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Tratamiento Farmacol gico DE: Presente y Futuro Prof. Dr. Edgardo F Becher Div. Urolog a Hospital de Cl nicas Jos de San Mart n Universidad de Buenos Aires – PowerPoint PPT presentation

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Title: Tratamiento Farmacol


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

2
(No Transcript)
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
respondersChronic treatment can help salvage
them to sildenafil therapy?
Behr-Roussel D, et al. AUA 2004.
7
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

8
Effect of Chronic Sildenafil on Erectile
Responses in Rats
D
AUC
/MAP
ICP/MAP
45
50
30


40

/MAP (s)
20
30
ICP/MAP ()

45
20
10
AUC
10
D
Vehicle
Vehicle
Sildenafil
0
0
Sildenafil
0
1
2
3
4
5
0
1
2
3
4
5
Frequency (Hz)
Frequency (Hz)
plt0.0001 Two-Way ANOVA
plt0.001 Two-Way ANOVA
plt0.05 Bonferroni's complementary analysis
AUC
/MAP
tot
30
/MAP (s)

Significant improvement of frequency-dependent
erectile responses in rats
20


tot
AUC
10
Vehicle
0
Sildenafil
0
1
2
3
4
5
Frequency (Hz)
plt0.0001 Two-Way ANOVA
plt0.05 Bonferroni's complementary analysis
9
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
  • 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)

10
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
0
CONTChronic SIL
-10
-10
Relaxation
( Phe)
Relaxation
( Phe)

-20
-20
ns
-30
-30
-40
-40
-9
-8
-7
-6
-5
-4
-9
-8
-7
-6
-5
-4
Log ACh (M)
Log A23 187 (M)
plt0.01 Two-Way ANOVA
Relaxation to SNP
0
Relaxation
( Phe)
-50
ns
-100
-9
-8
-7
-6
-5
-4
Log SNP (M)
11
Chronic Treatment with Sildenafil Potentiates
Erectile Responses Following Acute
Administration Lack of Tachyphylaxis
D
Effect of an acute administration of sildenafil
on ICP/MAP in control rats treated
chronically with vehicle or sildenafil
Chronic or acute sildenafil

Acute sildenafil
80

60
ICP/MAP ()
40
D
20
0
1
3
5
Frequency (Hz)
plt0.01 two-way ANOVA
plt0.05 Bonferroni's complementary analysis
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
Independent 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
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.
2002360895-900, 886-887
17
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 (Plt0.05) 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), 232675-80
18
Sildenafil Enhances Flow-mediated Dilation in CHF
Patients
6 4 2 0 -2
S 50 S 25 S 12.5 Placebo
plt.05 plt.05
Change in FMD ()
1 2
5 Minutes
Brachial Artery
Katz. JACC. 200036845.
19
Acute Effect of Sildenafil on Flow-mediated
Dilation in Diabetic Patients
p0.006
20
15
15
p1.0
Brachial artery flow-mediated dilation (
increase)
8
8
10
5
0

Pretreatment
Placebo
Sildenafil
Patients with type 2 diabetes
DeSouza et al. Diabetes Care. 2002251336.
20
Chronic Effect of Sildenafil on Flow-mediated
Dilation in Diabetic Patients
20
p0.003
14
p0.4
15
Brachial artery flow-mediated dilation (
increase)
9
8
10
5
0

Pretreatment
Placebo
Sildenafil
Patients with type 2 diabetes
DeSouza et al. Diabetes Care. 2002251336.
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. 200392(6)595-597. Ku
kreja RC, et al. Cardiovasc Res.
200360(3)700-701. Das A, et al. Am J Physiol
Heart Circ Physiol. 2004286(4)H1455-H1460. Kukre
ja RC, et al. J Mol Cell Cardiol.
200436(2)165-173.
22

Lichtenstein JR. Arthritis Rheum. 2003
48282-3                   Use of sildenafil
citrate in Raynaud's phenomenon.
23
Sher G, Fisch JD. Hum Reprod. 2000
Apr15(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
Nov78(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 Apr81(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
cGMP-binding sites
Catalytic domain
  • 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

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
  • a 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 a-MSH
  • En todos el AMPc es el 2do mensajero
  • Melanotan II y PT-141 clínicamente estudiados
    para DE

31
PT-141
32
PT-141Efectos adversos
  • Náuseas 36 6 mg SC 17 intranasal
  • Cefaleas 27
  • Flushing 17
  • Vómitos 9
  • Lumbalgia 9

33
Drogas de Acción PeriféricaNuevos 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.)
  • TMaxlt 1 h, T1/21 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 a-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.
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