Acute and Chronic Toxicity Studies of Antiretroviral Regimens in Albino Rats

Uade Richard OVIOSUN, M. G. Abubakar, S. W. Hassan, B. M. Agaie, S. M. Sahabi


The acute and chronic oral toxicity studies of antiretroviral regimens were evaluated in albino rats. For chronic toxicity study, the antiretroviral drugs were administered singly and in combination (CMB). Lamivudine (3TC), Zidovudine (AZT) and Nevirapine (NVP) at single doses of 5000 mg/kg each produced treatment related signs of toxicity in tested animals during the first few hours but returned to normal after 48 hours therefore the 48 hours LD50 of each drug was estimated to be more than 5000 mg/kg. Chronic toxicity showed an initial percentage increase in weight between 0-6 weeks and a corresponding decrease in weight from 6-13 weeks was observed. There was no significant (P>0.05) change in serum electrolyte levels in the treated groups when compared to the control group. Aspartate transaminase (AST) was significantly (P<0.05) increased in groups administered with 3000 mg/kg of CMB, 4000 mg/kg of CMB and at all administered doses of NVP.

Similarly all administered doses of NVP caused a significant (P<0.05) increase in the level of 5 nucleotidase (5NT). At administered doses of 2000 mg/kg and 4000 mg/kg body weight, NVP caused a significant (p<0.05) increase in total cholesterol (TC) upon comparison with the control. Administered doses of CMB and NVP, except at 1000 mg/kg body weight respectively, showed a significant (p<0.05) increase in the level of malondialdehyde (MDA) when compared with the control group. Catalase activity recorded a significant (P<0.05) decrease at doses of 3000 mg/kg and 4000 mg/kg body weight of CMB and NVP. Histopathological examination of the liver showed changes in the treated group when compared with the control group. These changes were corroborated by the non-invasive results. The above results indicate that NVP was the potent hepatotoxic agent, followed by CMB, AZT and 3TC. The hepatotoxicity was also dose dependent.


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R. A. Weiss. How does HIV cause AIDS? Science journal, vol. 260(5112), pp. 12739, 1993.

United States Center for Disease Control and Prevention (US CDC). Kaposis sarcoma and pneumocystis pneumonia among homosexual men- New York City and California. Morbility Mortality Weekly Report, vol. 30, pp. 305-308, 1981.

S. G. Deeks and D. B. Walker. The immune response to AIDS virus infection: good, bad, or both? J.Clin Invest, vol. 113(6), pp. 808-810, 2004.

V. Nissapatorn and N. Sawangjaroen. Parasitic infections in HIV infected individuals: diagnostic and therapeutic challenges. Indian J Med Res, vol. 134(6), pp. 878-897, 2011.

H. C. Stetler, T. C. Granade, C. A. Nunez, R. Meza, S. Terrell, L. Amador and J. R. George. Serologic tests for screening and confirming HIV-1 infection in Honduras. AIDS, vol. 11(3), pp. 369-75, 1997.

J. Cervia, B. Kaplan, S. Schuval and S. Weiss. Virological testing in the management of perinatal HIV exposure. AIDS Read, vol. 13(1), pp. 39-47, 2003.

P. Lemey, O. G. Pybus, B. Wang B, N. K.Saksena, M. Salemi and A. M. Vandamme A. M. (2003): Tracing the Origin and History of the HIV-2 Epidemic. Proceeding National Academy Science U.S.A.,100(11): 6588-92.

B. F. Keele, F. Van Heuverswyn, Y. Li Y, E. Bailes , J. Takehisa, M. L. Santiago et al. Chimpanzee reservoirs of pandemic and non-pandemic HIV-1. Science ,vol. 313(3786), pp. 523-6, 2006.

M. A. Shampo and R. A. Kyle. Luc Montagnier-discoverer of the AIDS virus. Mayo. Clinical. Proc, vol. 77(6), pp. 506, 2002.

L. O. Kallings. The first postmodern pandemic: 25 years of HIV/AIDS. J Intern Med, vol. 263 (3), pp. 21843, 2008.

Federal Ministry of Health (FMOH). National HIV seroprevalence sentinel survey, 2010; Technical Report. Office of the National Coordinator/National AIDS/STI Control Programme/ Department of Public Health/Federal Ministry of Health, Abuja, Nigeria, 2010 pp 1-110.

