EVALUATION OF REPEATED DOSE-90-DAY ORAL TOXICITY STUDY OF L-DOPA AND HYOSCINE HYDRBROMIDE COMBINATION IN RATS
Objective: The present study was done to evaluate repeated-dose 90-day oral toxicity studies of l-dopa and hyoscine hydrbromide combination in rats.
Methods: Repeated-dose 90-day oral toxicity study was performed according to the Organisation for Economic Co-operation and DevelopmentÂ (OECD) guidelines 408. In the present study, combination of L-dopa and hyoscine hydrobromide was administered at 5 times the upper limit of therapeutic dose of each drug which is 1200 mg per day for L-dopa and 0.75 mg per day for hyoscine hydrobromide for adult human being and which was converted to required dose for Wistar rats (5 males and 5 females).
Results: The combination of L-dopa and hyoscine hydrobromide at 5 times the upper therapeutic dose produced no treatment-related signs of toxicity or mortality in any of the animals tested during 90 d of the study. The subchronic administration of the combination of L-dopa and hyoscine hydrobromide did not produce any significant difference in any of the assigned parameters between the control and all treatment groups.
Conclusion: It is established that the combination of L-dopa and hyoscine hydrobromide therapy is safe on repeated dose 90-day oral toxicity at 5 times the upper limit of therapeutics dose of each drug.
2. Serra PA, Esposito G, Enrico P, Mura MA, Migheli R, Delogu MR, et al. Manganese increases l-DOPA auto-oxidation in the striatum of the freely moving rat: potential implications to l-DOPA long-term therapy of Parkinsonâ€™s disease. Br J Pharmacol 2000;130:937-45.
3. Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM, et al. Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria. Lancet Neurol 2009;8:1150-7.
4. Tolosa E, Marti MJ, Valldeoriola F, Molinuevo JL. History of levodopa and dopamine agonists in Parkinsonâ€™s disease treatment. Neurology 1998;50:S2-S10.
5. Lee PH, Park HJ. Bone marrow-derived mesenchymal stem cell therapy as a candidate disease-modifying strategy in Parkinsonâ€™s disease and multiple system atrophy. J Clin Neurol 2009;5:1-10.
6. Hauser RA. Levodopa: past, present, and future. Eur Neurol 2009;61:1-8.
7. Maharaj H, Maharaj DS, Scheepers M, Mokokong R, Daya S. l-DOPA administration enhances 6-hydroxydopamine generation. Brain Res 2005;1063:180-6.
8. Ostock CY, Dupre KB, Jaunarajs KL, Walters H, George J, Krolewski D, et al. Role of the primary motor cortex in L-DOPA-induced dyskinesia and its modulation by 5-HT1A receptor stimulation. Neuropharmacol 2011;61:753-6.
9. Buck K, Ferger B. Intrastriatal inhibition of aromatic amino acid decarboxylase prevents L-DOPA-induced dyskinesia: A bilateral reverse in vivo microdialysis study in 6-hydroxydopamine lesioned rats. Neurobiol Dis 2008;29:210-20.
10. Katzung BG. Pharmacological management of parkinsonism and other movement disorders. In: Basic and Clinical Pharmacology. 12th ed. Lange Medical Books/McGraw Hill Companies, Inc; 2001.
11. AHFS drug information 2005. McEvoy GK, ed. Antimuscarinics/ Antispasmodics General Statement. Bethesda, MD: American Society of Health-System Pharmacists; 2005. p. 1229-36.
12. OECD Guideline for the testing of Chemicals: Repeated Dose 90 d oral toxicity study in rodents; 1998.
13. Hor SY, Ahmad M, Farsi E, Yam MF, Hashim MA, Lim CP, et al. Safety assessment of methanol extract of red dragon fruit (Hylocereus polyrhizus): Acute and subchronic toxicity studies. Regul Toxicol Pharmacol 2012;63:106-14.
14. Singh G, Kumar V. Acute and sub-chronic toxicity study of standardized extract of Fumaria indica in rodents. J Ethnopharmacol 2011;134:992-5.
15. Firenzuoli F, Gori L. â€œHerbal medicine today: clinical and research issueâ€. J Evidence-Based Complementary Altern Med 2007;4:37-40.
16. Veerappan A, Miyazaki S, Kadarkaraisamy M, Ranganathan D. Acute and subacute toxicity studies of agele Marmelos Corr., an Indian Medicinal plant. Phytomedicine 2004;14:209-15.
17. Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, et al. Concordance of toxicity of pharmaceuticals in humans and animals. Regul Toxicol Pharmacol 2000;32:56-67.
18. Fernanda de A, Claudia A C de A, Marcelo M, Edson L da S. Safety assessment of yerba mate (IIes paraguariensis) dried extract; results of acute and 90 d subchrnoic toxicity studies in rats and rabbits. Food Chem Toxicol 2012;50:328-34.
19. Lillie L, Temple N, Florence L. Reference values for your normal Sprague-Dawley rats: weight gain, hematology and clinical chemistry. Hum Exp Toxicol 1996;15;612-6.
20. Weiss D, Wardrop K. Schlamâ€™s Veternary Haematology. 6th edition Wiley-Blackwell, Hoboken, NJ, USA; 2010.
21. Siva MG, Aragao TP, Vasconcelos CF, Ferreira PA, Andrade BA, Costa IM, et al. Acute and subacute toxicity of cassia occidentalis L. stem and leaf in Wistar rats. J Ethnopharmacol 2011;36:341-6.
22. Moss DW, Handerson AR, Kachmar JF. In: Fundamentals of Clinical Chemistry. 3rd Eds. (Ed. NW Tietz). Philadelphia: W. B. Saunders Company; 1987. p. 346-421.
23. Navarro CM, Montilla PM, Martin A, Jimenez J, Utrilla PM. Free radicals scavenger and antihepatotoxic activity of rosmarinus tomentosus. Plant Med 1993;59:312-4.
24. Fowler BA, Woods JS, Schiller CM. Ultrastructural and biochemical effects of prolonged oral arsenic exposure on liver mitochondria of rats. Environ Health Perspect 1997;19:197-204.
25. Ojo OA, Oloyede OI, Olarewaju OI, Ojo AB, Ajiboye BO, Onikanni SA. Toxicity studies of the crude Aqueous Leaves extract of Ociumum gratissiumum in Albino Rats. J Enviorn Sci Toxicol Food Technol 2013;6:34-9.