Darifenacin

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Mukund K. Gurjar - One of the best experts on this subject based on the ideXlab platform.

Chinmoy Pramanik - One of the best experts on this subject based on the ideXlab platform.

Gamal A. E. Mostafa - One of the best experts on this subject based on the ideXlab platform.

  • validated liquid chromatographic fluorescence method for the quantitation of Darifenacin in mice plasma and its application to a pharmacokinetic study
    Talanta, 2014
    Co-Authors: Mohammed M. Hefnawy, Amer M. Alanazi, M. A. Abounassif, Mostafa Mohammed, Sabry M. Attia, Gamal A. E. Mostafa
    Abstract:

    A highly selective, sensitive, and rapid high-performance liquid chromatography (HPLC) method has been developed and validated for the quantification of Darifenacin in mouse plasma. Bisoprolol was used as an internal standard (IS). Darifenacin and the IS were extracted using the deproteinisation technique, followed by injection of an aliquot of the supernatant into the chromatographic system. The chromatographic separation was achieved on a reversed phase C18 column with a mobile phase of acetonitrile: 0.1% diethyl amine (pH 3.5) (60:40, v/v) pumped at a flow rate of 1.0 mL min(-1). The analytes were detected at 210 and 314 nm for excitation and emission, respectively. The assay exhibited a linear range of 100-3000 ng mL(-1), with a lower detection limit of 35 ng mL(-1). The method was statistically validated for linearity, accuracy, precision, selectivity and stability according to the FDA guidelines. The intra- and inter-assay coefficients of variation did not exceed 13.5% from the nominal concentration. The accuracy for Darifenacin was within ±15% of the theoretical value. The assay was successfully applied in a pharmacokinetic study.

  • Validated liquid chromatographic–fluorescence method for the quantitation of Darifenacin in mice plasma and its application to a pharmacokinetic study
    Talanta, 2013
    Co-Authors: Mohammed M. Hefnawy, Amer M. Alanazi, M. A. Abounassif, Mostafa Mohammed, Sabry M. Attia, Gamal A. E. Mostafa
    Abstract:

    A highly selective, sensitive, and rapid high-performance liquid chromatography (HPLC) method has been developed and validated for the quantification of Darifenacin in mouse plasma. Bisoprolol was used as an internal standard (IS). Darifenacin and the IS were extracted using the deproteinisation technique, followed by injection of an aliquot of the supernatant into the chromatographic system. The chromatographic separation was achieved on a reversed phase C18 column with a mobile phase of acetonitrile: 0.1% diethyl amine (pH 3.5) (60:40, v/v) pumped at a flow rate of 1.0 mL min(-1). The analytes were detected at 210 and 314 nm for excitation and emission, respectively. The assay exhibited a linear range of 100-3000 ng mL(-1), with a lower detection limit of 35 ng mL(-1). The method was statistically validated for linearity, accuracy, precision, selectivity and stability according to the FDA guidelines. The intra- and inter-assay coefficients of variation did not exceed 13.5% from the nominal concentration. The accuracy for Darifenacin was within ±15% of the theoretical value. The assay was successfully applied in a pharmacokinetic study.

Michael Steel - One of the best experts on this subject based on the ideXlab platform.

  • clinical relevance of health related quality of life outcomes with Darifenacin
    BJUI, 2008
    Co-Authors: Paul Abrams, Con Kelleher, Jasper Huels, Erhard Quebefehling, Mohamed Omar, Michael Steel
    Abstract:

    OBJECTIVE To determine the clinical relevance of changes in health-related quality of life (HRQoL) in patients with overactive bladder (OAB) treated with Darifenacin. PATIENTS AND METHODS Data were pooled from three randomized, placebo-controlled, parallel-group, fixed-dose, 12-week studies. After 2-week washout, treatment-free or placebo run-in periods, patients with OAB (n = 1059; 85% women; age 19–88 years) were randomized to 12 weeks’ treatment with Darifenacin controlled-release 7.5 mg (n = 337) or 15 mg once daily (n = 334) or placebo (n = 388). The King’s Health Questionnaire (KHQ) was used to assess HRQoL at baseline and Week 12. The clinical significance of changes in KHQ domain scores was assessed using the concept of minimum important difference (MID), using two different methods. RESULTS Darifenacin treatment was associated with significantly greater improvements than placebo in six primary KHQ domain scores known to be of importance to patients with OAB. In addition, a significantly greater proportion of Darifenacin-treated patients met or exceeded reference MID vs placebo in these domains (Incontinence Impact, Severity Measures, Role Limitations, Social Limitations, Emotions and Physical Limitations; P = 0.01). In Darifenacin-treated patients, there were significant correlations between the reductions in incontinence episodes per week and improvements in KHQ scores (P < 0.001). The strongest correlations were in the Incontinence Impact, Social Limitations, Role Limitations, Severity Measures and Emotions domains. CONCLUSIONS Darifenacin treatment was associated with significant, clinically relevant improvements in HRQoL in patients with OAB, shown using the concept of MID to interpret change in KHQ scores.

