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The influence of chronic met-enkephaline and alpha-melanostimulatin hormone use on biochemical parameters of rat
Abstracts / Toxicology Letters 180S (2008) S32–S246
Z06 Safety evaluation of CIGB-500, therapeutic option in the treatment of Acute Myocardium Infarct Dania Bacardi Fernández ∗ , Karelia Cosme Díaz, José Suárez Alba, Ariel Vázquez Bonachea, Lizet Aldana Velazco, Jorge Berlanga Acosta, Dioslaida Urquiza Noa, Lourdes Hernández Pérez Center for Genetic Engineering and Biotechnology, Havana City, Cuba The GHRP-6 is hexapéptido that works like artificial secretagogo of the growth hormone (GH). It acts activating specific receptors causes the secretion of GH, through a different route of employee intracellular signaling by this hormone. At the Center for Genetic Engineering and Biotechnology were made toxicology studies in order to evaluate the safety of this peptide in a formulation denominated CIGB-500, target to clinical treatment of the Acute Myocardium Infarct (AMI). A set of designed studies included: Acute toxicity, Local tolerance and Repeated Dose Toxicity. In the scheme with unique administration were explored three levels of dose, 50 times above to therapeutic dose (TD), by intraperitoneal route, in Sprague-Dawley rats. At the local tolerance was evaluated DT and above to 10 times the same one, inoculated repeatedly until completed 5 administrations, every 72 h, to F1 rabbits, by endovenous route. In the repeated dose study were evaluated 3, 6 and 9 times up DT and was included a satellite group, inoculated daily by intraperitoneal route, to Sprague-Dawley rats, during 15 days. Complementary determinations and the histologic evaluation of the key organs were made. The results showed that the animals did not present toxic signs neither deaths were registered during these studies. The found pattern of local answer was normal and the reiterated administration of the product did not cause metabolic or behavior alterations. We can conclude that in the explored levels of CIGB-500 doses is not toxic at well tolerated at systemic level and after repeated administrations by endovenous route. doi:10.1016/j.toxlet.2008.06.029 Z07 Aconitine-intoxication from the perspective of the occurrence of heart rhythm disorders and possibility of therapeutic intervention of a newly synthesized compound 44Bu Ladislava Bartosova ∗ , Klara Berankova, Irena Souckova, Tomas Parak, Marketa Bebarova, Marek Frydrych, Pavel Suchy University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic Aconitine, one of the most violent toxins, inhibits inactivation of the sodium channels, which causes their persistent activation resulting in heart rhythm disorders. At present, no specific antidote is known; the treatment of aconitine intoxication is just supportive. In previous experiments we concluded that the new synthesized compound 44Bu is more efficient in suppressing aconitine-induced arrhythmias than lidocaine (Bartosova et al., 2007a) and propaphenone (Bartosova et al., 2007b). The antiarrhythmic efficiency of the 44Bu compound is incurred by its effect on ionic currents (INa , Ito , IK , IK1 ). This effect on ionic currents is not the same in stereoisomers of 44Bu, therefore we suppose a different antiarrhythmic effect of these substances. The aim of this work was to monitor the occurrence of the given types of atrial and ventricular arrhythmias and changes of the conduction of excitement in intoxicated rats during a given time interval, and to evaluate these arrhythmias disorders after administering the racemate, R-isomer and S-isomer of the 44Bu compound.
S229
According to our result it seems that the antiarrhythmic impact of S-isomer is better than the impact of R-isomer. Racemate has the best effect regarding the suppression of ventricular fibrillation, but at the same time it initiates excitement conduction blockades. Acknowledgement: This study was supported by grants GA CR No. 305/06/0863 and IGA MZ CR No. NR9126-3/2006. References Bartosova, L., et al., 2007a. European Journal of Pharmacology 575, 127–133. Bartosova, L., et al., 2007b. ChemListy 101, 164.
doi:10.1016/j.toxlet.2008.06.030 Z08 The influence of chronic met-enkephaline and alphamelanostimulatin hormone use on biochemical parameters of rat Fahir Becic ∗ , Nedˇzad Mulabegovic, Maida Rakanovic-Todic, Jasna Kusturica, Svjetlana Loga-Zec Medical Faculty, Sarajevo, Bosnia and Herzegovina The aim of the study was to determine the influence of chronic use of combination of two peptide components: met-enkephaline and alpha-melanostimulating hormone after repeated application in heightened doses on biochemical parameters in rat. The study was carried out on three experimental groups, which were treated with the combination of test substances and on one control group, which was treated with saline solution. Each group consisted of 40 rats (20M + 20F). The investigation period was six months. Biochemical analyses were carried out on fasting animals, as well as on blood samples taken from 12 animals in each experimental group and 24 animals from the control group, before sacrificing. The following biochemical analyses were carried out: calcium, potassium, sodium, chloride, phosphorus, glucose, AST, ALT, alkaline phosphatase, GGT, total proteins, urea, cholesterol, albumins, globulins, total bilirubin, creatinine, lipids, cholinesterase. In certain groups of treated males biochemical findings showed significant change of values of phosphorus, alkaline phosphatase, urea, triglycerides and ALT in comparison with the control group. Biochemical parameters in females indicated the presence of statistically significant difference in values of phosphorus, alkaline phosphatase, urea, triglycerides and ALT in comparison to the control group. The statistical analyses of the results obtained after biochemical analyses have shown that the differences were not statistically significant (including both the female and male groups) for the following parameters: calcium, potassium, sodium, chlorides, glucose, total proteins, albumins, globulins, total bilirubin, creatinine, cholesterol, cholinesterase, AST, GGT. doi:10.1016/j.toxlet.2008.06.031
