Intravesical treatment of overactive bladder

doi:10.1016/S0090-4295(99)00498-7

Urology

Volume 55, Issue 5, Supplement 1, May 2000, Pages 60-64

https://doi.org/10.1016/S0090-4295(99)00498-7 Get rights and content

Abstract

Intravesical agents for overactive bladder have mostly been used in patients with neurogenic bladder disorders. The patients have usually had severe detrusor hyperreflexia (DH) plus a disorder of bladder emptying, and because of residual urine have been performing intermittent self-catheterization. Intravesical medication has therefore been appropriate. Strategies for treating DH have been either to lessen the parasympathetic efferent activity or to de-afferent the bladder. Two types of treatment have been used: intravesical medications that block pelvic nerve–detrusor smooth muscle cholinergic transmission, or agents that block the afferent arm of the reflex that causes detrusor contraction. Intravesical oxybutynin is thought to have some local anesthetic effect, although its main mode of action is to block cholinergic transmission. It has been demonstrated to be effective in resistant DH. Intravesical atropine has been demonstrated to increase bladder capacity but its usefulness in the clinical management of DH has yet to be demonstrated. Local anesthetics can increase bladder capacity, but the effect is short-lived. Longer-acting agents may have a selective neurotoxic effect on capsaicin-sensitive bladder afferents. Many patients worldwide have now been treated with intravesical capsaicin. Resiniferatoxin (RTX) is an ultrapotent capsaicin analog that has the significant advantage of being a nonirritant. Intravesical agents appear to be attractive alternatives to oral medication and hold the exciting possibility of selectively targeting end organs implicated in pathophysiologic responses.

Section snippets

Intravesical agents that block cholinergic transmission

The aim of this treatment is to achieve cholinergic blockade in the bladder tissues, without producing high systemic drug levels. The duration of action is determined by the drug’s half-life and frequency of administration, which can be several times in 24 hours. This type of therapy has the advantage of being likely to act irrespective of the cause of the hyperreflexia. It may be equally effective in treating detrusor hyperreflexia from suprapontine as well as subpontine causes, and may even

Agents that act on afferent innervation

As with any reflex response, it is afferent input that determines efferent output. In the case of reflex bladder emptying, detrusor contractions are triggered by the stimulus of bladder filling signaled by the afferents that lie in the suburothelial layer of the bladder wall. Drugs that have been used so far to lessen DH by their action on afferents do so either by transiently blocking conduction of afferent nerve fibers by a local anesthetic effect or by the longer-term effect of

Conclusion

Intravesical agents appear to be attractive alternatives to oral medication and hold the exciting possibility of selectively targeting end organs implicated in pathophysiologic responses. However, the number of patients who are likely to use such medications may be small compared with the number with incontinence due to detrusor instability or even nonspinal detrusor hyperreflexia. Furthermore, modern developments in pharmacology and drug design mean that an oral medication that acts against DH

