Development and validation of single analytical HPLC method for determination of flavoxate HCl in bulk, tablets and biological fluids.

A simple, sensitive and precise high performance liquid chromatographic (HPLC) method was developed and validated for determination of flavoxate HCI in raw material, tablets and biological fluids. The method followed by using the Zorbax XDB-C18 column containing Di-isobutyl n-octadeceylsilane (4.6mm×150mm, 5µm). The mobile phase consisted of acetonitrile: methanol: 0.15M sodium perchlorate (17:35:48 v/v) having pH 3. UV detection was carried out at 229nm at 40°C. Results indicated that the method has successfully established and validated in accordance with ICH guidelines acceptance criteria for linearity (0.03-7.5µg), accuracy (101.18-101.28%), robustness of column age and column lot (peak area %CV<0.04, purity %CV< 0.006) and robustness of HPLC condition (%CV<0.02), precision (intra and inter day precision assay, %CV values for peak area and percent purity of flavoxate HCl<2%) and system suitability parameters. The average noise, theoretical LOD and LOQ were found to be 0.01 mAU, 0.03 mAU and 0.6ng, respectively. The Coefficient of determination (r2) ranging from 0.03µg to 7.5µg, 0.99 which was within acceptable criteria of r2 & gt 0.99. The spiked recoveries of samples were 101.28, 101.18 and 101.18% respectively. All data revealed that this method can be used for in-vitro & in-vivo determination of flavoxate HCI in various pharmaceutical preparations.

Simple and rapid LC-MS/MS method for simultaneous determination of flavoxate and 3-methyl-flavone-8-carboxylic acid in human plasma: Application to a bioequivalence study.

A simple, rapid, sensitive, and reproducible LC-MS/MS method was developed for simultaneous quantification of flavoxate and 3-methyl-flavone-8-carboxylic (MFCA) in human plasma, using diphenhydramine HCl as internal standard (IS). The chromatographic separation was achieved using Agilent Poroshell 120 EC-C18 - Fast LC column (100 × 2.1mmID, 2.7 µm) fitted with UHPLC Guard Poroshell 120 EC-C18 (5 × 2.1 mmID, 2.7 µm). The mobile phase consisted of 0.1 % v/v formic acid and acetonitrile (30:70, v/v) run at a flow rate of 0.40 mL/min. The standard calibration curve was linear over the concentration range of 2.00 - 2,000.31 ng/mL and 240.00 - 24,000.04 ng/mL for flavoxate and MFCA. For flavoxate and MFCA, the within-run precision was 0.81-6.67 % and 1.68-4.37 %, while accuracy was 100.21-108.25 % and 103.99-110.28 %. The between-run precision was 2.01-9.14 % and 2.31-11.11 %, and accuracy was 96.09-103.33 % and 102.37-109.52 %. The extended run precision was 7.78-11.04 % and 2.22-3.33 %, while accuracy was 100.72-101.88 % and 102.34-105.60 %. Flavoxate and MFCA in plasma were stable 4 h at bench top (short term), 24 h in autosampler and instrumentation room (post-preparative), after 7 freeze-thaw cycles, and 89 days in the freezer. Both analytes and IS stock solutions were stable for 31 days when kept at room temperature (25 ± 4 °C) and refrigerated (2-8 °C). The validated method was successfully applied to a bioequivalence study of two flavoxate formulations involving 24 healthy volunteers.

RP-HPLC Method for the Simultaneous Determination of a Quaternary Mixture of Propyphenazone, Flavoxate HCl and Two of Their Official Impurities with Dissolution Profiling of Their Tablets.

