Toddlers Retirees Apr 06

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Voiding Function

“Toddlers to Retirees”

April 6, 2006

Christopher French MD FRCSC

Adult and Pediatric Surgery



The Voiding Continuum

Potty Training 2

Bumps along the road 4

Normal Voiding pattern or sometimes

established dysfunctional voiding

Overactive Bladder

It’s my prostate, doc. >50

The aging bladder >70



Clinical Focus on VUR and BPH

Vesicoureteral reflux Deflux “sting’ procedure

BPH Identifying patients who have symptoms

related to the enlarged prostate (or is it anaging bladder)




Potty Training Why not start early

Development window Recurring patterns

Parenting styles




Potty Training Chinese culture- children learn at their own time

Much less dysfunctional voiding in china Is this reporting? What if asia becomes more

westernized?

Pediatric Urologists generally don’t recommend

potty training prior to 18mo of age. There isweak evidence that these children are more

likely to become dysfunctional voiders



The Voiding Continuum Bumps along the road

Dysfunctional voiders Constipation Anxiety Recurring cystitis

A toddler will hold as a response to painful voiding

A bladder that doesn’t empty always feel full



The Voiding Continuum Overactive Bladder

Typically this is urinary frequency without pain, occurs inmen and women in adultyears

Multifactorial Age 30-50 typically Change in body habitus, pelvic fatty deposition,

abdominal girth. Long time dysfunctional voiders may develop autonomic

sensitivity and this may lead to conditions sometimesdescribed as interstitial cystitis




It’s my prostate, doc. All voiding problems for men tend to lay blame on the

prostate OAB symptoms in a 40 man is rarely BPH

But a 60 yo man with symptoms associated with slow

stream is classic for BPH

Men over 80 are more likely to have some degree of impaired contractility. (maybe the BPH becomes

symptomatic more at this point)




The aging bladder The bladder muscle weakens with age Urodynamically impaired contractility Men and women in their 80’s Men tend to have a component of BPH and thus may

respond to treatment General vascular impairment ages the bladder

Diabetics and PVD patients are more likely to havepoorly contractile bladders.




Potty Training

Bumps along the road

Normal Voiding pattern or sometimes

established dysfunctional voiding

Overactive Bladder

It’s my prostate, doc.

The aging bladder



VUR: raising the standard

An educational meetingfor

Pediatric Surgeons/Adult



Vesicoureteral Reflux

(VUR)

Introduction to VUR



Affects approximately 1% of all children

Found in 30–40% of children with recurrenturinary tract infections

Most children are <4 years of age 75–80% of children diagnosed with VUR are

girls

Some congenital anomalies of the

genitourinary tract are associatedwith a high percentage of VUR

[Sargent MA. Pediatr Radiol 2000; 30: 587]

Prevalence



Prevalence

[American Academy of Pediatrics. Pediatrics 1999; 103: 843]

Prevalence

ofVUR

(perce

ntage

ofthe

genera l

pediatricp

op

ulat

ion)

Average Age[Reproduced with permission]



Factors known to affect the risk of VUR

include: Age

Gender

Race

Family history

These factors likely contribute tovariations between prevalence studies

Prevalence



Who to screen

Family history: Sibling with reflux (incidence 24–

51%) Many of these children have no

documented history of symptomaticinfection

Young children are at the greatest risk

Parent with reflux (incidence 66%)

Screen all siblings and offspringof patients with known VUR

[Chertin B and Puri P. J Urol 2003; 169: 1804.Noe HN et al. J Urol 1992; 148: 1869]



VUR d bl dd



VUR and bladder

dysfunction

Approximately half of children with

VUR have detrusor activity and/or

voiding dysfunction In these patients, bladder training

is usually undertaken initially



VUR and the risk of UTI

VUR predisposes to infection of the upper urinarytract Presence of reflux facilitates spread of infected urine

towards the kidneys

Associated likelihood of febrile illness andpyelonephritis – increased morbidity

Significant reduction in febrile UTI observedamong VUR patients treated with open surgery

P t ti l li ti f



Potential complications of

VUR

Renal scarring

Impaired renal growth and renal function

Hypertension End stage renal disease

Pregnancy complications

Pre-eclampsia



Renal scarring

Incidence of renal scars at diagnosisof VUR: 5–30%

Risk of new renal scars: ~2–5%/year

(with antibiotic prophylaxis) 5.6% of children undergoing kidney

transplantation had the primary diagnosisof reflux nephropathy (RN)

Of patients ≥ 15 years of age with refluxnephropathy: 24% had impaired kidney function 38% had hypertension

[Benfield MR et al. Pediatr Transplant 1999; 3: 152.Zhang Y et al. N Z Med J 1995; 108: 142]



Renal scarring

Surgical intervention for VUR reported tohave no significant effect on renal outcomeversus antibiotic prophylaxis

Also no decrease in the incidence of VUR-associated end-stage renal disease

Likely explanation:

Presence of reflux prenatally, or UTI duringearly infancy, may be the primary risks for renal impairment



Reduce UTI-associated morbidity

Eliminate on-going health problem

Avoid the need for future VCUG examinations

No evidence of improved renal prognosis butethical arguments in support of intervention,particularly in high-risk cases

Without treatment, reflux persists for at least 4–5 years in at least half of all cases

The need to treat VUR



Conclusions

Antibiotic prophylaxis may be appropriatein grade I VUR or in infants, but: Potential for development of resistance

Issues of compliance Open surgery is associated with high cure

rates but carries some risk of complications

Endoscopic treatment provides aminimally-invasive treatment alternative for most VUR grades Patients’ parents prefer this option



Managing Patients with

Vesicoureteral Reflux (VUR)



