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71.
Pharmacokinetics, in-situ absorption and protein binding studies of a new neuroleptic agent centbutindole in rats. 总被引:1,自引:0,他引:1
Manish Issar Shio K Singh Bhrameshwar Mishra Ram C Gupta 《European journal of pharmaceutical sciences》2003,19(2-3):105-113
The present study reports the absorption kinetics, plasma protein binding and pharmacokinetic profile of the centbutindole (I) after i.v. and oral dosing in rats. In addition, an in-situ absorption study was carried out using a closed-loop technique at pH 2.6 and 7.4. The rate of absorption at pH 2.6 was 5-fold less compared to that observed at pH 7.4. In-vitro and in-vivo protein binding (ultra filtration technique) was independent of substrate concentration over a range of 1.25-10.0 microg/ml. Pharmacokinetic parameters of I were determined in male rats after administering a single 4 mg/kg oral dose and 2 mg/kg intravenous dose. The peak serum concentration of I was found to be 50.1 ng/ml at 30 min after oral administration followed by a secondary Cmax of 43.2 ng/ml at 180 min. For the hydroxy metabolite (II), a Cmax of 6.4 ng/ml was measured at 360 min after oral administration of I. After oral dosing an irregular concentration-time profile with secondary peaks was observed for both I and II. The terminal half-lives for I and II after oral dosing were 163 and 263 min, respectively. After intravenous dosing, the levels of I decreased biexponentially with a distribution (t(1/2) alpha) and elimination (t(1/2) beta) half-lives of 5.7 and 128 min, respectively. Comparison of the AUC after oral and intravenous dosing of I indicates that only about 24% of the oral dose reaches the systemic circulation. The limited bioavailability can either be due to the poor solubility of the compound and/or extensive first pass metabolism in the gastrointestinal (GI) tract. Co-administration of polyethylene glycol (PEG) at oral dosing improves solubilization and increases bioavailability. 相似文献
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Treatment of chronic myelogenous leukemia with a specific inhibitor of the Bcr/Abl tyrosine kinase, imatinib, has shown great promise. However, acute lymphoblastic leukemias that express Bcr/Abl only transiently respond to imatinib. Therefore, alternative treatments for this type of leukemia are urgently needed. Here, we examined the activity of the farnesyltransferase inhibitor SCH66336 as a single chemotherapeutic agent in a nude mouse model representative of very advanced stage Bcr/Abl P190-positive lymphoblastic leukemia/lymphoma. Our results show that oral administration of the inhibitor was able to significantly increase the survival of these mice compared to controls treated with vehicle (P<0.005), and caused marked regression of the tumor burden in the treated mice. Upon prolonged treatment, lymphomas re-emerged and a subset of cells from two of such lymphomas tested was able to survive in the presence of increased concentrations of SCH66336. The same cells, however, remained sensitive towards imatinib. A combination of the two drugs, preceded by a therapy to reduce the initial tumor burden, could be very effective in the treatment of Ph-positive ALL. We conclude that SCH66336, on its own, is remarkably effective in eradicating large numbers of lymphoblastic lymphoma cells and causing visible reduction in tumor size, with minimal toxicity. 相似文献
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S. K. Mishra P. K. Dash P. Keshri S. Jena S. Sur 《Indian journal of otolaryngology and head and neck surgery》2003,55(1):28-29
A case of Myxoma involving left Maxilla, presenting as swelling of left side of face and Oral cavity with bilateral nasal obstruction is reported. 相似文献
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BACKGROUND: Older women are at increasing risk of various forms of familial violence, yet detection is poor and very little is known of the long-term health effects of this psychosocial problem. The effectiveness of the 'Vulnerability to Abuse' Screening Scale (VASS) in predicting three year health outcomes was investigated among women enrolled in the Australian Longitudinal Study on Women's Health, now known as Women's Health Australia. METHODS: The sample comprised a cohort of 10,421 women aged 73-78 who completed the 1996 and 1999 postal surveys (attrition rate 19.5%). The Time 2 sample had a small bias towards lower risk for elder abuse at Time 1 and better health on SF-36 and self-rated health. The VASS is a 12-item self-report measure with 4 factors: vulnerability, coercion, dependence and dejection. RESULTS: Overall, physical health (PCS) declined while mental health (MCS) increased over the three year period. Decline in physical health was predicted by only the dejection factor, but not by factors which seem to more directly measure abuse. The predictive validity of the VASS for three year mental health outcomes was given partial support. Three of the four VASS factors (dejection, vulnerability, and coercion) predicted decline in mental health at the univariate level, however, after adjusting for confounders, only one VASS factor (dejection) independently predicted decline in mental health. CONCLUSIONS: While the VASS shows some promise as a marker of health risk in older women, only the dejection factor proved consistently predictive of declining health status. Further research is needed to determine longer term predictive validity of the scale and to gain a clearer picture of how abusive experiences impact on older women's health. 相似文献
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