Phosphodiesterases(PDEs) and PDE inhibitors for treatment of LUTS

1
Phosphodiesterases(PDEs) and PDE inhibitors for
treatment of LUTS
Hyun Woo Kim The Catholic University of Korea
2
MSAM-7 Erectile Function Declines With
Increasing Severity of LUTS Independent of Age
Average score on a scale from 130 (6
questions), measured by IIEF Per question 1
Negative to 5 Positive
30
LUTS
20
None
Average EF Score (IIEF)
Mild
Moderate
10
Severe
0
5059 y
6069 y
7079 y
Base Men sexually active/sexual intercourse
during past 4 weeks
IIEF, International Index of Erectile Function
MSAM-7, Multinational Survey of the Aging Male
Rosen R et al. Eur Urol. 200344637.
3
The recent use of PDE-5 ?
Treatment for ED ? Interest in the
possibility of using to treat LUTS
4
PDE5 Inhibitors Mechanism of Action
Endothelial cell
Sexual stimulation
Cavernous nerve
Smooth muscle cell
Nitricoxide
cGMP-specificprotein kinase
Decreased Ca2
Guanylate cyclase
cGMP
GTP
PDE5
Smooth muscle relaxation erection
K
5'GMP
PDE5 Inhibitor
Ca2
5
Phosphodiesterase-5 inhibitors

• Sildenafil (Viagra) 50mg, 100mg
• Tadalafil (Cialis) 5mg, 10mg, 20mg
• Vardenafil (Levitra) 10mg, 20mg
• Udenafil (Zydena, DA 8159) 100mg, 200mg
• Mirodenafil (Mvix, SK3530) 100mg

6
Phosphodiesterase-5 inhibitors

• Action on
• 1. Corpus cavernosum
• 2. Bladder neck
• 3. Urethra
• 4. Prostate

7
Introduction

• Rationale

? Increase SM tension play a central role in
LUTS pathophysiology
(a-blockers, antimuscarinics) ? Human lower
urinary tract ? expression of NO/cGMP/PDE5
pathway ? PDE5 inhibitors regulating SM
activity lower
urinary tract SM relaxation
? Early clinical evidence ? PDE5-Is
(tadalafil) successful in treating LUTS and ED.
8

• Immunohistologic study ( Uaket S st al Eur
  Urol, 2006)
• PDE 4 fibromuscular stroma and glandular
  structures of the TZ
• PDE 5, 11 glandular and stromal
  subglandular areas

? Possible use of inhibitors of PDE4,5 for
treating urinary obstruction
secondary to BPE
9
BJU 2006
PDE-5 mRNA expression in Rat
Tinel H et at. BJU 2006
10
BJU 2006

• Improves male LUTS via NO/cGMP mediated
  relaxation of SM

Rat prostate
Rat urethra
Rat bladder
11
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5. ?? ????.
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Data on file. Pfizer, New York, NY.
12
??? ??

• ??? ??? ???? ?? ??? ?? ?? ??? ????? (?, ?? ? ??
  ???)
• 1. ???, 2. ? ?? ?? ??,3. ? ?? ??. 4. ?
  ??? ?? ??,5. ? ?? ?? ??.

• ??? ? 62? ??? ??? ? ?? ??? ????, 25?
  ??? ??? ??? ?? ?? ??? ??? ??.

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Sildenafil on LUTS in men with ED

• Multicenter, 12 weeks, double-blind,
  placebo-controlled study
• Men ? 45 yrs with IIEF-EF ? 25
• IPSS ? 12
• Sildenafil 50 mg every night or
• 30min-1h before sexual activity
• After 2 wks, dose was increased to
• 100 mg
• Changes of IIEF-EF score after 12 wks
• (plt0.0001)

( IIEF baseline and end of treatment scores on EF
domain )
McVary KT, et al. J Urol 20071771071
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Sildenafil on LUTS in men with ED

• Change in LUTS scores after 12 wks (plt0.0001)

McVary KT, et al. J Urol 20071771071
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Tadalafil in men with ED LUTS

• Men with IPSS ? 13 Qmax 415ml/sec
• Tadalafil 5 mg once daily for 6 wks
• ? 20 mg for 6 weeks
• Changes in IPSS, QoL index, BPH impact index and
  URM after 6, 12wks
• greater improvements over baseline in IPSS, IPSS
  QoL Index and BPH II.
• Qmax changes similar in placebo and
  tadalafil-treated groups.

