RESUMEN
Tolterodine tartrate (TOT) is a selective anti-muscarinic drug to treat urinary urgency and overactive urinary bladder (OAB) occurring in children, renal disease and elderly patients. Oral delivery is associated with several adverse effects. We addressed HSPiP and QbD (quality by design)-oriented TOT loaded cationic nanoemulsions for transdermal delivery. Hansen solubility parameters (HSP) screened excipients based on theoretical solubility whereas, QbD optimized cationic nanoemulsions (CNE-TOT-6). Formulation characteristic parameters were desirable to execute targeted in vitro drug release and ex vivo permeation profiles. In vitro hemolysis was conducted at varied concentrations whereas, histopathological study supported the safety aspect of CNE-TOT6. A comparative bioavailability was carried out in a rat model. Capmul PG8 (CAP), tween 80, and PEG 400 (polyethylene glycol 400) were screened based on HSP and experimental solubility data. QbD suggested optimized content of CAP, tween 80, and PEG 400 to achieve the lowest value of size (184 nm), maximum % entrapment efficiency (87.2 %), high zeta potential (+32.6 mV), optimum viscosity (47.19 cP), and high extrudability (96 %) as compared to its gel. High gel consistency slowed down the drug release and permeation flux as compared to CNE-TOT6 suspension. Hemocompatible CNE-TOT6 increased pharmacokinetic parameters as compared to the control and gel without causing skin toxicity after application. Thus, HSPiP and QbD oriented cationic nanoemulsions are promising carriers to treat overactive urinary bladder.
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Administración Cutánea , Disponibilidad Biológica , Liberación de Fármacos , Emulsiones , Antagonistas Muscarínicos , Polietilenglicoles , Polisorbatos , Absorción Cutánea , Solubilidad , Tartrato de Tolterodina , Animales , Masculino , Tartrato de Tolterodina/administración & dosificación , Tartrato de Tolterodina/farmacocinética , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/toxicidad , Polisorbatos/química , Polietilenglicoles/química , Ratas , Excipientes/química , Nanopartículas/química , Cationes/química , Caprilatos/química , Hemólisis/efectos de los fármacos , Ratas Wistar , Sistemas de Liberación de Medicamentos/métodos , Piel/metabolismo , Ratas Sprague-Dawley , Glicéridos , Polímeros , Glicoles de PropilenoRESUMEN
In part I, we reported Hansen solubility parameters (HSP, HSPiP program), experimental solubility at varied temperatures for TOTA delivery. Here, we studied dose volume selection, stability, pH, osmolality, dispersion, clarity, and viscosity of the explored combinations (I-VI). Ex vivo permeation and deposition studies were performed to observe relative diffusion rate from the injected site in rat skin. Confocal laser scanning microscopy (CLSM) study was conducted to support ex vivo findings. Moreover, GastroPlus predicted in vivo parameters in humans and the impact of various critical factors on pharmacokinetic parameters (PK). Immediate release product (IR) contained 60% of PEG400 whereas controlled release formulation (CR) contained PEG400 (60%), water (10%) and d-limonene (30%) to deliver 2 mg of TOTA. GastroPlus predicted the plasma drug concentration of weakly basic TOTA as function of pH (from pH 2.0 to 9). The cumulative drug permeation and drug deposition were found to be in the order as B-VIË C-VIËA-VI across rat skin. This finding was further supported with CLSM. Moreover, IR and CR were predicted to achieve Cmax of 0.0038 µg/ mL and 0.00023 µg/mL, respectively, after sub-Q delivery. Added limonene in CR extended the plasma drug concentration over period of 12 h as predicted in GastroPlus. Parameters sensitivity analysis (PSA) assessment predicted that sub-Q blood flow rate is the only factor affecting PK parameters in IR formulation whereas this was insignificant for CR. Thus, sub-Q delivery CR would be promising alternative with ease of delivery to children and aged patient.
