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Mahmoud A Ghannoum - One of the best experts on this subject based on the ideXlab platform.

  • vt 1161 dosed once daily or once weekly exhibits potent efficacy in treatment of dermatophytosis in a Guinea Pig Model
    Antimicrobial Agents and Chemotherapy, 2015
    Co-Authors: Edward P Garvey, W J Hoekstra, William R Moore, R J Schotzinger, Lisa Long, Mahmoud A Ghannoum
    Abstract:

    ABSTRACT Current therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potent in vitro antifungal activity against dermatophytes, with MIC values in the range of ≤0.016 to 0.5 μg/ml. In pharmacokinetic studies supporting testing in a Guinea Pig Model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potential in vivo efficacy with once-daily and possibly once-weekly dosing. Subsequently, in a Guinea Pig dermatophytosis Model utilizing Trichophyton mentagrophytes and at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction ( P P P

  • vt 1161 dosed once daily or once weekly exhibits potent efficacy in treatment of dermatophytosis in a Guinea Pig Model
    Antimicrobial Agents and Chemotherapy, 2015
    Co-Authors: Edward P Garvey, W J Hoekstra, William R Moore, R J Schotzinger, Lisa Long, Mahmoud A Ghannoum
    Abstract:

    Current therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potent in vitro antifungal activity against dermatophytes, with MIC values in the range of ≤0.016 to 0.5 μg/ml. In pharmacokinetic studies supporting testing in a Guinea Pig Model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potential in vivo efficacy with once-daily and possibly once-weekly dosing. Subsequently, in a Guinea Pig dermatophytosis Model utilizing Trichophyton mentagrophytes and at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction (P < 0.001) and improvement in clinical scores (P < 0.001). The efficacy profile of VT-1161 was equivalent to those for doses and regimens of itraconazole and terbinafine except that VT-1161 was superior to itraconazole when each drug was dosed once weekly (P < 0.05). VT-1161 was distributed into skin and hair, with plasma and tissue concentrations in all treatment and regimen groups ranging from 0.8 to 40 μg/ml (or μg/g), at or above the MIC against the isolate used in the Model (0.5 μg/ml). These data strongly support the clinical development of VT-1161 for the oral treatment of onychomycosis using either once-daily or once-weekly dosing regimens.

  • efficacy of terbinafine compared to lanoconazole and luliconazole in the topical treatment of dermatophytosis in a Guinea Pig Model
    Medical Mycology, 2010
    Co-Authors: Mahmoud A Ghannoum, Lisa Long, H G Kim, A J Cirino, A R Miller, P Mallefet
    Abstract:

    The in vivo efficacy of terbinafine was compared to lanoconazole and luliconazole in the topical treatment of dermatophytosis caused by Trichophyton mentagrophytes using a Guinea Pig Model. Topical antifungal treatment commenced three days post-infection, and each agent was applied once daily for seven consecutive days. Upon completion of the treatment period, evaluations of clinical and mycological efficacies were performed, as was scanning electron microscopy (SEM) analyses. Data showed that while all tested antifungals demonstrated significant mycological efficacy in terms of eradicating the fungi over untreated control, terbinafine and luliconazole showed superior clinical efficacy compared to lanoconazole (P-values < 0.001 & 0.003, respectively). Terbinafine demonstrated the highest clinical percent efficacy. SEM analysis revealed hairs from terbinafine and lanoconazole-treated animals had near complete clearance of fungi, while samples from luliconazole-treated animals were covered with debris and f...

  • determination of the efficacy of terbinafine hydrochloride nail solution in the topical treatment of dermatophytosis in a Guinea Pig Model
    Mycoses, 2009
    Co-Authors: Lisa Long, Mahmoud A Ghannoum, William R Pfister
    Abstract:

    Currently available topical antifungals are often not satisfactory for the treatment of nail infections, because of the inability to penetrate the nail plate. Terbinafine HCl nail solution is a novel antifungal formulation containing a nail penetration enhancer dodecyl-2-N,N-dimethylaminopropionate hydrochloride (DDAIP HCl, trade name NexACT-88). In this study, we used a Guinea Pig Model of Trichophyton mentagrophytes dermatophytosis and evaluated the clinical and mycological efficacy of different terbinafine HCl nail solutions (TNS) formulated with or without DDAIP HCl. Ciclopirox (8%) nail lacquer (Penlac), the only Food and Drug Administration approved topical treatment for onychomycosis, was used as a comparator. Following the IACUC Guidelines, the skin of male albino Guinea Pigs was abraded under anaesthesia. Each animal was infected with T. mentagrophytes ATCC 24953 (cell suspension containing 1 x 10(7) conidia). The experimental animals were divided into 11 groups (five animals per group) and tested with the following formulations: vehicle control, 0.5% DDAIP HCl, 1%, 5% and 10% TNS (without DDAIP HCl), 1% TNS with 0.5%, 2.5% and 5.0% DDAIP HCl, 5% and 10% TNS with 0.5% DDAIP HCl, 8% ciclopirox nail lacquer and an untreated control group. Evaluation of clinical and mycological efficacy was performed 72 h after completion of a 7-day treatment regimen. Skin biopsy samples were processed for histopathological examination. The infected untreated control Guinea Pigs showed patches of hair loss and ulcerated or scaly skin and fungal invasion of hair roots. The vehicle and 0.5% DDAIP HCl treated groups showed minimal clinical efficacy (only 11% and 5%, respectively). In contrast, all three concentrations of TNS (1%, 5% and 10% terbinafine HCl) formulated with or without 0.5% DDAIP HCl showed 100% mycological efficacy by the hair root invasion test. Clinical efficacy of the 5% and 10% TNS improved with addition of 0.5% DDAIP HCl (47.4% and 73.8% vs. 68.4% and 89.5%, respectively). In addition, no fungal elements were detected in the treated Guinea Pig skin. All formulations of TNS resulted in a higher clinical and mycological efficacy compared with the 8% ciclopirox nail lacquer (P = 0.0444). In conclusion, TNS containing 1%, 5% and 10% terbinafine HCl formulated with and without DDAIP HCl demonstrated high antifungal efficacy in experimental dermatophytosis. Addition of 0.5% DDAIP HCl to 5% and 10% TNS significantly enhanced the clinical and mycological efficacy of these formulations which were superior compared with the 8% ciclopirox nail lacquer. Evaluation of the 1%, 5% and 10% TNS in clinical trials for the treatment of dermatophytosis and onychomycosis is warranted.

  • antifungal activity of voriconazole uk 109 496 fluconazole and amphotericin b against hematogenous candida krusei infection in neutropenic Guinea Pig Model
    Journal of Chemotherapy, 1999
    Co-Authors: Mahmoud A Ghannoum, I Okogbulewonodi, N Bhat, Homayoon Sanati
    Abstract:

    AbstractVoriconazole (UK-109,496) is a new triazole with in vitro activity against a wide spectrum of fungi including yeasts intrinsically resistant to fluconazole such as Candida krusei. In this study the efficacy of voriconazole was compared to amphotericin B and fluconazole in a neutropenic Guinea Pig Model of hematogenously disseminated C. krusei infection. In Guinea Pigs, neutropenia was established by using cyclophosphamide (intraperitoneally, i.p., 100 mg/kg on day 1 and 4), and dexamethasone (orally, 2 mg/kg/day, for 8 days). Neutropenic Guinea Pigs were infected with 0.5 ml of yeast cell suspension (1×108 CFU) intravenously. Challenged animals were treated with antifungals starting 1 h postinfection for 7 days. The animals were divided into five groups: untreated control, amphotericin B (1 mg/kg i.p. on alternate days), fluconazole (20 mg/kg orally twice daily), and voriconazole (two groups: 5 and 10 mg/kg orally twice daily) groups. Guinea Pigs were sacrificed 1 day after the last treatment. Bra...

Lisa Long - One of the best experts on this subject based on the ideXlab platform.

  • vt 1161 dosed once daily or once weekly exhibits potent efficacy in treatment of dermatophytosis in a Guinea Pig Model
    Antimicrobial Agents and Chemotherapy, 2015
    Co-Authors: Edward P Garvey, W J Hoekstra, William R Moore, R J Schotzinger, Lisa Long, Mahmoud A Ghannoum
    Abstract:

    ABSTRACT Current therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potent in vitro antifungal activity against dermatophytes, with MIC values in the range of ≤0.016 to 0.5 μg/ml. In pharmacokinetic studies supporting testing in a Guinea Pig Model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potential in vivo efficacy with once-daily and possibly once-weekly dosing. Subsequently, in a Guinea Pig dermatophytosis Model utilizing Trichophyton mentagrophytes and at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction ( P P P

