Iranian Journal of Parasitology 2017. 12(3):339-347.

The Potential Use of Methotrexate in the Treatment of Cutane-ous Leishmaniasis: In Vitro Assays against Sensitive and Me-glumine Antimoniate-resistant Strains of Leishmania tropica
Hossein MAHMOUDVAND, Farnaz KHEIRANDISH, Seyed Reza MIRBADIE, Mohammad Hassan KAYEDI, Tahereh REZAEI RIABI, Abbas Ali GHASEMI, Mehdi BAMOROVAT, Iraj SHARIFI

Abstract


Background: The present study aimed to evaluate the effect of methotrexate (MTX) alone and in combination with meglumine antimoniate (MA, Glucantime) against sensitive and MA-resistant Leishmania tropica stages in vitro.

Methods: The present study was carried out in 2014 in Leishmaniasis Research Center at School of Medicine, Kerman University of Medical sciences, Kerman, Iran. The effects of MTX alone and along with MA on promastigote and amastigote stages of sensitive (SS) and MA-resistant (RS) L. tropica strains have been evaluated using a colorimetric MTT assay and in a macrophage model, respectively. In addition, the inhibitory effect of MTX on the Leishmania invasion of murine macrophages was assessed in promastigotes of both strains of L. tropica. Sensitive and MA resistant L. tropica are referred to those isolates that are responsive or non-responsive to one or two courses of treatment by MA systemically and/or intralesionally, respectively.

Results: The findings of OD and IC50 showed that MTX plus MA (SS: 16.1 μg/ml, RS: 39.8 μg/ml) had a higher anti-leishmanial effect than MA (SS: 52.2 μg/ml, RS: 170 μg/ml) or MTX alone (SS: 22.2 μg/ml, RS: 51.4 μg/ml) on promastigotes of both strains of L. tropica. The MTX plus MA caused a significant decrease (P<0.05) in the mean infection rate (MIR) and the mean number of amastigotes in each macrophage compared with positive control. Infectivity of promastigotes is significantly (P<0.05) reduced when it was preincubated with MTX.

Conclusion: This study indicated high potency and a synergistic effect of MTX on MA in inhibiting the growth rateof promastigote and amastigote stages of sensitive and meglumine antimoniate-resistant L. tropica. Further works are needed to evaluate the anti-leishmanial effects of MTX on L. tropica using a clinical setting.

Keywords


Meglumine antimoni-ate, Resistance, Leishmania tropica, Methotrexate, In vitro

Full Text:

PDF

References


World Health Organization. Control of the Leishmaniasis. Geneva: WHO (Technical Report Series 949); 2010, 5–12.

Desjeux P. Leishmaniasis: current situation and new perspectives. Comp Immunol Microbiol Infect Dis. 2004; 27(5):305–18.

Shirzadi MR, Esfahania SB1, Mohebalia M et al.Epidemiological status of leishmaniasis in the Islamic Republic of Iran, 1983–2012. East Mediterr Health J. 2015; 21(10):736-42.

Sharifi F, Sharifi I, Zarean M et al. Spatial distribution and molecular identification of Leishmania species from endemic foci of south-eastern Iran. Iran J Parasitol. 2012;7(1):45-52.

Noazin S, Khamesipour A, Moulton LH et al. Efficacy of killed whole-parasite vaccines in the prevention of leishmaniasis: a meta-analysis. Vaccine. 2009;27(35):4747-53.

Shirzadi MR, Gouya MM. National guideline for cutaneous leishmaniasis surveillance in Iran. Ministry of Health and Medical Education. Zoonoses control department, Tehran, I.R. Iran; 2012; p 1-78.

Postigo JA. Leishmaniasis in the World Health Organization Eastern Mediterranean Region. Int J Antimicrob Agents. 2010; 36 Suppl 1:S62-5.

