tratamiento farmacológico de: presente y futuro prof. dr. edgardo f becher div. urología hospital...
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Tratamiento Tratamiento Farmacológico DE:Farmacológico DE:Presente y FuturoPresente y Futuro
Prof. Dr. Edgardo F BecherDiv. Urología
Hospital de Clínicas “José de San Martín”Universidad de Buenos Aires
Silde/Tada/VardenafilSilde/Tada/Vardenafil
• Similar eficacia y seguridad
• Diferencias farmacocinéticas
• Eficacia en diversas etiologías DE
• Sólo 15-20% de pacientes con DE reciben tratamiento
Viagra Beyond ED
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.
Patients with severe ED are Viagra poor responders
Chronic treatment can help salvage them to sildenafil therapy?
Behr-Roussel D, et al. AUA 2004.
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
Effect of Chronic Sildenafil on Erectile Responses in Rats ICP/MAP
0 1 2 3 4 5
0
10
20
30
40
50
VehicleSildenafil
Frequency (Hz)
IC
P/M
AP
(%
)
†
†p<0.0001 Two-Way ANOVA*p<0.05 Bonferroni's complementary analysis
*
*
AUC45 /MAP
0 1 2 3 4 5
0
10
20
30
†p<0.001 Two-Way ANOVA
Frequency (Hz)
AU
C45
/MA
P (
s)
†
AUCtot /MAP
0 1 2 3 4 5
0
10
20
30
†
†p<0.0001 Two-Way ANOVA*p<0.05 Bonferroni's complementary analysis
**
Frequency (Hz)
AU
Cto
t/M
AP
(s)
Significant improvement of frequency-dependent
erectile responses in rats
VehicleSildenafil
VehicleSildenafil
Protocol• Endothelium-dependent relaxations
– via activation of muscarinic receptors concentration-response curves to acetylcholine– via increase Ca2+ intracellular concentration
• concentration-response curves to A23 187• Endothelium-independent relaxations
• response curves to sodium nitroprusside (SNP)
ObjectiveTo 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
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)
Re
laxa
tion
(% P
he
)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)
Re
laxa
tion
(% P
he
)
Relaxation to A23 187
-9 -8 -7 -6 -5 -4
-40
-30
-20
-10
0
ns
Log [A23 187] (M)
Re
laxa
tion
(% P
he
)
Effect of an acute administration of sildenafil on ICP/MAP in control rats treated chronically with vehicle or sildenafil
1 3 50
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)
IC
P/M
AP
(%
)
Chronic Treatment with Sildenafil Potentiates Erectile Responses Following Acute Administration
Lack of Tachyphylaxis
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
Independent
October 2001
Viagra in Pulmonary Arterial Hypertension (PAH)
• Pulmonary Arterial Hypertension: contraction of pulmonary artery
• Unknown etiology
• Right heart failure
• Bad prognosis
• Sildenafil can decrease PAH
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
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.
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
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
Ch
ang
e in
FM
D (
%)
6
4
2
0
-2
p<.05 p<.05
Acute Effect of Sildenafil on Flow-mediated Dilation in Diabetic Patients
0
5
10
15
20
Pretreatment Placebo Sildenafil
Bra
chia
l art
ery
flow
-med
iate
d di
latio
n (%
incr
ease
)
8% 8%
15%
p=1.0
p=0.006
Patients with type 2 diabetes
DeSouza et al. Diabetes Care. 2002;25:1336.
®
Chronic Effect of Sildenafil on Flow-mediated Dilation in Diabetic Patients
0
5
10
15
20
Pretreatment Placebo Sildenafil
Bra
chia
l art
ery
flow
-med
iate
d di
latio
n (%
incr
ease
)
8%9%
14%
p=0.4
p=0.003
Patients with type 2 diabetes
DeSouza et al. Diabetes Care. 2002;25:1336.
®
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.
Lichtenstein JR. Arthritis Rheum. 2003; 48:282-3 Use of sildenafil citrate in Raynaud's phenomenon.
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.
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.
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 sites Catalytic domain
Sildenafil Bound to PDE5 Catalytic Domain
Very specific structural requirements required access to catalytic domain
Conclusions
• Aspects of the pharmacology of Viagra appear to be unique and may translate into clinical benefits
• Viagra’s mechanism of action on the endothelium has important implications for cardioprotection and provides additional confidence in its cardiovascular safety profile
Agentes en InvestigaciónAgentes en Investigación
• Drogas de acción central
• Drogas de acción periférica– Nuevos IPDE5– Alprostadil tópico– α Bloqueantes S-nitroslados– IPDE5’s liberadores de ON– Activadores de la Guanilato Ciclasa– Inhibidores de la Rho-kinasa
Fármacos de Acción CentralFármacos de Acción Central
• Agonistas de receptores de melanocortina
• Otros potenciales– Ocitocina– Agonistas de receptores de 5-HT– Glutamato– Análogos de Hexarelin
Agonistas de receptores de Agonistas de receptores de melanocortina (RMC)melanocortina (RMC)
• 5 RMC’s (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
PT-141PT-141
PT-141PT-141Efectos adversosEfectos adversos
• Náuseas: 36% 6 mg SC; 17% intranasal
• Cefaleas: 27%
• Flushing: 17%
• Vómitos: 9%
• Lumbalgia: 9%
Drogas de Acción PeriféricaDrogas de Acción PeriféricaNuevos IPDE5’sNuevos IPDE5’s
• 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
Alprostadil tópico Alprox-TDAlprostadil tópico Alprox-TD
• 100-300 mcg• Aplicación en el
meato uretral• Pacientes orgánicos
incluyendo nitratos• Potencial efecto en
tratamiento combinado
Alfa-Bloquenates S-NitrosiladosAlfa-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
Otros compuestos potencialesOtros 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
Inhibidores de Rho-kinasaInhibidores 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.
Relaxation
Karl-Erik Andersson, AUA News, vol. 10, august 2005.
ConclusionesConclusiones
• 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.