Improvement by the phytotherapeutic agent Eviprostat® of detrusor overactivity, down-regulation of pharmacological receptors and urinary cytokines in rats with cyclophosphamide-induced cystitis, "Beyond the Abstract," by Shizuo Yamada, PhD

BERKELEY, CA (UroToday.com) - Interstitial cystitis (IC) is a chronic, abacterial, inflammatory disease of the bladder characterized by urinary frequency, urgency, and suprapubic pain associated with bladder filling and relieved by voiding. Over time, the impact of IC -- the effects on patients’ sleep, career, family life, and sexuality -- can negatively affect their quality of life. While IC can affect children and men, most of those affected are women. As the etiology and pathophysiology of IC are so far obscure, all treatment modalities are symptomatic, and there is no certain cure for IC at the present time.

The antineoplastic agent, cyclophosphamde (CYP), is widely used for therapy of various diseases (malignancy, bone marrow transplantation, and multiple sclerosis). One of the most common and severe (68-78% of patients) side effects of CYP therapy is hemorrhagic cystitis. Therefore, in humans, CYP can induce hemorrhagic cystitis, urgency, increased frequency, and pain through its toxic metabolite, acrolein. The intraperitoneal injection of CYP in rats induces a reproducible dose-dependent chemical cystitis and therefore has been used as an experimental model of hemorrhagic cystitis.

Previously, we showed that treatment with CYP in rats caused a down-regulation of pharmacologically relevant (muscarinic and purinergic) receptors in the bladder. Urine is a potentially easily accessible source of biomarkers for inflammatory bladder diseases, including IC. Previous studies have implied that urinary cytokines or chemokines are involved in rats with CYP-induced cystitis and in patients with cystitis. Therefore, cytokines might serve as direct therapeutic targets or as potential biomarkers for the development of targeted therapies designed to prevent chronic bladder inflammatory conditions such as IC.

Phytotherapy, the use of extracts taken from the roots, fruit, seeds, flowers, stems, or bark of plants/herbs as medicine or health-promoting agents is increasing in popularity. These remedies are commonly used to treat urological disorders such as benign prostatic hyperplasia, chronic prostatitis/chronic pelvic pain syndrome, overactive bladder, and interstitial cystitis/painful bladder syndrome. Although these agents show some promise for symptom relief, their use remains controversial due to the lack of established mechanisms of action, efficacy, and safety. Eviprostat is one of the most widely used phytotherapeutic agents for the treatment of urological disorders. Eviprostat is composed of five plant extracts: Chimaphila umbellate, Populus tremula, Pulsatilla pratensis, Equisetum arvense and germ oil from Tritium aestivum. Previous studies have revealed that Eviprostat prevented carrageenan-induced paw swelling in a rat model of inflammation, due to its antioxidant and anti-inflammatory activities. In addition, it has been shown that Eviprostat treatment improved bladder overactivity in rats with CYP-induced cystitis and in acetic acid-treated rats. It was also shown that Eviprostat maintained low levels of plasma catecholamines and inhibited bladder overactivity by decreasing ATP release from the bladder.

Our current study aimed to characterize pharmacological effects of a phytotherapeutic agent, Eviprostat, on urodynamic parameters, bladder muscarinic and purinergic receptors, and urinary cytokines in rats with cystitis induced by CYP. It was shown that, in the cystometry of CYP-treated rats compared with sham rats, micturition interval and micturition volume were significantly decreased, and the frequency of micturition, basal pressure, and residual urine volume were significantly increased. Repeated oral administration of Eviprostat in CYP-treated rats significantly increased micturition interval and micturition volume and decreased the frequency of micturition, basal pressure, and residual urine volume. The number of pharmacological (muscarinic and ATP) receptors in the bladder of CYP-treated rats compared with sham rats was significantly decreased. Such receptor downregulation in the bladder was significantly attenuated by the repeated treatment with Eviprostat. The elevation in urinary cytokine levels in CYP-treated rats was also effectively attenuated by the Eviprostat treatment.

Thus, the current study revealed repeated treatment with EVI improved significantly detrusor overactivity, down-regulated expression of bladder muscarinic and purinergic receptors, and elevated urinary cytokines levels in rats with CYP-induced cystitis, indicative of a significant role for bladder pharmacological receptors and urinary cytokines in the pathogenesis of cystitis. Notably, these changes were effectively attenuated by the repeated oral administration of Eviprostat at a pharmacological dose. Thus, the antioxidant and anti-inflammatory activities of Eviprostat may contribute partly to the amelioration of bladder dysfunction in rats with CYP-induced cystitis. Therefore, our study provides a significant impact for the pharmacological usefulness of Eviprostat in a phytotherapy of cystitis.

Written by:
Shizuo Yamada, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Professor and Chairman, Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan

Improvement by the phytotherapeutic agent Eviprostat® of detrusor overactivity, down-regulation of pharmacological receptors and urinary cytokines in rats with cyclophosphamide-induced cystitis - Abstract

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