BACKGROUND: Determination of different drugs in the presence of their impurities is now receiving attention from regulatory authorities such as the ICH and the United States Food and Drug Administration (USFDA). OBJECTIVE: To develop and validate a reversed-phase (RP)-HPLC method for the simultaneous separation and quantification of a quaternary mixture of propyphenazone, flavoxate HCl, and their official impurities; phenazone and 3-methylflavone-8-carboxylic acid, respectively. Then utilize the validated method as an in vitro methodology to monitor the rate of release of the active ingredients from Cistalgan® tablets. METHODS: RP-HPLC method was applied using Kinetex® coreshell C8 column (250 mm × 4.6 mm I.D., particle size 5 µm) and acetonitrile: phosphate buffer pH 3.50 (42:58, v/v) as the mobile phase with UV detection at 240.0 nm. RESULTS: The studied components were eluted with average retention times of 2.80, 3.40, 4.20, and 5.90 min for phenazone, flavoxate HCl, 3-methylflavone-8-carboxylic acid, and propyphenazone, respectively within linearity range of 1.00-60.00 µg/mL propyphenazone, 3.00-60.00 µg/mL flavoxate HCl and 0.50-40.00 µg/mL of the specified impurities. CONCLUSIONS: The suggested method could be considered as the first validated analytical method for the simultaneous determination of the studied components and proved to be accurate, precise, sensitive, and robust. HIGHLIGHTS: The proposed method displays a useful analytical tool for dissolution profiling and clear discrimination of both active ingredients from their impurities along with impurities profiling.

Simultaneous Determination of Moxifloxacin and Flavoxate by RP-HPLC and Ecofriendly Derivative Spectrophotometry Methods in Formulations.

Simple, fast, and precise reversed-phase (RP)-high-performance liquid chromatography (HPLC) and two ecofriendly spectrophotometric methods were established and validated for the simultaneous determination of moxifloxacin HCl (MOX) and flavoxate HCl (FLX) in formulations. Chromatographic methods involve the separation of two analytes using an Agilent Zorbax SB C18 HPLC column (150 mm × 4.6 mm; 5 µm) and a mobile phase consisting of phosphate buffer (50 mM; pH 5): methanol: acetonitrile in a proportion of 50:20:30 v/v, respectively. Valsartan was used as an internal standard. Analytes were monitored by measuring the absorbance of elute at 299 nm for MOX and 250 nm for FLX and valsartan. Two environmentally friendly spectrophotometric (first derivative and ratio first derivative) methods were also developed using water as a solvent. For the derivative spectrophotometric determination of MOX and FLX, a zero-crossing technique was adopted. The wavelengths selected for MOX and FLX were -304.0 nm and -331.8 nm for the first derivative spectrophotometric method and 358.4 nm and -334.1 nm for the ratio first-derivative spectrophotometric method, respectively. All methods were successfully validated, as per the International Conference on Harmonization(ICH) guidelines, and all parameters were well within acceptable ranges. The proposed analytical methods were successfully utilized for the simultaneous estimation of MOX and FLX in formulations.

Análisis de impacto presupuestal de flavoxato, oxibutinina, tolterodina, solifenacina, darifenacina y mirabegrón para el tratamiento de incontinencia urinaria de urgencia en Colombia / Budget impact analysis of flavoxate, oxybutynin, tolterodine, solifenacin, darifenacin and mirabegron for the treatment of incontinence Urinary urgency in Colombia

