المؤلفون: Casselini, Carolina M, Parson, Henri K, Frizzi, Katie E, Marquez, Alex, Smith, Darrell R, Guernsey, Lucie, Nemmani, Rakesh, Tayarani, Alireza, Jolivalt, Corinne G, Weaver, Jessica, Fernyhough, Paul, Vinik, Aaron I, Calcutt, Nigel A

المصدر: Acta Neuropathologica. 147(1)

مصطلحات موضوعية: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Neurodegenerative, Peripheral Neuropathy, Clinical Research, Chronic Pain, Diabetes, Clinical Trials and Supportive Activities, Pain Research, Development of treatments and therapeutic interventions, 6.1 Pharmaceuticals, 5.2 Cellular and gene therapies, Evaluation of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Metabolic and endocrine, Neurological, Diabetic neuropathy, Epidermal nerve fibres, Muscarinic antagonist, Neuropathic pain, Oxybutynin, Randomized clinical trial, Animals, Humans, Mice, Rats, Diabetic Neuropathies, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Mandelic Acids, Receptors, Muscarinic, Muscarinic Antagonists, Quality of Life, Adult, Diabetes Mellitus, Type 1, Neurology & Neurosurgery

الوصف: 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.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8jf8v1cqTest

المؤلفون: Sollini, Maria Laura, Pellegrino, Chiara, Barone, Giulia, Capitanucci, Maria Luisa, Zaccara, Antonio Maria, Crescentini, Leonardo, Castelli, Enrico, Della Bella, Gessica, Scorletti, Federico, Papetti, Laura, Monte, Gabriele, Ferilli, Michela Ada Noris, Valeriani, Massimiliano, Mosiello, Giovanni

المصدر: Children; May2024, Vol. 11 Issue 5, p601, 12p

مصطلحات موضوعية: URINARY organ physiology, MULTIPLE sclerosis, RESEARCH funding, URINARY incontinence, URINARY organs, URINARY organ diseases, RETROSPECTIVE studies, RETENTION of urine, OXYBUTYNIN (Drug), NEUROGENIC bowel, CASE studies, INTERMITTENT urinary catheterization, DISEASE complications, CHILDREN

مستخلص: Background: Multiple sclerosis (MS) is increasing in the pediatric population and, as in adults, symptoms vary among patients. In children the first manifestations can sometimes overlap with acute neurological symptoms. Urological symptoms have not been much studied in childhood. We shared our experience with MS urological manifestation in children. Methods: This article is a retrospective evaluation of all children with MS, according to the Krupp criteria, who also present with urological symptoms. We collected demographic and clinical history, the MR localization of demyelinating lesions, urological symptoms, and exams. Results: We report on six MS pediatric cases with urological manifestation. Urinary symptoms, characterized by urinary incontinence in five patients and urinary retention in one patient, appeared in a different time frame from MS diagnosis. Urodynamic exams showed both overactive and underactive bladder patterns. Treatment was defined according to lower urinary tract dysfunction, using clean intermittent catheterization, oxybutynin, and intradetrusor Onabotulinum Toxin-A injection. A low acceptance rate of invasive evaluation and urological management was observed. Conclusions: The MS diagnosis was traumatic for all our patients. We believe it is important to address urological care in young people from the time of diagnosis for prompt management; it could be useful to include a pediatric urologist in multidisciplinary teams. [ABSTRACT FROM AUTHOR]

: Copyright of Children is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Welk, Blayne

المصدر: Indian Journal of Urology; Apr-Jun2024, Vol. 40 Issue 2, p82-87, 6p

مصطلحات موضوعية: COGNITION disorder risk factors, PARASYMPATHOMIMETIC agents, URINARY tract infections, RISK assessment, NEUROGENIC bladder, COGNITIVE testing, TOLTERODINE, OXYBUTYNIN (Drug), DEMENTIA, DISEASE complications

