New Treatment Modalities for New Treatment Modalities for Benign Benign ProstaticProstatic HyperplasiaHyperplasia

SeungSeung--June Oh, MDJune Oh, MDDepartment of Urology, Department of Urology,

Seoul National University HospitalSeoul National University Hospital

Options for Treating BPHOptions for Treating BPH

PharmacotherapyPharmacotherapyαα blockerblockerAgents for BPH + OABAgents for BPH + OABPhytotherapyPhytotherapy

IntraprostaticIntraprostatic injection:injection:Anhydrous ethanol Anhydrous ethanol BotulinumBotulinum toxintoxinOthers

Less invasive Less invasive TxTxThermotherapyThermotherapyLaserLaserOthersOthers

Invasive Invasive TxTxTURTUR--PPOpen prostatectomy Open prostatectomy

OthersOthers Others

Human Human AdrenoceptorsAdrenoceptors ((ARsARs))TypesTypesαα1: 1A, 1B, 1D1: 1A, 1B, 1Dαα2: 2A, 2B, 2C2: 2A, 2B, 2Cββ: 1, 2, 3 : 1, 2, 3

αα1A1A--AR AR Predominant in human Predominant in human prostaticprostatic stromastromaDynamic component of obstruction and related voiding symptomsDynamic component of obstruction and related voiding symptoms

αα1D1D--AR AR Predominantly expressed in the bladderPredominantly expressed in the bladderRegulating Regulating detrusordetrusor contractility and bladder function in storage phasecontractility and bladder function in storage phasePartly contributes to the OAB 2Partly contributes to the OAB 2°° to BPOto BPOExact mechanism: unknown Exact mechanism: unknown

Pharmacotherapy: Pharmacotherapy: αα blockerblocker

NonsubtypeNonsubtype selective selective αα11--AR blockerAR blockerTerazosinTerazosinDoxazosinDoxazosinAlfuzosinAlfuzosin

Subtype selective Subtype selective αα11--AR blockerAR blockerTamsulosinTamsulosin αα1A/1D1A/1D--AR blocker (AR blocker (αα1A>1D)1A>1D)NaptopidilNaptopidil: : αα1A/1D1A/1D--AR blocker (AR blocker (αα1A<1D)1A<1D)SilodosinSilodosin: : αα1A1A--AR blocker AR blocker Others Others

NaftopidilNaftopidil

Newly synthesized Newly synthesized αα blocker (KT 611)blocker (KT 611)Phenyl Phenyl piperazinepiperazine derivativederivative5050--75 mg 75 mg p.op.o. . qdqdIn the Japanese market since 1999In the Japanese market since 1999Commercial nameCommercial name

FlivasFlivas Tablet Tablet 2525, , 50mg50mg ((旭化成旭化成ファーマファーマ))AvishotAvishot Tablet 25, 50mg (Tablet 25, 50mg (日本オルガノン日本オルガノン) )

NaftopidilNaftopidil: : in vitroin vitro study (1)study (1)

Mesenteric and carotid arteries (dog); thoracic Mesenteric and carotid arteries (dog); thoracic aortaeaortae (rabbit, guinea pig and rat)(rabbit, guinea pig and rat)

Mechanism of action: Mechanism of action: αα11--AR antagonist AR antagonist

Muramatsu I at al. Jpn J Pharmacol. 1991

NaftopidilNaftopidil: : in vitroin vitro studystudy (2)(2)

Using cloned human Using cloned human αα11--adrenoceptor adrenoceptor subtypessubtypesSelective for the Selective for the αα1D1D--AR with approximately AR with approximately 33-- and 17and 17--fold higher affinity than for the fold higher affinity than for the ααAA--and and αα1B1B--AR subtypes, respectively. AR subtypes, respectively.

Takei R et al. Jpn J Pharmacol. 1999

NaftopidilNaftopidil: : in vivoin vivo studystudy

i.vi.v. administration of . administration of naftopidilnaftopidil, , tamsulosintamsulosinand and prazosinprazosin in an anesthetized dog model in an anesthetized dog model Antagonist potency against Antagonist potency against PhePhe--mediated mediated increases in increases in prostaticprostatic pressure and mean BP pressure and mean BP Selectivity index: Selectivity index: naftopidilnaftopidil (3.7), (3.7), tamsulosintamsulosin(1.2), (1.2), prazosinprazosin (0.6)(0.6)

Takei R et al. Jpn J Pharmacol 1999

NaftopidilNaftopidil: C: Clinical study (1)linical study (1)

NaftopidilNaftopidil appears to have been effective in thappears to have been effective in thee shortshort--term treatment of BPH. term treatment of BPH. Yamanishi T et al. Int J Urol 2004

NaftopidilNaftopidil: C: Clinical study (2)linical study (2)single blind, RCTsingle blind, RCT

Predominant efficacy on storage symptoms as well as voiding Predominant efficacy on storage symptoms as well as voiding symptoms associated with BPH.symptoms associated with BPH.EEffective for ffective for nocturianocturia in patients with BPH regardless of the in patients with BPH regardless of the existence of nocturnal existence of nocturnal polyuriapolyuria.. Takahashi S et al. Int J Urol 2006

NaftopidilNaftopidil: C: Clinical study (3)linical study (3)Randomized crossover studyRandomized crossover study

NNaftopidilaftopidil and and tamsulosintamsulosin provided similar efficacy provided similar efficacy in the treatment of LUTS with BPH. However, in the treatment of LUTS with BPH. However, naftopidilnaftopidil was better than was better than tamsulosintamsulosin for for nocturianocturia. .