INTRODUCCIÓN: El análisis de impacto presupuestal (AIP) de medicamentos anticolinérgicos para pacientes con incontinencia urinaria de urgencia en Colombia, se desarrolló en el marco del mecanismo técnico-científico para la ampliación progresiva del Plan de Beneficios en Salud con cargo a la UPC (PBSUPC) y la definición de la lista de exclusiones, establecido en el artículo 15 de la Ley 1751 de 2015. Estas tecnologías fueron seleccionadas por la Dirección de Beneficios, Costos y Tarifas del Aseguramiento en Salud del Ministerio de Salud y Protección Social (MinSalud), y remitidas al Instituto de Evaluación Tecnológica en Salud (IETS) para su evaluación. La incontinencia urinaria o perdida involuntaria de orina es causada por la pérdida del control de la vejiga (1). Este problema de alta ocurrencia en la población general no cuenta con una prevalencia bien establecida (2,3), se estima que cerca de la mitad de los pacientes con problemas de vejiga nunca consultan esta condición con su médico tratante, aspecto por el cual no es tratada ni registrada. Por otra parte, si se conoce que el mayor número de casos de incontinencia urinaria se presentan en la población adulta y en mayor proporción en el sexo femenino durante el embarazo, el parto o la menopausia; llegando a considerarse el doble de frecuencia en sexo femenino frente al masculino. La incontinencia urinaria suele clasificarse en cuatro tipos de acuerdo a la posible causal asociada a esta condición: Incontinencia de esfuerzo, como aquella donde la vejiga no puede controlar el aumento de presión ante el ejercicio, la tos o los estornudos; este tipo de incontinencia es más frecuente en hombres que han tenido cirugía de próstata. Incontinencia de urgencia, es causada por la contracción súbita e involuntaria de la vejiga. Incontinencia mixta, es aquella donde se combina la incontinencia de esfuerzo y de urgencia, este tipo de incontinencia es más frecuente en las mujeres en edad adulta. Incontinencia funcional, como aquella incapacidad para retener la orina por razones distintas neuropáticas asociadas a otra condición de salud. Así mismo, el tratamiento de esta condición depende principalmente del tipo de incontinencia urinaria, la causa de la misma y las condiciones del paciente. Dentro de las alternativas de tratamiento se listan: la rehabilitación del músculo pélvico, tratamiento dirigido a las mujeres jóvenes; las terapias comportamentales, a fin de asumir hábitos que favorezcan la recuperación del control de vejiga; las terapia farmacológicas y finalmente, las intervenciones quirúrgicas. En el caso de la incontinencia urinaria de urgencia y mixta, una de las alternativas usadas en la primera y segunda línea son los esquemas farmacológicos (4). El principal grupo de medicamentos son los agentes antiespasmódicos y anticolinérgicos agrupados por la clasificación Anatómica, Terapéutica y Química (ATC por sus siglas en ingles) de la Organización Mundial de la Salud (OMS) con el código G04BD. Actualmente, este grupo de medicamentos no es parte del Plan de Beneficios en Salud con cargo a la UPC (PBSUPC). Por lo anterior, el alcance de este análisis de impacto presupuestal es determinar el esfuerzo presupuestal necesario para incorporar este grupo de medicamentos al PBSUPC, excluyendo así estos medicamentos de las Prestaciones No Incluidas en el PBSUPC. Para el desarrollo de este documento se realizó una revisión de literatura, la consulta de registros nacionales y la consulta a expertos clínicos; con el fin de identificar la prevalencia de la incontinencia urinaria de urgencia, la frecuencia y costos asociados a eventos adversos, y a la estimación de los posibles escenarios de adopción de estas tecnologías sanitarias al ser financiadas en el Plan de Beneficios en Salud con cargo a la UPC. Para determinar el precio de las tecnologías, se consultó como fuente primaria el Sistema de información de. Precios de Medicamentos (SISMED) y finalmente, los posibles impactos presupuestales para en el Sistema General de Seguridad Social en Salud (SGSSS) colombiano. TECNOLOGÍAS EVALUADAS: Tratamiento actual: Actualmente no existen alternativas farmacológicas u otro tipo de intervención dirigida al tratamiento de la incontinencia urinaria de urgencia, en el Plan de Beneficios en Salud con cargo a la Unidad de Pago por Capitación (UPC). Incorporación reglamentada por la Resolución 6408 de 2016 del Ministerio de Salud y Protección Social. De este modo, el presente AIP no incorporó costos asociados al tratamiento actual. Tecnología evaluada: Los medicamentos evaluados son los agentes antiespasmódicos y anticolinérgicos agrupados por la clasificación Anatomica, Terapéutica y Química (ATC) con el código G04BD que cuenten con registro sanitario vigente en Colombia. Este grupo incluye los principios activos: flavoxato, oxibutinina, tolterodina, solifenacina, darifenacina y mirabegrón. A continuación, se presenta una descripción de cada uno de estos principios activos incorporando dosificación para el tratamiento de incontinencia urinaria de urgencia, indicación aprobada por Instituto Nacional de Vigilancia de Medicamento (INVIMA) y algunas consideraciones especiales para su prescripción. Flavoxato: INSUMOS Y MÉTODOS: Se presenta los supuestos, parámetros y métodos utilizados para el modelo de estimación del impacto presupuestal. Perspectiva: La perspectiva usada es la del Sistema General de Seguridad Social en Salud (SGSSS), siguiendo las recomendaciones del manual para la elaboración de análisis de impacto presupuestal del IETS (9). De forma específica este análisis corresponde a las tecnologías y gastos médicos incorporados al Plan de Beneficios en Salud con cargo de la UPC. Horizonte temporal: El horizonte temporal de este AIP en el caso base corresponde a un año. Adicionalmente, se reportan las estimaciones del impacto presupuestal para los años 2 y 3, bajo el supuesto de la incorporación de los medicamentos evaluados para el Plan de Beneficios con cargo a la UPC en el año 1. Población total: Para el desarrollo del AIP se parte de la población general afiliada al SGSSS colombiano sin distinción de sexo o edad. Población objeto de análisis: Se delimita la población total a aquellos que tiene la condición de incontinencia urinaria de urgencia, incluyendo los que padecen incontinencia urinaria mixta. Para lo cual, se efectuó una búsqueda de prevalencias y proporciones en guías de práctica clínica, revisión de literatura especializada, búsqueda registros administrativos y consulta a expertos clínicos. RESULTADOS: Impacto Total e incremental: Dado que no existe tratamiento actual financiado en el Plan de Beneficios de salud con cargo a la UPC para la incontinencia urinaria de urgencia, la incorporación de los medicamentos con principios activos: flavoxato, oxibutinina, tolterodina, solifenacina, darifenacina y mirabegrón generará un esfuerzo presupuestal equivalente al costo de las nuevas tecnologias. Impacto por escenarios: En el primer escenario, se refleja la distribución actual del mercado de acuerdo con la información obtenida de SISMED para el año 2016. Esta distribución de acuerdo con la consulta de los expertos clínicos no tiene una tendencia a cambiar en las siguientes dos anualidades, debido a que no existe una diferencia significativa entre estas tecnologías que permita estimar una sustitución de tratamiento. Por otra parte, en el segundo escenario se modela una sustitución entre las alternativas terapéuticas que privilegia aquellos medicamentos que tienen una forma farmacéutica modificada para permitir una liberación prolongada del principio activo. Esta tendencia pese a ser mencionada por uno de los expertos clínicos, no es parte del consenso logrado en la etapa de consulta. Análisis de sensibilidade: Los análisis de sensibilidad estiman las variaciones del valor del impacto presupuestal incremental en el año 1 para los escenarios 1 y 2. Para cada caso se tomaron los precios mínimos, los base y los máximos, y con cada uno se calculó el valor de impacto presupuestal incremental; además, para cada uno se desarrolla un análisis de tipo determinístico y otro probabilístico.