  • Clinical relevance of health-related quality of life outcomes with Darifenacin.
    BJU international, 2008
    Co-Authors: Paul Abrams, Con Kelleher, Jasper Huels, Mohamed Omar, Erhard Quebe-fehling, Michael Steel
    Abstract:

    OBJECTIVE To determine the clinical relevance of changes in health-related quality of life (HRQoL) in patients with overactive bladder (OAB) treated with Darifenacin. PATIENTS AND METHODS Data were pooled from three randomized, placebo-controlled, parallel-group, fixed-dose, 12-week studies. After 2-week washout, treatment-free or placebo run-in periods, patients with OAB (n = 1059; 85% women; age 19–88 years) were randomized to 12 weeks’ treatment with Darifenacin controlled-release 7.5 mg (n = 337) or 15 mg once daily (n = 334) or placebo (n = 388). The King’s Health Questionnaire (KHQ) was used to assess HRQoL at baseline and Week 12. The clinical significance of changes in KHQ domain scores was assessed using the concept of minimum important difference (MID), using two different methods. RESULTS Darifenacin treatment was associated with significantly greater improvements than placebo in six primary KHQ domain scores known to be of importance to patients with OAB. In addition, a significantly greater proportion of Darifenacin-treated patients met or exceeded reference MID vs placebo in these domains (Incontinence Impact, Severity Measures, Role Limitations, Social Limitations, Emotions and Physical Limitations; P = 0.01). In Darifenacin-treated patients, there were significant correlations between the reductions in incontinence episodes per week and improvements in KHQ scores (P 

  • Long-term Darifenacin treatment for overactive bladder in patients aged 65 years and older: analysis of results from a 2-year, open-label extension study.
    Current medical research and opinion, 2007
    Co-Authors: Simon Hill, Karine Lheritier, Peter L. Dwyer, Mostafa M. Elhilali, Richard J. Millard, Fernando T. Kawakami, Michael Steel
    Abstract:

    ABSTRACTObjectives: This analysis evaluated the long-term safety, tolerability and efficacy of Darifenacin, a muscarinic M3 selective receptor antagonist, in the treatment of overactive bladder (OAB) in patients ≥ 65 years of age.Methods: Patients who completed one of two 12-week, placebo-controlled, double-blind, feeder studies received once-daily (o.d.) treatment with Darifenacin 7.5 mg for the first 2 weeks of the 2-year, open-label extension study. The dose could be subsequently adjusted (7.5 or 15 mg o.d.) according to need. Safety and tolerability were assessed, and efficacy variables/endpoints were evaluated from patient diary data.Results: 214 patients (65–89 years) entered and 137 (64.0%) completed the 2-year extension study, amounting to 308 patient-years’ drug exposure. Darifenacin was well tolerated with no new safety concerns. The most common adverse events (AEs) were dry mouth and constipation, which infrequently resulted in discontinuation (2.3% and 4.2%, respectively). Darifenacin produced...

  • long term treatment with Darifenacin for overactive bladder results of a 2 year open label extension study
    BJUI, 2006
    Co-Authors: François Haab, Karin Glavind, Michael Steel, Peter L. Dwyer, Jacques Corcos, Fernando T. Kawakami, Paul Siami, K Lheritier, William D. Steers
    Abstract:

    OBJECTIVE To examine, in a 2-year, non-comparative, open-label extension study, the safety, tolerability and efficacy of Darifenacin controlled-release (CR) 7.5/15 mg once daily in patients with overactive bladder (OAB) who completed two 12-week randomized, double-blind, placebo-controlled ‘feeder’ studies. PATIENTS AND METHODS Patients entering the extension received Darifenacin 7.5 mg once daily for 2 weeks, after which a voluntary increase in dose to 15 mg was permitted. Thereafter, patients could adjust the dose (either 7.5 or 15 mg). Safety and tolerability were assessed from adverse events (AEs) and discontinuations. Efficacy was determined using various endpoints. RESULTS In all, 716 patients entered the extension (mean age 57.3 years; 85.1% women) and 475 (66.3%) completed it (1089.9 patient-years of exposure). Darifenacin was well tolerated with no significant safety concerns. The most commonly reported AEs were dry mouth and constipation (all-causality rates 23.3% and 20.9%, respectively), leading to discontinuation in 1.3% and 2.4% of patients, respectively. Constipation infrequently required intervention, and analysis of bowel-habit questionnaires revealed that the reporting of constipation was related to minor changes in bowel habit rather than true constipation. The efficacy of Darifenacin was maintained, including significant improvements in the number of incontinence episodes/week (median change −84.4% at 2 years, P  40% of patients achieved a ≥90% reduction in incontinence episodes/week. CONCLUSION In the first published 2-year, open-label study of a CR antimuscarinic agent, Darifenacin 7.5/15 mg once daily had a favourable safety, tolerability and efficacy profile during the long-term treatment of OAB. As such, Darifenacin represents a valuable therapeutic option for OAB.