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Absorción Cutánea , Solubilidad , Tartrato de Tolterodina , Animales , Ratas , Humanos , Absorción Cutánea/efectos de los fármacos , Absorción Cutánea/fisiología , Tartrato de Tolterodina/administración & dosificación , Tartrato de Tolterodina/farmacocinética , Termodinámica , Solventes/química , Piel/metabolismo , Concentración de Iones de Hidrógeno , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/administración & dosificación , Terpenos/química , Terpenos/administración & dosificación , Terpenos/farmacocinética , Administración Cutánea , Limoneno/administración & dosificación , Limoneno/farmacocinética , Limoneno/química , Masculino , Polietilenglicoles/química , Sistemas de Liberación de Medicamentos/métodos , Química Farmacéutica/métodos , Ciclohexenos/química , Ciclohexenos/farmacocinética , Ciclohexenos/administración & dosificación , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: Tolterodine tartrate (TOTA) is a first-line therapy to treat overactive urinary bladder (OAB). Oral delivery causes high hepatic clearance, xerostomia, headache, constipation, and blurred vision. We addressed Hansen solubility parameter (HSP) and Design Expert oriented optimized cationic elastic liposomes for transdermal application. METHODS: The experimental solubility was conducted in HSPiP predicted excipients to tailor formulations using surfactants, stearylamine, ethanol, and phosphatidylcholine (PC). These were evaluated for formulation characteristics. The optimized OTEL1 and OTEL1-G (gel) were compared against the drug solution (DS) and liposomes. In vitro and ex vivo studies were accomplished to investigate the insights into the mechanistic understanding of TOTA release and permeation ability. Finally, confocal laser scanning microscopy (CLSM) supported ex vivo results. RESULTS: HSP values of TOTA were closely related to tween-80, stearylamine, and human's skin. The size (153 nm), %EE (87.6%), and PDI (0.25) values of OTEL1 were in good agreement to the predicted values (161 nm, 80.4%, and 0.31) with high desirability (0.963). Spherical and smooth OTEL1 (including OTEL1-G and liposomes) vesicles followed non-Fickian drug release as compared to DS (Fickian) as evidence with n > 0.5 (Korsmeyer and Peppas coefficient). OTEL1 (containing lipid and surfactant as 90 mg and 13.8 mg, respectively) exhibited 2.6 and 1.8-folds higher permeation flux than DS and liposomes, respectively. Biocompatible cationic OTEL1 was safe and non-hemolytic. CONCLUSIONS: OTEL1 was promised as a lead vesicular approach and an alternative to conventional oral therapy to treat OAB in children and advanced age patients.
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Administración Cutánea , Cationes , Liposomas , Absorción Cutánea , Solubilidad , Tartrato de Tolterodina , Humanos , Animales , Tartrato de Tolterodina/administración & dosificación , Tartrato de Tolterodina/farmacocinética , Cationes/química , Piel/metabolismo , Liberación de Fármacos , Excipientes/química , Masculino , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Composición de Medicamentos/métodos , AminasRESUMEN
Tolterodine tartrate (TOTA) is associated with adverse effect, high hepatic access, varied bioavailability, slight aqueous solubility, and short half-life after oral delivery. Hansen solubility parameters (HSP, HSPiP program), experimental solubility (T = 298.2 to 318.2 K and p = 0.1 MPa), computational (van't Hoff and Apelblat models), and thermodynamic models were used to the select solvent(s). HSPiP predicted PEG400 as the most suitable co-solvent based on HSP values (δd = 17.88, δp = 4.0, and δh = 8.8 of PEG400) and comparable to the drug (δd = 17.6, δp = 2.4, and δh = 4.6 of TOTA). The experimental mole fraction solubility of TOTA was maximum (xe = 0.0852) in PEG400 confirming the best fit of the prediction. The observed highest solubility was attributed to the δp and δh interacting forces. The activity coefficient (Ïi) was found to be increased with temperature. The higher values of r2 (linear regression coefficient) and low RMSD (root mean square deviation) indicated a good correlation between the generated "xe" data for crystalline TOTA and the explored models (modified Apelblat and van't Hoff models). TOTA solubility in "PEG400 + water mixture" was endothermic and entropy-driven. IR (immediate release product) formulation can be tailored using 60% PEG400 in buffer solution for 2 mg of TOTA in 0.25 mL (dosing volume). The isotonic binary solution was associated with a pH of 7.2 suitable for sub-Q delivery. The approach would be a promising alternative with ease of delivery to children and aged patients.
