Management of the refractory nocturnal enuresis patient to desmopressin in a pediatric population: Desmopressin + oxybutynin vs. desmopressin + imipramine.

INTRODUCTION AND OBJECTIVE: Desmopressin is well accepted as first-line medical therapy for enuresis. If ineffective, combination therapy of desmopressin + oxybutynin or desmopressin + imipramine has been used. This study assessed the efficacy of adjunct therapy with either imipramine or oxybutynin in the management of enuresis patients who failed desmopressin treatment. STUDY DESIGN: A retrospective chart review of our database for patients with enuresis was performed. Patients who were prescribed desmopressin, oxybutynin, and imipramine over 14 years for enuresis were included. Two cohorts of patients were examined; group OXY was treated with desmopressin and oxybutynin, and group IMP received desmopressin and imipramine. Pretreatment measurement of Vancouver Symptom Scores (VSS) were used to compare groups using the VSS question "I wet my bed at night" where 4: every night, 3: 4-5 nights per week, 2: 1-2 nights per week, 1: 3-4 nights per month, and 0: never. International Children's Continence Society (ICCS) criteria for continence success was utilized to determine outcomes. RESULTS: 2521 patients prescribed one of the 3 medications were identified. Among them, 81 patients (mean age: 10.5 ± 2.8 years) received combination therapy. Of which, 55 were male and 26 female. Specifically, 58 were prescribed both desmopressin and imipramine (group IMP), 23 desmopressin and oxybutynin (group OXY), and 4 transitioned from OXY to IMP. Mean pretreatment VSS showed no difference between groups. Both groups experienced minimal drops in wet nights with desmopressin alone. A comparison revealed that group IMP reduced wet nights significantly more than group OXY (VSS wet night score 0.7 ± 1.2 vs. 2.3 ± 1.1 respectively, p < 0.0001). Non-intent-to-treat complete response rate was 68% vs 5% (OR = 42.5, p < 0.001) (IMP vs. OXY respectively). Intent-to-treat response rates were 58%. DISCUSSION: Although first-line desmopressin treatment for enuresis is effective, it does not work for all patients, and many parents and children desire nighttime dryness. Clinicians have combined desmopressin with oxybutynin or imipramine for improved results, but research comparing these modalities is scarce. Our study suggests that the desmopressin and imipramine combination is superior at reducing nights wet compared to desmopressin and oxybutynin, attributed to imipramine's probable central mechanism rather than its secondary anticholinergic properties. Limitations include a modest sample size, retrospective design, and subjective responses to the Vancouver questionnaire. CONCLUSION: A combination of desmopressin and imipramine was more effective in reducing wet nights and had a complete response rate that was 42.5 times greater than desmopressin and oxybutynin.

Fragility of overactive bladder medication clinical trials: A systematic review.

PURPOSE: Overactive bladder (OAB) syndrome significantly impairs quality of life, often necessitating pharmacological interventions with associated risks. The fragility of OAB trial outcomes, as measured by the fragility index (FI: smallest number of event changes to reverse statistical significance) and quotient (FQ: FI divided by total sample size expressed as a percentage), is critical yet unstudied. MATERIALS AND METHODS: We conducted a systematic search for randomized controlled trials on OAB medications published between January 2000 and August 2023. Inclusion criteria were trials with two parallel arms reporting binary outcomes related to OAB medications. We extracted trial details, outcomes, and statistical tests employed. We calculated FI and FQ, analyzing associations with trial characteristics through linear regression. RESULTS: We included 57 trials with a median sample size of 211 participants and a 12% median lost to follow-up. Most studies investigated anticholinergics (37/57, 65%). The median FI/FQ was 5/3.5%. Larger trials were less fragile (median FI 8; FQ 1.0%) compared to medium (FI: 4; FQ 2.5%) and small trials (FI: 4; FQ 8.3%). Double-blinded studies exhibited higher FQs (median 2.9%) than unblinded trials (6.7%). Primary and secondary outcomes had higher FIs (median 5 and 6, respectively) than adverse events (FI: 4). Each increase in 10 participants was associated with a +0.19 increase in FI (p < 0.001). CONCLUSIONS: A change in outcome for a median of five participants, or 3.5% of the total sample size, could reverse the direction of statistical significance in OAB trials. Studies with larger sample sizes and efficacy outcomes from blinded trials were less fragile.

