Propiverine hydrochloride vs previous anticholinergic agents (For Overactive Bladder)
Future treatment modality of overactive bladder
description
Transcript of Future treatment modality of overactive bladder
LOGO
Future treatment
modality of overactive
bladder
Future treatment
modality of overactive
bladder
Duk Yoon Kim
Professor, Department of Urology
Daegu Catholic University Medical Center(DCUMC)
Daegu, Korea
Contents
Summary Summary
ApproachApproach
Alternatives Alternatives
Candidates: Pharmaceuticals
OAB Management: where we stand?
1. Terminology -Symptom complex of storage symptoms ≠ urodynamically proven detrusor overactivity (DO)
OAB syndrome LUTS/OAB OAB in male (men)/female (women) Idiopathic/Neurogenic OAB OAB wet/dry
Multifactorial
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2. Epidemiology- NOBLE(National Overactive Bladder Evaluation)
16%:16.9% (M:W)- Japanese survey 12.4%(>40), 20%(>70), 35%(>80)- EPIC: 11/13 % (M:W)- K-EPIC: similar- Overall: 8.0-13.9%
Cartwright R. et al. Current opinion in OB & GY 2008
3. Still hidden Disease?
Yes, it is.
4. Natural history ?
Symptoms fluctuate over time
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Summary Summary
ApproachApproach
Alternatives Alternatives
Candidates: Pharmaceuticals
Neurotransmitters
Understanding of Pathways, Neurotransmitters
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Central
- Gabepentin
- NK1 receptor
antagonists
- Tramadol
- Opioids
- 5-HT/Na re-uptake
inhibitor
Peripheral
- Mucosal signaling drugs
- Myocyte signaling drugs
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Centrally acting:Gabapentin
Anticonvulsant Peripheral neuropathic pain relieve
Action mechanisms in bladder : Inhibitory activity on afferent C-fibers activity High affinity to the ɑ-2- σ subunit Ca channels reduce L-type current(A-, σ-fibers) reduce detrusor contraction after submucosal
receptor stimulation - Modify afferent input from periphery - Decreases the glutamate release modulated by substance-P facilitated effect
Carbnone A. clin Neuropharm.., 2006
Gabapentin: Refractory OAB
Refractory OAB(tolterodine, oxy. 8 weeks)/nocturia
100-300mg3,000mg, bedtime
YT KIM et al. Int. Braz. J Urol, 2004
Baseline 12 weeks
Frequency(n=31) Improved(n=11) 14.1± 2.2 10.0±2.1* p=0.01
No Improvement(n=20) 13.6±1.9 12.5±3.1
Nocturia(n=7) Improved(n=3) 4.0±1.3 1.0±0.3** p=0.03
No Improvement(n=4) 4.3±1.3 4.0±1.0
Gabapentin: Neurogenic OAB
Neurogenic OAB, 16 pts
31 days
300mgX 3days
600mgX 3days900mg
Carboe A. et al. Clin. Neuropharma, 2006
Results
Before Treatment After Treatment
Micturition/day 7±4 5±1.2
Urgency/day 13±3 8±0.7
Incontinence/day 3±2 1±0.3
Pad use/day 2±0.76 1±0.5
Centrally acting:Tramadol
Analgesic drug Action on IDO
Inhibit the function of M1, M3 Rc Inhibit serotonin, noradrenalin reuptake : bladder relaxation through ß-Rc, dopamine activation, stimulation of µ- & delta-opioid
Rat: inhibit micturition below analgesic level suppress apomorphine-induced IDO (dopaminergic)
Grond S. Clinical Phramcokinet. 2004
Iran Study Double-blind, placebo-controlled, randomized
study in efficacy and safety of tramadol IDO 76>18 100mg SR bid X 12 weeks
Safarinejad MR J Clin Pharmacol. 2006
Voiding and urodynamic variables
Adverse events
Tramadol (%) Placebo (%) P-value
Adverse events 13(34) 6(15.8) <0.05
Nasea 7(18.4) 2(5.3) <0.05
Vomiting 3(7.9) 2(5.3) NS
Dizziness 2(5.3) 1(2.6) NS
Constipation 1(2.6) 0 NS
Centrally acting: Aprepitant
Selective, CNS penetrating NK-1-Rc antagonist Originally, agents for chemotherapy-induced N/V
double-blind, randomized, placebo controlled, parallel group pilot study
postmenopausal women with urge urinary incontinence or mixed incontinence (with predominantly urge urinary incontinence)
160 mg capsule of aprepitant (61) or placebo (64) once daily for 8 weeks.
