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The neuroprotective effects of progesterone on experimental diabetic neuropathy in rats
Abstracts / Toxicology Letters 189S (2009) S57–S273
adjust the dosing schedule, according to the needs and responses of patients under treatment. doi:10.1016/j.toxlet.2009.06.395
P27 Development and validation of a nonaqueous capillary electrophoresis method for the quantification of donepezil in human plasma Miriana Gubandru ∗ , Dan Balalau, Mihaela Ilie, Carmen Purdel
S265
in sciatic nerve and the numbers of MFs with infolding into the axoplasm, irregularity of fibers, myelin sheath with unclear boundaries and alteration in myelin compaction were also increased. Long-term treatment with PROG increased MNCV significantly and prevented all these abnormalities in treated diabetic rats. Our findings indicated that PROG as a therapeutic approach can protect neurophysiologic and histomorphologic alterations induced by peripheral diabetic neuropathy. Keywords: Progesterone; Sciatic nerve; Diabetic neuropathy; Nerve conduction velocity; Histomorphometry doi:10.1016/j.toxlet.2009.06.397
UMF Carol Davila, Toxicology, Bucharest, Romania The bioavailability and non-compliance to treatment with donepezil represent major issues, mainly in clinical trials and adjusting dose settings, so frequently drug-level measurement is a desirable tool to improve clinical outcomes with Alzheimer drugs. A simple, rapid and sensitive procedure using nonaqueous capillary electrophoresis (NACE) to measure donepezil levels has been developed and validated. Optimum detection of donepezil was obtained at 315 nm, using a 64.5 cm (56 to the detector) × 50 m i.d. fused-silica capillary. The nonaqueous mobile phase consisted in 15 mM ammonium acetate in methanol–acetonitrile (7:3, v/v), the operating voltage was set at 25 kV. Injection was performed in the hydrodynamic mode (0.5 psi, 10 s). In these conditions, the peak of donepezil was obtained at 14.41 ± 0.15 min. The calibration curve was linear in the range of 0.5–5 g/mL (R2 > 0.992). Intra/interday accuracy and precision were found to be less than 10% and 5%, respectively, at three control concentration levels. The results obtained prove that the NACE method is suitable to monitor plasma levels of donepezil and can properly be used to assess patient’s compliance to medication. doi:10.1016/j.toxlet.2009.06.396
P28 The neuroprotective effects of progesterone on experimental diabetic neuropathy in rats Marzieh Panahi ∗ , Mohammadreza Sameni Jundishapour Ahwaz University, Anatomical Sciences, Ahwaz, Islamic Republic of Iran Diabetic neuropathy is one of the most common complications affecting more than 50–60% of diabetic patients and it is a common cause of non-traumatic amputation and autonomic failure. Neuroactive steroids, such as progesterone (PROG), have been recently identified as promising neuroprotective agents in several models of neurodegeneration. In this study we investigated the potential neuroprotective effect of PROG in experimental model of diabetic neuropathy. Animals were randomly divided into 3 groups (with 10 rats in each), control (nondiabetic), untreated diabetic and diabetic PROG-treated. Diabetes was induced in adult male rats by a single dose injection of streptozotocin (STZ, 55 mg kg−1 , i.p.). In the PROGtreated group, 4 weeks after induce of diabetes; rats were treated with PROG (8 mg kg−1 , i.p., every 2 days) for 6 weeks. Diabetic rats showed a significant reduction in motor nerve conduction velocity (MNCV), mean myelinated fibers (MFs) diameter, axon diameter and myelin sheath thickness in the sciatic nerve after 6 weeks. In the untreated diabetic group endoneurial edema was observed
P29 The innovative medicines initiative IMI—A new collaborative 夽 approach to drug safety testing and beyond Matthias Gottwald Bayer Schering Pharma AG, Global Drug Discovery Operations External R&D Policy, Berlin, Germany Despite huge spendings in pharmaceutical R&D, the attrition rate of drug development projects is still at an unacceptable high level with limited safety and/or efficacy of the tested compounds being major reasons. Validated methods for an early reliable prediction of safety and efficacy of new medicines are urgently needed. In 2004 the idea for a new collaborative approach was born to address these issues via a new public–private-partnership model, equally funded by the European Commission and the European Federation of Pharmaceutical Industries and Associations EFPIA. Together with all stakeholders a research agenda has been developed which sets the frame for annual rounds of big collaborative projects, bringing together experts from many pharmaceutical companies, academia, SMEs, patient organisations and public authorities. In 2008 the first call for proposal within IMI has been published with several topics in the area of safety prediction. The new collaborative approach of IMI and an overview on the first projects and future plans will be presented. 夽 Selected for Oral Presentation. doi:10.1016/j.toxlet.2009.06.398
P30 Hepatoprotective and antioxidant activity of phytic acid and/or catechin against carbon tetrachloride-induced hepatotoxicity in rats Sohair Hassan 1,∗ , Maha Zaki Rizk 1 , Fathia El-Sharkawi 2 , Osama Badary 3 , Mai Osman Kadry 3 1
Advanced Dental and Medical Institute, Biochemistry, Pinang, Egypt, Helwan University, Biochemistry Department, Helwan, Egypt, 3 Ain Shams University, Clinical Pharmacy Department, Ain Shams, Egypt
2
In this study, the rat model of carbon tetrachloride (CCl4 )-induced hepatotoxicity was used to assess the effect of daily intraperitoneal injections of catechin, phytic acid and their combination on the indices of cirrhosis. Liver enzymes profiling, oxidative status and histological examinations revealed that catechin and phytic acid significantly arrested progression of hepatic cirrho-