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Solubilidad , Solventes , Termodinámica , Tartrato de Tolterodina , Humanos , Tartrato de Tolterodina/administración & dosificación , Tartrato de Tolterodina/química , Tartrato de Tolterodina/farmacocinética , Solventes/química , Polietilenglicoles/química , Disponibilidad Biológica , Química Farmacéutica/métodos , Inyecciones Subcutáneas , Sistemas de Liberación de Medicamentos/métodosRESUMEN
To assess the pharmacologically relevant and selective muscarinic receptor occupancy in the bladder mucosa, we considered not only plasma drug concentrations but also urinary drug concentrations. The purpose of this study was to predict muscarinic receptor occupancy in the human bladder mucosa based on urinary concentrations in response to clinical dosages of antimuscarinic agents used to treat overactive bladder. The calculated mean plasma or serum unbound steady state concentrations were 0.06-11 nM in clinical dosages of five antimuscarinic agents. Urinary concentrations calculated from the mean plasma or serum and renal clearance ranged between 19 nM and 2 µM, which were >10-fold higher than the Ki values for bladder muscarinic receptors excluding propiverine. Bladder mucosal muscarinic receptor occupancy estimated from the urinary concentrations and the Ki values was >90 % at a steady state in clinical dosages of five antimuscarinic agents. The bladder muscarinic receptor occupancy was higher than that in the parotid gland calculated based on the mean plasma or serum unbound concentrations and Ki values for muscarinic receptors in the parotid gland. These results suggest that sufficient and selective muscarinic receptor occupancy by antimuscarinic agents, to exert pharmacological effects, in the bladder mucosa can be predicted using urinary concentrations.
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Membrana Mucosa , Antagonistas Muscarínicos , Receptores Muscarínicos , Vejiga Urinaria Hiperactiva , Vejiga Urinaria , Humanos , Antagonistas Muscarínicos/farmacocinética , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Vejiga Urinaria Hiperactiva/metabolismo , Vejiga Urinaria Hiperactiva/orina , Receptores Muscarínicos/metabolismo , Vejiga Urinaria/metabolismo , Vejiga Urinaria/efectos de los fármacos , Membrana Mucosa/metabolismo , Membrana Mucosa/efectos de los fármacos , Masculino , Femenino , Persona de Mediana Edad , Adulto , AncianoRESUMEN
Tolterodine tartrate (TTD) was the first antimuscarinic medication developed exclusively for the treatment of overactive bladder syndrome and was approved by the FDA in 1998. As a result of the drug's extensive utilization within the local community following its authorization, there is a pressing need to develop and validate a spectrofluorometric method that is economically efficient, easily reproducible, environmentally sustainable, and possesses high sensitivity. The developed approach relies on enhancing the fluorescence intensity of TTD to reach a level 720 % higher than its initial value, achieved through the application of an aqueous sodium dodecyl sulfate (SDS) solution. A strong correlation was observed with a correlation coefficient of 0.9998 between the concentration of TTD and the fluorescence intensity within the range of 25.0-500.0 ng mL-1. This approach could be employed to quantify TTD in its pure form and to examine pharmaceutical tablets for the purposes of verifying uniform content. Additionally, it was utilized for the evaluation of TTD concentrations in spiked human plasma.