Flavoxate in the symptomatic treatment of overactive bladder: a meta-analysis.

OBJECTIVE: Overactive bladder is a syndrome of urinary frequency and urgency, with or without urge incontinence, in the absence of local pathological factors. Since multiple causes are responsible for OAB, it requires proper diagnosis and comprehensive management. For decades, flavoxate is a globally used and accepted molecule by the urologists and the general physicians for the symptomatic treatment of OAB. In spite of its extensive use in OAB, a meta-analysis of the available publications for efficacy, safety and tolerability of flavoxate has not been conducted. This paper evaluates the strength of evidence of clinical effectiveness of safety and tolerability of flavoxate in the symptomatic treatment of OAB. METHODS: Review articles, original studies and case reports on MEDLINE, the Cochrane Library, Google Scholar, Scirus, internal repository, etc. were searched using the keyword "flavoxate". For the primary outcome, the comparative data of flavoxate versus comparator was extracted for following parameters - overall efficacy and its side effect profile. Similarly as for secondary outcome, data were extracted for flavoxate per se for overall efficacy, frequency, urinary incontinence, mixed incontinence, nocturia, unpleasant urination, stranguria and its side effect profile and were analyzed using Comprehensive Meta-Analysis (CMA) software version 2.0. RESULTS: In the current meta-analysis, 43 relevant published studies were considered which clearly demonstrated that flavoxate had improved clinical efficacy than placebo, emepronium, propantheline, and phenazopyridine. CONCLUSIONS: Amongst all the interventions studied, flavoxate was effective and well-tolerated, with almost negligible side effects, making it worthy of consideration for the treatment of OAB.

