The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: Pathophysiology and Pharmacotherapy of Overactive Bladder

Overactive bladder (OAB) syndrome, which is characterized by a complex of storage symptoms (urinary urgency, frequency, nocturia, and urgency incontinence) is highly prevalent within the general population, causing major distress to patients in terms of their psychosocial and physical functioning. Muscarinic receptors of bladder smooth muscles are involved in both normal and disturbed bladder contraction. The muscarinic receptor functions may change in bladder disorders associated with OAB, implying that mechanisms, which normally have little clinical importance, may be up-regulated and contribute to the pathophysiology of OAB. In addition, several reports have suggested that various stimulations release many substances, including adenosine triphosphate, prostaglandins, nitric oxide, and acetylcholine, from bladder urothelium, which contribute to pathophysiology of the increased bladder sensation, OAB symptoms, and detrusor overactivity. Bladder urothelium possesses a non-neuronal cholinergic system and high density of muscarinic receptors. The roles and functions of the non-neuronal cholinergic system in OAB are now being evaluated. In the pharmacotherapy of OAB, antimuscarinic agents are the first choice drugs. Furthermore, new therapeutic targets at the levels of the urothelium, detrusor muscles, autonomic and afferent pathways, spinal cord, and brain are proposed. In this review, the pathophysiology of OAB, especially the role of non-neuronal acetylcholine, is discussed. In addition, new drugs with new action mechanisms will be introduced.     

Incidence of Common Cancers in Users of Antimuscarinic Medications for Overactive Bladder: A Danish Nationwide Cohort Study

The purpose of this study was to estimate the incidence rate (IR) of 10 common cancers in new users of antimuscarinic overactive bladder (OAB) medications. We conducted a cohort study using data recorded in Danish registers for patients newly exposed to the OAB drugs, darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine or trospium in years 2004–2012, aged ≥18 years and without cancer before treatment initiation. We estimated IRs for each study cancer (bladder, breast, colorectal, lung, melanoma, non‐Hodgkin lymphoma, pancreas, prostate, renal and uterine), standardised by age and sex and explored IR trends over time since treatment initiation. For all cancer analyses, only the first incident targeted cancer was considered. Of 72,917 patients (60% women; mean age at treatment start: 66 years), 3475 developed a study cancer during 259,072 person‐years of follow‐up. The most common study cancers were prostate (48.1% of study cancers in men), breast (40.0% of study cancers in women) and lung (15.4% of all study cancers). The overall standardised study cancer IR was 5.4 per 1000 person‐years (95% confidence interval, 5.3–5.6); IRs were similar across individual OAB drugs. The standardised IRs for bladder and prostate cancers, which have symptoms in common with OAB, were highest in the first 6 months of treatment initiation and lower thereafter. In contrast, IRs for other study cancers were nearly constant during follow‐up. Cancer IRs did not vary substantially by individual OAB drug. Protopathic bias is a plausible explanation for the higher rates of bladder and prostate cancers observed soon after starting OAB drug treatment.     

Effectiveness and Safety of Intradetrusor OnabotulinumtoxinA Injection for Neurogenic Detrusor Overactivity and Overactive Bladder Patients in Taiwan—A Phase IV Prospective,Interventional, Multiple-Center Study (Restore Study)

We conducted a phase IV, pre/post multi-center study to evaluate the efficacy and safety of intradetrusor onabotulinumtoxinA injection in patients with neurogenic detrusor overactivity (NDO, n = 119) or overactive bladder (OAB, n = 215). Patients received either 200U (i.e., NDO) and 100U (i.e., OAB) of onabotulinumtoxinA injection into the bladder, respectively. The primary endpoint for all patients was the change in the PPBC questionnaire score at week 4 and week 12 post-treatment compared with baseline. The secondary endpoints were the changes in subjective measures (i.e., questionnaires: NBSS for patients with NDO and OABSS for those with OAB) at week 4 and week 12 post-treatment compared with baseline. Adverse events included symptomatic UTI, de novo AUR, gross hematuria and PVR > 350mL were recorded. The results showed that compared with baseline, PPBC (3.4 versus 2.4 and 2.1, p < 0.001) and NBSS (35.4 versus 20.4 and 18.1, p < 0.001) were significantly improved at 4 weeks and 12 weeks in NDO patients. In addition, compared with baseline, PPBC (3.5 versus 2.3 and 2.0, p < 0.001) and OABSS (9.1 versus 6.2 and 5.7, p < 0.001) were significantly improved at 4 weeks and 12 weeks in OAB patients. Eight (6.7%) had symptomatic UTI and 5 (4.2%) had de novo AUR in NDO patients. Twenty (9.3%) had symptomatic UTI but no de novo AUR in OAB patients. In conclusion, we found that intradetrusor onabotulinumtoxinA injections were safe and improved subjective measures related to NDO or OAB in our cohort.     