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Vejiga Urinaria Hiperactiva , Humanos , Tartrato de Tolterodina , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Espectrometría de Fluorescencia/métodos , Antagonistas Muscarínicos/uso terapéutico , Dodecil Sulfato de SodioRESUMEN
Background: Managing overactive bladder (OAB) symptoms in Parkinson's disease (PD) is challenging. This study aimed to investigate the medical management of OAB symptoms in patients with PD. Methods: Patients with OAB symptoms who were newly treated with tolterodine and/or tamsulosin were screened from a database of 187 PD patients. Before treatment, the Hoehn-Yahr scale, International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS), and urodynamic evaluation were evaluated. On day 21 of treatment, the IPSS and OABSS were re-evaluated. The changes of these scores and urinary symptoms were analyzed. Results: Seventy patients with a mean age of 62.2±7.9 years and median Hoehn-Yahr stage of 2 (IQR 2-3) were enrolled. Tolterodine, tamsulosin, and tolterodine + tamsulosin were used in 43, 20, and 7 patients, respectively. The IPSS storage symptoms (9.4±3 vs. 3.5±2.3) and OABSS (9±2.8 vs. 4.8±3.3) improved significantly after treatment (both P<0.01). However, 28 (40%) patients displayed moderate urinary symptoms, and nocturia and urgency still affected more than half of the patients after treatment. Conclusions: Tolterodine and/or tamsulosin can significantly improve OAB symptoms in PD patients. Nocturia and urgency remain common after treatment.
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Bacterial endotoxin lipopolysaccharide (LPS)-induced inflammatory response and ferroptosis play an important role in urinary tract infections. Tolterodine has been used as a urinary tract antispasmodic and anticholinergic agent. However, the effects of Tolterodine against LPS-induced insults in human bladder epithelial cells (hBECs) have not been reported before. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase release assays to determine the cell viability, reactive oxygen species (ROS) and malondialdehyde level detection were used to determine the level of oxidative stress, enzyme-linked immunosorbent assay and Western blot analysis were used to detect the protein level. In the current study, we found that Tolterodine ameliorated LPS-induced production of ROS and lipid oxidation in hBECs. Interestingly, Tolterodine inhibited the production of interleukin 6, interleukin-1ß, and tumor necrosis factor α. Also, Tolterodine reduced the levels of Fe2+ and suppressed ferroptosis by reducing the levels of glutathione peroxidase 4, prostaglandin-endoperoxide synthase 2, and acyl-CoA synthetase long-chain family member 4 in LPS-challenged bladder epithelial cells. Mechanistically, it was shown that Tolterodine restored the nuclear factor E2-related factor 2 (Nrf2)/nuclear factor-κB signaling. Importantly, inhibition of Nrf2 with its specific inhibitor ML385 abolished the protective effects of Tolterodine in the inflammatory response and ferroptosis, suggesting that the effects of Tolterodine are mediated by Nrf2. Based on these findings, we conclude that Tolterodine might serve as a promising agent for the treatment of LPS-induced bladder inflammation.
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Ferroptosis , Lipopolisacáridos , Humanos , Especies Reactivas de Oxígeno/metabolismo , Lipopolisacáridos/toxicidad , Tartrato de Tolterodina , Factor 2 Relacionado con NF-E2/metabolismo , Vejiga Urinaria/metabolismo , Células Epiteliales/metabolismoRESUMEN
Background and purpose: The present study aimed to obtain a taste-masked oral disintegrating tablet (ODT) containing tolterodine tartrate (TT) intercalated into montmorillonite (MMT). Experimental approach: The TT-MMT hybrid was prepared by ion exchange reaction. The effect of the initial concentration of TT, MMT, temperature, and pH on the encapsulation efficiency (EE) % of the drug in MMT was evaluated. The selected TT-MMT hybrid was characterized by X-ray diffraction (XRD), Fourier transforms infrared (FTIR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Then, the optimized TT-MMT hybrid was incorporated in the ODT prepared by direct compression method and taste-masking assessment performed by a human test panel. Findings/Results: The EE% of TT was in the range of 22.67 to 71.06% in different formulations. It was found that increases in MMT concentration significantly increased EE%. DSC and XRD studies indicated that the TT was intercalated in the MMT interlayer space in an amorphous or molecular state. In-vitro release studies at pH 6.8 showed that the amount of the drug released from the TT-MMT hybrid was negligible for the first 3 min. The post-compression of ODT also showed satisfactory results in terms of friability, hardness, disintegration time, and taste. Conclusion and implications: MMT-ODT could be a suitable vehicle for the taste masking of TT, with the potential for use in patients with swallowing problems.