Repurposing of US-FDA-approved drugs as negative modulators of ubiquitin specific protease-7 (USP7).

Ubiquitin-specific protease7 (USP7) regulates the stability of the p53 tumor suppressor protein and several other proteins critical for tumor cell survival. Aberrant expression of USP7 facilitates human malignancies by altering the activity of proto-oncogenes/proteins, and tumor suppressor genes. Therefore, USP7 is a validated anti-cancer drug target. In this study, a drug repurposing approach was used to identify new hits against the USP7 enzyme. It is one of the most strategic approaches to find new uses for drugs in a cost- and time-effective way. Nuclear Magnetic Resonance-based screening of 172 drugs identified 11 compounds that bind to the catalytic domain of USP7 with dissociation constant (Kd) values in the range of 0.6-1.49 mM. These 11 compounds could thermally destabilize the USP7 enzyme by decreasing its melting temperature up to 9 °C. Molecular docking and simulation studies provided structural insights into the ligand-protein complexes, suggesting that these compounds bind to the putative substrate binding pocket of USP7, and interact with its catalytically important residues. Among the identified 11 hits, compound 6 (oxybutynin), 7 (ketotifen), 10 (pantoprazole sodium), and 11 (escitalopram) also showed anti-cancer activity with an effect on the expression of proto-oncogenes and tumor-suppressor gene at mRNA level in HCT116 cells. The compounds identified in this study can serve as potential leads for further studies.

Development and characterization of 3D printed ethylene vinyl acetate (EVA) as drug delivery device for the treatment of overactive bladder.

The overactive bladder is a condition characterized by a sudden urge to urinate, even with small volumes of urine present in the bladder. The current treatments available for this pathology consist on conservative approaches and the continuous administration of drugs, which when made by conventional methods has limitations related to the first pass metabolism, bioavailability, severe side effects, and low patient adherence to treatments, ultimately leading to low effectiveness. Within this context, the present work proposes the design, manufacture, and characterization of an intravesical implant for the treatment of overactive bladder pathology, using EVA copolymer as a matrix and oxybutynin as a drug. The fabrication of devices through two manufacturing techniques (extrusion and additive manufacturing by fused filament fabrication, FFF) and the evaluation of the implants through characterization tests was proposed. The usability and functionality were evaluated through simulated insertion of the device/prototype in a bladder model through catheter insertion tests. The safety and effectiveness of the devices was investigated from mechanical testing as well as drug release assays. Drug release assays presented a burst release in the first 24 h, followed by a release of 1.8 and 2.8 mg/d, totalizing 32 d. Mechanical tests demonstrated an increase in the stiffness of the specimens due to the addition of the drug, showing a change in maximum stress and strain at break. The released dose was higher than that usually presented when considering the oral administration route, showing the optimization of the development of this implant has the potential to improve the quality of life of patients with overactive bladder.

A muscarinic receptor antagonist reverses multiple indices of diabetic peripheral neuropathy: preclinical and clinical studies using oxybutynin.

Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

A Double-blind, Randomised Four-way Crossover Study to Compare the Effects of Fesoterodine 4 and 8 mg Once Daily and Qxybutynin 5 mg Twice Daily After Steady-state Dosing Versus Placebo on Cognitive Function in Overactive Bladder-wet Patients over the Age of 75 Years with Mild Cognitive Impairment.

