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1.
Life Sci ; 330: 122004, 2023 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37544378

RESUMO

AIMS: Depression is one of the common neurological comorbidities in patients with inflammatory bowel disease (IBD). The current study aimed to investigate the potential impact of niacin on colitis-induced depressive-like behavior in rats. MATERIALS AND METHODS: Animals were given 5 % dextran sulfate sodium (DSS) in drinking water for one week to induce colitis. Niacin (80 mg/kg), with or without mepenzolate bromide (GPR109A blocker), was administered once per day throughout the experimental period. Rats were tested for behavioral changes using open field and forced swimming tests. KEY FINDINGS: Niacin significantly ameliorated DSS-induced behavioral deficits and alleviated macroscopic and microscopic colonic inflammatory changes. It also augmented the hippocampal levels of ZO-1, occludin, and claudin-5 proteins, indicating the ability of niacin to restore the blood-brain barrier (BBB) integrity. Moreover, niacin decreased hippocampal IL-1ꞵ and NF-ĸB contents but increased GSH, Sirt-1, Nrf-2, HO-1 concentrations. All these beneficial effects were partially abolished by the co-administration of mepenzolate bromide. SIGNIFICANCE: The neuroprotective effect of niacin against DSS-induced depressive-like behavior was partially mediated through GPR109A-mediated mechanisms. Such mechanisms are also involved in modulating neuronal oxidative stress and inflammation via Sirt-1/Nrf-2/HO-1 signaling pathways.


Assuntos
Colite , Niacina , Animais , Ratos , Benzilatos/efeitos adversos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colo/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Niacina/farmacologia
3.
AAPS J ; 25(3): 36, 2023 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-37016156

RESUMO

The extent and rate of bioavailability are fundamental measures to characterize the pharmacokinetics of drugs after oral administration. Together with bioavailability (F), the mean absorption time (MAT) can be used to define the rate of bioavailability, i.e., the rate of drug absorption. Previous results suggest that F may depend on MAT. Estimates of F and MAT were obtained from the input function (sum of two inverse Gaussian functions) used to model the oral absorption process. The estimation was performed by population analysis (nonlinear mixed-effects modeling) based on data from bioavailability studies in healthy volunteers. For trospium and ketamine, F decreased significantly with increasing MAT, while for propiverine, a significant increase was observed. Thus, the interindividual variability in F could be largely attributed to the interindividual variability in MAT. For trospium and propiverine, the relative dispersion (normalized variance) of the absorption time distribution increased significantly with MAT. For trospium and propiverine, the plot of F versus MAT provides information about the effect of gastrointestinal transit on drug absorption. In contrast, an increase in hepatic extraction with increasing MAT is responsible for the dependence of F on MAT. The F versus MAT plot is suggested as a simple diagnostic tool in evaluating the results of bioavailability studies.


Assuntos
Benzilatos , Fígado , Humanos , Disponibilidade Biológica , Administração Oral , Antagonistas Muscarínicos/farmacocinética
4.
Luminescence ; 37(10): 1785-1792, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35922904

RESUMO

Two facile spectroscopic methodologies were designed for estimating trospium chloride (TPM) in raw material and tablets with high operational reliability and selectivity. The methods were based on using erythrosine B (EB) as a spectroscopic tool for ion-pair complex formation with the drug. In a mild acidic medium of Britton Robinson buffer (pH 4.0), the ionized hydroxyl group in the reagent interacted with the ionized amine in the studied drug. Method I was based on the spectrophotometric measuring of the absorbance of the reaction product at 557 nm. Method II was based on spectrofluorimetric measurement of the quenching effect of TPM on the inherent fluorescence of EB at 550 nm (λex. = 528 nm). The two methods showed linearity through ranges 1.0-10.0 and 0.5-10.0 µg/ml for Methods I and II, respectively. The suggested methods were exploited for analyzing TPM in Trospamexin® tablets and showed good applicability. The designed systems were validated as per International Conference on Harmonization guidelines. Experimental conditions were modulated to obtain the best sensitivities. The quenching mechanism was investigated and the quenching constant was computed relying on the Stern-Volmer equation. Environmental impact was appraised using novel metric green tools, GABI, and AGREE. The suggested systems excelled over other reported methods in terms of greenness, sensitivity, and cost-effectiveness.