مستخلص: This narrative review discusses the relationship between anticholinergic medications and cognitive change specifically in patients with neurogenic lower urinary tract dysfunction (NLUTD). NLUTD is prevalent in various conditions, including spinal cord injury (SCI), spina bifida (SB), multiple sclerosis (MS), Parkinson's, stroke, and dementia and often requires anticholinergic overactive bladder (OAB) medications. In the general population, and among those with OAB, several studies have found a significant association between this class of medications and cognitive side effects, mostly when used for > 90 days. These cognitive side effects may be particularly relevant to people with NLUTD due to their higher baseline risk of cognitive impairment. Two studies (one in people with SCI and another in MS) found evidence of cognitive impairment with the use of OAB anticholinergics (specifically oxybutynin and tolterodine). People with dementia commonly use OAB anticholinergics, and there is evidence that oxybutynin and tolterodine may impair cognition in this population. Two recent studies in children with SB studied 12 months of solifenacin and 6 months of fesoterodine/oxybutynin and found there was no significant change in neuropsychological testing. Clinical studies in people with Parkinson's disease and prior stroke have not shown that trospium, darifenacin, or fesoterodine have a significant impact on cognitive measures. In summary, oxybutynin and tolterodine may pose a higher risk of cognitive impairment than newer OAB anticholinergics in people with NLUTD; there is no evidence that children with SB experience cognitive impairment with OAB anticholinergics. Further study is necessary to confirm cognitive safety, particularly as the NLUTD population may have a high exposure to OAB anticholinergics. Advocating for potentially safer OAB medications is necessary if there is concern about cognitive risks. [ABSTRACT FROM AUTHOR]

: Copyright of Indian Journal of Urology is the property of Wolters Kluwer India Pvt Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Vereen, M. S., Harms, F., Stolker, R. J., Dirckx, M.

المصدر: Anaesthesia Reports; Jan-Jun2024, Vol. 12 Issue 1, p1-4, 4p

مصطلحات موضوعية: MORPHINE, PHYSIOLOGIC salines, ABDOMINAL surgery, POSTOPERATIVE pain, PATIENT-controlled analgesia, TREATMENT effectiveness, EPIDURAL analgesia, OXYCODONE, NAPROXEN, URINARY catheters, PROPOFOL, RECTUS abdominis muscles, ELECTIVE surgery, OXYBUTYNIN (Drug), GENERAL anesthesia, PATIENT satisfaction, BUPIVACAINE, NERVE block, ACETAMINOPHEN

مستخلص: Summary: Optimal pain management after open abdominal surgery is essential but can be difficult to achieve. The effects of inadequate analgesia go beyond the first few postoperative days; severe acute postoperative pain may contribute to the development of chronic postsurgical pain. Thoracic epidural analgesia is a traditional approach to the management of acute pain after open abdominal surgery but has multiple possible contraindications and can be technically challenging. In our hospital, we typically offer ultrasound‐guided rectus sheath blocks with catheters when epidural analgesia is not feasible. However, the recent registration of long‐acting liposomal bupivacaine in the Netherlands as well as logistical and equipment‐related issues have led us to consider liposomal bupivacaine as an alternative to the use of catheters. Here, we present a short case series to describe our first clinical experiences with the use of liposomal bupivacaine in ultrasound‐guided rectus sheath blocks after midline laparotomy for three patients in whom epidural insertion was contraindicated. [ABSTRACT FROM AUTHOR]

: Copyright of Anaesthesia Reports is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Jean Jacques Vanden Eynde

المصدر: Drugs and Drug Candidates, Vol 2, Iss 4, Pp 865-882 (2023)

مصطلحات موضوعية: bladder, breast cancer, hot flashes, hyperhidrosis, obstructive sleep apnea, oxybutynin, Pharmacy and materia medica, RS1-441, Chemistry, QD1-999

الوصف: For decades, oxybutynin hydrochloride has been prescribed to improve bladder control in cases of incontinence and excessive urination frequency. This review summarizes synthetic methods enabling the preparation of the racemic drug and, in a detailed manner, preparation of (S)-2-cyclohexyl-2-hydroxy-2-phenylacetic acid, a key intermediate in the synthesis of (S)-oxybutynin. The mode of action and metabolism are briefly addressed in order to explain the main adverse effects associated with its use and to justify the evolution observed in the diverse commercial formulations. Repositioning opportunities are discussed in terms of clinical trials for the management of hyperhidrosis, hot flashes, and obstructive sleep apnea.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2813-2998/2/4/43Test; https://doaj.org/toc/2813-2998Test

الوصول الحر: https://doaj.org/article/46d50ef02dd04ba6bda7bb501bbeec5dTest

المؤلفون: Attallah, Heba¹, El-Gilany, Abdel-Hady², Bayoumy Youssef, Youssef¹, Abdelshaheed, Mohamed³, Ahmed Sharaf, Elshahat¹

المصدر: Indian Journal of Dermatology. May/Jun2022, Vol. 67 Issue 3, p222-227. 6p.

