Tratamiento
Farmacológico DE:
Presente y Futuro
Prof. Dr. Edgardo F Becher
Div. Urología
Hospital de Clínicas “José de San Martín”
Universidad de Buenos Aires
Silde/Tada/Vardenafil
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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.
Effect of Chronic Sildenafil on
Erectile Responses in Rats
Acute
sildenafil iv
Wash-out
33-36 hours
Chronic treatment with sildenafil sc
8 weeks
• In vivo evaluation of
erectile response (intracavernous
pressure elicit by eletric stimulation)
• Isometric tension studies
Effect of Chronic Sildenafil on Erectile Responses in Rats
D ICP/MAP
*
40
*
30
20
10
Vehicle
Sildenafil
0
0
1
2
3
4
30
†
AUC45 /MAP (s)
D ICP/MAP (%)
50
AUC45 /MAP
20
†
10
Vehicle
Sildenafil
0
0
5
1
2
3
4
5
Frequency (Hz)
Frequency (Hz)
†p<0.0001
†p<0.001
Two-Way ANOVA
*p<0.05 Bonferroni's complementary analysis
Two-Way ANOVA
Significant improvement of
frequency-dependent
erectile responses in rats
AUC tot /MAP (s)
AUCtot /MAP
30
*
20
*
†
10
Vehicle
Sildenafil
0
0
1
2
3
4
5
Frequency (Hz)
†p<0.0001
Two-Way ANOVA
*p<0.05 Bonferroni's complementary analysis
Investigation of Endothelial Function: In
Vitro
Objective
To explore the mechanisms by which chronic sildenafil exerts
its beneficial effect on erectile function by isometric tension
studies on isolated corporal strips
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)
Effect of Chronic Sildenafil Administration on Relaxations to
ACH, A23 187 And SNP In Corporal Strips of Control Rats
Relaxation to ACH
Relaxation to A23 187
CONT
0
*
-20
-30
Relaxation
(% Phe)
CONT+Chronic SIL
-10
-10
-20
ns
-30
-40
-40
-9
-8
-7
-6
-5
-4
-9
Log [ACh] (M)
*p<0.01 Two-Way ANOVA
0
-50
ns
-100
-9
-8
-7
-6
Log [SNP] (M)
-8
-7
-6
Log [A23 187] (M)
Relaxation to SNP
Relaxation
(% Phe)
Relaxation
(% Phe)
0
-5
-4
-5
-4
Chronic Treatment with Sildenafil Potentiates Erectile
Responses Following Acute Administration
Lack of Tachyphylaxis
Effect of an acute administration of sildenafil on D
ICP/MAP in
control rats treated chronically with vehicle or sildenafil
Chronic or acute sildenafil
Acute sildenafil
D ICP/MAP (%)
80
*
†
60
40
20
0
1
3
Frequency (Hz)
*p<0.01 two-way ANOVA
†p<0.05 Bonferroni's complementary analysis
5
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
Independen
t
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
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 es promisorio para el tratamiento a largo plazo de la
hipertensión pulmonar crónica debida a fibrosis
Ghofrani HA & cols.(Germany). The Lancet. 2002;360:895-900, 886-887
Sildenafil (Viagra) Induces Neurogenesis an Promotes Functional Recovery After Stroke
in Rats
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
Zhang R & cols. Stroke (2002), 23:2675-80
Sildenafil Enhances Flow-mediated Dilation
in CHF Patients
S 50
S 25
S 12.5
Placebo
Change in FMD (%)
6
4
2
p<.05
0
-2
1
Katz. JACC. 2000;36:845.
2
Brachial Artery
5 Minutes
p<.05
Brachial artery flow-mediated dilation
(% increase)
Acute Effect of Sildenafil on
Flow-mediated Dilation in Diabetic Patients
p=0.006
20
15%
15
p=1.0
10
8%
8%
5
0
Pretreatment
Placebo
Patients with type 2 diabetes
DeSouza et al. Diabetes Care. 2002;25:1336.
®
Sildenafil
Brachial artery flow-mediated dilation
(% increase)
Chronic Effect of Sildenafil on
Flow-mediated Dilation in Diabetic Patients
20
p=0.003
14%
15
p=0.4
9%
10
8%
5
0
Pretreatment
Placebo
Patients with type 2 diabetes
DeSouza et al. Diabetes Care. 2002;25:1336.
®
Sildenafil
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 8bromo-cGMP treatments on semen parameters and
sperm function.
Protein Structure of PDE5
cGMP-binding sites
P
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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
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 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 Central
• Agonistas de receptores de melanocortina
• Otros potenciales
– Ocitocina
– Agonistas de receptores de 5-HT
– Glutamato
– Análogos de Hexarelin
Agonistas de receptores de
melanocortina (RMC)
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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-141
PT-141
Efectos adversos
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Náuseas: 36% 6 mg SC; 17% intranasal
Cefaleas: 27%
Flushing: 17%
Vómitos: 9%
Lumbalgia: 9%
Drogas de Acción Periférica
Nuevos 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-TD
• 100-300 mcg
• Aplicación en el
meato uretral
• Pacientes orgánicos
incluyendo nitratos
• Potencial efecto en
tratamiento
combinado
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
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
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.
Relaxation
Karl-Erik Andersson, AUA News, vol. 10, august 2005.
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.
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Tratamiento Oral DE: Presente y Futuro - FMV