McVary KT, et al. J Urol 20071771401
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Combination of alfuzosin sildenafil

• 62 Men aged 50-76 with untreated LUTS ED
• Randomized to receive (12 wks)
• 1) alfuzosin 10mg once daily (n20)
• 2) sildenafil 25 mg once daily n21)
• 3) combination of both (n21)
• ? IPSS, voiding diary, Qmax, PVRU, IIEF

Kaplan SA, et al. Eur Urol 2007511717
17
Combination of alfuzosin sildenafil
Kaplan SA, et al. Eur Urol 2007511717
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Clinical trials
IPSS5?(37), QoL1.4?
IPSS1624?, Qmax1.12?
Multicenter, randomized, placebo-controlled,
double-blind IPSS8.6 ? in severe 3.6 ? in
moderate
randomized, double-blind, placebo-controlled
IPSS5.9?, Qmaxns
Kedia et al. World J Urol (2008)
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Study Synopsis
To evaluate the Efficacy and Safety of Once-a-Day
Dosing of Udenafil in the Treatment of Erectile
Dysfunction
Purpose
Randomized, placebo-controlled, double-blind,
parallel design phase II study
Design
Group
Placebo, Udenafil 25mg, 50mg, 75mg
No. of Subjects
Total 208 subjects (52 subjects per group)
Period
June 19, 2008 March 05, 2009
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SEP Q3 Did your erection last long enough for
you to complete intercourse with
ejaculation?
Left baseline, Right at 12 week



p lt 0.0001
21
I-PSS Subgroup analysis
No BPH / not on medication / IPSS 8
BPH / on medication / IPSS 8
(N17)
(N17)
(N19)
(N16)
(N12)
(N15)
(N19)
(N19)

p0.027
22
??

• ???? 50mg ??? ??? ??? ???? 100mg On-demand ? ???
  ??
• On- demand? ?? ??? ??
• ???? ?? ?? ??
• ?? ??
• ??? ?? ? ??? ??? ??

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Conclusion

• Preliminary studies ? encouraging!
• Now what we need?
• Basic research
• to elucidate the NO/cGMP/PDE5 pathway mechanism
  in Tx. Of BPH/LUTS
• Clinical trials (III)
• Larger-scale, well designed
• safety, efficacy and cost-effectiveness

24
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??? ???? ??? ?? ? ????? ???? ??? ??? ??? ?????
?????. 1. ?? ???? ??, 4. ?? ????.

• ??? ???? ??? ???
• ???? ????? ?? ????
• ?? ????? ???.

??? ???? ??? ???? ?? ? ????? ???? ??? ??? ???
???? ?????. 1. ?? ???? ??, 4. ?? ????.

• ??? ???? ??? ???
• ??? ?? ????? ????
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Unanswered questions

• Most studies included 12 weeks of treatment.
  Furthermore?
• Improvement of UFM parameters is possible?
• Most studies failed to observe significant
  improvement in uroflowmetry
• Parameters at end point.
• Is it safe to use drugs in combination?
• The safety of long-term daily treatment of BPH
  with PDE5 inhibitors
• has not been investigated. (Both a-blockers and
  PDE5 inhibitors can
• have an impact on blood pressure.)

26
Suggested Management
Pts with LUTS ED
LUTS gtgt ED
ED gtgt LUTS
CC
Mx 1
a-blocker
PDE5 inhibitor
a-blocker PDE5 inhibitor
PDE5 inhibitor a-blocker
Mx 2
27
Summary

• PDE5- inhibitors
• ? will be used as an add-on Tx
• The use as monotherapy
• ? attractive considering that
• PDE5 administration as the all-
• in-one pill for the most
• common urologic conditions of
• voiding and erectile function
• ? increase patient convenience
• and compliance and reduce
• treatment cost compared with
• combination treatment.

Kaplan SA (13? ???????????)