مصطلحات موضوعية: *DRUG efficacy, *OXYBUTYNIN (Drug), *ALUMINUM chloride, *ORAL drug administration, *HYPERHIDROSIS, *RANDOMIZED controlled trials, *COMPARATIVE studies, *HAND, *QUALITY of life, *QUESTIONNAIRES, *DESCRIPTIVE statistics, *CUTANEOUS therapeutics, *STATISTICAL sampling, *EVALUATION

مستخلص: Background: Palmar hyperhidrosis is characterized by excessive sweating beyond the physiological needs of the patient's body and the most frequent form is primary or essential. Different treatments protocols have been proposed to control or decrease sweating. Aims and Objectives: This study aimed to compare the efficacy and safety of oral oxybutynin versus topical aluminum chloride hexahydrate (ACH) in treating primary palmar hyperhidrosis. Also, to assess quality of life (QOL) as a measure of improvement of hyperhidrosis state. Materials and Methods: Patients were randomized using the block randomization with sealed envelope method into two treatment groups; oral oxybutynin group and topical ACH group. Hyperhidrosis Disease Severity Scale (HDSS) was used as a primary outcome measure to assess the efficacy of the drug in both groups. Clinical grading and the QOL were used as secondary outcome measures. The safety was evaluated by recording side effects in the follow-up visits. Results: HDSS, clinical grading and QOL score showed a statistically significant improvement in the oral oxybutynin groups. One week after stoppage of treatment, the symptoms recurred again in both groups with return of HDSS and QOL scores to pretreatment levels. The most common side effects were dry mouth (65.8%) and itching (65.0%) for oral oxybutynin group and topical ACH group; respectively. Conclusion: Treatment of primary palmar hyperhidrosis with oxybutynin is a good initial alternative for treatment given that it gives better results and much more improvement in QOL when compared to topical ACH. QOL questionnaire and clinical grading should also be considered as useful tools in the assessment of response to treatment. [ABSTRACT FROM AUTHOR]

المؤلفون: Zadi, Seema, Javaid, Sumaira, Atia-tul-Wahab, Zafar, Humaira, Awais, Muhammad, Maslennikov, Innokentiy, Choudhary, M. Iqbal

المصدر: Pharmacy Faculty Articles and Research

مصطلحات موضوعية: Drug repurposing, Deubiquitinase, USP7, Anti-cancer agents, STD-NMR, Gene expression analysis, Oxybutynin, Ketotifen, Pantoprazole sodium, Escitalopram, Amino Acids, Peptides, and Proteins, Cancer Biology, Medicinal and Pharmaceutical Chemistry, Oncology, Other Pharmacy and Pharmaceutical Sciences

الوصف: 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.

وصف الملف: application/pdf

العلاقة: https://digitalcommons.chapman.edu/pharmacy_articles/1053Test; https://digitalcommons.chapman.edu/context/pharmacy_articles/article/2054/viewcontent/Repurposing_of_US_FDA_approved_drugs_as_negative_modulators_of_ubiquitin_specific_protease_7__USP7_.pdfTest; https://digitalcommons.chapman.edu/context/pharmacy_articles/article/2054/filename/0/type/additional/viewcontent/Supplemental_data.zipTest

الإتاحة: https://doi.org/10.1016/j.heliyon.2024.e26345Test
https://digitalcommons.chapman.edu/pharmacy_articles/1053Test
https://digitalcommons.chapman.edu/context/pharmacy_articles/article/2054/viewcontent/Repurposing_of_US_FDA_approved_drugs_as_negative_modulators_of_ubiquitin_specific_protease_7__USP7_.pdfTest
https://digitalcommons.chapman.edu/context/pharmacy_articles/article/2054/filename/0/type/additional/viewcontent/Supplemental_data.zipTest

المؤلفون: Gustavo Ferrari, Loise Silveira da Silva, Renata Cerruti, Izabelle de Mello Gindri, Gean Vitor Salmoria, Carlos Rodrigo de Mello Roesler

مصطلحات موضوعية: Biophysics, Medicine, Cell Biology, Physiology, Pharmacology, Biotechnology, Cancer, Computational Biology, Space Science, Polymers, ethylene vinyl acetate, high density polyethylene, oxybutynin, overactive bladder, drug delivery

الوصف: 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.

العلاقة: https://figshare.com/articles/journal_contribution/Development_and_characterization_of_3D_printed_ethylene_vinyl_acetate_EVA_as_drug_delivery_device_for_the_treatment_of_overactive_bladder/25415113Test

الإتاحة: https://doi.org/10.6084/m9.figshare.25415113.v1Test

المؤلفون: Kretschmar, Melanie¹ melanie.kretschmar@online.de, Suleiman, Ahmed Abbas¹, Krause, Petra², Albrecht, Uwe³, Stein, Raimund⁴, Rubenwolf, Peter⁵, Fuhr, Uwe¹, Taubert, Max¹

المصدر: Journal of Clinical Pharmacology. Jul2021, Vol. 61 Issue 7, p961-971. 11p.