Stewart AG et al. J Urol 2006
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Average daily micturitionsAverage daily urgency
episodes
Peripheral-mucosal
Inhibitors/Antagonists of COX/Prostanoid Receptors
Clinical evidence: scare Non-selective: flurbiprofen, indomethacin urodynamically, clinically- effective N/V/GI, headache- high : Ketoprofen, intravesical, oncex4weeks 18/30 women, IDO symptom free
Company LogoCardozo LD, et al. Br Med J 1980. Cardozo LD. J Urol 1980 Palmer J. 1983. Sprem M, et al. Croat Med J 2000
Cardozo LD, et al. Br Med J 1980. Cardozo LD. J Urol 1980 Palmer J. 1983. Sprem M, et al. Croat Med J 2000
Transient Receptor Potential (TRP) channel subfamily
TRPV1: essential for the generation of noxious input, bladder reflex overactivity
GRC-6211, TRPV1 antagonist: highly effective for decreasing the bladder reflex overactivity, noxious input (Capsaicin/LPS model)
Ana C et al. J Urol 2009
Acetic acid model
Peripheral-myocyte
β3-Rc: detrusor>urothelium
Trp 64 Arg polymorphism in the β3-AR gene is associated with idiopathic
OAB symptom
Relaxation of detrusor muscle
β3-adrenoceptor agonists :YM-178(14/16), GW427353, KUC7483
Yamaguchi, Neurourol. 2007
PDE5 inhibitors
Relaxation effects on urethral smooth muscles in afferent signal
PDE5i -Sildenafil, suppress smooth muscle spontaneous activity -Vardenafil, sig. reduced nonvoiding contractions -DA8159, decreased urethral pressure
PDE4i - IC485, reduce bladder overactivity - rolipram, decreased amplitude/frequency of contractility
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Vitamin D3 agonist:elocalcitol
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• Development by BioXell SpA
• Synthetic derivative of vitamin D3
• Regulates cell proliferation, apoptosis via its binding to the vitamin D receptor
• Preclinical studies: inhibited the androgen-dependent and androgen-independent proliferation of benign prostatic hyperplasia (BPH) cells more potently than finasteride
• Development by BioXell SpA
• Synthetic derivative of vitamin D3
• Regulates cell proliferation, apoptosis via its binding to the vitamin D receptor
• Preclinical studies: inhibited the androgen-dependent and androgen-independent proliferation of benign prostatic hyperplasia (BPH) cells more potently than finasteride
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• phase IIb trial, BPH: a significantly reduced prostate volume compared with placebo; irritative urinary symptoms (frequency, urgency and nocturia) and urodynamic parameters- comparable to tamsulosin.
• phase IIa trial in patients with prostatitis: significantly reduced levels of IL-8 in semen, improved quality and forward motility of sperm.
• phase IIb trial data, overactive bladder (OAB): failed to meet the primary endpoint
• BioXell: decided to terminate all further clinical development of elocalcitol, including an uncompleted phase IIa trial in patients with male infertility.• Given the novel mechanism of action, efficacy profile and improved tolerability of elocalcitol over existing classes of drugs, the compound could have potentially added to the armamentarium in the expanding therapeutic markets of BPH, OAB and male infertility. • This possibility appears to have been negated by BioXell's recent decision to terminate all further development of elocalcitol.
• phase IIb trial data, overactive bladder (OAB): failed to meet the primary endpoint
• BioXell: decided to terminate all further clinical development of elocalcitol, including an uncompleted phase IIa trial in patients with male infertility.• Given the novel mechanism of action, efficacy profile and improved tolerability of elocalcitol over existing classes of drugs, the compound could have potentially added to the armamentarium in the expanding therapeutic markets of BPH, OAB and male infertility. • This possibility appears to have been negated by BioXell's recent decision to terminate all further development of elocalcitol.
Drugs in clinical phases of development (2007)
Drugs in clinical phases of development (2008)
Summary Summary
ApproachApproach
Alternatives Alternatives
Candidates: Pharmaceuticals
Alternatives/2ndary modalities
sacral neuromodulation (SNM)
• botulinum toxin (BTX)
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Cystoplasty/diversion: 20cm ileumLaparoscopic/robotic
Medical therapy
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Complete Continence: treatment Success Definition by Intervention
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≥50% Improvement in Incontinence episodes or Other Symptoms: Treatment Success Definition by Intervention
Ways to go
Target therapy (receptor, organ, origin) possible?