Endoscopic treatment:

historical perspectives

Technique first investigated >20years ago

Rationale, circa 1984: Open surgery entailed hospitalization

for ≥1 week Surgery not free from complications

First injectable agent approved byFDA in 2001

[O’Donnell B and Puri P. Br Med J (Clin Res Ed) 1984; 289: 7]

E d i t t t




STING

Support under the refluxing ureteric orifice

Improved valve mechanism

Fixation of the distal ureter at the

ureterovesical junction

Increased submucosal tunnel length

Ureter

Bladder wall

Bladdermucosa

Defluxinjection




advantages

Like open surgery, a curativetreatment

Outpatient procedure 30-minute operating room time Usually, no need for hospitalization

Efficacy rates can approach thosewith open surgery (depending onreflux grade, injection technique andexperience with the procedure)




disadvantages

Cure is generally less certain than

with open surgery

Possible need for repeattreatments

Poorly recognized in the present

AUA guidelines (published 1997) Anesthesia still required




outcomes

Overall cure rates approximately70–80%

Cure rates potentially affected by: Reflux severity (grade) Surgeon’s experience Injection technique

Need to consider long-termdurability of treatment response

[Austin JC & Cooper CS. Urol Clin North Am 2004; 31: 543.Läckgren G et al. AUA Update series 2003; Volume XXII, Lesson 37: 294]



f



AUA guidelines for managing

VUR

Published in 1997 before US introduction of Deflux®

Extensive literature review: 1965–1994

Seven treatment modalities were examined: Treatment outcomes examined for each

(resolution of reflux, incidence of UTIs, renalscarring etc)

Treatment recommendations developed on

the basis of these data Stepwise decision-making process is

summarized on the following slides

[AUA treatment guidelines 1997, www.auanet.org]



AUA guidelines: infants

(<1 year old)No renal scarring

Grade I–V reflux: antibiotic prophylaxis

Persistent grade I–II reflux: no consensus

Persistent grade III–V reflux: open surgery

Renal scarring present at diagnosis

Grade I–IV reflux: antibiotic prophylaxis

Grade V reflux: antibiotic prophylaxis or open surgery

Persistent grade I–II reflux: no consensus

Persistent grade III–V reflux: open surgery




AUA guidelines: pre-school

children (1–5 years old)No renal scarring Grade I–IV: antibiotic prophylaxis Grade V: antibiotic prophylaxis or open surgery (bilateral:

open surgery is preferred) Persistent grade I–II: no consensus Persistent grade III–V: open surgery

Renal scarring present at diagnosis Grade I–IV reflux: antibiotic prophylaxis (bilateral grade

III–IV: open surgery is a reasonable alternative)

Grade V: open surgery Persistent grade I–II: no consensus Persistent grade III–V: open surgery




AUA guidelines: school

children (6–10 years old)No renal scarring Grade I–II: antibiotic prophylaxis Grade III–IV (unilateral): antibiotic prophylaxis Grade III–IV (bilateral): open surgery

Grade V: open surgery Persistent grade I–II: no consensus Persistent grade III–IV: open surgery

Renal scarring present at diagnosis

Grade I–II: antibiotic prophylaxis Grade III–IV (unilateral): antibiotic prophylaxis Grade III–IV (bilateral): open surgery Grade V: open surgery Persistent grade I–II: no consensus

Persistent grade III–IV: open surgery[AUA treatment guidelines 1997, www.auanet.org]

P d t t t



Proposed new treatment

algorithm

Announced in 2003 Reconsideration of the treatment

options for VUR Major difference from 1997:

availability of Deflux®

Introduction of endoscopictreatment as a routine treatmentoption

[Läckgren G et al. AUA Update Series 2003; Vol XXII, Lesson 37: 294]

P d t t t



*Deflux is approved in the USA for reflux grades II–IV andin children over 1 year of age.

[LäckgrenG et al. AUA Update Series 2003; Vol XXII, Lesson 37: 294]

Proposed new treatment

algorithm

[Reproduced with permission]



Advantages of the new

algorithm

Reduced use of antibiotics

Reduced number of children

undergoing open surgery Patients’ parents prefer endoscopic

treatment over open surgery

Reduced operating room time



Conclusions

Antibiotic prophylaxis may be appropriate ingrade I VUR or in infants, but: Potential for development of resistance

Issues of compliance

Open surgery is associated with high curerates but carries some risk of complications

Endoscopic treatment provides aminimally-invasive treatment alternative for most VUR grades Patients’ parents prefer this option



Issues and

Considerations

pon aneous reso u on



pon aneous reso u onrate

[Elder JS et al. J Urol 1997; 157: 1846]

0

10

20

30

40

5060

70

80

90

100

Grade I Grade II Grade IV -

unilateral

Grade IV -

bilateral

Year 5

Year 4

Year 3

Year 2 Year 1

Resolu

tion

(%)

It takes at least 5 years for grade II

reflux to resolve in 80% of cases



History of prophylaxis Antibiotic prophylaxis was first

conceptualized >40 years ago

Based on limited data from early studies: 75 children with VUR aged 3 weeks to 12 years

received continuous low-dose prophylaxis Followed for 7–15 years 71% spontaneous resolution of VUR 2 cases of new scarring

Early observations of efficacy have notbeen reproduced [Normand ICS and Smellie JM. BMJ 1965; 17.

