benefits Viagras mechanism of action on the endothelium has important implications for cardioprotection and provides additional confidence in its cardiovascular safety profile

28 Agentes en Investigación Drogas de acción central Drogas de acción periférica –Nuevos IPDE5 –Alprostadil tópico –α Bloqueantes S-nitroslados –IPDE5s liberadores de ON –Activadores de la Guanilato Ciclasa –Inhibidores de la Rho-kinasa

29 Fármacos de Acción Central Agonistas de receptores de melanocortina Otros potenciales –Ocitocina –Agonistas de receptores de 5-HT –Glutamato –Análogos de Hexarelin

30 Agonistas de receptores de melanocortina (RMC) 5 RMCs (sólo RMC3 y 4 relac. c/ erección) Activados por ACTH y α-MSH En todos el AMPc es el 2do mensajero Melanotan II y PT-141 clínicamente estudiados para DE

31 PT-141

32 PT-141 Efectos adversos Náuseas: 36% 6 mg SC; 17% intranasal Cefaleas: 27% Flushing: 17% Vómitos: 9% Lumbalgia: 9%

33 Drogas de Acción Periférica Nuevos IPDE5s DA-8159 Udenafil (Zydena®) Dong-A Pharmaceutical Co. (Corea) –TMax: 1-1.5 H; T1/2: 11-13 H –100 – 200 mg –FIII (Aprobado en Corea) TA-1790 Avanafil (Vivus, Inc.) –TMax:< 1 h, T1/2:1 H –50-200 mg –RigiScan: superior al sildenafil a 20-40 min –FII Slx-2101 (Surface Logix, Inc) –Acción prolongada: 36-48 H –5 – 80 mg –Fase I

34 Alprostadil tópico Alprox-TD 100-300 mcg Aplicación en el meato uretral Pacientes orgánicos incluyendo nitratos Potencial efecto en tratamiento combinado

35 Alfa-Bloquenates S-Nitrosilados Nitrosilación de α-bloquenates no afecta la interacción con el receptor Agrega donación de ON Investigado con Moxisylite No hay estudios clínicos relevantes

36 Otros compuestos potenciales IPDE5 liberadores de ON: NCX-911: superior a sildenafil en ausencia de ON endógeno (conejos) Activadores de la GC: YC-1, BAY 41-2272 potencial efecto en DBT

37 Inhibidores de Rho-kinasa Y-27632 (Welfide Corp., Osaka). Inhibe a la Rho-kinasa, la cual es responsable del tono contráctil basal del musc. liso a través de la inhibición de la fosfatasa de la cadena liviana de miosina (MLC-P). Nexo entre DE y LUTS? En la ICC, CAD, HTA, LUTS, etc. habría una sobre- expresión del sistema RhoA/Rho-kinasa.

38 Relaxation Karl-Erik Andersson, AUA News, vol. 10, august 2005.

39 Conclusiones Nuevos fármacos y tecnologías están en camino. Trascendental aporte de la biología molecular. DE, HTA, IC, CAD, LUTS, podrían tener el mismo tratamiento (!?). La prevención de los factores de riesgo desde la niñez sigue siendo lo más efectivo y económico.