BACKGROUND AND OBJECTIVE: There is a reported association between overactive bladder (OAB) treated with antimuscarinic drugs and an increased risk of a dementia diagnosis, although short-term data suggest that newer OAB antimuscarinics are cognitively safe. This study examined the cognitive safety of fesoterodine in older adults with mild cognitive impairment (MCI) and OAB. METHODS: This four-way randomised crossover study examined the cognitive effects of fesoterodine 4 and 8 mg and oxybutynin 5 mg b.i.d. compared with placebo. Older adult patients with OAB and MCI were included. Treatment and washout periods were of 1-week duration, to reach steady-state drug levels. The primary outcome was continuity of attention at 1 and 4 h after the dose. The secondary outcomes included other cognitive domains, change in Montreal Cognitive Assessment score, and alertness. KEY FINDINGS AND LIMITATIONS: Twenty-three patients completed the study (16 females and seven males). For the primary outcome, at 1 h after the dose, a trend towards worsening of continuity of attention was observed for fesoterodine 4 mg (p = 0.09) compared with placebo. At 4 h after the dose, a nonstatistically significant trend towards improvement compared with placebo was observed in the fesoterodine 4 mg group (p = 0.0633) compared with placebo. No differences were observed in any other treatment group at either time point. Apart from quality of working memory, associated with a statistically significant improvement with fesoterodine 4 mg, there was no difference in any comparison for other secondary outcomes. CONCLUSIONS: Exposure to steady-state dosing of fesoterodine 4 and 8 mg or oxybutynin 5 mg b.i.d. was not associated with any detectable effect on cognitive function using a sensitive battery of cognitive tests in a group of older adult patients with MCI and OAB. PATIENT SUMMARY: In this report, we investigated whether the medication fesoterodine, a member of a family of drugs called anticholinergics, commonly used for the treatment of a condition called overactive bladder that leads to accidental leakage of urine, affected the memory function of older adults with mild memory impairment. These people might be more sensitive to memory side effects. We found that at the doses most used by doctors, the drug had no effect on any of the memory functions we tested.

Severe night sweating treated by oxybutynin.

Sleep hyperhidrosis is defined as profuse nocturnal sweating that disrupts sleep. Although the mechanism is unknown, some cases are secondary to hot flushes during the menopausal period, medical, mental and sleep disorders, and medication, while dysregulation of thermoregulation during sleep is suspected in primary cases. We present the case of a woman with severe primary sleep hyperhidrosis, occurring nightly for 23 years, which definitively resolved after brief treatment with oxybutynin (a muscarinic receptor-blocking anticholinergic). An ammoniacal odor in the sweat and a sensation of coldness on awakening during sweating episodes suggest that the mechanism of her night sweating was not an exacerbation of thermoregulation during the night but shares the mechanical properties of emotional/psychological sweating. This extreme case of sleep hyperhidrosis was treated with excellent efficacy and minimal side effects using oxybutynin, which could benefit other patients with nighttime discomfort. CITATION: Dias L, Martinot C, Vaillant G, Arnulf I. Severe night sweating treated by oxybutynin. J Clin Sleep Med. 2024;20(1):169-172.

Topical Anticholinergics in the Management of Focal Hyperhidrosis in Adults and Children. A Narrative Review. / Anticolinérgicos tópicos en el manejo de la hiperhidrosis focal en adultos y niños. Una revisión narrativa.

Hyperhidrosis, or excessive sweating, is characterized by overactivity of the eccrine sweat glands, usually associated with dysfunction of the autonomic nervous system. Primary focal hyperhidrosis is the most common form and can affect the axillae, palms, soles, and/or face, often leading to significantly impaired quality of life and social functioning. Treatment is complex. Topical antiperspirants are normally recommended as the first-line treatment for mild hyperhidrosis. Multiple clinical trials and prospective studies support the efficacy and tolerability of oral and topical anticholinergics in the management of hyperhidrosis. Topical glycopyrronium, which has been investigated in at least 8 clinical trials enrolling more than 2000 patients, is probably the first-line pharmacological treatment for axillary hyperhidrosis in patients with moderate to severe disease poorly controlled with topical antiperspirants. Second-line treatments include botulinum toxin injections, microwave treatment, and oral anticholinergics. We review the use of topical anticholinergics in the management of focal hyperhidrosis in adults and children.