C. L Da Fonseca, F. J. Martins, R. C. Vieira, R. M. Pereira, S. A. Ferreira and N. R. Raposo. Evaluation of inadequate anti-retroviral treatment in patients with HIV/AIDS. Rev Soc Bras Med Trop, vol. 45(2), pp. 151-5, 2012.

Joint United Nations Programme on HIV/AIDS (UNAIDS). UNAIDS World AIDS Day report 2011. ISBN:978-92-9173-904-2/UNAIDS/JC2216E, pp 1-52, 2011.

R. A. Umar, S. W. Hassan, M. J. Ladan, I. K. Matazu and B. Shehu. Adverse hepatic effects associated with administration of antiretroviral drugs (nevirapine, lamivudine and stavudine) to albino rats: Implication for managing patients with HIV/AIDS. Asian Journal Biochemistry, vol. 3, pp. 19-25, 2008.

H. Samji, A. Crescon, R. S. Hogg, S. P. Modur and K. N Altholl. North American AIDS Cohort Collaboration on Research and Design (NA-Accord) of leDEA.; Closing the Gap: Increases in Life Expectancy among Treated HIV-Positive Individuals in the United States and Canada. PLoS One. 2013.

C. Smit, R. Geskus, S. Walker, C. Sabin, R. Coutinho, K. Porter and M. Prins. Effective therapy has altered the spectrum of cause-specific mortality following HIV seroconversion. AIDS. vol. 20(5), pp. 741-9, 2006.

G. Panos, G. Samonis, V. G. Alexiou, G. A. Kavarnou, G. Charatsis and M. E. Falagas. Mortality and morbidity of HIV-infected patients receiving HAART: A cohort study. Current HIV Research, vol. 6(3), pp. 257-60, 2008.

S. Darak, T. Darak, S. Kulkarni, V. Kulkarni, R. Parchure, I. Hutter and F. Janssen. Effect of highly active antiretroviral treatment (HAART) during pregnancy outcomes: Experiences from a PMTCT program in Western India. AIDS Patient Care STDs, vol. 27(3), pp. 163-70, 2013.

S. Pan, S. Hsleh, C. Hung, P. Huang, M. Chen and S. Chang. Dose reduction for the management of indinavir-related toxicity in human immune virus type 1 infected patients in Taiwan: Clinical and pharmaco kinetic assessment. J Microbiol Immunol Infect, vol. 38, pp. 31-34, 2004.

K. Reisler. High hepatotoxicity rate seen among HAART patients. AIDS Alert, vol. 16(9), pp. 118-9, 2001.

N. Apostolova, A. Blas-Garcia and J. V. Esplugues. Mitochondrial toxicity in HAART: an overview of in vitro evidence. Curr Pharm Des, vol. 17(20), pp. 2130-44, 2011.

G. Ellis, D. M. Goldberg, R. J. Spooner and A. M. Ward. Serum enzyme tests in diseases of the liver and biliary tree. Am J Clin. Pathol, vol. 70(2), pp. 248-258, 1978.

P. Clerc-Renaud, G. Souillet, C. Lahet, C. Sotta, M. Mathieu and B. Mousson. Serum 5- nucleotidase and alkaline phosphatase activities after high dose chemotherapy and bone marrow transplantation in cases of malignancy in children. Ann. Biol.Clin, vol. 53(3), pp. 125-30, 1995.

Organisation for Economic and Cultural Development (OECD). Acute Oral Toxicity - Up - and - Down Procedure (UDP). OECD guidelines for the testing of chemicals, 2001.

A. Bertrand and J. Buret. A one-step determination of serum 5- nucleotidase using a centrifugal analyzer. Clin Chim Acta, vol. 119, pp. 275 284, 1982.

R. Sood. Medical laboratory technology, Methods and Interpretation. 5th ed, Jaypee Brothers medical Publishers Ltd, 1999, pp. 488-490.

S. Reitman and A. S. Frankel. A colorimetric method for determination of serum glutamic oxaloacetic and glutamic pyruvic transaminase. Amer J Clin Path, vol. 28, pp. 56, 1957.

A. G Gomall, C. S. Bardawill and M. M. David. Determination of serum proteins by means of biuret reaction. J Biol Chem, vol.177, pp. 751, 1949.

B. T. Doumas, W. Watson and H.G. Briggs. Albumin standards and the measurement of serum albumin with bromocresol green. Clin Chem Aca, vol. 31, pp. 87-96, 1971.