Short-Term Flavoxate Treatment Alters Detrusor Contractility Characteristics: Renewed Interest in Clinical Use?

OBJECTIVES: Flavoxate has had a long history of use in the treatment of overactive bladder, despite the lack of documentation on its clinical efficacy and mechanism(s) of action. This study was conducted to understand how contractility characteristics of the detrusor are affected after a short period of flavoxate treatment. METHODS: Eight-week-old mice were treated with flavoxate for 5 days and detrusor contractile responses were examined ex vivo under different pharmacological and electrical stimuli. RESULTS: K(+) -Krebs'-induced contraction developed more slowly while 64 Hz electrical field stimulation-induced contraction developed faster in flavoxate-treated strips when compared to control. Amplitudes of maximal and steady-state contraction induced by 3 µmol/L carbachol were also larger after flavoxate treatment. Control strips showed an overall greater dependence on stimulus strength in eliciting the responses. CONCLUSIONS: These findings provided new information of how short-term flavoxate treatment altered contractility characteristics at the bladder level, which may instill new interest in investigating the use of this drug in bladder disorders not responding well to conventional treatments.

Flavoxate: present and future.

OBJECTIVE: This non-systematic review discusses the available evidence on the use of flavoxate in the treatment of overactive bladder (OAB). METHODS: Medline was searched for inclusion of relevant studies. No limitations in time were considered. RESULTS: Flavoxate hydrochloride is an antispasmodic agent which exerts an inhibition of the phosphodiesterases, a moderate calcium antagonistic activity, and a local anesthetic effect. Results from preclinical and clinical studies show that flavoxate significantly increases bladder volume capacity (BVC), with greater results if compared to other drugs such as emepronium bromide and propantheline. Moreover in clinical trials, both versus placebo or versus active comparators, flavoxate treatment was associated with a significant improvement in different low urinary tract symptoms, such as diurnal and night frequency, urgency and urinary incontinence, suprapubic pain, dysuria, hesitancy and burning. In addition flavoxate was associated with an overall more favourable safety profile than competitors. CONCLUSIONS: Several researches and a number of years of clinical practice have proven the efficacy and tolerability of flavoxate administration in the treatment of OAB and associated symptoms. However, new studies are necessary to collect more evidence on the role of this molecule in the treatment of OAB and to further explore its use in other indications such as symptomatic treatment of lower urinary tract infections.

Spectrofluorimetric determination of 3-methylflavone-8-carboxylic acid, the main active metabolite of flavoxate hydrochloride in human urine.

A simple, sensitive and selective spectrofluorimetric method has been developed for the determination of 3-methylflavone-8-carboxylic acid as the main active metabolite of flavoxate hydrochloride in human urine. The proposed method was based on the measurement of the native fluorescence of the metabolite in methanol at an emission wavelength 390 nm, upon excitation at 338 nm. Moreover, the urinary excretion pattern has been calculated using the proposed method. Taking the advantage that 3-methylflavone-8-carboxylic acid is also the alkaline degradate, the proposed method was applied to in vitro determination of flavoxate hydrochloride in tablets dosage form via the measurement of its corresponding degradate. The method was validated in accordance with the ICH requirements and statistically compared to the official method with no significant difference in performance.

Flavoxate in urogynecology: an old drug revisited.