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Purpose: This study aimed to retrospectively compare the efficacy and safety of micro-radiofrequency (RF) therapy through the urethra vs. oral tolterodine tartrate in the treatment of newly diagnosed overactive bladder (OAB). Materials and methods: In this study, 46 patients who were newly diagnosed with moderate-to-severe OAB were included; 23 of them underwent the micro-RF treatment procedure, and the other 23 patients took tolterodine. Bladder diaries were recorded 3 days before treatment and during the follow-up period on 1, 3, and 7 weeks after micro-RF therapy or oral tolterodine. Micturition parameters including daily voiding times, daily urge urinary incontinence (UI) episodes, daily urgency episodes, mean volume per micturition, post-void residual volume (PVR), maximum urine flow rate (Qmax), overactive bladder symptom score (OABSS), and quality of life (QoL) score were analyzed. Results: All 46 patients underwent either micro-RF or oral tolterodine treatment, as well as a complete follow-up. The incidence of adverse events in the micro-RF group was 8.7% (2/23), and that in the tolterodine group was 43.5% (10/23). The following two adverse events happened in the micro-RF group: an injury to the urethra during catheterization in a man and a urinary tract infection in a woman, both of which were relieved or disappeared after day 3. The adverse effects in the tolterodine group were mainly dry mouth (4/23), dysuria (5/23), and constipation (8/23), but none of the patients withdrew from the drug therapy. Compared to pre-therapy, all parameters of both groups, including daily voiding times, daily urgency episodes, mean volume per micturition, OABSS, and QoL score, demonstrated significant improvements during follow-up in 7 weeks after therapy, except for daily UI episodes in the tolterodine group, while the above parameters showed bigger improvements in the micro-RF group than in the tolterodine group. Besides, the general treatment efficacy of micro-RF was 73.9% (17/23), which was significantly better than tolterodine (10/23, 43.5%), and the difference was 30.4% [95% CI: 3.4-57.5%, p = 0.036]. Conclusion: In this retrospective study, we found that micro-RF therapy is safe and more effective than oral tolterodine for newly diagnosed moderate-to-severe OAB in a short-term follow-up. Stronger evidence would be provided through a well-designed, prospective, randomized controlled trial.
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Background: Enuresis, defined as involuntary nocturnal urination without any underlying organic disorder in a child expected to control urination, poses a common problem. This study evaluated the effectiveness of Tolterodine and Oxybutynin in children presenting with primary desmopressin-resistant enuresis. Materials and Methods: A randomized clinical trial was undertaken involving 68 participants aged between 5 and 16 years, all suffering from primary enuresis. These patients were randomly assigned to one of two treatment groups for a three-month period: Group 1, treated with Oxybutynin and Desmopressin, and Group 2, treated with Tolterodine and Desmopressin. Data on demographics, clinical and laboratory findings, and subjective responses to treatment were gathered. The response was measured based on the frequency of wetting incidents per night and week and compared with pre-treatment data. Results: Patients were divided into two groups (30 patients in Group 1 and 38 patients in Group 2). The mean age of the patients was 88.97±27.09 months. In the first treatment group, 6 out of 30 patients (20%) experienced a complete treatment response, as did 5 out of 38 patients (13.2%) in the second treatment group. This difference between the groups was not statistically significant. Seven patients (23%) in the Oxybutynin group and 13 patients (34%) in the Tolterodine group reported a lack of response to treatment, a difference that also lacked statistical significance. Conclusion: For patients resistant to Desmopressin, the addition of anticholinergic drugs elicited a significant response in over half of the patients. However, no benefit was observed in using either Oxybutynin or Tolterodine in the treatment of Desmopressin-resistant enuresis.