Oxybutynin ameliorates LPS-induced inflammatory response in human bladder epithelial cells.

Urinary tract infection (UTI) mainly results from bacterial infections in the urinary tract and markedly impacts the normal lives of millions of patients worldwide. The infection and damage to urethral epithelial cells is the first and key step of UTI development and is a critical target for treating clinical UTI. Oxybutynin, an agent for treating urinary incontinence, is recently claimed with protective effects on bladder ultrastructure. Our study will assess the impact of Oxybutynin on inflammation in lipopolysaccharide (LPS)-stimulated bladder epithelial cells. Bladder epithelial T24 cells were treated with 1 µg/mL LPS with or without 10 and 20 µM Oxybutynin for 24 h. Increased levels of oxidative stress (OS) biomarkers, such as reactive oxygen species, 8-hydroxy-2'-deoxyguanosine, malondialdehyde, as well as upregulated inducible nitric oxide synthase and promoted release of nitric oxide, were observed in LPS-managed T24 cells, all of which were signally suppressed by Oxybutynin. Furthermore, severe inflammatory responses, including enhanced release of cytokines, upregulated matrix metallopeptidase-2 (MMP-2) and MMP-9, and raised monocyte chemoattractant protein-1 level, were found in LPS-challenged T24 cells, which were markedly reversed by Oxybutynin. Moreover, the activated toll-1ike receptor 4/nuclear factor-κB pathway observed in LPS-managed T24 cells was repressed by Oxybutynin. Collectively, Oxybutynin mitigated LPS-induced inflammatory response in human bladder epithelial cells.

Reversible Cerebral Vasoconstriction Syndrome Associated With Oxybutynin Use; a Brief Review of Pathophysiology.

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by reversible vasospasm of the central nervous system vasculature. It usually presents as a classic thunderclap headache, but complications like a stroke, seizure, or intracranial hemorrhage may occur at the onset. Most cases are linked temporally to secondary agents. The most common suggested mechanism underlying the RCVS is vascular tone dysregulation. Our report describes the RCVS incidence associated with oxybutynin use in a young female. We aim to describe the potential pathophysiology linking oxybutynin use and RCVS.

Oxybutynin for Primary Palmer Hyperhidrosis Attenuates Migraine Attacks and Burdens.

Migraine is a neurological disorder with recurrent headaches accompanied by burdens in social life. Primary palmar hyperhidrosis is a chronic condition with excessive sweating of the palms that can significantly impair quality of life. Primary hyperhidrosis can cause anxiety, and stress, including anxiety, is the most common inducer of migraine headaches. Recently, oxybutynin has been used for primary palmar hyperhidrosis. We herein describe a 26-year-old female migraine patient with primary palmar hyperhidrosis whose migraine attacks and burdens were attenuated after the prescription of an oxybutynin lotion formula. The patient's monthly headache days (MHD) and monthly acute medication intake days (AMD) at the first visit were 10 and 9. Headache Impact Score 6 (HIT-6) at the initial visit was 63. After the prescription of Japanese herbal kampo medicine Goreisan (TJ-17), Goshuyuto (TJ-31), and 200 mg of valproic acid, MHD, AMD, and HIT-6 decreased gradually. However, these parameters could not improve sufficiently at nine months: MHD 4, AMD 4, and HIT-6 52. We first prescribed a lotion formulation of 20% oxybutynin hydrochloride at nine months. After this, migraine was further attenuated, and stress related to primary palmar hyperhidrosis was reduced; at 12 months, the patient had achieved MHD 2, AMD 2, and HIT-6 48. She will continue receiving primary palmar hyperhidrosis treatment while tapering off migraine prophylaxis. While the exact mechanisms connecting migraine and primary hyperhidrosis remain uncertain, this case raises important questions about the potential interplay between stress, sweating, and migraine triggers.