INTRODUCTION AND HYPOTHESIS: Since its emergence in 1967, flavoxate has been used to treat several urogenital tract disorders irrespective of the etiology of the underlying disease, but the main indications have been overactive bladder and urge symptomatology. With the advances in anticholinergic drugs, its popularity has decreased in recent decades. METHODS: In this review we summarize the current status of flavoxate in urogynecological practice focusing on its historical background, mechanism of action, efficacy, clinical experiences, outcomes, side effects and tolerability. We reviewed and analyze all the data and draw the major conclusions. We searched MEDLINE and the Cochrane Library using the keyword "flavoxate", and summarized review articles, original studies and case reports published from 1970 to 2013. RESULTS AND CONCLUSION: We conclude that the minimal side effects and high tolerability of flavoxate make it worthy of consideration for the treatment of several clinical urogynecological conditions. It deserves more clinical studies to assess its efficacy as no randomized controlled trials have been performed with flavoxate during the last decade. More studies and novel drug formulations may reveal or improve its efficacy in daily practice.

[Fluorescence enhancement of flavoxate hydrochloride in alkali solution and its application in pharmaceutical analysis].

Fluorescence enhancement reaction of flavoxate hydrochloride (FX) in strong alkali solution was studied, the mechanism of the reaction was investigated, and a novel fluorimetric method for analysis of FX in drug sample was established. FX has no intrinsic fluorescence, but it can slowly produce fluorescence in strong alkali solution. Heating can promote the fluorescence enhancement reaction. In 3D fluorescence spectra of the decomposition product of FX, two fluorescence peaks, located respectively at excitation wavelengths λex/ emission wavelength λem =223/410 nm, and 302/410 nm, were observed. Using quinine sulfate as a reference, fluorescence quantum yield of the decomposition product was measured to be 0.50. The structural characteriza- tion and spectral analysis of the decomposition product reveal that ester bond hydrolysis reaction of FX is firstly occurred during heating process, forming 3-methylflavone-8-carboxylic acid (MFA), then a cleavage reaction of the γ-pyrone ring of MFA occurred, producing α, ß-unsaturated ketone. This product includes adjacent hydroxyl benzoic acid group in its molecule, which can form intramolecular hydrogen bond under alkaline condition, so that increase the conjugate degree and enhance the rigidity of the molecule, and thereby cause fluorescence enhancement. Based on this fluorescence enhancement reaction, a fluorimetric method was proposed for the determination of FX. A linear calibration curve covered the concentration range 0.020 3-0.487 µg · mL. The regression equation was I(F) = 23.9 + 5357.3 c, with correlation coefficient r = 0.999 7 (n = 8), detection limit D = 1.1 ng · mL(-1). The method was applied to the analysis of FX tablets, with a spiked recovery rate of 100.2%. The reliability of the method was verified by a UV-spectrophotometric method.

Fluorescence enhancement of flavoxate hydrochloride in alkali solution and its application in pharmaceutical analysis / 药学学报

Fluorescence enhancement reaction of flavoxate hydrochloride (FX) in strong alkali solution was studied, the mechanism of the reaction was investigated, and a novel fluorimetric method for analysis of FX in drug sample was established. FX has no intrinsic fluorescence, but it can slowly produce fluorescence in strong alkali solution. Heating can promote the fluorescence enhancement reaction. In 3D fluorescence spectra of the decomposition product of FX, two fluorescence peaks, located respectively at excitation wavelengths λex/ emission wavelength λem =223/410 nm, and 302/410 nm, were observed. Using quinine sulfate as a reference, fluorescence quantum yield of the decomposition product was measured to be 0.50. The structural characteriza- tion and spectral analysis of the decomposition product reveal that ester bond hydrolysis reaction of FX is firstly occurred during heating process, forming 3-methylflavone-8-carboxylic acid (MFA), then a cleavage reaction of the γ-pyrone ring of MFA occurred, producing α, β-unsaturated ketone. This product includes adjacent hydroxyl benzoic acid group in its molecule, which can form intramolecular hydrogen bond under alkaline condition, so that increase the conjugate degree and enhance the rigidity of the molecule, and thereby cause fluorescence enhancement. Based on this fluorescence enhancement reaction, a fluorimetric method was proposed for the determination of FX. A linear calibration curve covered the concentration range 0.020 3-0.487 µg · mL. The regression equation was I(F) = 23.9 + 5357.3 c, with correlation coefficient r = 0.999 7 (n = 8), detection limit D = 1.1 ng · mL(-1). The method was applied to the analysis of FX tablets, with a spiked recovery rate of 100.2%. The reliability of the method was verified by a UV-spectrophotometric method.