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Desamino Arginina Vasopresina , Ácidos Mandélicos , Tartrato de Tolterodina , Humanos , Tartrato de Tolterodina/uso terapéutico , Niño , Ácidos Mandélicos/uso terapéutico , Masculino , Femenino , Desamino Arginina Vasopresina/uso terapéutico , Adolescente , Resultado del Tratamiento , Preescolar , Enuresis Nocturna/tratamiento farmacológico , Antagonistas Muscarínicos/uso terapéutico , Fármacos Antidiuréticos/uso terapéutico , Agentes Urológicos/uso terapéutico , Enuresis/tratamiento farmacológico , Resistencia a MedicamentosRESUMEN
INTRODUCTION: Overactive bladder (OAB) is a chronic condition highly prevalent in children and causing bothersome symptoms. It is often associated with deterioration of quality of life and can be devastating for patients and their families. Prompt initiation of conservative measures should be the backbone of treatment. When conservative management fails, pharmacological options must be considered. AREAS COVERED: Although antimuscarinics are considered the mainstay of pharmacological treatment for OAB, only two agents are currently approved for the pediatric population. Oxybutynin and propiverine are discussed in this review, as well as other non-approved antimuscarinic agents and ß3-agonists with related literature to substantiate their use in children. Dual therapy along with medication adherence and persistence is also discussed. EXPERT OPINION: The treatment of OAB in children is demanding and one must rely on a structured, stepwise approach to achieve success. Discussing conservative measures and prescribing medication is not enough. Clinicians should actively involve children and their families in the treatment, set realistic expectations, and closely monitor side effects and medication adherence to ensure maximal efficacy.
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Vejiga Urinaria Hiperactiva , Acetanilidas/uso terapéutico , Niño , Enfermedad Crónica , Humanos , Cumplimiento de la Medicación , Antagonistas Muscarínicos , Calidad de Vida , Vejiga Urinaria Hiperactiva/diagnóstico , Vejiga Urinaria Hiperactiva/tratamiento farmacológicoRESUMEN
INTRODUCTION AND HYPOTHESIS: Obstructive sleep apnea syndrome is associated with urological symptoms, including overactive bladder (OAB). This study aims to determine whether combined tolterodine and CPAP therapies are more effective for patients with OSAS than CPAP treatment only. METHODS: Women who underwent polysomnography test and were diagnosed with moderate-to-severe OSAS with apnea-hypopnea index (AHI) were included in the study. Data were collected on AHI, OAB awareness-8-item tool (OAB-V8), incontinence questionnaire-urinary incontinence short form (ICIQ-UI-SF), total daily urine volume (DUV), and the Benefit, satisfaction with treatment and willingness (BSW) tool. Eligible patients were randomized to receive either CPAP treatment only or combined CPAP and tolterodine treatment for 3 months. RESULTS: Among 103 participants, a total of 60 were included. Patients in both treatment arms showed significant improvements in OAB-V8, ICIQ-UI-SF, and total DUV compared to their baseline. The mean OAB-V8 was 15.7 at baseline and 5.6 at 3 months for the combined treatment arm and 16.6 and 7.6 at 3 months for the CPAP group only (mean baseline-adjusted between-group difference -1.1 [95% CI, -12.3 to -7.4]; p < 0.001). The improvement in the mean ICIQ-UI-SF was also statistically more significant in the combined therapy group than in the CPAP only arm (mean baseline-adjusted between-group difference -3.27 [95% CI, -4.6 to -1.59]; p < 0.001). No statistical significance was found in the improvement of total DUV between the groups. CONCLUSIONS: In this study, combined use of tolterodine with CPAP provides beneficial effects to CPAP treatment only regarding OAB symptoms. Further research is required to confirm these findings in a large cohort.