Assuntos
Aminas , Eritrosina , Benzilatos , Eritrosina/química , Nortropanos , Reprodutibilidade dos Testes , Espectrometria de Fluorescência/métodos , Comprimidos
5.
Adv Ther ; 39(6): 2489-2501, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35325367

RESUMO

INTRODUCTION: Unmet expectations are a major cause of perceived treatment failure and discontinuation of treatment. To enable evidence-based counselling of patients on realistic expectations, we determined the chance of patients with overactive bladder becoming free of a given symptom upon treatment with a muscarinic antagonist in a non-interventional setting. METHODS: Two non-interventional studies included 1335 and 745 patients, respectively, who received 30 or 45 mg q.d. propiverine ER for 12 weeks. They were monitored for becoming free of urgency, urinary incontinence, frequency, or nocturia. Analyses were also performed in subgroups defined by basal symptom severity, age, and gender. Categorical data are shown as a percentage of the respective population. Continuous data are expressed as means or as median depending on whether the variability was considered to exhibit a normal distribution. RESULTS: The probability of becoming symptom-free was largest for incontinence and frequency (about 50%), but lesser for urgency (about 20%) and nocturia (about 10%). Greater basal severity of a symptom reduced the chance to become free of that symptom upon treatment, but the chance to become free of incontinence and frequency was still considerable. Age and gender had only minor if any effects on the chance of becoming symptom-free. These findings are in line with those of a limited number of randomized controlled trials. CONCLUSION: These data provide an evidence base for the counselling of patients with overactive bladder on realistic expectations of treatment outcomes. We propose that realistic expectations can lead to greater long-term adherence.


Unmet expectations are a major reason why patients with overactive bladder syndrome discontinue treatment. To enable evidence-based counselling of patients on realistic expectations, we have determined the chance that patients with overactive bladder become free of urgency, incontinence, voiding frequency, and nocturia. Two non-interventional studies included 1335 and 745 patients, respectively, who received 30 or 45 mg q.d. propiverine ER for 12 weeks. Analyses were also performed in subgroups defined by basal symptom severity, age, and gender. The probability of becoming symptom-free was largest for incontinence and voiding frequency (about 50%), but lesser for urgency and nocturia (about 20%). Greater basal severity of a symptom reduced the chance to become free of that symptom upon treatment, but the chance to become free of incontinence and frequency was still considerable. Age and gender had only minor if any effects on the chance of becoming symptom-free. These data provide an evidence base for the counselling of patients with overactive bladder on realistic expectations of treatment outcomes. We propose that realistic expectations can lead to greater long-term adherence.


Assuntos
Noctúria , Bexiga Urinária Hiperativa , Incontinência Urinária , Benzilatos/uso terapêutico , Humanos , Motivação , Noctúria/tratamento farmacológico , Resultado do Tratamento , Bexiga Urinária Hiperativa/tratamento farmacológico
6.
Urologiia ; (6): 71-77, 2022 Dec.
Artigo em Russo | MEDLINE | ID: mdl-36625617

RESUMO

AIM: To evaluate the efficiency of long-term use of trospium chloride (Spazmex) for the treatment of patients with neurogenic overactive bladder due to Parkinson's disease (PD) and to determine the influence of therapy on the cognitive status of patients. MATERIALS AND METHODS: 60 patients with PD and neurogenic overactive bladder with stages 2.5, 3 and 4 according to Hoehn-Yahr scale were included in the main group. The mean age was 58.2+/-5.7 years. All patients were prescribed trospium chloride at entry into the study, with doses titrated gradually according to clinical efficacy (30 to 90 mg). The comparison group included 15 patients with PD and neurogenic overactive bladder at stages 2,5 and 3, who received tibial neuromodulation according to the standard technique with skin electrodes. The mean age of patients was 56.4+/-4.6 years. At baseline, both groups were comparable in terms of gender, age and cognitive status (p=0.801). All patients received treatment for 52 weeks. The efficiency of therapy was assessed according to bladder diaries, while safety outcomes included postvoid residual, side effects, cognitive status according to the MoCA scale and quality of life according to the SF-Qualiveen questionnaire. RESULTS: clinical efficacy and satisfaction were achieved in all patients who completed the study (47 patients in the main group and 15 patients in the comparison group). Good clinical efficacy was demonstrated in both groups, since there was a decrease in the number of urinations, episodes of urgency and urinary incontinence. In addition, there was an improvement in the quality of life according to the SF-Qualiveen scale. The cognitive status during the entire follow-up period remained without significant changes in both groups. CONCLUSION: Trospium chloride is an effective drug in patients with PD. It does not affect cognitive functions during long-term use. Trospium chloride should be considered as first-line drug in those with urologic manifestations of PD.


