Effects of Melatonin on Metabolic Abnormalities in HIV Patients Treated with Antiretroviral Drugs
Journal of Advances in Medical and Pharmaceutical Sciences,
Aims: Highly Active Antiretroviral Therapy (HAART) is the current care standard for treating patients with HIV/AIDS. Although HAART has is the only regimen potent enough to decrease viral load, adverse events may limit its efficacy. Metabolic disorders are common in patients treated with HAART. Melatonin (N-acetyl-5-methoxytryptamine) was initially thought to be exclusively of pineal origin but recent studies have shown that melatonin synthesis may occur in several cells and organs. Melatonin has been shown to have a variety of functions and research during the last decade has proven the indole to be a direct free radical scavenger and indirect antioxidant. Due to these activities and possibly others that remain to be defined, melatonin has been shown to reduce toxicity and increase the efficacy of a large number of drugs. This study evaluated the effects of melatonin supplementation (6mg / day / 30 days) in AIDS patients using antiretroviral therapy (HAART).
Methodology: Current study was carried out in a double-blind, placebo-controlled and completely randomized design. AIDS patients who had metabolic alterations were selected. Patients were divided into two groups: Group I (HAART) consisted of patients receiving placebo once a day in the evening. Group II (HAART+ Melatonin) comprised patients who received the melatonin (6 mg) once a day in the evening for one month. Clinical and laboratorial evaluation was performed before and after 30 days. Clinical evaluation was performed to assess the patients´ overall clinical state. Patients were instructed to report any complications. Laboratorial evaluation was performed. Glucose levels were determined by glucose oxidase method and ELISA (Genway Biotechnology, USA), respectively, following manufacturer’s instructions. Plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) were performed by the kinetic colorimetric method; triglycerides, total cholesterol and creatinine were performed by enzymatic colorimetric method, both provided by Gold Analisa Diagnóstica Ltda.
Results: Sixty patients who had some metabolic abnormalities (glucose levels above 100.0 mg/dL or total cholesterol above 200 mg/dL or triglycerides above 200 mg/dL) participated in the study. All had been using HAART therapy for at least five years, with an average 15-year infection period. Patient´s age ranged between 35 and 49 years, with a mean of 43.7 years. Fasting glucose was significantly lower in subjects in Group I treated with melatonin when compared with subjects included in the control group not treated with melatonin after one month of treatment. Levels of blood glucose were 23% lower in patients who used melatonin, with reference rates after one month of treatment. Current study revealed that 40% (12/30) of the patients had changes in AST liver enzymes (> 38 U/I), 30% (9/30) had changes in ALT levels (> 38 U/I) and 30% (9/30) had GGT levels (> 40 U/I). Results obtained after the use of melatonin suggest melatonin activity on the liver. Significant differences between groups in plasma cholesterol indicate that melatonin exerted better improvement of blood lipid composition. Melatonin would lower cholesterol in liver and decrease plasma cholesterol. Above all, melatonin could decrease oxidative stress and improve dyslipidemia.
Conclusion: Considering the low toxicity of melatonin and its ability to reduce the side effects and increase the efficacy of the drugs, its use may be important and significant as a combination therapy with HAART. Current study which investigated the effect of melatonin associated with antiretroviral treatment demonstrated beneficent effects on metabolic abnormalities in AIDS patients.
- metabolic abnormalities
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Nduka C, Sarki A, Uthman O, Stranges S.. Impact of antiretroviral therapy on serum lipoprotein levels and dyslipidemias: a systematic review and meta-analysis. Int J Cardiol. 2015;199:307-18.
Lo Re Rd V, Zeldow B, kallan MJ, tate JP, Carbonari DM, Hennessy S, Kostman JR, Lim JK, Goetz MB, Gross R, Justice AC, Roy JA. Risk of liver descompensation with cumulative use of mitochondrial toxic nucleoside analogues in HIV/hepatites C virus coinfection. Pharmacoepidemiol Drug Saf. 2017;19:4258.
Rogalska-Plonska M, Rogalski P, Leszczyszyn-Pynka M, Stempkowska J, Kocbach P, Kowalczuk-Kot A, Janczarek M, Grzeszczuk A. Hypertension, dyslipidemia and cardiovascular risk in HIV infected adults in Poland. Kardiol Pol. 2017;199:307-18.
Castelnuovo B, John L, Lutwama F, Ronald A, Spacek LA, bates M, kamya MR, Colebunders R. Three years outcome data of second-line anti-retroviral therapy an Ugandan adults; good virological response but high rate of toxicity. J Int Assoc Physicians AIDS care. 2009; 8(1):52-9.
Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, reddy KR, Watkins PB, Navarro V, Bamhart H, Gu J, Serrano J. Features and outcomes of 899 patients with drug-induced liver injury; The DILIN prospective study. Gastroenterology. 2015;148(7):1340-52.
Vogel M, Rockstroh JK. Hepatotoxicity and liver disease in the context of HIV therapy. Curr Opin HIV AIDS. 2007;2(4):306-13.
Sulkowski MS. Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors.Clin Infect Dis. 2004;38(2):90-7.
Wit FW, Weverling GJ, Weel J, Jurriaans S, Lange JM. Incidence of and risk factors for severe hepatotoxicity assicated with antiretroviral combination therapy. J Infect Dis. 2002;186(1):23-31.
Echenique IA, Rich JD. EFV/FTC/TDF-associated hepatotoxicity: A case report and review. AIDS Patient Care STDS. 2013;27(9):493-7.
Girault V. The treatment of HIV infection. Presse Med. 2005;19:34-1605-8.
Chan-Tack KM, Struble KA, Birnkrant DB. Intracranial hemorrhage and liver-associated deaths associated with tipranavir/ritonavir: a review of cases from the FDA’s Adverse Event Reporting System. AIDS Patient Care STDS. 2008; 22(11):843-50.
Sanchez Hellin V, Gutierrez Rodero F. Toxicogenetics of antiretroviral treatment (II): neurotoxicity, hepatotoxicity, lactic acidosis, kidney damage, and other adverse effects of antiretroviral drugs. Enferm Infecc Microbiol Clin. 2008; 26(6):24-33.
Bertz R, Child MJ, Hosey L, Alston-Smith B, Acosta APHaas DW, Koletar SL, Laughlin L, Kendall MA, Suckow C, Gerber JG, Zolopa AR, Bertz R, Child MJ, Acosta EP; A5213 StudyTeam. Hepatotoxicity and gastrointestinal intolerance when healthy volunteers taking rifampin add twice-daily atazanavir and ritonavir. J Acquir Immune Defic Syndr. 2009; 50(3):290-3.
Marfatia YS, Talwar M, Agrawal M, Sharma A, Mehta K. Mitochondrial toxicities of nucleoside analogue reverse transcriptase inhibitors in AIDS cases. Indian J Sex Transm Dis. 2014;35(2):96-9.
Tasias M, Aldequer JL. Lopinavir/ritonavir in patients with human immunodeficiency virus infection in special situations. Enferm Infecc Microbiol Clin. 2014;32(3):18-21.
Morishima I, Matsui H, Mukawa A, Hayashi K, Toki Y, Okumura K, Ito T, Hayakawa T. Melatonin, a pineal hormone with antioxidant property, protects against adriamycin-induced cardiomyopathy in rats. Life Sci. 1998;68:511-521.
Lissoni P. Is there a role for melatonin in supportive care? Support Care Cancer. 2002;10:110-116.
Anwar MM, Mahfouz HA, Sayed AS. Potential protective effects of melatonin on bone marrow of rats exposed to cytotoxic drugs. Comp Biochem Physiol.1998; 119(1):493-501.
Alarcon de la Lastra C, Motilva V, Marin MJ, Nieto A, Barranco MD, Cabezza J, Herrerias JM. Protective effect of melatonin on indomethacin-induced gastric injury in rats. J Pineal Res. 1999;26:101-107.
Reiter RJ, Tan DX, Sainz RM, Mayo JC, Lopez-Burillo S. Melatonin: reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmacol. 2002; 54(10):1299-321.
Li Z, Nickkholgh A, Yi X. Melatonin protects kidney grafts from ischemia/reperfusion injury through inhibition of NF-kB and apoptosis after experimental kidney transplantation. J Pineal Res. 2009;46:365-72.
Petrosillo G, Di Venosa N, Pistolese M. protective effect of melatonin against mitochondrial dysfunction associated with cardiac ischemia-reperfusion: role of cardiolipin. FASEB J, 2006;20:269-76.
Jimenez-Arant A, Fernandez-Vazquez G, Serrano MM, Reiter RJ, Agil A. melatonin improves mitochondrial function in inguinal white adipose tissue of Zucker diabetic fatty rats. J Pineal res, 2014;57(1):103-9.
Reppert SM, Weaver DR, Ebisawa T. Cloting and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron, 1994;13:1177-85.
Reppert SM, Godsonr C, mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF. Molecular characterization of a second melatonin receptor ecxpressed in human retina and brais: The Mel 1b melatonin receptor. Proc Natl Acad Sci USA, 1995; 92:8734-38.
Rasmussen DD, Boldt BMI, Wilkinson CW, Yellon SM, Matsumoto AM. Daily melatonin administration at middle age suppresses male rate visceral fat, plasm leptin and plasma insulin to youthful levels. Endocrinology, 1999; 140:1009-1012.