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Apnea Obstructiva del Sueño , Vejiga Urinaria Hiperactiva , Incontinencia Urinaria , Presión de las Vías Aéreas Positiva Contínua , Femenino , Humanos , Polisomnografía , Apnea Obstructiva del Sueño/diagnóstico , Apnea Obstructiva del Sueño/terapia , Tartrato de Tolterodina/uso terapéutico , Vejiga Urinaria Hiperactiva/complicaciones , Vejiga Urinaria Hiperactiva/tratamiento farmacológicoRESUMEN
Introducción y objetivo La vejiga hiperactiva (VH) impacta negativamente en la calidad de vida de los pacientes y puede asociarse a un elevado consumo de recursos. Nuestro objetivo fue describir el uso de recursos, costes y persistencia asociados al tratamiento de la VH con mirabegrón (MB) o antimuscarínicos (AM).Materiales y métodos Estudio observacional retrospectivo en registros médicos en adultos que iniciaron tratamiento para VH con MB o AM en Cataluña. Se analizó el uso de recursos sanitarios (visitas, hospitalizaciones, pruebas, medicación, absorbentes para incontinencia) en el primer año tras el inicio del tratamiento, estimando sus costes asociados (, 2019) y la persistencia terapéutica. Se definió abandono como la falta de prescripción durante ≥ 45 días o el cambio de tratamiento.Resultados El coste medio por paciente (desviación estándar [DE]) con MB fue 1.640,20 (1.227,60) vs. 2.159,20 (2.264,60) con AM; el coste asociado al uso de recursos sanitarios fue inferior en MB vs. AM, exceptuando el coste del tratamiento farmacológico con MB. La persistencia al tratamiento a los 12 meses fue superior en MB (42,1 vs. 33,0%), así como el tiempo (mediana) hasta el abandono del tratamiento: 299 (IC 95%: 270,11-327,89) vs. 240 días (IC 95%: 230,46-249,54).Conclusiones Los pacientes tratados con MB mostraron menor uso de recursos, resultando en un coste medio por paciente/año más bajo, a pesar del mayor coste del fármaco respecto a AM. La mayor persistencia al tratamiento y el uso racional de las terapias disponibles mejoran el manejo de la VH y la calidad de vida de los pacientes (AU)
Introduction and aim Overactive bladder (OAB) negatively impacts patient quality of life and may be associated with high resource use. Our aim was to describe the resource use, costs and persistence associated with mirabegron (MB) or antimuscarinic (AM) treatment in patients with OAB.Materials and methods Observational retrospective study of medical records in adult patients initiating OAB treatment with MB or AM in Catalonia. Healthcare resource use (visits, hospital stays, tests, medication, absorbent pads) in the first year after treatment initiation was collected. Associated costs were estimated (, reference year 2019), as well as treatment persistence. Treatment discontinuation was defined as the absence of prescription for at least 45 days or treatment change.Results The mean cost per patient (SD) was 1,640.20 ( 1,227.60) with MB and 2,159.20 ( 2,264.40) with AM; the associated healthcare resource use cost was lower with MB compared to AM, except for OAB drug costs. Persistence after 12 months of treatment initiation was higher in MB (42.1%) compared to AM (33.0%), as was the median time until treatment discontinuation: 299 (95% CI: 270-328) vs 240 days (95% CI: 230-250).Conclusions Lower healthcare resource use was observed with MB compared to AM in the first year of index treatment, resulting in a lower mean direct cost per patient and year, despite its higher acquisition cost. Increased treatment persistence, as well as rational use of available treatments improves OAB management and, in return, patients quality of life (AU)
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Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Vejiga Urinaria Hiperactiva/economía , Agentes Urológicos/uso terapéutico , Estudios Retrospectivos , Acetanilidas , Costos de la Atención en Salud , Antagonistas Muscarínicos/uso terapéutico , Calidad de Vida , Tiazoles , EspañaRESUMEN
INTRODUCTION AND AIM: Overactive bladder (OAB) negatively impacts patient quality of life and may be associated with high resource use. Our aim was to describe the resource use, costs and persistence associated with mirabegron (MB) or antimuscarinic (AM) treatment in patients with OAB. MATERIALS AND METHODS: Observational retrospective study of medical records in adult patients initiating OAB treatment with MB or AM in Catalonia. Healthcare resource use (visits, hospital stays, tests, medication, absorbent pads) in the first year after treatment initiation was collected. Associated costs were estimated (Ñ, reference year 2019), as well as treatment persistence. Treatment discontinuation was defined as the absence of prescription for at least 45 days or treatment change. RESULTS: The mean cost per patient (SD) was Ñ 1,640.20 (Ñ 1,227.60) with MB and Ñ 2,159.20 (Ñ 2,264.40) with AM; the associated healthcare resource use cost was lower with MB compared to AM, except for OAB drug costs. Persistence after 12 months of treatment initiation was higher in MB (42.1%) compared to AM (33.0%), as was the median time until treatment discontinuation: 299 (95% CI: 270-328) vs 240 days (95% CI: 230-250). CONCLUSIONS: Lower healthcare resource use was observed with MB compared to AM in the first year of index treatment, resulting in a lower mean direct cost per patient and year, despite its higher acquisition cost. Increased treatment persistence, as well as rational use of available treatments improves OAB management and, in return, patients' quality of life.