Assuntos
Nortropanos , Doença de Parkinson , Bexiga Urinaria Neurogênica , Bexiga Urinária Hiperativa , Incontinência Urinária , Humanos , Pessoa de Meia-Idade , Bexiga Urinária Hiperativa/complicações , Bexiga Urinária Hiperativa/tratamento farmacológico , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Qualidade de Vida , Incontinência Urinária/tratamento farmacológico , Bexiga Urinaria Neurogênica/tratamento farmacológico , Nortropanos/efeitos adversos , Benzilatos/uso terapêutico , Resultado do Tratamento
7.
Urologiia ; (5): 35-40, 2021 Nov.
Artigo em Russo | MEDLINE | ID: mdl-34743429

RESUMO

BACKGROUND: An overactive bladder and cognitive impairment are two medical and social problems, which have an outmost importance, affecting the quality of life. Both disorders are common in the practice of a urologist, neurologist, internist, and other physicians. Parkinsons disease and multiple sclerosis are the most common neurological diseases, which often manifest by pelvic dysfunction and cognitive dysfunction. The clinician needs to understand the pathogenesis of the underlying disease and the pharmacologic properties of drugs, which can be used both in neurology and urology, as well as in other related specialties. AIM: To evaluate cognitive functions in patients with neurogenic overactive bladder treated with trospium chloride. MATERIALS AND METHODS: A total of 45 patients with neurological disease (28 with Parkinsons disease [group 1] and 17 with multiple sclerosis [group 2]) were included in the study. All patients had symptoms of an overactive bladder. Trospium chloride was administered in an individually adjusted dose for 12 weeks. Cognitive functions were assessed using the international Montreal Cognitive Assessment (MoCA) before and after the therapy. A change of total scores over time was assessed using the paired Wilcoxon test. The level of significance of <0.05 was used (confidence level of 95%). RESULTS: A significant decrease in all studied parameters of an overactive bladder in both groups was seen. The baseline evaluation of the total score on the MoCA scale prior to the start of taking trospium chloride revealed the presence of moderate cognitive impairment (21.3+/-2.9 points) in patients of the group 1. After 12 weeks of therapy, no significant change in cognitive functions was observed (21.7+/-3.1 points; p>0.05). In group 2, moderate cognitive impairment (MoCA 22.5+/-3.7 points) was found at baseline. After taking trospium chloride, no significant changes were noted (MoCA 22.9+/-4.1 points) (p>0.05). No central nervous system side effects were reported in any group. CONCLUSION: Trospium chloride is an effective drug, which does not affect cognitive functions in patients with neurogenic overactive bladder. This drug is safe to use in both Parkinsons disease and multiple sclerosis, considering the low risk of cognitive impairment in polypharmacy.


Assuntos
Nortropanos , Bexiga Urinaria Neurogênica , Bexiga Urinária Hiperativa , Benzilatos , Cognição , Humanos , Qualidade de Vida , Bexiga Urinaria Neurogênica/tratamento farmacológico , Bexiga Urinária Hiperativa/tratamento farmacológico
8.
New Phytol ; 232(5): 1904-1908, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34537960

RESUMO

Cantil is reported as a new-found organ specific to the model plant Arabidopsis thaliana that is prominent only in short-day-grown wild-type accessions or long-day-grown genetic mutants with delayed vegetative to reproductive transition. Here, we show that cantils (previously known as nubbins) arise as one of the many phenotypic consequences of aneuploidy resulting from chromosome dosage imbalances in Arabidopsis polyaneuploids despite normal reproductive transition in long-day photoperiods. Without a demonstrated function or adaptive significance, we view cantils as a morphological oddity rather than a separate organ, and as a manifestation of physiological perturbations triggered by genetic and environmental factors. We also note a striking phenotypic resemblance between 'cantil' and 'gynophore', a floral morphological structure that is naturally present in the allopolyploid Arabidopsis suecica.


