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Bethanechol chloride is a cholinergic agent used to treat acute postoperative and postpartum nonobstructive (functional) urinary retention and for neurogenic atony of the urinary bladder with retention. It is available in the United States as tablets for oral administration in four dosage strengths: 5 mg, 10 mg, 25 mg, and 50 mg. A review of the therapeutic uses of bethanechol chloride reveals the need for flexibility in dosing. This flexibility is readily achieved using an oral liquid dosage form. However, no commercial liquid dosage form of bethanechol chloride currently exists. An extemporaneously compounded suspension from pure drug powder or commercial tablets would provide a flexible, customizable option to meet unique patient needs with convenient and accurate dosing options. The purpose of this study was to determine the physicochemical and microbiological stability of extemporaneously compounded bethanechol chloride suspensions using two brands of commercially available tablets (Amneal and Upsher-Smith) in the PCCA Base, SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two bethanechol chloride concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stability-indicating ultra-high-performance liquid chromatographic assay for the determination of the chemical stability of bethanechol chloride in PCCA SuspendIt was validated. Suspensions of bethanechol chloride were prepared from the tablets in PCCA SuspendIt at 1-mg/mL and 5-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in amber plastic prescription bottles at room temperature (25°C). Samples were assayed initially, and on the following time points (days): 14, 30, 60, 90, and 180. Physical data such as pH and appearance were also noted. Microbiological stability was tested. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period and is protected against microbial growth. Using this criterion, no significant degradation of the bethanechol chloride was observed over the 180-day test period for either concentration at room temperature. Drug concentrations were at, or above 93% of initial values for both brands of commercially available tablets. No microbial growth was observed. pH values remained fairly constant. This study demonstrates that bethanechol chloride tablets are physically, chemically, and microbiologically stable in PCCA SuspendIt for 180 days at room temperature at both concentrations studied, thus providing a viable, compounded alternative for bethanechol chloride in a liquid dosage form, with an extended BUD to meet patient needs., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)

Purpose: Few medical treatment options exist for detrusor underactivity or urinary retention in women. Bethanechol, a cholinergic agonist, may improve detrusor contractility in these conditions; however, its clinical efficacy is limited. We sought to examine the patterns of Bethanechol use by physicians in an ambulatory care setting using a national database to determine if it is still prescribed for patients with bladder dysfunction., Materials and Methods: The National Ambulatory Medical Care Survey (NAMCS) database was queried for a sample of patient visits to office-based physicians from 2003-2013. Visits were included for women aged 18 years or older with diagnosed lower urinary tract symptoms (LUTS), neurogenic bladder, or urinary retention based on ICD-9-CM codes. Visits in which Bethanechol was prescribed were analysed with descriptive statistics. Sampling weights were adjusted for nonresponders to yield an unbiased national estimate of ambulatory care visits., Results: Out of a weighted sample of 17 321 630 included patient visits, 132 281 (0.8%) visits included a prescription for Bethanechol. Patients prescribed Bethanechol had a mean age of 62.3 ± 2.1 and were predominantly Caucasian (67%) followed by African American (18%). The primary diagnosis associated with Bethanechol was atony of bladder (35%), urinary retention (20%), neurogenic bladder (18%), urinary incontinence (16%), and incomplete bladder emptying (10%). Visits were primarily for chronic conditions (63%). It was typically prescribed as a continued medication (79%) most often by urologists (92%) followed by internal medicine clinicians (8%)., Conclusions: Bethanechol continues to be prescribed in elderly women primarily for detrusor atony, urinary retention, or incomplete bladder emptying., (© 2018 John Wiley & Sons Ltd.)