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For instance, orally administrated oxybutynin encounters first-pass metabolism, resulting in release of metabolite N-desethyloxybutynin which contributes to occurrence of dry mouth (Zacchè et al., 2015). To reduce side effects, some studies have investigated the efficacy of intravesically delivered antimuscarinic drugs, with some promising reports showing reduced side effects and drug levels in the serum, as well as increased efficiency of the treatment (Fowler, 2000; Reitz and Schurch, 2004; Evans, 2005; Hayashi et al., 2007). However, intravesical use of antimuscarinic drugs to treat OAB has not been licenced yet.
Bladder diseases affect millions of patients worldwide and compromise their quality of life with a substantial economic impact. The not fully understood aetiologies of bladder diseases limit the current diagnosis and therapeutic options to primarily symptomatic treatment. In addition, bladder targeted drug delivery is challenging due to its unique anatomical features and its natural physiological function of urine storage and frequent voiding. Therefore, current treatment options often fail to provide a highly effective, precisely targeted and long-lasting treatment. With the growing maturity of gene therapy, comprehensive studies are needed to provide a better understanding of the molecular mechanisms underpinning bladder diseases and help to identify novel gene therapeutic targets and biomarkers for treating bladder diseases. In this review, molecular mechanisms involved in pathology of bladder cancer, interstitial cystitis and overactive bladder syndrome are reviewed, with focus on establishing potential novel treatment options. Proposed novel therapies, including gene therapy combined with nanotechnology, localised drug delivery by nanoparticles, and probiotics, are discussed in regard to their safety profiles, efficacy, treatment lenght, precise targeting, and in comparison to conventional treatment methods.
A sensitive bioanalytical method for quantitative determination of resiniferatoxin in rat plasma using ultra-high performance liquid chromatography coupled to tandem mass spectrometry and its application in pharmacokinetic study
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Various studies and clinical trials have used intravenous administration of RTX to evaluate its use in various diseases resulting in devitalizing bladder symptoms and improves urodynamic parameters in patients with neurogenic detrusor overactivity. It also reduces bladder pain in patients with hypersensitivity disorders [5]. It desensitizes the J-receptors to capsaicin as well as to phenyl diguanide, a commonly used agent to stimulate these receptors [2,6].
Resiniferatoxin (RTX) is a daphnane diterpene isolated from the latex of Euphorbia resinifera O. Berg, a potent activator of transient receptor potential vanilloid 1 (TrpV1), with a potency 10³-10⁵ times greater than pure capsaicin. Intravenous administration of RTX at very low concentration improves urodynamic parameters in patients with neurogenic detrusor overactivity and also reduces bladder pain in patients. Herein, a simple, rapid, selective and sensitive method for determination of RTX with silydianin as an internal standard was developed using ultra-high performance liquid chromatography coupled to tandem mass spectrometry with electrospray ionization source (UHPLC-ESI-MS/MS) in multiple reaction monitoring mode. The mass spectrometer was operated in positive electrospray ionization ((+) ESI) mode. Multiple reaction monitoring (MRM) mode was performed with ion pairs of m/z: 629.23→283.2 for RTX and 483.24→153.1 for IS. The limit of detection achieved in this method for RTX was 0.05 ng/mL and had good linearity in calibration range of 0.2–50 ng/mL ( r² = 0.99). Precision and accuracy values were found to be < 15% (within acceptable limit), extraction recovery (≥ 88.2%), matrix effect (≥ 89.7%) and stability were in accordance with the bioanalytical guidelines. The sensitivity of this bio-analytical method supported the successful pharmacokinetic evaluation of RTX on rat plasma (2.5 μg/kg dose; i.v.) and has demonstrated pharmacokinetic parameters V_d and AUC_0-∞ as 191.0 ± 71.31 mL/kg and 981.6 ± 137.40 min*ng/mL, respectively. The clearance was found to be 2.6 ± 0.38 mL/min/kg and half-life was 53.6 ± 23.51 min. This efficient, rapid and reliable method promises the quantification at low concentration of RTX, allowing determination of the pharmacokinetic profile, which is essential in future drug delivery and clinical application.
Basic and clinical aspects of antimuscarinic agents used to treat overactive bladder
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The antagonistic potencies (pKi, pA2,) of oxybutynin for carbachol-induced responses in rat and human bladder tissues were 8.75 (Ohtake et al., 2010) and 8.33 (Yamanishi et al., 2015). Oxybutynin was previously shown to act intravesically through its local anesthetic effects as well as by cholinergic blockade (Mohler, 1990; Brendler et al., 1989; Fowler, 2000). Intravesically-instilled oxybutynin bound to muscarinic receptors in the bladder (Oki et al., 2004).
Antimuscarinic agents are now widely used as the pharmacological therapy for overactive bladder (OAB) because neuronal (parasympathetic nerve) and non-neuronal acetylcholine play a significant role for the bladder function. In this review, we will highlight basic and clinical aspects of eight antimuscarinic agents (oxybutynin, propiverine, tolterodine, solifenacin, darifenacin, trospium, imidafenacin, and fesoterodine) clinically used to treat urinary dysfunction in patients with OAB. The basic pharmacological characteristics of these eight antimuscarinic agents include muscarinic receptor subtype selectivity, functional bladder selectivity, and muscarinic receptor binding in the bladder and other tissues. The measurement of drug-receptor binding after oral administration of these agents allows for clearer understanding of bladder selectivity by the integration of pharmacodynamics and pharmacokinetics under in vivo conditions. Their central nervous system (CNS) penetration potentials are also discussed in terms of the feasibility of impairments in memory and cognitive function in elderly patients with OAB. The clinical aspects of efficacy focus on improvements in the daytime urinary frequency, nocturia, bladder capacity, the frequency of urgency, severity of urgency, number of incontinence episodes, OAB symptom score, and quality of life (QOL) score by antimuscarinic agents in patients with OAB. The safety of and adverse events caused by treatments with antimuscarinic agents such as dry mouth, constipation, blurred vision, erythema, fatigue, increased sweating, urinary retention, and CNS adverse events are discussed. A dose-dependent relationship was observed with adverse events, because the risk ratio generally increased with elevations in the drug dose of antimuscarinic agents. Side effect profiles may be additive to or contraindicated by other medications.
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Few studies have investigated the feasibility of using pudendal neuromodulation to regulate bladder function in spinal cord-injured (SCI) animals. The present study aimed to determine the effects of electrical activation of the pudendal sensory branch on improving voiding functions in rats 6 weeks after a spinal cord injury and to explore the underlying neuromodulatory mechanisms.
Two urodynamic measurements were used to assess the effects of electrical stimulation (ES) on bladder and urethral functions: simultaneous recordings of the intravesical pressure (IVP) during continuous isotonic transvesical infusion (i.e., isotonic IVP) and external urethral sphincter (EUS) electromyography (EUS-EMG), and simultaneous recordings of transvesical pressure under isovolumetric conditions (i.e., isovolumetric IVP) and urethral perfusion pressure (UPP).
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Citation Excerpt :
It is also well tolerated and associated with fewer adverse effects than its oral counterpart.8 The mechanism of action (MOA) of intravesical oxybutynin was believed to be the same as that of oral delivery, that is cholinergic blockade of the M3 muscarinic receptors in the bladder detrusor muscle.9 However, the last decade has seen significant changes in opinion as to the MOA of antimuscarinics as a whole.10
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Intravesical treatment of overactive bladder

Abstract

Section snippets

Intravesical agents that block cholinergic transmission

Agents that act on afferent innervation

Conclusion

J Urol

J Urol

J Urol

Lancet

J Urol

J Urol

J Urol

Pain

Lancet

J Urol

Relaxation of intestinal bladders by intravesical oxybutynin chloride

Neurourol Urodyn

Control of detrusor hyperreflexia by intravesical instillation of oxybutynin hydrochloride

Paraplegia

Intravesical atropine suppression of detrusor hypercontractility in the neuropathic bladder. A preliminary study

Paraplegia

Intravesical atropine suppression of detrusor hyperreflexia in multiple sclerosis

J Neurol Neurosurg Psychiatry