  • vt 1161 dosed once daily or once weekly exhibits potent efficacy in treatment of dermatophytosis in a Guinea Pig Model
    Antimicrobial Agents and Chemotherapy, 2015
    Co-Authors: Edward P Garvey, W J Hoekstra, William R Moore, R J Schotzinger, Lisa Long, Mahmoud A Ghannoum
    Abstract:

    Current therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potent in vitro antifungal activity against dermatophytes, with MIC values in the range of ≤0.016 to 0.5 μg/ml. In pharmacokinetic studies supporting testing in a Guinea Pig Model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potential in vivo efficacy with once-daily and possibly once-weekly dosing. Subsequently, in a Guinea Pig dermatophytosis Model utilizing Trichophyton mentagrophytes and at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction (P < 0.001) and improvement in clinical scores (P < 0.001). The efficacy profile of VT-1161 was equivalent to those for doses and regimens of itraconazole and terbinafine except that VT-1161 was superior to itraconazole when each drug was dosed once weekly (P < 0.05). VT-1161 was distributed into skin and hair, with plasma and tissue concentrations in all treatment and regimen groups ranging from 0.8 to 40 μg/ml (or μg/g), at or above the MIC against the isolate used in the Model (0.5 μg/ml). These data strongly support the clinical development of VT-1161 for the oral treatment of onychomycosis using either once-daily or once-weekly dosing regimens.

  • efficacy of terbinafine compared to lanoconazole and luliconazole in the topical treatment of dermatophytosis in a Guinea Pig Model
    Medical Mycology, 2010
    Co-Authors: Mahmoud A Ghannoum, Lisa Long, H G Kim, A J Cirino, A R Miller, P Mallefet
    Abstract:

    The in vivo efficacy of terbinafine was compared to lanoconazole and luliconazole in the topical treatment of dermatophytosis caused by Trichophyton mentagrophytes using a Guinea Pig Model. Topical antifungal treatment commenced three days post-infection, and each agent was applied once daily for seven consecutive days. Upon completion of the treatment period, evaluations of clinical and mycological efficacies were performed, as was scanning electron microscopy (SEM) analyses. Data showed that while all tested antifungals demonstrated significant mycological efficacy in terms of eradicating the fungi over untreated control, terbinafine and luliconazole showed superior clinical efficacy compared to lanoconazole (P-values < 0.001 & 0.003, respectively). Terbinafine demonstrated the highest clinical percent efficacy. SEM analysis revealed hairs from terbinafine and lanoconazole-treated animals had near complete clearance of fungi, while samples from luliconazole-treated animals were covered with debris and f...

  • determination of the efficacy of terbinafine hydrochloride nail solution in the topical treatment of dermatophytosis in a Guinea Pig Model
    Mycoses, 2009
    Co-Authors: Lisa Long, Mahmoud A Ghannoum, William R Pfister
    Abstract:

    Currently available topical antifungals are often not satisfactory for the treatment of nail infections, because of the inability to penetrate the nail plate. Terbinafine HCl nail solution is a novel antifungal formulation containing a nail penetration enhancer dodecyl-2-N,N-dimethylaminopropionate hydrochloride (DDAIP HCl, trade name NexACT-88). In this study, we used a Guinea Pig Model of Trichophyton mentagrophytes dermatophytosis and evaluated the clinical and mycological efficacy of different terbinafine HCl nail solutions (TNS) formulated with or without DDAIP HCl. Ciclopirox (8%) nail lacquer (Penlac), the only Food and Drug Administration approved topical treatment for onychomycosis, was used as a comparator. Following the IACUC Guidelines, the skin of male albino Guinea Pigs was abraded under anaesthesia. Each animal was infected with T. mentagrophytes ATCC 24953 (cell suspension containing 1 x 10(7) conidia). The experimental animals were divided into 11 groups (five animals per group) and tested with the following formulations: vehicle control, 0.5% DDAIP HCl, 1%, 5% and 10% TNS (without DDAIP HCl), 1% TNS with 0.5%, 2.5% and 5.0% DDAIP HCl, 5% and 10% TNS with 0.5% DDAIP HCl, 8% ciclopirox nail lacquer and an untreated control group. Evaluation of clinical and mycological efficacy was performed 72 h after completion of a 7-day treatment regimen. Skin biopsy samples were processed for histopathological examination. The infected untreated control Guinea Pigs showed patches of hair loss and ulcerated or scaly skin and fungal invasion of hair roots. The vehicle and 0.5% DDAIP HCl treated groups showed minimal clinical efficacy (only 11% and 5%, respectively). In contrast, all three concentrations of TNS (1%, 5% and 10% terbinafine HCl) formulated with or without 0.5% DDAIP HCl showed 100% mycological efficacy by the hair root invasion test. Clinical efficacy of the 5% and 10% TNS improved with addition of 0.5% DDAIP HCl (47.4% and 73.8% vs. 68.4% and 89.5%, respectively). In addition, no fungal elements were detected in the treated Guinea Pig skin. All formulations of TNS resulted in a higher clinical and mycological efficacy compared with the 8% ciclopirox nail lacquer (P = 0.0444). In conclusion, TNS containing 1%, 5% and 10% terbinafine HCl formulated with and without DDAIP HCl demonstrated high antifungal efficacy in experimental dermatophytosis. Addition of 0.5% DDAIP HCl to 5% and 10% TNS significantly enhanced the clinical and mycological efficacy of these formulations which were superior compared with the 8% ciclopirox nail lacquer. Evaluation of the 1%, 5% and 10% TNS in clinical trials for the treatment of dermatophytosis and onychomycosis is warranted.

Herman Meurs - One of the best experts on this subject based on the ideXlab platform.

  • arginase inhibition prevents inflammation and reModeling in a Guinea Pig Model of chronic obstructive pulmonary disease
    Journal of Pharmacology and Experimental Therapeutics, 2014
    Co-Authors: Tonio Pera, Marieke Smit, Annet B Zuidhof, Herman Meurs, Johan Zaagsma, Mark H Menzen, Theo Klein, Gunnar Flik, Harm Maarsingh
    Abstract:

    Airway inflammation and reModeling are major features of chronic obstructive pulmonary disease (COPD), whereas pulmonary hypertension is a common comorbidity associated with a poor disease prognosis. Recent studies in animal Models have indicated that increased arginase activity contributes to features of asthma, including allergen-induced airway eosinophilia and mucus hypersecretion. Although cigarette smoke and lipopolysaccharide (LPS), major risk factors for COPD, may increase arginase expression, the role of arginase in COPD is unknown. This study aimed to investigate the role of arginase in pulmonary inflammation and reModeling using an animal Model of COPD. Guinea Pigs were instilled intranasally with LPS or saline twice weekly for 12 weeks and pretreated by inhalation of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) or vehicle. Repeated LPS exposure increased lung arginase activity, resulting in increased l-ornithine/l-arginine and l-ornithine/l-citrulline ratios. Both ratios were reversed by ABH. ABH inhibited the LPS-induced increases in pulmonary IL-8, neutrophils, and goblet cells as well as airway fibrosis. Remarkably, LPS-induced right ventricular hypertrophy, indicative of pulmonary hypertension, was prevented by ABH. Strong correlations were found between arginase activity and inflammation, airway reModeling, and right ventricular hypertrophy. Increased arginase activity contributes to pulmonary inflammation, airway reModeling, and right ventricular hypertrophy in a Guinea Pig Model of COPD, indicating therapeutic potential for arginase inhibitors in this disease.

  • bronchoprotection by olodaterol is synergistically enhanced by tiotropium in a Guinea Pig Model of allergic asthma
    Journal of Pharmacology and Experimental Therapeutics, 2014
    Co-Authors: Marieke Smit, Annet B Zuidhof, Harm Maarsingh, Johan Zaagsma, Reinoud Gosens, Herman Meurs
    Abstract:

    The novel once-daily β₂-agonist bronchodilator drug olodaterol has recently been shown to be effective in patients with allergic asthma for >24 hours. An increased cholinergic tone common to these patients may decrease the effectiveness of β₂-agonists. This could provide a rationale for combination therapy with olodaterol and the long-acting anticholinergic tiotropium to aim for a once-daily treatment regimen. In Guinea Pigs, we evaluated the protective effects of olodaterol, alone and in combination with tiotropium, on airway responsiveness to histamine, which is partially mediated by a cholinergic reflex mechanism. In addition, using a Guinea Pig Model of acute allergic asthma, we examined the cooperative effects of these bronchodilators on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyper-responsiveness (AHR) to histamine, and airway inflammation. It was demonstrated that the protective effect of olodaterol against histamine-induced bronchoconstriction was synergistically enhanced and prolonged in the presence of tiotropium. In addition, tiotropium synergistically augmented both the reversal of and the protection against the allergen-induced AHR after the EAR by olodaterol. Olodaterol and tiotropium were highly effective in inhibiting the magnitude of the allergen-induced EAR and LAR, and both reactions were fully inhibited by the combination of these drugs. It is remarkable that these effects were not associated with an effect on inflammatory cell infiltration in the airways. In conclusion, the results indicate that combination therapy with olodaterol and tiotropium may be highly effective in the treatment of allergen-induced asthmatic reactions and AHR.

  • tiotropium inhibits pulmonary inflammation and reModelling in a Guinea Pig Model of copd
    European Respiratory Journal, 2011
    Co-Authors: Tonio Pera, Marieke Smit, Annet B Zuidhof, Harm Maarsingh, Johan Zaagsma, Reinoud Gosens, J Valadas, Regina Schoemaker, Herman Meurs
    Abstract:

    Airway reModelling and emphysema are major structural abnormalities in chronic obstructive pulmonary disease (COPD). In addition, pulmonary vascular reModelling may occur and contribute to pulmonary hypertension, a comorbidity of COPD. Increased cholinergic activity in COPD contributes to airflow limitation and, possibly, to inflammation and airway reModelling. This study aimed to investigate the role of acetylcholine in pulmonary inflammation and reModelling using an animal Model of COPD. To this aim, Guinea Pigs were instilled intranasally with lipopolysaccharide (LPS) twice weekly for 12 weeks and were treated, by inhalation, with the long-acting muscarinic receptor antagonist tiotropium. Repeated LPS exposure induced airway and parenchymal neutrophilia, and increased goblet cell numbers, lung hydroxyproline content, airway wall collagen and airspace size. Furthermore, LPS increased the number of muscularised microvessels in the adventitia of cartilaginous airways. Tiotropium abrogated the LPS-induced increase in neutrophils, goblet cells, collagen deposition and muscularised microvessels, but had no effect on emphysema. In conclusion, tiotropium inhibits reModelling of the airways as well as pulmonary inflammation in a Guinea Pig Model of COPD, suggesting that endogenous acetylcholine plays a major role in the pathogenesis of this disease.

  • the integrin blocking peptide rgds inhibits airway smooth muscle reModeling in a Guinea Pig Model of allergic asthma
    American Journal of Respiratory and Critical Care Medicine, 2010
    Co-Authors: Bart G J Dekkers, Johan Zaagsma, Reinoud Gosens, Sophie I T Bos, Andrew J Halayko, Herman Meurs
    Abstract:

    Rationale: Airway reModeling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyperresponsiveness in asthma. The mechanisms driving these changes are, however, incompletely understood. Recently, an important role for extracellular matrix proteins in regulating ASM proliferation and contractility has been found, suggesting that matrix proteins and their integrins actively modulate airway reModeling.Objectives: To investigate the role of RGD (Arg-Gly-Asp)–binding integrins in airway reModeling in an animal Model of allergic asthma.Methods: Using a Guinea Pig Model of allergic asthma, the effects of topical application of the integrin-blocking peptide RGDS (Arg-Gly-Asp-Ser) and its negative control GRADSP (Gly-Arg-Ala-Asp-Ser-Pro) were assessed on markers of ASM reModeling, fibrosis, and inflammation induced by repeated allergen challenge. In addition, effects of these peptides on human ASM proliferation and maturation were investigated in vitro.Measurements and M...

Zhengui Zheng - One of the best experts on this subject based on the ideXlab platform.