Edwards D et al. BMJ 1977; 2: 285]



Antibiotic prophylaxis: renal

protection

The International Reflux Study in Children: 12% (19/155) of medically-treated patients

developed new scars during 5 years of follow-

up

Preliminary report of the SouthwestPediatric Nephrology Study Group:

10% of medically-treated patients withgrade I–II VUR, and

28% of patients with grade III VUR

developed new scars during 5 years of

follow-up[Arant BS, Jr. J Urol 1992; 148: 1683.Olbing H et al. J Urol 1992; 148: 1653]



Incidence of breakthrough

urinary tract infections

Approximately 20–40% of patients willdevelop UTIs while on antibiotic prophylaxis for 5years

Infections experienced during ongoing antibioticprophylaxis can result from: Lack of patient compliance with the treatment regimen

Resistant bacterial strains

[Arant BS, Jr. J Urol 1992; 148: 1683. Wheeler D et al. Arch Dis Child 2003; 88: 688]



Patient compliance

Missed doses: Leave the patient open to UTIs Exacerbate the risk of antibiotic resistance

Poor compliance is more likely: In younger children During long-term antibiotic use

[Hoppe JE et al. Pediatr Infect Dis J 1999; 18: 1085]

Patient compliance



Patient compliance

(cont’d) 584 children with bacterial infection requiring oral antibiotics

Most common infections: tonsilitis, otitis media, lower respiratory tract infection, upper respiratory tract infection and sinusitis

Antibiotics received: amoxicillin, penicillin, clarithromycin, cefaclor, erythromycin

Compliance measured by telephone interview and urine bioassay

Overall compliance rate (positive urine test) of 69.5% Negative urine test despite claiming regular administration: 28.8%

[Hoppe JE et al. Pediatr Infect Dis J 1999; 18: 1085]

Patient compliance



Patient compliance

(cont’d)

54 patients underwent bone marrow transplantation

Oral antibiotics required post-transplantation

Retrospective review of patient records:

Only 48% complied with the oral antibiotic regimen

Compliance was significantly lower in preschool and school-agechildren compared with adolescents (p<0.05)

[Phipps S and DeCuir-Whalley S. J Pediatr Psychol 1990; 15: 459]



Compliance with antibiotic

prophylaxis decreases over time84

57

0

20

4060

80

100

6 months 12 months

Compliance

(%)

[Panaretto K et al. J Paediatr Child Health 1999; 35: 454]

n=69

th tibi ti d i



the antibiotic during

prophylaxis

After 12 months of prophylaxis,the urine of only 18% of VUR

patients tested positive for the

antibiotic

[Panaretto K et al. J Paediatr Child Health 1999; 35: 454]



antibiotic resistance

1985

Resistance to commonly-used antibiotics was low

Many classes of antibioticswere effective & available

New antibiotic classes werestill being developed

2005 Resistance to commonly-

used antibiotics is high &increasing

Reduced efficacy of commonly used antibioticclasses as a result of growing resistance levels

Few new antibioticproducts & classes indevelopment

A tibi ti l d i



Antibiotics commonly used in

patients with VUR

Trimethoprim Trimethoprim-sulfamethoxazole

(TMP/SMX) Nitrofurantoin Sulfisoxazole

Amoxicillin Cephalosporins, e.g. cephalothin (1st

generation), cefixime (3rd generation)



Resistance rates: USA 2004Escherichia coli

45.1

21.8

13.9

0

10

20

30

40

50

Ampicillin TMP/SMX Cephalothin

[USA antibiogram results 2004]

Resist a

nce(%)

R i t t



Resistance rates among

urinary tract pathogens

Study performed at a tertiary referralpediatric center in Canada

1,636 urinary tract isolates of Escherichiacoli (E. coli) analyzed from 967 children

Reported resistance rates (1992–94)

Ampicillin: 45% (736 isolates) TMP/SMX: 31% (514 isolates) Both: 22%

[Allen UD et al. CMAJ 1999; 160: 1436]

M lti d i t



Multi-drug resistance: a

global problem

Increase in hospital and community-acquiredcases worldwide

Affects treatment of many diseases including Respiratory infections Skin and soft tissue infections Urinary tract infections

Increased risk of treatment failure, even withthe newer antibiotic classes

[Manges AR et al. N Engl J Med 2001; 345: 1007.Sharma SK and Mohan A. Indian J Med Res 2004; 120: 354]



Multi-drug resistance in the



Multi drug resistance in the

USA

38,835 urinary tract isolates of Escherichia coli (January–September 2000)

Multi-drug resistance level (to three or moreantibiotics): 7.1%

[Sahm DF et al. Antimicrob Agents Chemother 2001; 45: 1402]

Most (58%) multi-drug resistant strains were

resistant to ampicillin, cephalothin andTMP/SMX



Ciprofloxacin resistance

trends in the USAPseudomonas aeruginosa

[Livermore DM. Clin Infect Dis 2002; 34: 634]

Resistance rates are increasingrapidly, even to the newer

antibiotics such as ciprofloxacin

20.523

2729

17.5

0

5

1015

20

25

30

1996 1997 1998 1999 2000Resistance

( %)

[Reproduced with permission

tibi ti i th i k



antibiotics increases the risk

of resistance

Children who had taken antibiotics

for >4 weeks during the previous 6months

were 23 times more likely to haveTMP/SMX-resistant strains of E.coli

[Allen UD et al. CMAJ 1999; 160: 1436]

Implications of antibiotic



Implications of antibiotic

resistance

Individual resistance: there is a high risk of breakthrough UTI

Community-acquired resistance: resistant strains may be

passed to individuals within the community

Multi-drug resistance: second and even third-line antibiotics

may fail to treat the infection

Hospital-acquired resistance: resistant strains may be

transferred between patients in hospital

Exposure to sub inhibitory



Exposure to sub-inhibitory

antibiotic doses

Urine samples taken morning, noon andnight from 14 children receiving TMP/SMX

Sub-inhibitory concentrations wereobserved in almost 1/3 of patients at 1 or more time points

Over 1/5 of samples had dropped into thesub-inhibitory range by the evening

[Pomeranz A et al. J Urol 2000; 164: 1070]

Exposure to sub-inhibitory antibioticconcentrations

encourages development of resistance

sub inhibitory antibiotic



The overall bactericidal effect of

TMP/SMX was sustained for only60% of a 24-hour period inchildren with VUR

No antibiotic coverage for atleast 40% of the day

[Pomeranz A et al. J Urol 2000; 164: 1070]

sub-inhibitory antibiotic

doses

ud i tibilit



decreasing susceptibility over

time

0

20

40

60

80

100

5 15

S u s c e p t i b

l e ( % )

AUC /MIC >10

AUC /MIC <10

Days

[Thomas JK et al. Antimicrob Agents Chemother 1998; 42: 521]

Long-term exposure to lowconcentrations of the antibioticencourages resistance [Reproduced with permission

antibiotic prophylaxis and



antibiotic prophylaxis and

resistance

Continuous antibiotic prophylaxis puts selective pressure on bacteria to mutate into drug-resistant strains

Low dosing increases the risk of exposure to sub-inhibitory concentrations

Poor compliance further reduces the dose received

management option for



management option for

VUR?