Assuntos
Arabidopsis , Arabidopsis/genética , Benzilatos , Flores , Fotoperíodo , Piperidinas
9.
Development ; 148(11)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34129030

RESUMO

We describe a previously unreported macroscopic Arabidopsis organ, the cantil, named for its 'cantilever' function of holding the pedicel at a distance from the stem. Cantil development is strongest at the first nodes after the vegetative to reproductive inflorescence transition; cantil magnitude and frequency decrease acropetally. Cantils develop in wild-type Arabidopsis accessions (e.g. Col-0, Ws and Di-G) as a consequence of delayed flowering in short days; cantil formation is observed in long days when flowering is delayed by null mutation of the floral regulator FLOWERING LOCUS T. The receptor-like kinase ERECTA is a global positive regulator of cantil formation; therefore, cantils never form in the Arabidopsis strain Ler. ERECTA functions genetically upstream of heterotrimeric G proteins. Cantil expressivity is repressed by the specific heterotrimeric complex subunits GPA1, AGB1 and AGG3, which also play independent roles: GPA1 suppresses distal spurs at cantil termini, while AGB1 and AGG3 suppress ectopic epidermal rippling. These G protein mutant traits are recapitulated in long-day flowering gpa1-3 ft-10 plants, demonstrating that cantils, spurs and ectopic rippling occur as a function of delayed phase transition, rather than as a function of photoperiod per se.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Benzilatos/metabolismo , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Piperidinas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Flores/genética , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Subunidades beta da Proteína de Ligação ao GTP/genética , Subunidades beta da Proteína de Ligação ao GTP/metabolismo , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas Heterotriméricas de Ligação ao GTP/genética , Mutação com Perda de Função , Fenótipo , Fotoperíodo , Plantas Geneticamente Modificadas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Subunidades Proteicas/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo
10.
AAPS J ; 23(4): 85, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34142242

RESUMO

Food can alter drug absorption and impact safety and efficacy. Besides conducting clinical studies, in vitro approaches such as biorelevant solubility and dissolution testing and in vivo dog studies are typical approaches to estimate a drug's food effect. The use of physiologically based pharmacokinetic models has gained importance and is nowadays a standard tool for food effect predictions at preclinical and clinical stages in the pharmaceutical industry. This manuscript is part of a broader publication from the IQ Consortium's food effect physiologically based pharmacokinetic model (PBPK) modeling working group and complements previous publications by focusing on cases where the food effect was predicted with low confidence. Pazopanib-HCl, trospium-Cl, and ziprasidone-HCl served as model compounds to provide insights into why several food effect predictions failed in the first instance. Furthermore, the manuscript depicts approaches whereby PBPK-based food effect predictions may be improved. These improvements should focus on the PBPK model functionality, especially better reflecting fasted- and fed-state gastric solubility, gastric re-acidification, and complex mechanisms related to gastric emptying of drugs. For improvement of in vitro methodologies, the focus should be on the development of more predictive solubility, supersaturation, and precipitation assays. With regards to the general PBPK modeling methodology, modelers should account for the full solubility profile when modeling ionizable compounds, including common ion effects, and apply a straightforward strategy to account for drug precipitation.


Assuntos
Interações Alimento-Droga , Modelos Biológicos , Administração Oral , Área Sob a Curva , Benzilatos/administração & dosagem , Benzilatos/farmacocinética , Disponibilidade Biológica , Simulação por Computador , Esvaziamento Gástrico/fisiologia , Voluntários Saudáveis , Humanos , Indazóis/administração & dosagem , Indazóis/farmacocinética , Absorção Intestinal/fisiologia , Nortropanos/administração & dosagem , Nortropanos/farmacocinética , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Solubilidade , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/farmacocinética
11.
Can J Urol ; 28(3): 10706-10712, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34129467

RESUMO

INTRODUCTION: To clarify the efficacy and safety of propiverine hydrochloride for incontinence after robot-assisted laparoscopic prostatectomy (RALP)/laparoscopic radical prostatectomy (LRP), along with changes in the urethral pressure profile (UPP) and quality of life in patients treated with propiverine hydrochloride. MATERIALS AND METHODS: In this randomized, comparative study, 104 patients who were aware of urinary incontinence after RALP or LRP were assigned to receive propiverine hydrochloride (treatment group) or not (controls). Pad test results, International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) scores, and UPP results [including maximum urethral closure pressure (MUCP) and functional urethral length (FUL)], were recorded immediately and at 6 months postoperatively. RESULTS: No serious intraoperative complications or adverse events were caused by propiverine hydrochloride. The pad-test negative rate was significantly greater in the treatment group than in controls (89.1% vs. 73.2%, p = 0.044). Changes in ICIQ-SF scores and MUCP were significantly greater in the treatment group than in controls [-6.5 vs. -4.5 points (p = 0.021), and +49.5 vs. +28.7 mmHg (p = 0.038), respectively]. FUL change did not significantly differ between groups [+4.5 vs. +3.8 mm (p = 0.091)]. In univariate logistic regression analyses, body mass index (BMI), MUCP, and treatment with propiverine hydrochloride were significantly associated with continence status. In multivariate analyses, BMI and MUCP were independently associated with continence status [odds ratio (OR), 1.266; 95% confidence interval (CI), 1.047-1.530 (p = 0.015), and OR, 0.986; 95% CI, 0.973-0.999 (p = 0.042), respectively]. CONCLUSIONS: Treatment with propiverine hydrochloride alleviated urinary incontinence while improving patient symptoms and quality of life after RALP or LRP.