Airway hyperreactivity is a hallmark feature of asthma and can be precipitated by airway insults, such as ozone exposure or viral infection. A proposed mechanism linking airway insults to airway hyperreactivity is augmented cholinergic transmission. In the current study, we tested the hypothesis that acute potentiation of cholinergic transmission is sufficient to induce airway hyperreactivity. We atomized the cholinergic agonist bethanechol to neonatal piglets and forty-eight hours later measured airway resistance. Bethanechol-treated piglets displayed increased airway resistance in response to intravenous methacholine compared to saline-treated controls. In the absence of an airway insult, we expected to find no evidence of airway inflammation; however, transcripts for several asthma-associated cytokines, including IL17A, IL1A, and IL8, were elevated in the tracheas of bethanechol-treated piglets. In the lungs, prior bethanechol treatment increased transcripts for IFNγ and its downstream target CXCL10. These findings suggest that augmented cholinergic transmission is sufficient to induce airway hyperreactivity, and raise the possibility that cholinergic-mediated regulation of pro-inflammatory pathways might contribute.

Unlabelled: Peripheral muscarinic acetylcholine receptors regulate insulin and glucagon release in rodents but their importance for similar roles in humans is unclear. Bethanechol, an acetylcholine analogue that does not cross the blood-brain barrier, was used to examine the role of peripheral muscarinic signaling on glucose homeostasis in humans with normal glucose tolerance (NGT; n = 10), impaired glucose tolerance (IGT; n = 11), and type 2 diabetes mellitus (T2DM; n = 9). Subjects received four liquid meal tolerance tests, each with a different dose of oral bethanechol (0, 50, 100, or 150 mg) given 60 min before a meal containing acetaminophen. Plasma pancreatic polypeptide (PP), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucose, glucagon, C-peptide, and acetaminophen concentrations were measured. Insulin secretion rates (ISRs) were calculated from C-peptide levels. Acetaminophen and PP concentrations were surrogate markers for gastric emptying and cholinergic input to islets. The 150 mg dose of bethanechol increased the PP response 2-fold only in the IGT group, amplified GLP-1 release in the IGT and T2DM groups, and augmented the GIP response only in the NGT group. However, bethanechol did not alter ISRs or plasma glucose, glucagon, or acetaminophen concentrations in any group. Prior studies showed infusion of xenin-25, an intestinal peptide, delays gastric emptying and reduces GLP-1 release but not ISRs when normalized to plasma glucose levels. Analysis of archived plasma samples from this study showed xenin-25 amplified postprandial PP responses ~4-fold in subjects with NGT, IGT, and T2DM. Thus, increasing postprandial cholinergic input to islets augments insulin secretion in mice but not humans., Trial Registration: ClinicalTrials.gov NCT01434901.

Objective: To re-examine the function of the urinary bladder in vivoas well as to determine the functional and biochemical characteristics of bladder muscarinic receptors in long-term alloxan-induced diabetes rats., Methods: Two-month-old male Wistar rats were injected with alloxan and the animals showing blood glucose levels >300mg/dL together with age-paired untreated animals were kept for 11 months. Body weight, bladder weight, blood glucose, and urinary volume over a period of 24 hours were determined in both groups of animals. A voiding cystometry in conscious control and diabetic rats was performed to determine maximal micturition pressure, micturition contraction interval and duration as well as voided and post-voiding residual volume. In addition, concentration-response curves for bethanechol in isolated bladder strips, as well as [3H]-N methyl-scopolamine binding site characteristics in bladder homogenates were determined., Results: Mean bladder weight was 162.5±21.2mg versus 290±37.9mg in control and treated animals, respectively (p<0.05). Micturition contraction amplitude (34.6±4.7mmHg versus 49.6±2.5mmHg), duration (14.5±1.7 seconds versus 23.33±4.6 seconds) and interval (87.5±17.02 seconds versus 281.11±20.24 seconds) were significantly greater in alloxan diabetic rats. Voided urine volume per micturition contraction was also significantly higher in diabetic animals. However the post-voiding residual volume was not statistically different. Bethanechol potency (EC50 3µM versus 5µM) and maximal effect (31.2±5.9g/g versus 36.1±6.8g/g) in isolated bladder strips as well as number (169±4fmol/mg versus 176±3fmol/mg protein) and affinity (0.69±0.1nM versus 0.57±0.1nM) of bladder muscarinic receptors were also not statistically different., Conclusion: Bladder function in vivo is altered in chronic alloxan-induced diabetes rats without changes in functional and biochemical characteristics of bladder muscarinic receptors.