Background: Increased brain P-glycoprotein (P-gp) expression may play important role in resistance to antiseizure drugs. The present work aimed to overcome the drug resistance that develop due to overexpression of P-g...Background: Increased brain P-glycoprotein (P-gp) expression may play important role in resistance to antiseizure drugs. The present work aimed to overcome the drug resistance that develop due to overexpression of P-gp with subsequent increase in brain phenytoin level in epileptic rats, using either non-selective (indomethacin) or selective (celecoxib) cyclooxygenase inhibitors. Methods: Fifty-six adult male albino rats were randomly divided into seven groups. Epilepsy was induced using the lithium pilocarpine model. Rats received indomethacin (2.5 mg/kg) or celecoxib (20 mg/kg), either alone or combined with phenytoin (50 mg/kg). Seizures were evaluated using Racine score. Motor coordination was assessed using open field and rotarod tests. Phenytoin brain level was measured using High Performance Liquid Chromatography (HPLC), glutamate expression was measured using Enzyme Linked Immunosorbent Assay (ELISA), ATP Binding Cassette Subfamily B Member 1 (ABCB1) gene expression was assessed using Real Time-Polymerase Chain Reaction (RT-PCR), and immunohistochemical analysis was done for P-gp expression. Results: Phenytoin combination with either indomethacin or celecoxib had improved the Racine score, motor coordination on rotarod apparatus, and open field test results. Also, phenytoin combination with either indomethacin or celecoxib decreased brain glutamate level, ABCB1 gene and P-gp expression, and increased brain phenytoin level compared to treatment with phenytoin alone. This indicated that both P-gp inhibitors indomethacin and celecoxib, increased the level of phenytoin that reached the brain of rats. However, brain uptake of phenytoin was significantly enhanced using celecoxib rather than indomethacin (CI 95%, 17.092: 32.808, P-value Conclusion: Cyclooxygenase inhibition using either celecoxib or indomethacin resulted in downregulation of P-gp expression, with subsequent increase in brain phenytoin level in epileptic rats.展开更多
Objective: To understand the relationship between C-erbB-2 and multidrug resistance (MDR) as well as its clini- cal significance. Methods: P-gp level was detected by flow cytometry and simultaneously to examine the C-...Objective: To understand the relationship between C-erbB-2 and multidrug resistance (MDR) as well as its clini- cal significance. Methods: P-gp level was detected by flow cytometry and simultaneously to examine the C-erbB-2 expression level by immunohistochemistry assay in the operating samples. Their relationship was analyzed from 59 cases with gastric carcinoma. Results: The P-gp positive expression was 38/59 (64.4%) cases with gastric carcinoma. The C-erbB-2 positive expression was 21/59 (35.6%) cases with gastric carcinoma. From the analysis of the P-gp and C-erbB-2 relationship, which was involving, range in the gastric carcinoma, that involving two or three sites were more than the site one, in the cases with C-erbB-2 negative. Compared this two groups, there was a significant difference (P = 0.026). When the C-erbB-2 was positive, the P-gp expression had a significant difference (P = 0.04) in comparing the III–IV stage (lymph node metastasis) with I–II stage (without lymph node metastasis). The tumor’s size, differentiation degree, ages and sex were not related to the C-erbB- 2 and P-gp expression. Conclusion: High level of P-gp expression was related to the C-erbB-2 positive expression in clinical III–IV stage patient with gastric carcinoma (lymph node metastasis). It suggested that the double positive patient might be a poor prognosis. However, when the C-erbB-2 was negative expression, the clinical staging (with lymph node metastasis) was not related to the P-gp expression in gastric carcinoma patients.展开更多
文摘Background: Increased brain P-glycoprotein (P-gp) expression may play important role in resistance to antiseizure drugs. The present work aimed to overcome the drug resistance that develop due to overexpression of P-gp with subsequent increase in brain phenytoin level in epileptic rats, using either non-selective (indomethacin) or selective (celecoxib) cyclooxygenase inhibitors. Methods: Fifty-six adult male albino rats were randomly divided into seven groups. Epilepsy was induced using the lithium pilocarpine model. Rats received indomethacin (2.5 mg/kg) or celecoxib (20 mg/kg), either alone or combined with phenytoin (50 mg/kg). Seizures were evaluated using Racine score. Motor coordination was assessed using open field and rotarod tests. Phenytoin brain level was measured using High Performance Liquid Chromatography (HPLC), glutamate expression was measured using Enzyme Linked Immunosorbent Assay (ELISA), ATP Binding Cassette Subfamily B Member 1 (ABCB1) gene expression was assessed using Real Time-Polymerase Chain Reaction (RT-PCR), and immunohistochemical analysis was done for P-gp expression. Results: Phenytoin combination with either indomethacin or celecoxib had improved the Racine score, motor coordination on rotarod apparatus, and open field test results. Also, phenytoin combination with either indomethacin or celecoxib decreased brain glutamate level, ABCB1 gene and P-gp expression, and increased brain phenytoin level compared to treatment with phenytoin alone. This indicated that both P-gp inhibitors indomethacin and celecoxib, increased the level of phenytoin that reached the brain of rats. However, brain uptake of phenytoin was significantly enhanced using celecoxib rather than indomethacin (CI 95%, 17.092: 32.808, P-value Conclusion: Cyclooxygenase inhibition using either celecoxib or indomethacin resulted in downregulation of P-gp expression, with subsequent increase in brain phenytoin level in epileptic rats.
基金the Zhejiang Medical and Health Science Foundation (No. 2005A09)
文摘Objective: To understand the relationship between C-erbB-2 and multidrug resistance (MDR) as well as its clini- cal significance. Methods: P-gp level was detected by flow cytometry and simultaneously to examine the C-erbB-2 expression level by immunohistochemistry assay in the operating samples. Their relationship was analyzed from 59 cases with gastric carcinoma. Results: The P-gp positive expression was 38/59 (64.4%) cases with gastric carcinoma. The C-erbB-2 positive expression was 21/59 (35.6%) cases with gastric carcinoma. From the analysis of the P-gp and C-erbB-2 relationship, which was involving, range in the gastric carcinoma, that involving two or three sites were more than the site one, in the cases with C-erbB-2 negative. Compared this two groups, there was a significant difference (P = 0.026). When the C-erbB-2 was positive, the P-gp expression had a significant difference (P = 0.04) in comparing the III–IV stage (lymph node metastasis) with I–II stage (without lymph node metastasis). The tumor’s size, differentiation degree, ages and sex were not related to the C-erbB- 2 and P-gp expression. Conclusion: High level of P-gp expression was related to the C-erbB-2 positive expression in clinical III–IV stage patient with gastric carcinoma (lymph node metastasis). It suggested that the double positive patient might be a poor prognosis. However, when the C-erbB-2 was negative expression, the clinical staging (with lymph node metastasis) was not related to the P-gp expression in gastric carcinoma patients.