Long-term evaluation of the safety and efficacy of a novel 20% oxybutynin hydrochloride lotion for primary palmar hyperhidrosis: An open-label extension study.

The long-term safety and efficacy of 52-week application of oxybutynin hydrochloride 20% lotion (20% OL) for the treatment of primary palmar hyperhidrosis (PPHH) in Japanese patients aged ≥12 years were evaluated in an open-label extension (OLE) of a 4-week, randomized, double-blind (DB) study. The OLE included 114 patients who completed the DB study and wished to continue treatment and 12 new patients. In the safety analysis population (125 patients), the incidence of adverse events (AEs) and adverse drug reactions (ADRs) was 79.2% and 36.0%, respectively. Serious AEs were observed in two patients but were considered unrelated to the investigational drug. The incidence of AEs that led to study discontinuation was 1.6%. The incidence of application site AEs and ADRs was 35.2% and 26.4%, respectively. The severity of most events was mild. The incidence of anticholinergic AEs related to dry mouth was 3.2% for thirst and 0.8% for dry throat. The long-term efficacy of 20% OL was confirmed by a long-lasting reduction in sweat volume and improvement in the Hyperhidrosis Disease Severity Scale and Dermatology Life Quality Index. This study has several limitations: First the results may include some bias because most of the participants were from the prior DB study; second, the results may not be generalizable because only a few participants were in the age group most susceptible to PPHH (i.e., < 15 years old); and third, the study did not obtain safety information from treatment for more than 52 weeks, so this information must be collected in clinical practice in the future. No reduced therapeutic effect was observed in patients with PPHH in this study after 52-week application of 20% OL. Also, few patients experienced serious AEs or AEs that led to study treatment discontinuation.

Pharmacotherapy for obstructive sleep apnea - A systematic review and meta-analysis of randomized controlled trials.

Continuous positive airway pressure is the first-line and gold-standard treatment for obstructive sleep apnea (OSA). Pharmacotherapy is not commonly used in treating OSA until recently. Combined noradrenergic and antimuscarinic agents have been clinically applied for OSA patients with variable results. This meta-analysis study aimed to investigate the efficacy of the combined regimen on OSA. A systematic literature search was performed up to November 2022 for the effects of the combined regimen on OSA. Eight randomized controlled trials were identified and systematically reviewed for meta-analysis. There were significant mean differences between OSA patients taking a combined regimen and placebo in apnea-hypopnea index (AHI) [mean difference (MD) -9.03 events/h, 95%CI (-16.22, -1.83 events/h; P = 0.01] and lowest oxygen saturation [MD 5.61%, 95% CI % (3.43, 7.80); P < 0.01]. Meta-regression showed that a higher proportion of male participants was associated with a greater reduction of AHI (p = 0.04). This study showed a positive but modest effect of pharmacotherapy in the reduction of OSA severity. The combination drugs are most applicable to male OSA patients based on their efficacy and pharmacological susceptibility. Pharmacotherapy may be applied as an alternative, adjunctive or synergistic treatment under careful consideration of its side effects.