  • differential cell proliferation and cell death during the urethral groove formation in Guinea Pig Model
    Pediatric Research, 2019
    Co-Authors: Shanshan Wang, Zhengui Zheng
    Abstract:

    Background Urethral groove (UG) formation is an important step in penile formation. Because commonly used animal Models do not have UG, the mechanisms of UG formation have never been discovered. We aim to discover the cellular mechanism of the UG formation using Guinea Pig Model. Methods Histology was used to study the ontogeny of UG. BrdU immunofluorescence was used to label proliferating cells, cell death was determined using LysoTracker Red and TUNEL staining, and stereology was used for quantification. To reveal Shh mRNA expression patterns, in situ hybridization was performed in Guinea Pig genital tubercles (GTs) and ShhGFPcre-LacZ-reporter mice were used for comparison. Results Cell proliferation in the outer layers and programmed cell death in the inner layers of urethral epithelium played key roles during urethral canal movement from dorsal to ventral aspect and final opening to form UG. Shh mRNA expression domain shifted out to the ventral surface of GT from proximal throughout to distal in Guinea Pigs, but was excluded from the ventral surface epithelium in midshaft and distal of mouse GT. Conclusion Differential cell proliferation and cell death in developing urethral epithelium lead to UG formation and Shh expression in ventral surface epithelium of GT may play an important role.

  • differential cell proliferation and cell death during the urethral groove formation in Guinea Pig Model
    Pediatric Research, 2019
    Co-Authors: Shanshan Wang, Zhengui Zheng
    Abstract:

    Urethral groove (UG) formation is an important step in penile formation. Because commonly used animal Models do not have UG, the mechanisms of UG formation have never been discovered. We aim to discover the cellular mechanism of the UG formation using Guinea Pig Model. Histology was used to study the ontogeny of UG. BrdU immunofluorescence was used to label proliferating cells, cell death was determined using LysoTracker Red and TUNEL staining, and stereology was used for quantification. To reveal Shh mRNA expression patterns, in situ hybridization was performed in Guinea Pig genital tubercles (GTs) and ShhGFPcre-LacZ-reporter mice were used for comparison. Cell proliferation in the outer layers and programmed cell death in the inner layers of urethral epithelium played key roles during urethral canal movement from dorsal to ventral aspect and final opening to form UG. Shh mRNA expression domain shifted out to the ventral surface of GT from proximal throughout to distal in Guinea Pigs, but was excluded from the ventral surface epithelium in midshaft and distal of mouse GT. Differential cell proliferation and cell death in developing urethral epithelium lead to UG formation and Shh expression in ventral surface epithelium of GT may play an important role.

Edward P Garvey - One of the best experts on this subject based on the ideXlab platform.

  • vt 1161 dosed once daily or once weekly exhibits potent efficacy in treatment of dermatophytosis in a Guinea Pig Model
    Antimicrobial Agents and Chemotherapy, 2015
    Co-Authors: Edward P Garvey, W J Hoekstra, William R Moore, R J Schotzinger, Lisa Long, Mahmoud A Ghannoum
    Abstract:

    ABSTRACT Current therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potent in vitro antifungal activity against dermatophytes, with MIC values in the range of ≤0.016 to 0.5 μg/ml. In pharmacokinetic studies supporting testing in a Guinea Pig Model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potential in vivo efficacy with once-daily and possibly once-weekly dosing. Subsequently, in a Guinea Pig dermatophytosis Model utilizing Trichophyton mentagrophytes and at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction ( P P P

  • vt 1161 dosed once daily or once weekly exhibits potent efficacy in treatment of dermatophytosis in a Guinea Pig Model
    Antimicrobial Agents and Chemotherapy, 2015
    Co-Authors: Edward P Garvey, W J Hoekstra, William R Moore, R J Schotzinger, Lisa Long, Mahmoud A Ghannoum
    Abstract:

    Current therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potent in vitro antifungal activity against dermatophytes, with MIC values in the range of ≤0.016 to 0.5 μg/ml. In pharmacokinetic studies supporting testing in a Guinea Pig Model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potential in vivo efficacy with once-daily and possibly once-weekly dosing. Subsequently, in a Guinea Pig dermatophytosis Model utilizing Trichophyton mentagrophytes and at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction (P < 0.001) and improvement in clinical scores (P < 0.001). The efficacy profile of VT-1161 was equivalent to those for doses and regimens of itraconazole and terbinafine except that VT-1161 was superior to itraconazole when each drug was dosed once weekly (P < 0.05). VT-1161 was distributed into skin and hair, with plasma and tissue concentrations in all treatment and regimen groups ranging from 0.8 to 40 μg/ml (or μg/g), at or above the MIC against the isolate used in the Model (0.5 μg/ml). These data strongly support the clinical development of VT-1161 for the oral treatment of onychomycosis using either once-daily or once-weekly dosing regimens.