Boden G, Ruiz J, Urbain JL, Chen X. Evidence for a circadian rhythm of insulin secretion. Am J Physiol, 1996; 271:E246-E252.
O’Brien IA, Lewin IG, O’Hare JP, Arendt J, Corrall RJ. Abnormal circadian rhythm of melatonin in diabetic autonomic neuropathy. Clin Endocrinology. 1986; 24:359-364.
Paskaloglu K, Sener G, Ayangolu-Dulger G. Melatonin treatment protects against diabetes-induced functional and biochemical changes in rat aorta and corpus cavernosum. Eur J Pharmacol. 2004;499:345-354.
Kanter M, Uysal H, Karaca T, Sagmanligil HO. Depression of glucose levels and partial restoration of pancreatic β-cells damage by melatonin in streptozotocin-induced diabetic rats. Arch Toxicol, 2006; 80:362-369.
Simsek N, Kaya M, Kara A, Can I, Karadeniz A, Kalkan Y. Effects of melatonin on islet neogenesis and β cell apoptosis in streptozotocin-induced diabetic rats: An immunohistochemical study. Domest Anim Endocrinol. 2012; 43:47-57.
Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA. 2000;283:74-80.
Guerra S, Mamede AC, Carvalho MJ, laranjo M, Tralhao JG, Abrantes AM, Maia CJ, Botelho MF. Liver diseases: What is known so far about the therapy with humanamniotic membrane? Cell Tissue Bank. 2016;17:653-663.
Ogeturk M, Kus I, Pekmez H, Yekeler H, Sahin S, Sarsilmaz M. Inhibition of carbon tetrachloride-mediated apoptosis and oxidative stress by melatonin in experimental liver fibrosis. Toxicol Ind Health. 2008;24:201-208.
Sharma S, Rana SVS. Melatonin improves liver function in benzene-treated rats. Arh Hig Rada Toksikol. 2013;64:219-227.
Sharma S, Rana SVS. Melatonin inhibits benzene-induced lipid peroxidation in the rat liver improves liver function in benzene-treated rats. Arh Hig Rada Toksikol. 2010; 61:11-18.
Tas U, Ogeturk M; Meydan S, Kus I, Koluglu T, Ilhan N, Kose E, Sarsilmaz M. Hepatotoxic activity of toluene inhalation and protective role of melatonin. Toxicol Ind Health. 2011;27:465-473.
El-Sokkary GH, Bdel-Rahman GH, Kamel ES. Melatonin protects against lead-induced hepatic and renal toxicity in male rats. Toxicology. 2005;213:25-33.
Borges JB, Sakurada T, Ciupa L, Spack M, Pupulin ART. Melatonin improves metabolic abnormalities inducet by HAART in mice. Brit J Pharm Res. 2016; 13(6):1-10.
Post F. Adverse events: ART and Kidney:alterations in renal function and renal toxicity. J Int AIDS Soc. 2014; 17(4Suppl 3):19513.
Wyatt CM. Antiretroviral therapy and the kidney. Top Antivir Med, 2014;22(3):655-8.
Daugas E, Rougier JP, Hill G. HAART-related nephropathies in HIV -infected patients. Kidney. 2005;67:393-403.
Ianas O, Olinescu R, Balescu I. Melatonin involved in oxidative processes. Rom Endocrinol. 1991;29:147-153.
Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ. Melatonin: a potent, endogenous hydroxyl radical scavenger, Endocr J. 1993;1:57-60.
Poeggeler B, Saarela S, Reiter RJ, Tan DX, Chen LD, Manchester LC, Barlow-Walden L. Melatonin-a highly potent radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole assessed in vitro. Ann NY Acad Sci. 1994;738:419-20.
Tan DX, Reiter RJ, Manchester LC, Yan MT, El-Sawi M, Sainz RM, Mayo JC, Kohen R, Allegra M, Handeland R Chemical and physical properties and potential mechanisms: Melatonin as a free radical scavenger. Curr Topics Med Chem. 2002;2:181-197.
Dubocovich ML, Mansana MI, Benloucif S. Molecular pharmacology and function of melatonin receptors. Adv Exp Med Biol. 1999;460:181-191.
Menendez—Pelaez A, Reiter RJ. Distribution of melatonina in mammalian tissues: relative importance of nuclear versus cytosolic localization. J Pineal Res. 1993;15:59-69.
Arendt J. Melatonin and the mammalian pineal gland. London Chapman and Hall. 1993;331.
Lane EA, Moss, HB. Pharmacokinetics of melatonin in man: First pass hepatic metabolism. J Clin Endocr Metab. 1985;61(6):1214-1216.
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