Mechanisms of the responses to Non-Cholinergic,Non-Adrenergic Nerve Stimulation and to ATP in Isolated Rabbit Urinary Bladder: Evidence for ADP Evoked Prostaglandin Release

Abstract: The contractile effects of ATP and related purine compounds on the isolated rabbit detrusor were investigated. It was found that ATP produced an initial rapid, phasic contraction followed by a slowly developing and maintained increase in tension. ADP caused a contraction closely mimicking the tonic response to ATP. The ADP induced contraction and the tonic response to ATP could both be abolished by indomethacin. β, γ-methylene ATP (APPCP), which is not degraded to ADP, elicited a rapid, phasic response, which could be abolished by nifedipine. AMP, dibutyryl-cAMP, and adenosine in low concentrations had no contractile effects; high concentrations of adenosine and 2-chloroadenosine, which is resistant to adenosine deaminase, decreased tone and spontaneous activity. The amplitude of the ATP induced contraction was positively correlated to the Ca²⁺-concentration in the extracellular medium; removal of Ca²⁺ abolished the ATP contraction before the responses to high K⁺ and carbachol disappeared. Responses to electrical field stimulation, mediated by non-cholinergic, non-adrenergic mechanisms were abolished by nifedipine and significantly reduced by indomethacin. It is concluded that in isolated rabbit detrusor, a direct contractile response can be elicited only by tripolyphosphates (ATP and APPCP), and that the diphosphate moiety ADP stimulates synthesis of prostaglandins. The similarity between the effects of stimulation of non-cholinergic, non-adrenergic neurones and the phasic response to ATP supports the view that in rabbit detrusor ATP may be involved in excitation.     

A Method to Study Drug Concentration–Depth Profiles in Tissues: Mitomycin C in Dog Bladder Wall

Determination of the depth of penetration of locally applied drug therapy and evaluation of possible mechanisms of drug transport require knowledge of drug concentration-versus-tissues depth profiles. A method to determine the drug concentration–depth profile is needed. We have devised such a method and used it to determine the penetration of mitomycin C (MMC) in the dog bladder wall after intravesical drug instillation. This method is based on sectioning of frozen tissue into 40-µm segments, followed by drug extraction and high-pressure liquid chromatography analysis. Tissue concentrations could be detected with a sensitivity of 1 ng/sample, or 20 ng/g for tissue samples of approximately 2 × 2 cm. This sensitivity was sufficient to describe the penetration of MMC in the bladder wall of dogs, using an identical instillation technique, dwell time, and MMC concentration as in human patients. Tissue concentrations were expressed relative to tissue weight or tissue protein contents. For MMC, standardization to tissue weight yielded a better mathematical fit of the concentration-versus-depth profiles than standardization to protein content. The time interval between tissue harvesting and freezing was critical. The MMC concentration at the urothelial side of dog bladders was 2- to 10-fold higher in samples processed immediately after harvesting, compared to samples processed after 1 hr or longer. This significant decrease was not due to drug metabolism in situ. In separate in vitro experiments, we found that the degradation of MMC in 8% tissue homogenate was relatively slow, with only a 30% decline in concentration over 24 hr. We speculate that the decrease in concentration was due to passive diffusion of MMC, away from the urothelial side. In summary, the present study demonstrates that determination of drug penetration into tissues in vivo is feasible.     

High Prevalence of Self-Reported Exposure to Adulterated Drugs Among People Who Experienced an Opioid Overdose in Canada: A Cohort Study

Background: In North America, rates of overdoses are increasing largely due to the adulteration of illicit drugs by illicit synthetic opioids. Objectives: We sought to examine the prevalence and correlates of self-reported exposure to adulterated drugs among people who experienced a non-fatal opioid overdose. Methods: Data were derived from three prospective cohort studies of people who use drugs in Vancouver, Canada between June and November 2016. Multivariable logistic regression analyses were used to examine the prevalence and correlates of self-reported exposure to adulterated drugs. Results: Among 117 participants who reported symptoms consistent with a non-fatal opioid overdose, 78 (66.7%) reported believing the drug was adulterated during their last overdose. Of those, 42 (53.8%) had not perceived adulteration prior to overdose. In the multivariable analysis, engagement in opioid agonist therapy (Adjusted Odds Ratio [AOR]?=?2.79, 95% Confidence Interval [CI]: 1.10, 7.45) was independently associated with having not perceived adulteration prior to overdose. Daily heroin use (AOR = 5.28; 95% CI: 1.92, 15.97) and reporting supervised injection site staff were present at most recent overdose (AOR = 6.16; 95% CI: 1.25, 47.27) were independently associated with having perceived adulteration prior to overdose. Conclusions/Importance: We found a high prevalence of believing adulterated drugs were present for the most recent overdose. Further, the high prevalence of unperceived adulteration prior to overdose supports the need to lower the risk of overdose by providing individuals with options to consume drugs in a safer manner, including supervised consumption sites.