L. Jendrassik and P. Grof. Simplified photometric methods for the determination of bilirubin. Biochem Zschr, vol. 297, pp. 81-89, 1938.

S. Natelson, M. L. Scott and C. A. Beffa. A rapid method for the estimation of urea in biologic fluids. Am J Clin Pathol, vol. 21(3), pp. 275-281, 1951.

R. J. Henry. Determination of serum creatinine, in Clinical Chemistry Principles and Techniques, 2nd ed., Harper and Row, USA, 1974, pp. 525.

H. Varley. Practical Clinical Biochemistry, 4th ed, Willliam Heineman Medical book limited and Inter Science book inc. New York, 1967, pp. 491-493.

N. W. Tietz. Clinical guide to laboratory tests, 2nd ed, W.B. Saunders Company, Philadelphia, USA, 1990, pp 554-556, 1990.

P. Trinder. A colorimetric method of determination of serum and plasma cholesterol. Ann. Clin. Biochem, vol.6, pp. 24-27, 1969.

M. F. Lopez-Virella, P. Stone, S. Ellis and J. A. Colwell. Cholesterol determination in high density lipoproteins separated by three different methods. Clinical Chemistry, vol. 23, pp. 882-884, 1977.

P. E. Hartman. Putative mutagens and carcinogens in foods, IV. Malondialdehyde (Malondialdehyde). Environ Mutagen, vol. 5(4), pp. 603-607, 1983.

J. W. Patterson and A. Lazarow. Methods of biochemical analysis, 2nd ed, D. Glick, New York, Inter Science, 1955, pp. 259.

R. F. Beers and I. W. Sizer I.W. A spectrophotometric method of for measuring the breakdown of hydrogen peroxide by catalase. J Biol Chem, vol.195, pp. 130-140, (1952).

J. M. McCord and I. Fridovich. Superoxide dismutase: an enzyme function for eurythrocuperin (hemocuperin). J Biol Chem, vol. 98, pp. 719-33, 1969.

J. A. Kiernan. Histological and Histochemical Methods: Theory and Practice; Pergamon Press; Oxford, New York, Toronto Sydney, Paris, Frankfurt, 1981, pp. 1-87.

World Health Organisation (WHO). The Who Recommended classification of pesticides by hazard and guidelines to classification. International Programme on Chemical Safety(IPCS)/Inter-Organization Programme For The Sound Management of Chemicals (a cooperative agreement among FAO, ILO, UNEP, UNIDO, UNITAR, WHO and OECD. Revision ISBN 9241546638, 2009.

S. O. Aniogu, F. C. Nwinyi, D. D. Akumka and G. A. Ajoku. Toxicity Studies in rats fed nature cure bitters. Afr J Biotechnol,vol . 4, pp. 72-8, 2005.

C. Deveaud, B. Beauvoit, A. Reynaud and J. Bonnet. Site-specific reduction of oxidative and lipid metabolism in Adipose Tissue of 3-Azido-3-Deoxythymidine-treated rats. Antimicrob Agents Chemother, vol. 51(2), pp. 583-590, 2006.

K. L. Moore and A. F. Dalley. Clinically Oriented Anatomy. 4th ed, Lippincott Williams and Williams, A Woller Klumner Corporation, Philadelphia, 1999, pp. 263.

M. J. Sawyer, J. R. Harrell, G. Shemer, J. Sullivan-Brown, M. Roh-Johnson and B. Goldstein B. Apical constriction: A cell shape change that can drive morphogenesis. Developmental Biology, vol. 341(1), pp. 5-19, 2009.

A.O Abolaji, A.H Adebayo and O.S Odesanmi. Effect of ethanolic extract of Parinari polyandra (Rosaceae) on serum lipid profile and some electrolytes in pregnant rabbits.Res J Med Plant, vol1, pp. 121- 127, 2007.

L. G. Whitby, A. F. Smith and G. J Becket. Lecture Notes on Clinical Chemistry. 9th ed., Blackwell Scientific Publications, Oxford, London, Edinburgh, Boston, Melbourne, 1989.

S. M. Tilkian, M. B. Conover and A. G. Tilkian. Clinical Implications of Laboratory Tests. C.V. Mosby Company, St Louis, Toronto, London, 1979.