Safety and efficacy of oxybutynin in patients with hyperhidrosis: systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Sweating is a physiologic mechanism of human thermoregulation. Hyperhidrosis is defined as a somatic disorder where the sweating is exaggerated in an exact area because the sweat glands are hyperfunctioning. It negatively affects the quality of life of the patients. We aim to investigate patient satisfaction and the effectiveness of oxybutynin in treating hyperhidrosis. METHODS: We prospectively registered the protocol of this systematic review and meta-analysis on PROSPERO (CRD 42022342667). This systematic review and meta-analysis were reported according to the PRISMA statement guidelines. We searched three electronic databases (PubMed, Scopus, Web of Science) from inception until June 2, 2022, using MeSH terms. We include studies comparing patients with hyperhidrosis who received oxybutynin or a placebo. We assessed the risk of bias using the Cochrane risk of bias assessment tool (ROB2) for randomized controlled trials. The risk ratio was calculated for categorical variables, and the mean difference was calculated for continuous variables using the random effect model with 95% confidence intervals (CI). RESULTS: Six studies were included in the meta-analysis, with a total of 293 patients. In all studies, patients were assigned to receive either Oxybutynin or Placebo. Oxybutynin represented an HDSS improvement (RR = 1.68 95% CI [1.21, 2.33], p = 0.002). It also can improve the quality of life. There is no difference between oxybutynin and placebo regarding dry mouth (RR = 1.68 95% CI [1.21, 2.33], p = 0.002). CONCLUSION: Our study suggests that using oxybutynin as a treatment for hyperhidrosis is significant and needs to be highlighted for clinicians. However, more clinical trials are needed to grasp the optimum benefit.

Oxybutynin gel versus nanoemulgel for treating primary palmar hyperhidrosis: A pilot double-blind randomized controlled trial.

INTRODUCTION: Palmar hyperhidrosis or excessive palmar sweating can reduce one's quality of life as it is associated with significant physical and occupational disabilities. We compared the gel and nanoemulgel of oxybutynin in treating these patients. MATERIALS AND METHODS: This pilot study was performed as a double-blind controlled randomized clinical trial at Shahid Faghihi Hospital, Shiraz, Iran. In two randomly allocated groups of 15, patients diagnosed with primary palmar hyperhidrosis by an attending dermatologist applied half a fingertip (roughly 0.25 g) of 1% oxybutynin topical gel or 1% oxybutynin nanoemulgel to both palms every 12 h for one month. The Hyperhidrosis Disease Severity Scale (HDSS), Visual Analog Scale (VAS), and Dermatology Life Quality Index (DLQI) were used to assess the patients at the beginning and end of the study. Statistical analysis was performed using SPSS version 25. RESULTS: The groups were similar in terms of age (p = 0.800), sex (p = 0.096), and baseline HDSS, VAS, and DLQI scores. The mean HDSS scores decreased significantly (p = 0.001) over time in patients receiving the gel (3.00 ± 1.00 vs. 2.33 ± 0.61) or nanoemulgel (2.92 ± 0.82 vs. 2.14 ± 0.53), without a significant difference between the groups. The same was true for the VAS and DLQI scores. Three patients in each group experienced transient, self-limited anticholinergic side effects (p = 0.983). CONCLUSION: Oxybutynin gel and nanoemulgel offer equal safety and similar efficacy in reducing the disease severity and increasing the quality of life of patients with palmar hyperhidrosis.

A novel lotion formulation of 20% oxybutynin hydrochloride for the treatment of primary palmar hyperhidrosis: A randomized, placebo-controlled, double-blind, phase III study.

BACKGROUND: No previous controlled studies have been specifically designed or adequately powered to show the efficacy of topical oxybutynin for palmar hyperhidrosis by using quantitative measures. OBJECTIVE: To evaluate efficacy of 20% oxybutynin hydrochloride lotion (20% OL) in reducing palmar sweat volume in patients with primary palmar hyperhidrosis (PPHH). METHODS: In a randomized controlled trial, Japanese patients with PPHH aged 12 years and older received either 20% OL (n = 144) or placebo (n = 140) on both palms once daily for 4 weeks. Palmar sweat volume was measured by the ventilated capsule method. For the primary outcome, response was defined as a reduction of sweat volume of at least 50% from baseline. RESULTS: At week 4, the responder rate for sweat volume was significantly higher in the 20% OL arm than in the placebo arm (52.8% vs 24.3%, respectively; treatment difference, 28.5% [95% CI, 17.7% to 39.3%]; P < .001). No serious adverse events occurred, and no adverse events led to treatment discontinuation. LIMITATIONS: The treatment period was only 4 weeks. CONCLUSIONS: In patients with PPHH, 20% OL is superior to placebo in reducing palmar sweat volume.