Assuntos
Benzilatos , Prostatectomia , Incontinência Urinária , Benzilatos/efeitos adversos , Humanos , Laparoscopia , Masculino , Prostatectomia/efeitos adversos , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Qualidade de Vida , Robótica , Incontinência Urinária/tratamento farmacológico , Incontinência Urinária/etiologia
12.
Investig Clin Urol ; 62(3): 331-339, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33834643

RESUMO

PURPOSE: To assess the efficacy of desmopressin plus anticholinergic combination therapy as first-line treatment for children with primary monosymptomatic nocturnal enuresis (PMNE) and to analyze this combination's effect on functional bladder capacity (FBC). MATERIALS AND METHODS: A total of 99 children with PMNE were prospectively enrolled from 2015 to 2019 and randomly allocated to a monotherapy group (n=49), with oral desmopressin lyophilisate (MELT) only; and a combination group (n=50), with desmopressin plus an anticholinergic (propiverine 5 mg). Efficacy and FBC were evaluated at 1 and 3 months after treatment initiation; the relapse rate was assessed at 6 months after treatment cessation. RESULTS: The combination therapy group showed a higher rate of complete response than the monotherapy group after 3 months of treatment (44.0% vs. 22.4%, p=0.002). A significant increase in mean FBC was observed only in the combination group, from 88.72±26.34 mL at baseline to 115.52±42.23 mL at 3 months of treatment (p=0.024). Combination therapy was significantly associated with treatment success at 3 months after treatment initiation (odds ratio [OR], 3.527; 95% confidence interval [CI], 1.203-6.983; p=0.011) and decreased risk of relapse at 6 months after treatment cessation (OR, 0.306; 95% CI, 0.213-0.894; p=0.021), by multivariable analysis. CONCLUSIONS: This study represents the first prospective, randomized controlled trial showing higher response rates and lower relapse rates with desmopressin plus anticholinergic combination therapy compared with desmopressin monotherapy as first-line treatment for children with PMNE.


Assuntos
Antidiuréticos/administração & dosagem , Benzilatos/administração & dosagem , Desamino Arginina Vasopressina/administração & dosagem , Antagonistas Muscarínicos/administração & dosagem , Enurese Noturna/tratamento farmacológico , Criança , Quimioterapia Combinada , Feminino , Humanos , Masculino , Estudos Prospectivos , Recidiva , Resultado do Tratamento
13.
N Engl J Med ; 384(8): 717-726, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33626254

RESUMO

BACKGROUND: The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown. METHODS: In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2. RESULTS: A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups. CONCLUSIONS: In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.).


Assuntos
Antipsicóticos/uso terapêutico , Benzilatos/uso terapêutico , Antagonistas Colinérgicos/uso terapêutico , Agonistas Muscarínicos/uso terapêutico , Nortropanos/uso terapêutico , Piridinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Tiadiazóis/uso terapêutico , Administração Oral , Adulto , Antipsicóticos/efeitos adversos , Benzilatos/efeitos adversos , Antagonistas Colinérgicos/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Agonistas Muscarínicos/efeitos adversos , Nortropanos/efeitos adversos , Piridinas/efeitos adversos , Tiadiazóis/efeitos adversos
14.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375004