Antibiotic resistance has become a seriousproblem – in general practice and in hospitals

A priority issue for the CDC and

WHO – classified as “epidemic”It should be noted that antibioticprophylaxis does not cure theunderlying condition (VUR)



Deflux®: a naturalchoice in the

treatment of VUR



Hyaluronic acid

Exists in all livingorganisms

Low potential for

hypersensitivityreactions (<1%)

Fully biodegradable Used extensively in eye

surgery and jointinjections



NASHA technology

Hyaluronic acid is produced using

cultured bacteria Limited potential for allergic reaction

The hyaluronic acid undergoes a

stabilization process Increased durability

ex ranomer



microspheres

Polymer of glucose (cross-linked

dextran)

Microspheres 80–250 µ m indiameter

Deflux does not migrate



Dextranomers labeled with 125 Iodine and mixedwith Deflux

Deflux injected into the submucosal space in the

bladder of 6 rabbits

Blood samples taken:1 hour, days 1–14, and

days 21 and 28

Whole-bodyautoradiography:

at days 1, 7 and 28Tissue samples taken: brain, lung, liver, spleen andbladder after 1, 7 and 28 days; urine was sampledat the same times


from the site of injection

[Stenberg ÅM et al. J Urol 1997; 158: 1937]





from the site of injection

Thyroid

BladderBladderThyroid

[Stenberg ÅM et al. J Urol 1997; 158: 1937]

Results

Preclinical safety



Preclinical safety

Preclinical study: methods

Pigs (n = 9)

urinary bladder

Rats (n= 34)

subcutaneous[Stenberg Å et al. Scand J Urol Nephrol 1999; 33: 355]

Histopathological results in



p g

animals

Blood

vessels

Capsule

Dextranomers

Collagen

fibersDextranomers

Pigs

Rats

[Stenberg Å et al. Scand J Urol Nephrol 1999; 33: 355]

[Reproduced with permission

I D fl f i h ?



Clinical study: method

Is Deflux safe in humans?

(histopathology)

[Stenberg A et al. J Urol 2003; 169: 1109]

13 children aged 1–11 years, with persistent reflux grade

III–V following treatment with Deflux

Referred for open surgery (ureteral reimplantation) 10 patients with a similar reflux grade, but no previous

endoscopic treatment, were included as controls

Sections of the Deflux implant were collected and

examined under the light microscope



Histopathological results:



Histopathological results:

conclusions

The observed inflammatory reaction was a

natural and expected response to any

foreign substance being introduced into the

body

No evidence of allergic reaction, granuloma

formation or development of tumors

Infiltration of collagen fibers stabilizes the

implant, increasing long-term durability



The Deflux treatment procedure

Deflux: the treatment procedure



Deflux: the treatment procedure

(Subureteric transurethral injection, STING)

Ureter

Position of the

Defluxinjectio

n

Bladder

Urethra

Cystoscope

Deflux: the treatment proced



Deflux: the treatment proced

(Subureteric transurethral injection, STI

Items required for endoscopic



Items required for endoscopic

injection of Deflux

1) Cystoscope: minimum 4 Fr channel

2) Narrow metal needle

3) Pre-filled Deflux syringes4) Video camera

5) Sodium chloride solution

[manufactured by Wolf]

How and where Deflux is



How and where Deflux is

injected

Ureter

Bladder wall Deflux is injectedinto the bladder

submucosa,

2–3 mm below the

refluxing ureter

Deflux implant

Technical aspects of Deflux




treatment: STING

• Semi-full bladder

• 6 o´clock position

• Inject submucosally

• Volcano shaped bulge• Crescent-like orifice




p

treatment (cont’d)

Standard follow-up



procedure

Ultrasound after 1 month

Voiding cystourethrogram (VCUG)

after 3 months

Bulge

Conclusion



Conclusion

Both components of Deflux are biodegradable andbiocompatible (both have established medicalapplications)

Long-term persistence (post-treatment infiltration with endogenous collagen)

corresponds with a long-term clinical response (see efficacy section; long-term data

are being generated in an ongoing study in the USA)

Low potential for allergic or immunogenic reactions



Clinical Experience

Deflux is indicated for treatment of

children with vesicoureteral reflux

Response to Deflux: early



data*

68

1319

0

2040

60

80

100

Resolved

(grade 0)

Improved

(grade I/II)

Unchanged

(grade III/IV)

Response to Deflux treatment

Urete

rs(%)

[Stenberg A and Läckgren G . J Urol 1995; 154: 800] *STING technique

110 ureters with grade III–IV reflux treated

Response to Deflux: recent



data*

[Kirsch AJ et al. J Urol 2004; 171: 2413]

89

7063

0

20

40

60

80

100

II (n=35) III (n=30) IV

(n=8)

Respo

nserate

(pat

ients,%

)

Baseline reflux grade

*STING technique

Ureterstreated:



Duration of response*

Study investigating Deflux* treatmentof VUR in uncomplicated cases

• Children over 12 months of age

• Persistent reflux, grade III–V†

• Contralateral reflux grade I–II also treated

• Patients with neurogenic bladder or those

who had received previous treatments for

VUR were excluded

[Läckgren G et al. J Urol 2001; 166: 1887] *STING technique

†Deflux is indicated for treatment of children withvesicoureteral reflux (VUR) grades II–IV

Duration of response*



Study population: 221 patients, 1–15 years old(72 boys, 149 girls; mean age 4.7 years)

Followed clinically for 2–7.5 years(mean 5 years)

67 patients retreated (29%)

*STING technique [Läckgren G et al. J Urol 2001; 166: 1887]

Duration of response



Initial response rates *

VUR resolved (grade ≤ 1) in

68% of 221 patients, tested by

VCUG3–12 months following Deflux

treatment




Repeated treatments*



Repeated treatments (if required)

*STING technique

0

20

40

60

1st treatment 2nd treatment3rd treatment

Responsera

te

(patie n

ts,%

)

[Läckgren G et al. J Urol 2001; 166: 1887]

L t t t t ff t



Long-term treatment effect *

Lack of deterioration after initial response

87% of ureters without reflux at

3–12 months post-treatment were

free from reflux at 2–5 yearsof follow-up

96% remained free of dilating reflux (grade III or

above)




Approved endoscopic



treatments

Deflux was approved by the FDA in 2001 for the treatment of

children over 1 year of age with VUR grades II to IV

Deflux is currently the only material approved by the FDA for this

indication

Studies using the STING technique were fundamental to approval of

Deflux by the FDA

Standard treatmentd



procedure

Implantation 2–3 mm below the

entrance to the ureter – subureteric

Access to the bladder gained via the

urethra – transurethral

Injection into the bladder submucosa

“STING”(Subureteric transuretral injection)



R lt i th HIT



Results using the HIT

71

89

0

20

40

60

80

100

STING HIT

Cure

rate

(patie

nts,%

)

Procedure


(n=52) (n=70)

T l bilit



Tolerability

Deflux has been used in Europe for over a decade

30,000 children with VUR have been

treated worldwide

Studies of Deflux treatment reveal: Low risk of complications No reported persistent adverse events No reported allergic reactions

Risk of treatment-related



adverse events

Adverseevent

Randomizedstudy (n=39)

Nonrandomizedstudies (n=170)

UTI 6 (15.4%)* 13 (7.6%)†

Ureteraldilatation

1 (2.6%) 6 (3.5%)

Nausea/vomiting/Abdominal pain

0 (0%) 2 (1.2%)

*Antibiotics continued for 1 month post-treatment.†Antibiotics continued for 3 months post-treatment and in cases of persistent reflux.



C t l t l fl



Contralateral reflux


• Contralateral reflux (de novo reflux inthe untreated ureter) is a possiblecomplication of both endoscopicinjection and open surgery

• De novo contralateral reflux has beenreported in between 5% and 16% of patients following Deflux treatment in

recent studies

Post treatment options



Post-treatment options

If Deflux treatment has failed

to resolve the VUR, presence

of the implant does notcomplicate subsequent

surgical procedures to correct

the reflux if required

Summary of Deflux tolerability

d t



data

Study Tolerability informationLäckgr en2001

Free from complications in all310 procedures. Post-treatmentUTIs in 8% (19/221) of patientsduring 5 years of follow-up.

Capozza 2002

Post-treatment UTIs in 6 of 39children – all successfully

treated with antibiotics.Kirsch2003

No hydronephrosis at 12 monthsof follow-up. New contralateralreflux in 4.5% (6/134).

[Läckgren G et al. J Urol 2001; 166: 1887. Capozza N and Caione P. J Pediatr2002; 140: 230. Kirsch AJ et al. J Urol 2003; 170: 211. Kirsch AJ et al. J Urol

2004; 171: 2413]

Conclusion



ConclusionMost patients can expect to be cured (reflux

grade 0) following Deflux treatment*

*Deflux is approved for reflux grades II–IV in children

over 1 year of age

Success rate is expected to rise further with increased experience andadaptations to the technique

Low risk of complications and treatment-related

adverse events

AUA guidelines recommend that parental preference is consideredwhen choosing an appropriate treatment for VUR

Contraindications



Contraindications

Non-functional kidney(s)

Hutch diverticuli

Duplicated ureters Active voiding dysfunction

Ongoing urinary tract infection

[Deflux package insert USA]

Warnings



Warnings

Do not inject Deflux intravascularly Injection of Deflux into blood vessels

may cause vascular occlusion


Precautions



Precautions DEFLUX should only be administered by qualified physicians

experienced in the use of a cystoscope and trained insubureteral injection procedures

The risks of infection and bleeding are associated with the

cystoscopic procedure used to inject DEFLUX. The usual

precautions associated with cystoscopy (e.g., sterile

technique, proper dilation, etc.) should be followed

The safety and effectiveness of the use of more than 6 ml of

DEFLUX (3 ml at each ureteral orifice) at the same treatment

session have not been established

The safety and effectiveness of DEFLUX in the treatment of

children under 1 year of age have not been established


Precautions (cont’d)



DEFLUX is supplied prefilled in a 1 ml syringe with a luer lock fitting, and is intended for single use only. Carefullyexamine the unit to verify that neither the contents nor thepackage has been damaged in shipment. DO NOT USE if damaged. Immediately return damaged product to Q-MedAB

DEFLUX is supplied sterile. Do not re-sterilize, as this maydamage or alter the product

DEFLUX is supplied in a syringe ready for use. Never mixDEFLUX with other products

DEFLUX is stored up to 25°C, and used prior to theexpiration date printed on its label. Do not expose DEFLUXto either sunlight or freezing, as this may damage or alter the product. Do not use DEFLUX after its expiration date

Precautions (cont d)