Z06 Safety evaluation of CIGB-500, therapeutic option in the treatment of Acute Myocardium Infarct Dania Bacardi Fernández ∗ , Karelia Cosme Díaz, José Suárez Alba, Ariel Vázquez Bonachea, Lizet Aldana Velazco, Jorge Berlanga Acosta, Dioslaida Urquiza Noa, Lourdes Hernández Pérez Center for Genetic Engineering and Biotechnology, Havana City, Cuba The GHRP-6 is hexapéptido that works like artificial secretagogo of the growth hormone (GH). It acts activating specific receptors causes the secretion of GH, through a different route of employee intracellular signaling by this hormone. At the Center for Genetic Engineering and Biotechnology were made toxicology studies in order to evaluate the safety of this peptide in a formulation denominated CIGB-500, target to clinical treatment of the Acute Myocardium Infarct (AMI). A set of designed studies included: Acute toxicity, Local tolerance and Repeated Dose Toxicity. In the scheme with unique administration were explored three levels of dose, 50 times above to therapeutic dose (TD), by intraperitoneal route, in Sprague-Dawley rats. At the local tolerance was evaluated DT and above to 10 times the same one, inoculated repeatedly until completed 5 administrations, every 72 h, to F1 rabbits, by endovenous route. In the repeated dose study were evaluated 3, 6 and 9 times up DT and was included a satellite group, inoculated daily by intraperitoneal route, to Sprague-Dawley rats, during 15 days. Complementary determinations and the histologic evaluation of the key organs were made. The results showed that the animals did not present toxic signs neither deaths were registered during these studies. The found pattern of local answer was normal and the reiterated administration of the product did not cause metabolic or behavior alterations. We can conclude that in the explored levels of CIGB-500 doses is not toxic at well tolerated at systemic level and after repeated administrations by endovenous route. doi:10.1016/j.toxlet.2008.06.029 Z07 Aconitine-intoxication from the perspective of the occurrence of heart rhythm disorders and possibility of therapeutic intervention of a newly synthesized compound 44Bu Ladislava Bartosova ∗ , Klara Berankova, Irena Souckova, Tomas Parak, Marketa Bebarova, Marek Frydrych, Pavel Suchy University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic Aconitine, one of the most violent toxins, inhibits inactivation of the sodium channels, which causes their persistent activation resulting in heart rhythm disorders. At present, no specific antidote is known; the treatment of aconitine intoxication is just supportive. In previous experiments we concluded that the new synthesized compound 44Bu is more efficient in suppressing aconitine-induced arrhythmias than lidocaine (Bartosova et al., 2007a) and propaphenone (Bartosova et al., 2007b). The antiarrhythmic efficiency of the 44Bu compound is incurred by its effect on ionic currents (INa , Ito , IK , IK1 ). This effect on ionic currents is not the same in stereoisomers of 44Bu, therefore we suppose a different antiarrhythmic effect of these substances. The aim of this work was to monitor the occurrence of the given types of atrial and ventricular arrhythmias and changes of the conduction of excitement in intoxicated rats during a given time interval, and to evaluate these arrhythmias disorders after administering the racemate, R-isomer and S-isomer of the 44Bu compound.
S229
According to our result it seems that the antiarrhythmic impact of S-isomer is better than the impact of R-isomer. Racemate has the best effect regarding the suppression of ventricular fibrillation, but at the same time it initiates excitement conduction blockades. Acknowledgement: This study was supported by grants GA CR No. 305/06/0863 and IGA MZ CR No. NR9126-3/2006. References Bartosova, L., et al., 2007a. European Journal of Pharmacology 575, 127–133. Bartosova, L., et al., 2007b. ChemListy 101, 164.
doi:10.1016/j.toxlet.2008.06.030 Z08 The influence of chronic met-enkephaline and alphamelanostimulatin hormone use on biochemical parameters of rat Fahir Becic ∗ , Nedˇzad Mulabegovic, Maida Rakanovic-Todic, Jasna Kusturica, Svjetlana Loga-Zec Medical Faculty, Sarajevo, Bosnia and Herzegovina The aim of the study was to determine the influence of chronic use of combination of two peptide components: met-enkephaline and alpha-melanostimulating hormone after repeated application in heightened doses on biochemical parameters in rat. The study was carried out on three experimental groups, which were treated with the combination of test substances and on one control group, which was treated with saline solution. Each group consisted of 40 rats (20M + 20F). The investigation period was six months. Biochemical analyses were carried out on fasting animals, as well as on blood samples taken from 12 animals in each experimental group and 24 animals from the control group, before sacrificing. The following biochemical analyses were carried out: calcium, potassium, sodium, chloride, phosphorus, glucose, AST, ALT, alkaline phosphatase, GGT, total proteins, urea, cholesterol, albumins, globulins, total bilirubin, creatinine, lipids, cholinesterase. In certain groups of treated males biochemical findings showed significant change of values of phosphorus, alkaline phosphatase, urea, triglycerides and ALT in comparison with the control group. Biochemical parameters in females indicated the presence of statistically significant difference in values of phosphorus, alkaline phosphatase, urea, triglycerides and ALT in comparison to the control group. The statistical analyses of the results obtained after biochemical analyses have shown that the differences were not statistically significant (including both the female and male groups) for the following parameters: calcium, potassium, sodium, chlorides, glucose, total proteins, albumins, globulins, total bilirubin, creatinine, cholesterol, cholinesterase, AST, GGT. doi:10.1016/j.toxlet.2008.06.031