Asunto(s)
Vejiga Urinaria Hiperactiva , Agentes Urológicos , Acetanilidas , Adulto , Femenino , Costos de la Atención en Salud , Humanos , Masculino , Antagonistas Muscarínicos/uso terapéutico , Calidad de Vida , Estudios Retrospectivos , España , Tiazoles , Vejiga Urinaria Hiperactiva/tratamiento farmacológicoRESUMEN
The aim was to assess the pharmacokinetics of tolterodine released from vaginal rings and of its active metabolite 5-hydroxymethyl tolterodine (5-HMT) compared to the respective pharmacokinetics resulting from oral administration of extended-release tolterodine in healthy, postmenopausal women. In this single-center, open-label trial, subjects received 4 treatments in a fixed sequence: fasted oral extended-release tolterodine 2.74 mg/d (reference, 5 days), single vaginal rings; tolterodine releasing rates: 0.95 mg/d (test 1, 13 days), 1.40 mg/d (test 2, 28 days), 1.90 mg/d (test 3, 28 days). Systemic exposure of tolterodine, 5-HMT, and the molar sum of unbound tolterodine/5-HMT (active moiety [AM]) in steady state was determined. Sixteen of 18 included women completed the study. For the oral formulation, peak-trough fluctuations of tolterodine, 5-HMT, and AM plasma concentrations (AM: mean maximum/minimum concentration, 2580/574 pmol/L = 4.5) were large. Intravaginal application led to steadier plasma concentrations (AM, test 3: mean maximum/minimum concentration, 1880/814 pmol/L = 2.3; fluctuation due to initial peak), which is the result of constant releasing rates after ring insertion over the 28-day application period. The vaginal rings demonstrated a favorable local tolerability. The most common adverse events with oral and vaginal tolterodine were headache (n = 11) and dry mouth (n = 8). Vaginal rings releasing tolterodine represent a promising new formulation for overactive bladder treatment with little fluctuation of drug plasma levels. This is expected to lead to a more predictable and continuous therapeutic effect and a reduced frequency of side effects compared to oral tolterodine.
Asunto(s)
Tartrato de Tolterodina , Vejiga Urinaria Hiperactiva , Femenino , Humanos , Proyectos Piloto , Posmenopausia , Tartrato de Tolterodina/efectos adversos , Vejiga Urinaria Hiperactiva/tratamiento farmacológicoRESUMEN
OBJECTIVES: This network meta-analysis aimed to assess the safety profiles of seven commonly used oral antimuscarinic drugs (darifenacin, fesoterodine, imidafenacin, oxybutynin, propiverine, solifenacin, and tolterodine) in patients with overactive bladder (OAB). METHODS: PubMed, Cochrane Library, EMBASE, CNKI, and Wanfang databases were searched for randomized controlled trials (RCTs). Studies comparing one or more antimuscarinic drugs for treating OAB with reported adverse effects (AEs) were eligible. Data were extracted, and a network meta-analysis was performed by two authors independently. RESULTS: Forty-five RCTs and 124,587 patients were included. The results demonstrated that tolterodine had better safety outcomes for 7 out of 12 major AEs, including dry mouth, constipation, urinary retention, dizziness, urinary tract infection, dry eyes, and dry skin. Darifenacin, fesoterodine, imidafenacin, oxybutynin, and solifenacin presented comparable safety profiles. CONCLUSIONS: Tolterodine may be preferable as it showed a reduced association with important AEs. Darifenacin, fesoterodine, imidafenacin, oxybutynin, and solifenacin have similar safety profiles in treating patients with OAB. Taken together, this analysis provides a valuable overview of the therapeutic safety for oral antimuscarinic drugs and is useful for personalized medicine in patients with OAB.Trial registration: This trial was retrospectively registered at INPLASY (https://inplasy.com/) with the registration number 202170095.