C



Evolving Concepts in

the Treatment & Management

of Benign ProstaticHyperplasia

(BPH)



Table of Contents

Epidemiology & Definitions

Evaluation

Treatment & Management BPH & Sexuality

Conclusions



Epidemiology

& Definitions

Prevalence of BPH



Prevalence of BPH

15 25 35 45 55 65 75 85

0

20

40

60

80

100

Age (years)(Oesterling JE. Arch Fam Med 1992;1(2):257-66)

%

PrevalenceMicroscopic

BPH

• USA• England• Denmark• Austria• India• Japan

Men Requiring Treatment



Men Requiring Treatment

25%25%

(Jacobsen SJ, et al. J Urol 1999;162:1301-6)

BPH Components



StaticStatic DynamicDynamic

Increased glandular

tissue & stroma

Increased

muscle tone

BPH Components

(Lepor H. Int J Clin Pharmacol Ther Toxicol 1989;27(4):151-5;

McNeal J. Urol Clin North Am 1990;17(3):477-86)

Lower Urinary Tract Symptoms(LUTS)



(LUTS)

ObstructiveObstructive

(voiding)(voiding)IrritativeIrritative

(filling)(filling)

• Weak stream

• Hesitancy

• Sensation of

incomplete emptying

• Intermittent stream

• Prolonged urination

• Frequency

• Nocturia

• Urgency

• Urge incontinence

(Barry MJ, et al. J Urol 2000;164:1559-64; Kursh ED. Urology News; clevelandclinic .org ;

Ouslander JG. Am J Med Sci 1997;314(4):214-8)

Q lit f Lif I d (Q L)

http://www.clevelandclinic.org/






Scale

Delighted

Terrible

Age (years)

Quality of Life Index (QoL)

0

1

2

3

4

5

6

50 - 59 60 - 69 70 - 79

Never

Mild

Moderate

Severe

0.2

1.2

2.9

4.5 4.4 4.3

2.9

2.7

1.4

0.4

1.2

0.4

(MSAM-7. Global Results.

XVIIth EAU Congress, Birmingham UK, Feb 2002, Sanofi-Synthelabo satellite)

Urinary problems (IPSS)

C lt ti f U i S t



0

10

20

30

40

5060

70

80

90

100

50 - 59 60 - 69 70 - 79

Mild

Moderate

Severe

% Patients

Age (years)

(Kirby R. XVIIth EAU Congress, Birmingham UK, Feb 2002, Sanofi-Synthelabo satellite)

5

25

63

9

34

70

15

43

74

Consultation for Urinary Symptoms

Urinary problems (IPSS)

M di ti f U i S t



0

10

20

30

40

5060

70

80

90

100

50 - 59 60 - 69 70 - 79

Mild

Moderate

Severe

% Men

treated

Age (years)

2

10

35

4

20

44

7

26

48

Medication for Urinary Symptoms

Urinary problems (IPSS)5% of men reported having undergone surgery

(MSAM-7. Global Results.

XVIIth EAU Congress, Birmingham UK, Feb 2002, Sanofi-Synthelabo satellite)

Epidemiology & Definitions:

C l i



Conclusions

BPH is a very common problem

BPH impacts on Quality of Life

Very few patients are treated



E l ti f LUTS



Evaluation of LUTS

• History

• Physical examination

• IPSS

• Urinalysis

• PSA (highly recommended)

(Roehborn CG. Rev Urol 2001(Roehborn CG. Rev Urol 2001;3(3):139-145, 5th Int Consultation on BPH)3(3):139-145, 5th Int Consultation on BPH)

Patient Histor



Patient History

• General health

• Dietary & fluid intake

• Urinary symptoms

• Previous surgery

• Previous urinary problems (infections, stones)

• Family history of prostate problems

• Medical review

Evaluation of Symptoms



Evaluation of Symptoms

International Prostate Symptom

Score(IPSS) Internally consistent, reliable

Easy to use

(Barry MJ. Urol 2001;58(Suppl 6A):25-32; Barry MJ et al. J Urol 1992;148(5):1549-57)



(Barry MJ. Urol 2001;58(Suppl 6A):25-32)



If you were to spend the rest of your life with your urinary condition just the way they have been during the last week, how would you feel about that?


Differential Diagnosis




Phimosis

Vesicosphincter

dyssynergia

Bladder cancer

Stenosis of Stenosis of

urinary meatusurinary meatus

Urethritis

Urethral carcinoma

Hypertrophy or stenosis of

bladder neck

Cystolithiasis

Neurogenic

MyogenicCystitis

Bladder Bladder dysfunction (diabetes)dysfunction (diabetes)

Polyuria

Extrinsic

pelvic mass

BPHBPH

Prostate Cancer Prostate Cancer

UrethralUrethral

stricturestricture

(Ouslander JG. Am J Med Sci 1997;314(4):214-8;

Kasraeian A. www.dcmsonline.org; other references upon request)


http://www.dcmsonline.org/








Stenosis of Stenosis of

urinary meatusurinary meatus

Bladder Bladder dysfunction (diabetes)dysfunction (diabetes)

BPHBPH

Prostate Cancer Prostate Cancer

UrethralUrethral

stricturestricture

(Ouslander JG. Am J Med Sci 1997;314(4):214-8;

Kasraeian A. www.dcmsonline.org; other references upon request)

MedicationsMedications• AnticholinergicsAnticholinergics

• AntidepressantsAntidepressants• DecongestantsDecongestants








Possible Findings on DRE



Possible Findings on DRE

NormalNormal TendernessTenderness

SymmetricalSymmetrical

Enlargement (BPH)Enlargement (BPH)

AsymmetryAsymmetry IndurationInduration NodularityNodularity



PSA Testing Yes or No?



PSA Testing – Yes or No?