Nishino Y et al. BJU Int. 2006

-- Controversy Controversy --Efficacy on BPH Storage SymptomsEfficacy on BPH Storage Symptoms

Predominant Predominant αα1D1D--AR in the human bladder AR in the human bladder (Malloy BJ et al. J (Malloy BJ et al. J UrolUrol 1998)1998)

Increase in Increase in αα1D1D--AR expression in obstructed AR expression in obstructed and hypertrophied rat bladder and hypertrophied rat bladder ((HampelHampel C et al. J C et al. J UrolUrol 2002)2002)

Nonselective Nonselective αα11--AR antagonist is effective for AR antagonist is effective for storage symptoms storage symptoms (Jensen D (Jensen D JrJr et al. Scand J et al. Scand J UrolUrol NephrolNephrol 1981)1981)

NaftopidilNaftopidil inhibits inhibits micturitionmicturition reflex by acting reflex by acting on on αα1D or 1D or αα1A1A--AR in the LS spinal cord AR in the LS spinal cord ((SugayaSugayaK et al. K et al. NeurosciNeurosci LettLett 2002) 2002)

SilodosinSilodosin (KMD(KMD--3213)3213)

UriefUrief®® capsulecapsule２２mg,mg,４４mg (Kissei mg (Kissei 薬品工業株薬品工業株式会社式会社))4mg 4mg popo bidbid일본일본제조시판허가제조시판허가(2006. 1.) (2006. 1.)

SilodosinSilodosin: Effect on the NE: Effect on the NE--induced induced Rabbit Prostate ContractionRabbit Prostate Contraction

Tatemichi S et al. α1-adrenoceptor subtype selectivity and organ specificity of silodosin (KMD-3213)] Yakugaku Zasshi. 2006

SilodosinSilodosin: : Receptor Subtype SelectivityReceptor Subtype Selectivity

MouseMouse--derived derived αα1 1 ARAR-- cell (3 human AR expressed)cell (3 human AR expressed)higher selectivity for the higher selectivity for the αα1A1A--AR subtype than AR subtype than tamsulosintamsulosin, , naftopidilnaftopidil or or prazosinprazosin

Tatemichi S et al. α1-adrenoceptor subtype selectivity and organ specificity of silodosin (KMD-3213)] Yakugaku Zasshi. 2006

SilodosinSilodosin: Tissue selectivity: Tissue selectivityMouseMouse--derived derived αα1 1 ARAR-- cell (3 human AR expressed)cell (3 human AR expressed)Selectivity for lower urinary tract was higher for Selectivity for lower urinary tract was higher for silodosinsilodosin than than for the other for the other αα11--AR antagonists AR antagonists

Tatemichi S et al. α1-adrenoceptor subtype selectivity and organ specificity of silodosin (KMD-3213)] Yakugaku Zasshi. 2006

SilodosinSilodosin: : Phase II dosePhase II dose--finding studyfinding studyStudy designStudy design

PlaceboPlacebo--controlled, doublecontrolled, double--bind, parallel group compbind, parallel group comp--arativearative studystudy

SubjectSubjectBPH patients with LUTSBPH patients with LUTS

Dosage and AdministrationDosage and Administration4 mg/day4 mg/day (n=86)(n=86), 8 mg/day , 8 mg/day (91) (91) or placeboor placebo (89)(89)Twice a day dosing (morning and evening)Twice a day dosing (morning and evening)

Treatment periodTreatment period4 weeks4 weeks

SilodosinSilodosin: : IPSS total score IPSS total score & & QoLQoLscore score at endat end--pointpoint

-7

-6

-5

-4

-3

-2

-1

0Placebo 4mg/day 8mg/day

Cha

nge

from

bas

elin

e in

I-P

SS

tota

l sco

re

p=0.0126

p=0.0000-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0Placebo 4mg/day 8mg/day

Cha

nge

from

bas

elin

e in

QO

L sc

ore

p=0.0451

p=0.0009

Changes in Qmax up to 52 weeks Changes in Qmax up to 52 weeks ((SilodosinSilodosin Extended)Extended)

Mean Changes in Qmax

-3

-2

-1

0

1

2

3

0 4 12 20 28 36 44 52

P: 32L: 37H: 36

P: 32L: 35H: 34

P: 29L: 29H: 26

P: 24L: 27H: 29

P: 18L: 30H: 26

P: 12L: 26H: 23

P: 5L: 26H: 22

P: 1L: 25H: 20

WeekWeek

Qm

ax (m

L/se

c) Placebo (P)

KMD 4mg/day BID (L)

KMD 8mg/day BID (H)

Only patients who continuously entered the long term study (KMD-203) with the blind maintained.