RESUMO

BACKGROUND: The muscarinic receptor antagonist trospium chloride (TCl) is used for pharmacotherapy of the overactive bladder syndrome. TCl is a hydrophilic positively charged drug. Therefore, it has low permeability through biomembranes and requires drug transporters for distribution and excretion. In humans, the organic cation transporters OCT1 and OCT2 and the multidrug and toxin extrusion MATE1 and MATE2-K carriers showed TCl transport. However, their individual role for distribution and excretion of TCl is unclear. Knockout mouse models lacking mOct1/mOct2 or mMate1 might help to clarify their role for the overall pharmacokinetics of TCl. METHOD: In preparation of such experiments, TCl transport was analyzed in HEK293 cells stably transfected with the mouse carriers mOct1, mOct2, mMate1, and mMate2, respectively. RESULTS: Mouse mOct1, mOct2, and mMate1 showed significant TCl transport with Km values of 58.7, 78.5, and 29.3 µM, respectively. In contrast, mMate2 did not transport TCl but showed MPP+ transport with Km of 60.0 µM that was inhibited by the drugs topotecan, acyclovir, and levofloxacin. CONCLUSION: TCl transport behavior as well as expression pattern were quite similar for the mouse carriers mOct1, mOct2, and mMate1 compared to their human counterparts.


Assuntos
Benzilatos/metabolismo , Proteínas da Membrana Plasmática de Transporte de Catecolaminas/metabolismo , Nortropanos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico/metabolismo , Animais , Benzilatos/farmacocinética , Transporte Biológico , Proteínas da Membrana Plasmática de Transporte de Catecolaminas/genética , Células HEK293 , Humanos , Cinética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antagonistas Muscarínicos/metabolismo , Antagonistas Muscarínicos/farmacocinética , Nortropanos/farmacocinética , Proteínas de Transporte de Cátions Orgânicos/genética , Transportador 2 de Cátion Orgânico/genética
15.
Clin Interv Aging ; 15: 1493-1503, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32921995

RESUMO

Overactive bladder syndrome (OAB) is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency incontinence, in the absence of urinary tract infection or other obvious pathology. The mainstay of treatment of OAB is anticholinergic/antimuscarinic medication. These drugs block muscarinic receptors throughout the body, not only the bladder, including in the brain, which may lead to cognitive side effects. Anticholinergic load or burden is the cumulative effect of taking drugs that are capable of producing anticholinergic adverse effects. The elderly are more susceptible to these effects, especially as there is increased permeability of the blood brain barrier. The anticholinergic drugs for OAB are able to enter the central nervous system and lead to central side effects. There is increasing evidence that a high anticholinergic load is linked to the development of cognitive impairment and even dementia. Some studies have found an increased risk of mortality. In view of this, care is needed when treating OAB in the elderly. Trospium chloride is a quaternary amine anticholinergic, which has a molecular structure, which theoretically means it is less likely to cross the blood brain barrier and exert central side effects. Alternatively, mirabegron can be used, which is a beta-3 adrenoceptor agonist, which does not add to the anticholinergic load or exert central nervous system side effects. Conservative therapy can be used as an alternative to pharmacological treatment in the form of behavioral modification, fluid management and bladder retraining. Neuromodulation or the use of botox can also be alternatives, but success may be less in the older adult and will require increased hospital attendances.


Assuntos
Antagonistas Colinérgicos/efeitos adversos , Disfunção Cognitiva/induzido quimicamente , Bexiga Urinária Hiperativa/tratamento farmacológico , Acetanilidas/efeitos adversos , Idoso , Terapia Comportamental , Benzilatos/efeitos adversos , Barreira Hematoencefálica/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Feminino , Humanos , Antagonistas Muscarínicos/uso terapêutico , Nortropanos/efeitos adversos , Tiazóis/efeitos adversos , Bexiga Urinária Hiperativa/psicologia
16.
Sci Rep ; 10(1): 14181, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843670

RESUMO

Glial fibrillary acidic protein expressing (GFAP+) glia modulate nociceptive neuronal activity in both the peripheral nervous system (PNS) and the central nervous system (CNS). Resident GFAP+ glia in dorsal root ganglia (DRG) known as satellite glial cells (SGCs) potentiate neuronal activity by releasing pro-inflammatory cytokines and neuroactive compounds. In this study, we tested the hypothesis that SGC Gq-coupled receptor (Gq-GPCR) signaling modulates pain sensitivity in vivo using Gfap-hM3Dq mice. Complete Freund's adjuvant (CFA) was used to induce inflammatory pain, and mechanical sensitivity and thermal sensitivity were used to assess the neuromodulatory effect of glial Gq-GPCR activation in awake mice. Pharmacogenetic activation of Gq-GPCR signaling in sensory SGCs decreased heat-induced nociceptive responses and reversed inflammation-induced mechanical allodynia via peripheral adenosine A1 receptor activation. These data reveal a previously unexplored role of sensory SGCs in decreasing afferent excitability. The identified molecular mechanism underlying the analgesic role of SGCs offers new approaches for reversing peripheral nociceptive sensitization.