Pros Increases cancer

detection rate

May detect cancersearlier

Inexpensive

No patient morbidity

Cons Substantial false

positive rate

False positives triggersadditional tests

False negative rate

Not proven to prolong

survival

(AUA. Oncology 2000;14:267-86;CMQ 1998;www.cmq.org/Prostateang.pdf;CPSM 1995;

www.umanitoba.ca/academic/colleges/cps/guidelines_and_statements/317.html;

Sarkar P,et al. Int J Pharm 2002;238(1-2):1-9;Gander L (HSURC) 2000;www.hsurc.sk.ca)

Guidelines for Early Detection of

Prostate Cancer



Prostate Cancer

DRE and PSA test Increase the early detection of prostate cancer

Indicated when prostate cancer is suspected

Indicated in the management of prostate cancer

(CUA 1996;www.cua.org/guidelines/earlydetection.html; CPSM 1995;

www.umanitoba.ca/academic/colleges/cps/guidelines_and_statements/317.html;

CMQ 1998; www.cmq.org/Prostateang.pdf)

Guidelines for PSA Testing



Guidelines for PSA Testing

“No Canadian organization currently recommends routine

screening of asymptomatic men for prostate cancer,

regardless of age [due to] lack of evidence that better

health outcomes result from screening.”

(Gander L (HSURC) 2000;www.hsurc.sk.ca)

“Men [considering these tests] should be made aware of

the potential benefits and risks.”

(CUA 1996;www.cua.org/guidelines/earlydetection.html)

Interpretation of PSA Values,

with Normal DRE



with Normal DRE

PSA ValuePSA Value InterpretationInterpretation0.5 – 2.5 ng/mL Very low risk of cancer

2.5 – 4 ng/mL Low risk of cancer

4 – 10 ng/mL Refer: 24% chance of cancer

> 10 ng/mL Refer: 63% chance of cancer

Rise > 20%/yr Refer

(CMQ 1998, www.cmq.org/Prostateang.pdf; AUA. Oncology 2000;14(2):267-86;

Kirby RS. Prog Clin Biol Res 1994;386:333-43)



Evaluation: Conclusions



Evaluation: Conclusions

Evaluation is simple

Majority of patients do not require

a urological evaluation



Treatment &Management

Management of BPH in Family

Medicine



MedicinePatient must be involved in all decision-

makingInitial EvaluationInitial Evaluation• HistoryHistory

• ExaminationExamination

• UrinalysisUrinalysis

• PSA recommendedPSA recommended

7 or less7 or less 8 or more8 or more

WatchfulWatchfulWaitingWaiting

Consider Consider treatmenttreatmentalternativesalternatives

(Roehborn CG. Rev Urol 2001;3(3):139-145, 5th Int Consultation on BPH

Gurunadha Rao Tunuguntla HS. Clin Geriat 2002;10(5):20-5)

BPH

complications

IPSS & QOL

Indications

for referral

No response toNo response totherapytherapy

AbnormalAbnormalbaseline testsbaseline tests

PatientsPatientspreferancepreferance

Indications for surgical therapy



Indications for surgical therapy

Patient must beinvolved in alldecision-making

Patient’s refusal toreceive pharmaco

therapy

Indications for surgical

intervention

Failure of drugFailure of drugtherapytherapy

ComplicationsComplications

Transurethral Resection of Prostate

(TURP)



(TURP)

ResectoscopeResectoscope

Bladder Bladder

ProstateProstate

Removal of Removal of

HypertrophiedHypertrophied

TissueTissue



in Favour of PharmacologicTreatment



(Holtgrewe HL. Urology 1998 Apr;51(4A Suppl):1-7;

Baine WB, et al. J Urol 1998 Sep;160(3 Pt 1):816-20)

Early 1990s: Surgical treatment sharply declined Due to the advent of medical therapy

Selective, long-lasting α 1-blockers aremost popular

Primary-care physicians have a veryactive role

Medical Therapy



Medical Therapy

55α -reductase-reductaseinhibitorsinhibitors

α -blockers-blockers

Non-selective Uroselective

(Narayan P, et al. Urol 1998;51(Suppl 4A):38-45)

5a-Reductase Inhibitors



5a Reductase Inhibitors

One agent – finasteride

Improves LUTS in men with large prostate

(DRE, PSA, TRUS)

Reduces risk of retention and surgery

Has long latency period before effect

Reduces PSA (50% at one year)

Alters sexual function

(Gurunadha Rao Tunuguntla HS. Clin Geriat 2002;10(5):20-5; Kasraeian A. www.dcmsonline.org ; Gormley GJ, et al. NEJM

1992;327:1185-91)

Finasteride 5mg Daily, 12-months








% Change

from Baseline

Prostate

Volume

P<0.001

Total

Symptom

Score

P<0.001

Peak

Urinary

Flow Rate

P<0.001(Gormley GJ, et al. NEJM 1992;327(17):1185-91)

P values are compared to placebo

Finasteride 5mg Daily, 12 months

-30

-20

-10

0

10

20

30 22%

-21%-19%

Finasteride – Long-Term Results



Finasteride Long Term Results

Open extension of the 12-month trial

3-year follow-up

Prostate volume continued to decrease 19 - 26% below baseline at 12 months

27% below at 36 months

Flow rates and symptoms continued to improve

Long-term results are based on a total of 297men

(Stoner E. Urol 1994;43(3):284-92)

α -Blockers in BPH

Mechanism of action



Mechanism of action

• Blockα -adrenoreceptors

• Relax smooth muscle

Ø the α -adrenoreceptor = relax smooth muscle

in the prostate and bladder neck

(Gurunadha Rao Tunuguntla HS. Clin Geriat 2002;10(5):20-5;

De Mey C. Eur Urol 2000;38(Suppl 1):25-39)