M. Cheesbrough. District laboratory practice in tropical countries. 2nd ed., Cambridge University Press.Part 1: 310-369 and Part 2: 267-314, 2005.

S. F. Friedman, P. Martin and J. S. Munoz. Laboratory evaluation of the patient with liver disease in Hepatology, a textbook of liver disease, 1st ed., Saunders publication, Philedelphia, 2003, pp. 661- 09.

H. Abdel-Baset, O. El-Ahmady, A. S. Hassab, F. Abdel-Galil, H. Yosir and A. Darwish. Biochemical effect of antioxidants on lipids and liver function in experimentally induced liver damage. Ann Clin Biochem.,vol. 34, pp. 656-663, 1997.

A. Sharma, R. Mathur and S. Shukla. Hepatoprotective action of a proprietary herbal preparation against carbon tetrachloride intoxication. Indian Drugs, vol. 32, pp. 120-124, 1995.

K. Nicholas and D. Dieterich. Hepatotoxicity of antiretroviral therapy. AIDS Rev, vol. 5, pp. 36-43, 2003.

G. Storz and J. A. Imlay. Oxidative stress. Curr Opin Microbiol, vol. 2, pp. 188-94, 1999.

W. M. Lee. Drug-induced hepatotoxicity. N Engl J Med, vol.349, pp. 474-485, 2003.

A. Pandit, T. Sachdeva and P. Bafna. Drug induced hepatotoxicity: A review. J Appl Pharm Sci, vol 02(05), pp. 233-43, 2012.

K. Tikoo, A. Tamta, I. Y. Ali, J. Gupta and A. B. Gaikwad. Tannic acid prevents azidothymidine (AZT) induced hepatotoxicity and genotoxicity along with change in expression of PARG and histone H3 acetylation. Toxicol Lett, vol.177, pp. 90-6, 2008.

M. T. Yakubu, M. A. Akanji and A. T. Oladiji. A. T. Alterations in serum lipid profile of male rats by oral administration of aqueous extract of Fadogia argrestis stem. Research Journal Medicinal Plant, vol. 2, pp. 66-73, 2008.

E. E. Kelly, B. A. Wagner, G. R. Buettner and C. K. Burns. Nitric oxide inhibits Iron-induced lipid peroxidation. Archives Biochemistry Biophysics,vol. 370, pp. 97-104, 1999.

H. Vaidya, M. Rajani, V. Sudarsanam, H. Padh and R. Goyal. Antihyperlipidaemic activity of swertiamarin a secoiridoid glycoside in poloxamer407 induced hyperlipidaemic rats. Journal National Medicine, 63, pp. 437-442, 2009.

F.Van Leth, P. Phanuphak, E. Stroes, B. Gazzard and P. Cahn. Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral therapy-naive patients infected with HIV-1. PLoS Med, vol 1(1), pp. 19, 2004.

J. L. Ngondi, J. Oben, D. M. Forkah, L. H. Etame and D. Mbanya. The effect of different combination therapies on oxidative stress markers in HIV infected patients in Cameroon. AIDS Res Ther, vol.3, pp. 19, 2006.

S. Majid, K. L. Khanduja, R. K. Gandhi, S. Kapur and R. R. Sharma. Influence of ellagic acid on antioxidant defense system and lipid peroxidation in mice. Biochem Pharmacol, vol. 42, pp. 1441-5, 1991.

C. Laurent, C. Kouanfack, S. Koulla-Shiro, N. Nkoue and A. Bourgeois. Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial. Lancet, vol. 364, pp. 29-34, 2004.

B. Halliwell. Oxidants and human disease: Some new concepts. FASEB J, vol. 1, pp. 358-64, 1987.

K. R. Manda, A. Banerjee, W. A. Banks and N. Ercal. Highly active antiretroviral therapy drug combination induces oxidative stress and mitochondrial dysfunction in immortalized human blood-brain barrier endothelial cells. Free Radic Biol Med, vol. 50 pp. 801-810, 2011.

R. Saravanan, N. Rajendra, N. R. Prasad and K. V. Pugalendi. Effect of Piper betle leaf extract on alcohol toxicity in the rat brain. J Med Food, vol.6(3), pp. 261-265, 2003.

M. Ookhtens and N. Kaplowitz. Role of the liver in inter-organ homeostasis of glutathione and cysteine. Semin Liver Dis, vol. 18, pp. 313-29, 1998.


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