Intravenous or local injections of flavoxate in the rostral pontine reticular formation inhibit urinary frequency induced by activation of medial frontal lobe neurons in rats.

PURPOSE: The rostral pontine reticular formation has a strong inhibitory effect on micturition by facilitating lumbosacral glycinergic neurons. We assessed the influence of the rostral pontine reticular formation on the micturition reflex after noradrenaline injection in the medial frontal lobe. We also examined the relation between the medial frontal lobe and the rostral pontine reticular formation. MATERIALS AND METHODS: Continuous cystometry was performed in 28 female rats. After the interval between bladder contractions was shortened by noradrenaline injection in the medial frontal lobe we injected glutamate or flavoxate hydrochloride in the rostral pontine reticular formation or intravenously injected flavoxate or propiverine. The change in bladder activity was examined. RESULTS: Noradrenaline injection in the medial frontal lobe shortened the interval between bladder contractions. In contrast to the bladder contraction interval before and after noradrenaline injection in the medial frontal lobe, the interval was prolonged after noradrenaline injection when glutamate or flavoxate was injected in the rostral pontine reticular formation, or flavoxate was injected intravenously. Noradrenaline injection in the medial frontal lobe plus intravenous propiverine injection also prolonged the interval compared to that after noradrenaline injection alone. However, the interval after noradrenaline injection in the medial frontal lobe plus intravenous injection of propiverine was shorter than that before noradrenaline injection only. CONCLUSIONS: Medial frontal lobe neurons excited by noradrenaline may facilitate the micturition reflex via activation of inhibitory interneurons, which inhibit descending rostral pontine reticular formation neurons that innervate the lumbosacral glycinergic inhibitory neurons. Therefore, the mechanism of micturition reflex facilitation by the activation of medial frontal lobe neurons involves the rostral pontine reticular formation.

Clarifying the mechanism of aggregation of particles in high-shear granulation based on their surface properties by using micro-spectroscopy.

The present study aimed to clarify, by means of micro-spectroscopy, the mechanism of aggregation of particles into granules during high-shear granulation. We used two types of pharmaceutical granules prepared by high-shear granulator, one containing mefenamic acid and the other containing flavoxate hydrochloride as poorly soluble active pharmaceutical ingredients (APIs). Lactose, cornstarch, and microcrystalline cellulose were used as excipients; and hydroxypropyl cellulose (HPC) was used as the binding agent. The distributions of components in granules were visualized by mapping cross-sections of individual granules with techniques utilizing mid-infrared spectroscopy at the SPring-8 synchrotron radiation facility and micro-Raman spectroscopy. In the distribution maps of mefenamic acid granules, distributions of mefenamic acid, cornstarch, and microcrystalline cellulose overlapped; in flavoxate hydrochloride granules, on the other hand, distributions of flavoxate hydrochloride and lactose overlapped. Assessment of the surface free energy of each component found that ingredients with overlapping distribution had similar surface properties. Therefore, it was revealed that in high-shear granulation, in addition to the granulator operating conditions and general properties of the formulation itself (such as the solubility and particle size of each ingredient), the surface properties of the ingredients and their interrelationships were also factors that determined the aggregation behavior of the particles.

An overview on mixed action drugs for the treatment of overactive bladder and detrusor overactivity.