Ø

α -Adrenoreceptors



α Adrenoreceptorsα

α 1 α 2

α 1A α 1B α 1D α 2A α 2B α 2Cα

1L

α -Blockers



α oc e s

Have rapid onset of action

Useful in large or small prostates

Two types: Non-Selective

terazosin

doxazosin

Selective Tamsulosin (α 1A subtype)

Alfuzosin (uroselective)

(Hofner K, et al. World J Urol 2002;19:405-12; Roehborn CG. Urol 2001;58(Suppl 6A):

55-64; Gurunadha Rao Tunuguntla HS. Clin Geriat 2002;10(5):20-5)

Effect of α -Blockers on Flow



A meta-analysis Placebo-controlled studies of 6,333 patients Direct comparative studies of α -blockers (alfuzosin, terazosin,

doxazosin and tamsulosin)

507 patients Efficacy defined as % improvement in total symptom score and

peak urinary flow (Qmax) All α 1-adrenoceptor antagonists seem to have similar efficacy in

improving symptoms and flow General improvement

Total symptom score by 30-40% Qmax by 16-25%

(Djavan B, et al. Eur Urol 1999;36(1):1-13)



Effect of α -Blockers on

Total Symptom Score*



(Chapple CR. Br J Urol 1998;81(Suppl 1):34-47)

y p

% Change from baseline% Change from baseline Drug Placebo P value

Alfuzosin SR** (n=390) -31 18 0.007

Terazosin (n=2084) -38 -18 <0.001

Doxazosin (n=156) -17 -9 <0.01

Tamsulosin (n=288) -35.8 -23.7 0.002

* Results from 4 clinical trials; dose/regimen is not comparative** SR = sustained-release formulation 5 mg BID

XATRAL® Once Daily



Swelling Eroding

Time (h)0

Alfuzosin extended-release

Three-layer GEOMATRIX ® Tablet

20

(Hofner K, et al. World J Urol 2002;19:405-12)

XATRAL® Delivery System



20

1. Swelling and slow diffusing2. Slow constant diffusing

3. Eroding & final dissolution

% Dose

Time (hours)

100

6 12

50

2

1.

3.

2.

(Hofner K, et al. World J Urol 2002;19:405-12;

Roehborn CG. Urol 2001;58(Suppl 6A):55-64)

Pharmacoscintigraphic Study inFed vs. Fasted Conditions



14 Fasted

Fed

2 4 6 148 10 12 2016 18 24220

2

4

6

8

10

12

Alfuzosinplasma

levels (ng/mL)

Time (hours)(Roehborn CG. Urol 2001;58(Suppl 6A):55-64)

XATRAL® Efficacy

IPSS Score



********

Time (days)

IPSS score

0 28 56 84

14

15

16

17

18

19

PlaceboAlfuzosin

10mg OD

P < 0.01P < 0.001*****

(Roehborn CG, et al. Urol 2001;58:953-9)

IPSS Score

XATRAL® Efficacy

Peak Urinary Flow Rate



******

Time (days)

Qmax(mL/s)

0 28 56 84

9

9.5

10

10.5

11

11.5

PlaceboAlfuzosin

10mg OD

P < 0.001***

12


Peak Urinary Flow Rate

Occurrence of OrthostaticHypotension at Anytime During Treatment




Placebo Alfuzosin

10mg OD

Hypertensive patients

Orthostatic hypotension* 9.3% 1.7%

Overall incidence

Orthostatic hypotension* 4.3% 4.3%

* Decrease on SBP ≥ 20 mmHg, standing compared to supine position

Tamsulosin vs. Alfuzosin:Symptom Score



Time (weeks)0 2 6 12

6.5

7.5

8.5

9.5

10.5Alfuzosin

2.5mg TID

Tamsulosin

0.4 mg OD

11.5

Mean

Total

Symptom

Score

(Buzelin JM, et al. Br J Urol 1997;80:597-605)

UroselectivityTamsulosin vs. Alfuzosin: Qmax



10

10.5

11

11.5

12

12.5

Mean Qmax

(mL/s)

0 2 6 12

Time (weeks)

Alfuzosin

2.5mg TID

Tamsulosin

0.4 mg OD

(Buzelin JM, et al. Br J Urol 1997;80:597-605)

Uroselectivity – α 1A Subtype

Tamsulosin



(Roehrborn CG. Urol 2001;58(6 Suppl 1):55-63)

Receptor distribution: 70% α 1A subtype is in prostate,

bladder neck & vas deferens

Functional impact: More effect on urethral pressure

compared to vascular effect

α 1A Uroselectivity

Tamsulosin



Could be advantageous when considering

cardiovascular side effects

Could also be a liability when considering

ejaculatory problems

Uroselectivity without selectivity for α 1A

should be advantageous for ejaculatory

health



Alfuzosin: Overview (cont’d)



Alfuzosin has been shown to concentrate in the

prostate

Alfuzosin does not penetrate the

blood/brain barrier

(Roehborn CG. Urol 2001;58(Suppl 6A):55-64;

Martin DJ, et al. Life Sci 1998;63(3):169-76)

α -Blockers: Overview



Similar efficacy

The efficacy remains long-term (5-year data is

currently available)

The difference between a1-adrenoceptor blockers is related to the side effect profile

(uroselective agents are better tolerated)

Alfuzosin and tamsulosin appear to be better tolerated than doxazosin, terazosin and prazosin

(Roehborn CG. Urol 2001;58(Suppl 6A):55-64)

Treatment & Management:

Conclusions



Some treatments can negatively impact

sexuality decreasing QoL

Alfuzosin 10mg OD has few side effects

Alfuzosin 10mg OD is as effective as other α -blockers in relieving LUTS due to BPH




Potty Training 2

Bumps along the road 4

Normal Voiding pattern or sometimesestablished dysfunctional voiding

Overactive Bladder

It’s my prostate doc >50

Toddlers Retirees Apr 06

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