Assuntos
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/fisiologia , Hiperalgesia/prevenção & controle , Inflamação/fisiopatologia , Neuroglia/enzimologia , Nociceptividade/fisiologia , Receptor A1 de Adenosina/fisiologia , Receptor Muscarínico M3/fisiologia , Animais , Benzilatos/farmacologia , Clozapina/análogos & derivados , Clozapina/farmacologia , Adjuvante de Freund/toxicidade , Genes Sintéticos , Temperatura Alta , Hiperalgesia/fisiopatologia , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Agonistas Muscarínicos/farmacologia , Neuroglia/fisiologia , Nortropanos/farmacologia , Regiões Promotoras Genéticas , Agonistas do Receptor Purinérgico P1/farmacologia , Antagonistas de Receptores Purinérgicos P1/farmacologia , Receptor A1 de Adenosina/efeitos dos fármacos , Receptor Muscarínico M3/efeitos dos fármacos , Receptor Muscarínico M3/genética , Receptores Acoplados a Proteínas G , Proteínas Recombinantes de Fusão/efeitos dos fármacos , Proteínas Recombinantes de Fusão/metabolismo , Teofilina/análogos & derivados , Teofilina/farmacologia , Tato , Xantinas/farmacologia
17.
Ann Pharm Fr ; 78(5): 408-414, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32681902

RESUMO

Two simple, accurate, sensitive and precise conductometric methods were developed for determination of trospium chloride in pure form and in pharmaceutical formulations. It is based on using two precipitating reagents; Phosphomolybdic acid (PMA) and Silver nitrate (AgNO3). The mean recovery for Silver nitrate is in the range (98-100.95%) and for Phosphomolybdic acid in the range (98-101.69%). A molar ratio has been determined conductometrically for the two reagents, revealed (1/1) for (drug/reagent). The proposed methods were validated and successfully applied for the determination of the studied drug in pure form and in its pharmaceutical preparation. The results of the proposed methods were compared to the results of reported method with no significant difference between them.


Assuntos
Benzilatos/análise , Molibdênio/química , Nortropanos/análise , Ácidos Fosfóricos/química , Nitrato de Prata/química , Condutometria , Indicadores e Reagentes , Reprodutibilidade dos Testes , Comprimidos/análise
18.
Int Braz J Urol ; 46(2): 185-193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32022506

RESUMO

OBJECTIVE: To evaluate the effects of solifenacin, darifenacin, and propiverine on nasal-, subfoveal-, temporal choroidal thicknesses (NCT, SFCT, TCT), intraocular pressure (IOP) and pupil diameter (PD). MATERIALS AND METHODS: Patients with overactive bladder (OAB) diagnosed according to The International Continence Society were administered with solifenacin, darifenacin or propiverine on a daily basis between November 2017 and May 2018. NCT, SFCT, TCT, IOP, and PD of these patients were measured and compared as initial, fourth and twelfth weeks. RESULTS: A total of 165 patients (330 eyes) with OAB were evaluated. Solifenacin (n=140) signifi cantly reduced IOP from 17.30±2.72 mmHg to 16.67±2.56 mmHg (p=0.006) and 16.57±2.41 mmHg (p=0.002), at the fourth and twelfth weeks, respectively. Darifenacin (n=110) signifi cantly reduced NCT from 258.70±23.96 µm to 257.51±22.66 µm (p=0.002) and 255.36±19.69 µm (p=0.038), at the fourth and twelfth weeks, respectively. Propiverine (n=80) signifi cantly increased PD from 4.04±0.48 mm to 4.08±0.44 mm (p=0.009) and 4.09±0.45 mm (p=0.001), at the fourth and twelfth weeks, respectively. CONCLUSION: These findings can help to decide appropriate anticholinergic drug choice in OAB patients. We finally suggest further well-designed randomized prospective studies with a larger population to evaluate the anticholinergic-related complications in eyes.