UrapidilUrapidil

αα1A1A--AR selectiveAR selectiveProspective Prospective placeboplacebo--controlled controlled multicentricmulticentric doubledouble--blind trial blind trial 214 214 BPH BPH patients: patients: 4 groups4 groups ((placebo, 15 mg/dplacebo, 15 mg/d, 60, 60mgmg/d,/d, 90 mg/d)90 mg/d)Day and night urinary frequencyDay and night urinary frequency, , QmaxQmax improved improved significantly (p < 0.05)significantly (p < 0.05)More patients in More patients in 90 mg/d90 mg/d group (7/55) and group (7/55) and 6060 mgmg/d/dgroup (4/51) had side effectsgroup (4/51) had side effects

Kawabe K et al. Urol Int. 1993

αα1 Antagonists Still in the Bench1 Antagonists Still in the Bench

WB 4101 hydrochlorideWB 4101 hydrochlorideBMY 7378 BMY 7378 dihydrochloridedihydrochlorideRSRS--1705317053NNiguldipineiguldipine

Advantages (in general):Advantages (in general):BBotulinumotulinum TToxinoxin (BTX) Injection(BTX) InjectionSystemic pharmacologic effects are rareSystemic pharmacologic effects are rare..PPermanent destruction of tissue does not occur. ermanent destruction of tissue does not occur. Graded degrees of relaxation may be achieved Graded degrees of relaxation may be achieved by varying the dose injectedby varying the dose injected..MoMost adverse effects are transient. st adverse effects are transient. PPatient acceptance is high. atient acceptance is high.

BTXBTX--A injection into the prostateA injection into the prostate

BTXBTX--A may potentially be the drug that has dual actions on A may potentially be the drug that has dual actions on the static and dynamic components of the static and dynamic components of BPHBPH.

••SD rat SD rat ••BTXBTX--A injectionA injection••Harvest at 1st and 2nd weekHarvest at 1st and 2nd week

•• inducing apoptosis inducing apoptosis •• inhibiting proliferation inhibiting proliferation •• downdown--regulating regulating αα1A 1A ARsARs

N/S

20U10U

5U

.

Chuang YC et al. J Urol. 2006

BTX BTX Injection:Injection: Clinical ResultsClinical ResultsAuthor Author (yr)(yr)

No. BPH ptNo. BPH pt Dose Dose Efficacy Efficacy A.E.A.E.

Maria G Maria G (2003)(2003)

RCT RCT 30 pts30 pts

BTA 200UBTA 200Uvsvs N/SN/S

SxSx score 65%score 65%↓↓PSA 51%PSA 51%↓↓

NoneNone

KuoKuo HC HC (2005)(2005)

ProspectiveProspective10 hi10 hi--risk pts w risk pts w URUR

BTA 200UBTA 200U 8 excellent; 2 improved 8 excellent; 2 improved ((PvoidingPvoiding, PVR, , PVR, VolVol, , QmaxQmax) )

NoneNone

Chuang YC Chuang YC (2005)(2005)

16 pts (small 16 pts (small prostate)prostate)

BTA 100UBTA 100U All pts improvedAll pts improved((VolVol, SS/, SS/QoLQoL, , QmaxQmax))

NoneNone

Chuang YC Chuang YC (2006)(2006)

8 pts8 pts BTA 200UBTA 200U All pts improvedAll pts improved((VolVol, SS/, SS/QoLQoL))

Chuang YC Chuang YC (2006a)(2006a)

41 pts41 pts BTA 100U BTA 100U (n=21); 200U (n=21); 200U (n=20)(n=20)

75.6% pts improves75.6% pts improves58.3% pts effective>1yr58.3% pts effective>1yr

None None

BTX BTX Injection: Injection: Issues to be solvedIssues to be solved

Detailed mechanism of action?Detailed mechanism of action?No. of injections?No. of injections?Injection route?Injection route?Optimal dose? Optimal dose?

ConclusionsConclusions

ΑΑ--AR antagonist remains to be a mainstay in AR antagonist remains to be a mainstay in the pharmacotherapy for BPH. the pharmacotherapy for BPH. Newer Newer αα--AR subtype antagonists are being AR subtype antagonists are being developed. developed. Extensive basic research on the AR subtypes Extensive basic research on the AR subtypes and the mechanism of action is needed.and the mechanism of action is needed.IntraprostaticIntraprostatic BTX injection may be used in a BTX injection may be used in a selected group of patients.selected group of patients.