  • Long‐term treatment with Darifenacin for overactive bladder: results of a 2‐year, open‐label extension study
    BJU international, 2006
    Co-Authors: François Haab, Karin Glavind, Karine Lheritier, Michael Steel, Peter L. Dwyer, Jacques Corcos, Fernando T. Kawakami, Paul Siami, William D. Steers
    Abstract:

    OBJECTIVE To examine, in a 2-year, non-comparative, open-label extension study, the safety, tolerability and efficacy of Darifenacin controlled-release (CR) 7.5/15 mg once daily in patients with overactive bladder (OAB) who completed two 12-week randomized, double-blind, placebo-controlled ‘feeder’ studies. PATIENTS AND METHODS Patients entering the extension received Darifenacin 7.5 mg once daily for 2 weeks, after which a voluntary increase in dose to 15 mg was permitted. Thereafter, patients could adjust the dose (either 7.5 or 15 mg). Safety and tolerability were assessed from adverse events (AEs) and discontinuations. Efficacy was determined using various endpoints. RESULTS In all, 716 patients entered the extension (mean age 57.3 years; 85.1% women) and 475 (66.3%) completed it (1089.9 patient-years of exposure). Darifenacin was well tolerated with no significant safety concerns. The most commonly reported AEs were dry mouth and constipation (all-causality rates 23.3% and 20.9%, respectively), leading to discontinuation in 1.3% and 2.4% of patients, respectively. Constipation infrequently required intervention, and analysis of bowel-habit questionnaires revealed that the reporting of constipation was related to minor changes in bowel habit rather than true constipation. The efficacy of Darifenacin was maintained, including significant improvements in the number of incontinence episodes/week (median change −84.4% at 2 years, P  40% of patients achieved a ≥90% reduction in incontinence episodes/week. CONCLUSION In the first published 2-year, open-label study of a CR antimuscarinic agent, Darifenacin 7.5/15 mg once daily had a favourable safety, tolerability and efficacy profile during the long-term treatment of OAB. As such, Darifenacin represents a valuable therapeutic option for OAB.

William D. Steers - One of the best experts on this subject based on the ideXlab platform.

  • long term treatment with Darifenacin for overactive bladder results of a 2 year open label extension study
    BJUI, 2006
    Co-Authors: François Haab, Karin Glavind, Michael Steel, Peter L. Dwyer, Jacques Corcos, Fernando T. Kawakami, Paul Siami, K Lheritier, William D. Steers
    Abstract:

    OBJECTIVE To examine, in a 2-year, non-comparative, open-label extension study, the safety, tolerability and efficacy of Darifenacin controlled-release (CR) 7.5/15 mg once daily in patients with overactive bladder (OAB) who completed two 12-week randomized, double-blind, placebo-controlled ‘feeder’ studies. PATIENTS AND METHODS Patients entering the extension received Darifenacin 7.5 mg once daily for 2 weeks, after which a voluntary increase in dose to 15 mg was permitted. Thereafter, patients could adjust the dose (either 7.5 or 15 mg). Safety and tolerability were assessed from adverse events (AEs) and discontinuations. Efficacy was determined using various endpoints. RESULTS In all, 716 patients entered the extension (mean age 57.3 years; 85.1% women) and 475 (66.3%) completed it (1089.9 patient-years of exposure). Darifenacin was well tolerated with no significant safety concerns. The most commonly reported AEs were dry mouth and constipation (all-causality rates 23.3% and 20.9%, respectively), leading to discontinuation in 1.3% and 2.4% of patients, respectively. Constipation infrequently required intervention, and analysis of bowel-habit questionnaires revealed that the reporting of constipation was related to minor changes in bowel habit rather than true constipation. The efficacy of Darifenacin was maintained, including significant improvements in the number of incontinence episodes/week (median change −84.4% at 2 years, P  40% of patients achieved a ≥90% reduction in incontinence episodes/week. CONCLUSION In the first published 2-year, open-label study of a CR antimuscarinic agent, Darifenacin 7.5/15 mg once daily had a favourable safety, tolerability and efficacy profile during the long-term treatment of OAB. As such, Darifenacin represents a valuable therapeutic option for OAB.