OBJECTIVES: To provide an overview on the efficacy, tolerability, safety and health-related quality of life (HRQoL) of drugs with a mixed action used in the treatment of overactive bladder (OAB). EVIDENCE ACQUISITION: MEDLINE database and abstract books of the major conferences were searched for relevant publications from 1966 to 2011 and using the key words 'overactive bladder', 'detrusor overactivity', 'oxybutynin', 'propiverine', and 'flavoxate'. Two independent reviewers considered publications for inclusion and extracted relevant data, without performing a meta-analysis. EVIDENCE SYNTHESIS: Old and conflicting data do not support the use of flavoxate, while both propiverine and oxybutynin were found to be more effective than placebo in the treatment of OAB. Propiverine was at least as effective as oxybutynin but with a better tolerability profile even in the pediatric setting. Overall, no serious adverse event for any product was statistically significant compared to placebo. Improvements were seen in HRQoL with treatment by the oxybutynin transdermal delivery system and propiverine extended release. CONCLUSIONS: While there is no evidence to suggest the use of flavoxate in the treatment of OAB, both oxybutynin and propiverine appear efficacious and safe. Propiverine shows a better tolerability profile than oxybutynin. Both drugs improve HRQoL of patients affected by OAB. Profiles of each drug and dosage differ and should be considered in making treatment choices.

Molecularly imprinted polymer for selective extraction of 3-methylflavone-8-carboxylic acid from human urine followed by its determination using zwitterionic hydrophilic interaction liquid chromatography.

A novel water-compatible molecularly imprinted SPE combined with zwitterionic hydrophilic interaction liquid chromatography method for selective extraction and determination of 3-methylflavone-8-carboxylic acid (MFA), the main active metabolite of flavoxate in human urine, was developed and validated. The effects of progenic solvents, pH, cross linker and amount of monomer were studied to optimize the efficiency and selectivity. The molecularly imprinted polymer showed good specific adsorption capacity with an optimum of 200 µmol/g at pH 7.5 and selective extraction of MFA from human urine. The recovery of MFA from human urine was >98%. The lower limit of quantification was 1.20 µg/mL. The proposed method overcomes the matrix effects of endogenous substances generally encountered during direct analysis of urine sample.

Lipophilic cationic drugs increase the permeability of lysosomal membranes in a cell culture system.

Lysosomes accumulate many drugs several fold higher compared to their extracellular concentration. This mechanism is believed to be responsible for many pharmacological effects. So far, uptake and release kinetics are largely unknown and interactions between concomitantly administered drugs often provoke mutual interference. In this study, we addressed these questions in a cell culture model. The molecular mechanism for lysosomal uptake kinetics was analyzed by live cell fluorescence microscopy in SY5Y cells using four drugs (amantadine, amitriptyline, cinnarizine, flavoxate) with different physicochemical properties. Drugs with higher lipophilicity accumulated more extensively within lysosomes, whereas a higher pK(a) value was associated with a more rapid uptake. The drug-induced displacement of LysoTracker was neither caused by elevation of intra-lysosomal pH, nor by increased lysosomal volume. We extended our previously developed numerical single cell model by introducing a dynamic feedback mechanism. The empirical data were in good agreement with the results obtained from the numerical model. The experimental data and results from the numerical model lead to the conclusion that intra-lysosomal accumulation of lipophilic xenobiotics enhances lysosomal membrane permeability. Manipulation of lysosomal membrane permeability might be useful to overcome, for example, multi-drug resistance by altering subcellular drug distribution.

Liquid chromatographic fingerprint of 3-methylflavone-8-carboxylic acid established for its synthesis control analysis.

A high-performance liquid chromatographic method was proposed for the separation of relative impurities in industrial 3-methylflavone-8-carboxylic acid (MFCA) and its intermediate methyl 3-propionylsalicylate (MPS). Benzoic acid (BA), MPS, 6-chloro-3-methylflavone-8-carboxylic acid (MFCA-Cl) and methyl 5-chloro-3-propionylsalicylate (MPS-Cl) in MFCA, and MPS-Cl in MPS were respectively quantified by an external standard method. As results showed, the linearity of standard curves was excellent with the relative coefficients of over 0.999 for all the detected components, and the intra- and inter-day precisions of impurities determination were satisfactory with the relative standard deviation of not more than 8.0%. Under the selected experimental condition, the chromatographic fingerprints of MFCA and MPS were drawn synthetically, and the transfer of impurities in the stepwise reactions of MFCA manufacture was elucidated. The fingerprints have great potential in instructing the production of MFCA for industrial use and in conducting the conversion of relative impurities.