adjust the dosing schedule, according to the needs and responses of patients under treatment. doi:10.1016/j.toxlet.2009.06.395
P27 Development and validation of a nonaqueous capillary electrophoresis method for the quantification of donepezil in human plasma Miriana Gubandru ∗ , Dan Balalau, Mihaela Ilie, Carmen Purdel
S265
in sciatic nerve and the numbers of MFs with infolding into the axoplasm, irregularity of fibers, myelin sheath with unclear boundaries and alteration in myelin compaction were also increased. Long-term treatment with PROG increased MNCV significantly and prevented all these abnormalities in treated diabetic rats. Our findings indicated that PROG as a therapeutic approach can protect neurophysiologic and histomorphologic alterations induced by peripheral diabetic neuropathy. Keywords: Progesterone; Sciatic nerve; Diabetic neuropathy; Nerve conduction velocity; Histomorphometry doi:10.1016/j.toxlet.2009.06.397
UMF Carol Davila, Toxicology, Bucharest, Romania The bioavailability and non-compliance to treatment with donepezil represent major issues, mainly in clinical trials and adjusting dose settings, so frequently drug-level measurement is a desirable tool to improve clinical outcomes with Alzheimer drugs. A simple, rapid and sensitive procedure using nonaqueous capillary electrophoresis (NACE) to measure donepezil levels has been developed and validated. Optimum detection of donepezil was obtained at 315 nm, using a 64.5 cm (56 to the detector) × 50 m i.d. fused-silica capillary. The nonaqueous mobile phase consisted in 15 mM ammonium acetate in methanol–acetonitrile (7:3, v/v), the operating voltage was set at 25 kV. Injection was performed in the hydrodynamic mode (0.5 psi, 10 s). In these conditions, the peak of donepezil was obtained at 14.41 ± 0.15 min. The calibration curve was linear in the range of 0.5–5 g/mL (R2 > 0.992). Intra/interday accuracy and precision were found to be less than 10% and 5%, respectively, at three control concentration levels. The results obtained prove that the NACE method is suitable to monitor plasma levels of donepezil and can properly be used to assess patient’s compliance to medication. doi:10.1016/j.toxlet.2009.06.396
P28 The neuroprotective effects of progesterone on experimental diabetic neuropathy in rats Marzieh Panahi ∗ , Mohammadreza Sameni Jundishapour Ahwaz University, Anatomical Sciences, Ahwaz, Islamic Republic of Iran Diabetic neuropathy is one of the most common complications affecting more than 50–60% of diabetic patients and it is a common cause of non-traumatic amputation and autonomic failure. Neuroactive steroids, such as progesterone (PROG), have been recently identified as promising neuroprotective agents in several models of neurodegeneration. In this study we investigated the potential neuroprotective effect of PROG in experimental model of diabetic neuropathy. Animals were randomly divided into 3 groups (with 10 rats in each), control (nondiabetic), untreated diabetic and diabetic PROG-treated. Diabetes was induced in adult male rats by a single dose injection of streptozotocin (STZ, 55 mg kg−1 , i.p.). In the PROGtreated group, 4 weeks after induce of diabetes; rats were treated with PROG (8 mg kg−1 , i.p., every 2 days) for 6 weeks. Diabetic rats showed a significant reduction in motor nerve conduction velocity (MNCV), mean myelinated fibers (MFs) diameter, axon diameter and myelin sheath thickness in the sciatic nerve after 6 weeks. In the untreated diabetic group endoneurial edema was observed
P29 The innovative medicines initiative IMI—A new collaborative 夽 approach to drug safety testing and beyond Matthias Gottwald Bayer Schering Pharma AG, Global Drug Discovery Operations External R&D Policy, Berlin, Germany Despite huge spendings in pharmaceutical R&D, the attrition rate of drug development projects is still at an unacceptable high level with limited safety and/or efficacy of the tested compounds being major reasons. Validated methods for an early reliable prediction of safety and efficacy of new medicines are urgently needed. In 2004 the idea for a new collaborative approach was born to address these issues via a new public–private-partnership model, equally funded by the European Commission and the European Federation of Pharmaceutical Industries and Associations EFPIA. Together with all stakeholders a research agenda has been developed which sets the frame for annual rounds of big collaborative projects, bringing together experts from many pharmaceutical companies, academia, SMEs, patient organisations and public authorities. In 2008 the first call for proposal within IMI has been published with several topics in the area of safety prediction. The new collaborative approach of IMI and an overview on the first projects and future plans will be presented. 夽 Selected for Oral Presentation. doi:10.1016/j.toxlet.2009.06.398
P30 Hepatoprotective and antioxidant activity of phytic acid and/or catechin against carbon tetrachloride-induced hepatotoxicity in rats Sohair Hassan 1,∗ , Maha Zaki Rizk 1 , Fathia El-Sharkawi 2 , Osama Badary 3 , Mai Osman Kadry 3 1
Advanced Dental and Medical Institute, Biochemistry, Pinang, Egypt, Helwan University, Biochemistry Department, Helwan, Egypt, 3 Ain Shams University, Clinical Pharmacy Department, Ain Shams, Egypt
2
In this study, the rat model of carbon tetrachloride (CCl4 )-induced hepatotoxicity was used to assess the effect of daily intraperitoneal injections of catechin, phytic acid and their combination on the indices of cirrhosis. Liver enzymes profiling, oxidative status and histological examinations revealed that catechin and phytic acid significantly arrested progression of hepatic cirrho-