Assuntos
Benzilatos/efeitos adversos , Benzofuranos/efeitos adversos , Corioide/efeitos dos fármacos , Pressão Intraocular/efeitos dos fármacos , Antagonistas Muscarínicos/efeitos adversos , Pupila/efeitos dos fármacos , Pirrolidinas/efeitos adversos , Succinato de Solifenacina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzilatos/administração & dosagem , Benzofuranos/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Estudos Prospectivos , Pirrolidinas/administração & dosagem , Succinato de Solifenacina/administração & dosagem , Bexiga Urinária Hiperativa/tratamento farmacológico , Adulto Jovem
19.
Korean J Anesthesiol ; 73(2): 145-150, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31602966

RESUMO

BACKGROUND: Catheter-related bladder discomfort (CRBD) is a frequent complaint after awakening from anesthesia in patients receiving perioperative bladder catheterization. Overactive bladder (OAB) and CRBD show similar symptoms; thus, drugs used for the management of OAB influence symptoms of CRBD. Trospium chloride has been found effective in managing resistant cases of OAB. We evaluated the efficacy of oral trospium on CRBD in the postoperative period. METHODS: Sixty-four male and female adult patients, with planned spinal surgery and requiring urinary bladder catheterization, were randomly divided into two groups of 32 each. Group T patients received 60 mg extended-release oral trospium (extended-release) 1 h before induction of anesthesia and Group C patients received a similar-looking placebo. The anesthetic technique was identical in both groups. The CRBD score was evaluated in the postoperative ward using a 4-point scale (1 = no discomfort, 2 = mild, 3 = moderate, 4 = severe). Readings were recorded on arrival (0 h), and 1 h, 2 h, and 6 h postoperatively. All patients received fentanyl for postoperative pain relief. RESULTS: The incidence of CRBD was significantly higher in group C than in group T at 0 h (66% vs 22%, P=0.001) and 1 h postoperatively (72% vs 28%, P=0.001). The incidence of moderate to severe CRBD was higher in group C at postoperative 2 h (82% vs 14%, P=0.004). There was no significant difference in postoperative fentanyl requirements. CONCLUSIONS: Pretreatment with 60 mg ER trospium reduced the incidence and severity of CRBD in the early postoperative period.


Assuntos
Benzilatos/uso terapêutico , Nortropanos/uso terapêutico , Cuidados Pré-Operatórios/métodos , Bexiga Urinária/efeitos dos fármacos , Cateterismo Urinário/efeitos adversos , Cateteres Urinários/efeitos adversos , Agentes Urológicos/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Bexiga Urinária/fisiologia
20.
Low Urin Tract Symptoms ; 12(1): 68-80, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31571403

RESUMO

OBJECTIVE: This analysis was conducted to investigate the cardiovascular (CV) safety outcomes from the MILAI II study. MILAI II was conducted to evaluate the long-term safety and efficacy of antimuscarinic add-on therapy to mirabegron over 52 weeks in patients with overactive bladder (OAB) symptoms. METHODS: MILAI II consisted of a 2-week screening period (patients received mirabegron 50 mg once daily) plus a 52-week treatment period (patients were randomized to receive a combination of mirabegron 50 mg/d plus solifenacin 5 mg/d, propiverine 20 mg/d, imidafenacin 0.2 mg/d, or tolterodine 4 mg/d). CV safety was assessed using treatment-emergent adverse events (TEAEs), vital signs, and 12-lead electrocardiograms (ECGs). Vital signs and ECG data were evaluated for each patient using worst post-baseline values reported. RESULTS: Of 647 patients, 570 (88.1%) were female with a mean age of 65 years. CV history at baseline and CV-related concomitant medication use throughout the study were balanced between groups. The incidences of overall and drug-related CV TEAEs were ≤8.1% and ≤6.2%, respectively, for all groups. The most common TEAEs were ECG T wave amplitude decreased, ECG QT prolonged, and ventricular extrasystoles. Overall, 36 TEAEs of interest related to the CV system that were possibly/probably related to treatment were reported with similar incidences for each group. For the worst post-baseline vital signs and ECGs, no relationships were noted in terms of either timing or treatment group. CONCLUSION: A favorable CV safety profile was observed following long-term combination treatment with mirabegron and an antimuscarinic in patients with OAB symptoms.


Assuntos
Acetanilidas/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/efeitos adversos , Tiazóis/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Agentes Urológicos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Benzilatos/administração & dosagem , Benzilatos/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Japão , Masculino , Pessoa de Meia-Idade , Succinato de Solifenacina/administração & dosagem , Succinato de Solifenacina/efeitos adversos , Tartarato de Tolterodina/administração & dosagem , Tartarato de Tolterodina/efeitos adversos , Resultado do Tratamento
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