Individually selectives possible?
Adequate Efficacy without AE possible?
Complete remission possible?
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Thought to ponder Take Home Point
Summary & Conclusion
Development of therapeutic options of OAB is complicated.
Future promising drugs -phosphdiesterase inhibitors -GnRH antagonists -VitD3 analogs -EP-1-receptor antagonists -TRPV1-receptor antagonists -Central-acting drugs (gabapentin)
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Selective targeting of receptors/ion channels or a disease–specific form of the receptor may represent a viable therapeutic target.
감사합니다 . 교실의 무궁한 발전을 기원합니다 .그리스전 승리와 함께 !!
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Integrated diagram of CNS and peripheral mechanisms
Completed A Study to Investigate the Food Effect on the Pharmacokinetics of YM178 in Healthy, Non-elderly Volunteers Conditions: Healthy Volunteer; Pharmacokinetics of YM178Intervention: Drug: YM1782
Completed A Clinical Study to Determine the Effect of YM178 on the Pharmacokinetics of Warfarin in Healthy Subjects Condition: Overactive BladderInterventions: Drug: warfarin; Drug: YM1783
Completed A Study of YM178 in Men With Lower Urinary Tract Symptoms (LUTS) and Bladder Outlet Obstruction (BOO) Conditions: Lower Urinary Tract Symptoms; Bladder Outlet ObstructionInterventions: Drug: YM178; Drug: Placebo4
Completed Pharmacokinetic Interaction Study to Assess the Effect of Repeat Doses of Rifampin on Mirabegron (YM178) in Healthy Volunteers Condition: Pharmacokinetics of YM178Interventions: Drug: mirabegron; Drug: rifampin5
Completed A Pharmacokinetic Study of YM178 in Normal Subjects and Those With Mild, Moderate, and Severe Renal Impairment Condition: Renal ImpairmentIntervention: Drug: YM1786
Completed A Long-term Study of YM178 in Symptomatic Overactive Bladder Patients Condition: Urinary Bladder, OveractiveIntervention: Drug: YM1787Active,
not recruiting A Study to Evaluate Safety and Efficacy of YM178 in Patients With Overactive Bladder Condition: Urinary Bladder, OveractiveInterventions: Drug: YM178; Drug: Placebo; Drug: tolterodine8
Recruiting A Study of YM178 in Subjects With Symptoms of Overactive Bladder Condition: Urinary Bladder, OveractiveInterventions: Drug: YM178; Drug: Placebo; Drug: tolterodine ER9
Completed Study to Test the Efficacy and Safety of the Beta-3 Agonist YM178 in Patients With Symptoms of Overactive Bladder Condition: Urinary Bladder, OveractiveInterventions: Drug: YM178; Drug: Placebo
10Completed A Study to Test the Efficacy and Safety of the Beta-3 Agonist YM178 in Subjects With Symptoms of Overactive Bladder Condition: Urinary Bladder, OveractiveInterventions: Drug: YM178; Drug: Placebo
11Completed Study to Test the Efficacy and Safety of the Beta-3 Agonist YM178 in Subjects With Symptoms of Overactive Bladder Condition: Urinary Bladder, OveractiveInterventions: Drug: YM178; Drug: Tolterodine 4 mg; Drug: Placebo
12Active, not recruiting Study to Test the Long Term Safety and Efficacy of the Beta-3 Agonist YM178 in Patients With Symptoms of Overactive Bladder Condition: Urinary Bladder, OveractiveInterventions: Drug: YM178; Drug: Tolterodine 4 ng
13Completed A Study of YM178 in Patients With Symptomatic Overactive Bladder Condition: Urinary Bladder, OveractiveInterventions: Drug: YM178; Drug: Placebo
14Completed A Study of YM178 in Patients With Symptomatic Overactive Bladder (DRAGON) Condition: Overactive BladderIntervention: Drug: YM178
15Completed Pharmacokinetics of Oral Mirabegron With Different Release Rates Versus Intravenous (IV) Mirabegron Conditions: Healthy; Pharmacokinetics of MirabegronIntervention: Drug: mirabegron
16Completed Study of the Effect of Food on the Pharmacokinetics of Mirabegron Conditions: Healthy; Pharmacokinetics of MirabegronIntervention: Drug: mirabegron