مصطلحات موضوعية: *OXYBUTYNIN (Drug), *ORAL drug administration, *INTRAVESICAL administration, *BLOOD plasma, *HEALTH status indicators, *DESCRIPTIVE statistics, *COMPUTER-assisted molecular modeling, *METABOLITES

مستخلص: Oxybutynin is a racemic anticholinergic drug used for the symptomatic treatment of detrusor overactivity. The formation of active metabolites related to tolerability problems depends on the route of administration. The objective of this evaluation was to develop a pharmacokinetic model for oral/intravesical administration as the basis for simulations with different dosages. Data from a published changeover clinical study with 18 healthy adults receiving a single oral dose of 5 mg immediate‐release oxybutynin and single and multiple intravesical doses of 10 mg oxybutynin solution was evaluated. Enantioselective plasma concentrations of oxybutynin and N‐desethyloxybutynin (NDO) were used to establish a population pharmacokinetic model using nonlinear mixed‐effects modeling with NONMEM 7.4.1. For both enantiomers, the data were described well by a 2‐compartment model for oxybutynin with an additional compartment for NDO. Oxybutynin absorption was modeled by transit compartments for oral and first‐order absorption for intravesical application. Bioavailability of the more active (R)‐enantiomer was 7% for oral and 10%‐22% for intravesical administration. In simulations, intravesical doses of 5 to 15 mg (R)‐oxybutynin administered 2 to 3 times daily decreased peak‐trough fluctuations of NDO to 8% compared with 24% after oral administration. The NDO/oxybutynin ratio was reduced from 17 after oral administration to unity. Chronic intravesical versus oral administration of (R)‐oxybutynin generates distinctly lower and less variable concentrations of (R)‐NDO. Pharmacokinetic simulations suggest that exposure for 12.5 mg (R)‐oxybutynin administered twice daily might not compromise efficacy and tolerability compared with exposure for standard thrice‐daily administrations. This assumption needs to be assessed in clinical studies. [ABSTRACT FROM AUTHOR]

المؤلفون: Chen, Tien-Yu^1,2 (AUTHOR), Chung, Chi-Hsiang^3,4,5 (AUTHOR), Chang, Hsin-An^1,6 (AUTHOR), Kao, Yu-Chen^1,7 (AUTHOR), Chang, Shan-Yueh^8,9 (AUTHOR), Kuo, Terry B. J.^2,10 (AUTHOR), Yang, Cheryl C. H.² (AUTHOR), Chien, Wu-Chien^3,4,11 (AUTHOR) chienwu@mail.ndmctsgh.edu.tw, Tzeng, Nian-Sheng^1,6 (AUTHOR) pierrens@mail.ndmctsgh.edu.tw

المصدر: Scientific Reports. 6/15/2021, Vol. 11 Issue 1, p1-9. 9p.

مصطلحات موضوعية: *ATOMOXETINE, *OXYBUTYNIN (Drug), *SLEEP apnea syndromes, *DISEASE incidence, *TREATMENT duration

مستخلص: One recent study showed that atomoxetine-oxybutynin combination (AOC) use is effective in reducing obstructive sleep apnea (OSA) severity. We used a nationwide database to examine the association between AOC use and the risk of OSA incidence. This retrospective cohort study used Taiwan's National Health Insurance Research Database between the years 2000 and 2015. The patients who used atomoxetine or oxybutynin were included as an exposed cohort. The exposed and unexposed groups were selected in a ratio of 1:3 with sex, age, and index year matching. We used the multivariate Cox proportional regression model to evaluate the association between AOC use and the risk of an incident diagnosis of OSA. The incidence rates of OSA in the exposed cohort (N = 8940) and the unexposed cohort (N = 26,820), were 21.92 and 22.93 per 100,000 person-years, respectively. The adjusted hazard ratio of oxybutynin use only and AOC with a treatment duration of ≥ 366 days were 0.307 (95% CI 0.204–0.995, P = 0.045) and 0.299 (95% CI 0.102–0.933, P = 0.002), respectively. Long-term atomoxetine-oxybutynin combination therapy may be beneficial to reduce the risk of obstructive sleep apnea. Further studies to examine these mechanisms are warranted. [ABSTRACT FROM AUTHOR]