  • Long‐term treatment with Darifenacin for overactive bladder: results of a 2‐year, open‐label extension study
    BJU international, 2006
    Co-Authors: François Haab, Karin Glavind, Karine Lheritier, Michael Steel, Peter L. Dwyer, Jacques Corcos, Fernando T. Kawakami, Paul Siami, William D. Steers
    Abstract:

    OBJECTIVE To examine, in a 2-year, non-comparative, open-label extension study, the safety, tolerability and efficacy of Darifenacin controlled-release (CR) 7.5/15 mg once daily in patients with overactive bladder (OAB) who completed two 12-week randomized, double-blind, placebo-controlled ‘feeder’ studies. PATIENTS AND METHODS Patients entering the extension received Darifenacin 7.5 mg once daily for 2 weeks, after which a voluntary increase in dose to 15 mg was permitted. Thereafter, patients could adjust the dose (either 7.5 or 15 mg). Safety and tolerability were assessed from adverse events (AEs) and discontinuations. Efficacy was determined using various endpoints. RESULTS In all, 716 patients entered the extension (mean age 57.3 years; 85.1% women) and 475 (66.3%) completed it (1089.9 patient-years of exposure). Darifenacin was well tolerated with no significant safety concerns. The most commonly reported AEs were dry mouth and constipation (all-causality rates 23.3% and 20.9%, respectively), leading to discontinuation in 1.3% and 2.4% of patients, respectively. Constipation infrequently required intervention, and analysis of bowel-habit questionnaires revealed that the reporting of constipation was related to minor changes in bowel habit rather than true constipation. The efficacy of Darifenacin was maintained, including significant improvements in the number of incontinence episodes/week (median change −84.4% at 2 years, P  40% of patients achieved a ≥90% reduction in incontinence episodes/week. CONCLUSION In the first published 2-year, open-label study of a CR antimuscarinic agent, Darifenacin 7.5/15 mg once daily had a favourable safety, tolerability and efficacy profile during the long-term treatment of OAB. As such, Darifenacin represents a valuable therapeutic option for OAB.

  • Darifenacin: Pharmacology and clinical usage
    The Urologic clinics of North America, 2006
    Co-Authors: William D. Steers
    Abstract:

    Darifenacin is one of several recently approved antimuscarinics for the treatment of overactive bladder (OAB) and urge urinary incontinence. Darifenacin is an effective drug for the treatment of OAB and is tolerated by patients. Darifenacin's M3 selectivity is unique among antimuscarinics. This M3 selectivity could confer advantages in patients who have cardiovascular side effects (tachycardia), impaired cognition, complaints of dizziness, or sleep disturbances. In some studies, Darifenacin caused less dry mouth than oxybutynin. Rates of constipation, although significant, are tolerated and rarely a cause for discontinuation in clinical trials. This review describes the role of M3 receptors and covers the mechanism of action, pharmacokinetic properties, clinical efficacy safety and tolerability, drug interactions, and dosing guidelines for Darifenacin.

  • a pooled analysis of three phase iii studies to investigate the efficacy tolerability and safety of Darifenacin a muscarinic m3 selective receptor antagonist in the treatment of overactive bladder
    BJUI, 2005
    Co-Authors: Christopher R. Chapple, Karin Glavind, Georg Kralidis, William D. Steers, Richard J. Millard, Peggy Norton, Paul Abrams
    Abstract:

    An international group of authors present a pooled analysis of data from their phase III multicentre double-blind clinical trials in patients with overactive bladder, which evaluated the efficacy, tolerability and safety of Darifenacin. They found the drug, a muscarinic M3 selective receptor antagonist, to be effective in the treatment of this condition, with excellent tolerability and safety. A paper from Denmark compares the efficacy and safety of alfuzosin and tamsulosin in a large randomized, double-blind, placebo-controlled, multicentre study. There were similar improvements in urinary symptoms and maximum urinary flow with the two drugs compared to placebo, but the incidence of sexual function adverse events was higher with tamsulosin than placebo. OBJECTIVE To evaluate the efficacy, tolerability and safety of Darifenacin, a muscarinic M3 selective receptor antagonist (M3 SRA), from an analysis of pooled data from three phase III, multicentre, double-blind clinical trials in patients with overactive bladder (OAB). PATIENTS AND METHODS After a 4-week washout/run-in period, 1059 adults (85% women) with symptoms of OAB (frequency and urgency with urge incontinence) for ≥ 6 months were randomized to once-daily oral treatment with Darifenacin (7.5 mg, 337; or 15 mg, 334) or matching placebo (388) for 12 weeks. Efficacy was evaluated using electronic patient diaries that recorded incontinence episodes (including those resulting in a change of clothing or pads), frequency and severity of urgency, voiding frequency, and bladder capacity (volume voided). Safety was evaluated by analysis of adverse events (AEs), withdrawal rates and laboratory tests. RESULTS Relative to baseline, 12 weeks of treatment with Darifenacin resulted in a significant reduction in the median (% change, interquartile range) number of incontinence episodes per week; 7.5 mg (−8.8, −68.4%, −15.1 to −4.4); 15 mg; (−10.6, −76.8%, −17.3 to −5.8: both P < 0.01 vs placebo). There was a significant dose–response trend in each study for which Darifenacin 7.5 and 15 mg were evaluated (P < 0.01). There were also significant decreases in the frequency and severity of urgency, voiding frequency, and number of significant leaks (incontinence episodes resulting in a change of clothing or pads; both P ≤ 0.001 vs placebo), together with an increase in bladder capacity (both P < 0.01 vs placebo). Darifenacin was well tolerated; the most common AEs were dry mouth and constipation, although together these resulted in few discontinuations (Darifenacin 7.5 mg 0.6% of patients; 15 mg 2.1%; placebo 0.3%). The incidence of peripheral/central nervous system and cardiovascular AEs were comparable with those on placebo. CONCLUSIONS Darifenacin (7.5 and 15 mg once daily) is effective in the treatment of patients with OAB. As predicted by its M3 selectivity and associated M1/M2-sparing profile, Darifenacin was well tolerated with no central nervous system or cardiovascular safety concerns.

  • an investigation of dose titration with Darifenacin an m3 selective receptor antagonist
    BJUI, 2005
    Co-Authors: William D. Steers, Jenelle Foote, Jacques Corcos, Georg Kralidis
    Abstract:

    OBJECTIVES To evaluate the efficacy, tolerability and safety of a flexible-dosing strategy with Darifenacin, an M3-selective receptor antagonist, in patients with symptoms of overactive bladder (OAB). PATIENTS AND METHODS In this multicentre double-blind 12-week study, 395 patients (aged 22–89 years; 84% female) with OAB symptoms for >6 months were randomized (2 : 1) and received once-daily treatment with Darifenacin controlled-release tablets 7.5 mg (268 patients) or matching placebo (127). After 2 weeks of treatment, the efficacy, safety and tolerability were assessed and the dose increased to 15 mg once daily (pseudo-increase for placebo recipients) if additional efficacy was required by both the patient and physician. In the week before clinic visits (at 2 and 12 weeks), patients recorded incontinence episodes (primary efficacy endpoint) and several secondary efficacy variables in an electronic daily diary. Safety and tolerability were evaluated from withdrawal rates and adverse-event reports. RESULTS The treatment groups had comparable baseline characteristics. Similar proportions of Darifenacin (59%) and placebo (68%) recipients increased the dose at 2 weeks; at 12 weeks patients on Darifenacin (overall group) had a significantly greater reduction in the median number of incontinence episodes per week than had those on placebo, at − 8.2 (−62.9%) and − 6.0 (−48.1%), respectively (P = 0.035). There were also significant improvements in voiding frequency (P = 0.001), bladder capacity (volume voided; P= 0.036), frequency of urgency (P < 0.001), severity of urgency (P = 0.013) and number of significant leaks/week (i.e. incontinence episodes needing a change of clothing or pads, per week; P = 0.010) for Darifenacin over placebo. Subset analysis suggested that some patients (those remaining on Darifenacin 7.5 mg) were more sensitive to Darifenacin than those who increased the dose, based on both efficacy and adverse events. Continued treatment with 7.5 mg for ‘sensitive’ patients, and an increased dose (to 15 mg) for remaining patients, resulted in comparable outcomes by 12 weeks. The most common treatment-related adverse events were mild-to-moderate dry mouth and constipation, which led to discontinuation in < 3.0% of Darifenacin-treated patients and <1.0% of the placebo group. Central nervous system and cardiovascular adverse events were comparable to those with placebo. CONCLUSIONS Darifenacin appears to be an effective, well-tolerated and flexible treatment for patients with OAB, allowing individualized dosing according to patient needs.

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