Mahmoudvand H, Sepahvand P, Jahanbakhsh S et al. Evaluation of the antileishmanial and cytotoxic effects of various extracts of garlic (Allium sativum) on Leishmania tropica. J Parasit Dis. 2016; 40(2): 423-26.

Santos DO, Coutinho CE, Madeira MF et al. Leishmaniasis treatment -a challenge that remains: a review. Parasitol Res. 2008; 103(1):1-10.

Ezatpour B, Saedi Dezaki E2, Mahmoudvand H et al. In vitro and in vivo antileishmanial effects of Pistacia khinjuk against Leishmania tropica and Leishmania major. Evid Based Complement Alternat Med. 2015;2015:149707.

Mahmoudvand H, Shakibaie M, Tavakoli R et al. In vitro study of leishmanicidal activity of biogenic selenium nanoparticles against Iranian isolate of sensitive and glucantime-resistant Leishmania tropica. Iran J Parasitol. 2014;9(4):452–60.

Mahmoudvand H, Tavakoli R, Sharififar F et al.Leishmanicidal and cytotoxic activities of Nigella sativa and its active principle, thymoquinone.Pharm Biol. 2015; 53(7):1052-57.

Kheirandish F, Delfan B, Mahmoudvand H et al. Antileishmanial, antioxidant, and cytotoxic activities of Quercusinfectoria Olivier extract. Biomed Pharmacother. 2016; 82: 208–16.

Firooz A, Khamesipour A, Ghoorchi MH et al. Imiquimod in combination with meglumine antimoniate for cutaneous leishmaniasis. Arch Dermatol. 2006; 142(12):1575–79.

Barnhart K, Coutifaris C, Esposito M. The pharmacology of methotrexate. Expert Opin Pharmacother. 2001; 2(3):409-17.

Barredo J, Bunni MA, Kamasamudram R. An antifolate drug in cancer therapy. Humana Press. 1999; 323–37.

Dahl MG, Gregory MM, Scheuer PJ. Methotrexate hepatotoxicity in psoriasis—comparison of different dose regimens. Br Med J. 1972; 1(5801): 654–56.

Dar O, Khan MS, Adagu I.. The potential use of methotrexate in the treatment of falciparum malaria: in vitro assays against sensitive and multidrug-resistant falciparum strains. Jpn J Infect Dis. 2008; 61(3):210-1.

Nduati E, Diriye A, Ommeh S et al. Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer. Parasitol Res. 2008; 102(6):1227-34.

Mol F, Mol BW, AnkumWM et al. Current evidence on surgery, systemic methotrexate and expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis. Hum Reprod Update. 2008; 14 (4): 309–19.

Sheehy TW. Dempsey H. Methotrexate therapy for Plasmodium vivax malaria. JAMA. 1997; 214:109–14.

Hübner C, Wiehr S, Kocherscheidt L et al. Effects of in vitro exposure of Echinococcus multilocularis metacestodes to cytostatic drugs on in vivo growth and proliferation of the parasite. Parasitol Res. 2010; 107(2):459-63.

Imwong M, Russell B, Suwanarusk R et al. Methotrexate is highly potent against pyrimethamine-resistant Plasmodium vivax. J Infect Dis. 2011; 203(2):207-10.

Kóczán G, Ghose AC, Mookerjee A et al. Methotrexate conjugate with branched polypeptide influences Leishmania donovani infection in vitro and in experimental animals. Bioconjug Chem. 2002; 13(3):518-24.

Mahmoudvand H, Ezzatkhah F, Sharififar F et al. Antileishmanial and cytotoxic effects of essential oil and methanolic extract of Myrtus communis L. Korean J Parasitol. 2015; 53 (1):21–27.

Saedi Dezaki E, Mahmoudvand H, Sharififar F et al. Chemical composition along with anti-leishmanial and cytotoxic activity of Zataria multiflora. Pharm Biol. 2016; 54(5):752-58.

Mahmoudvand H, Sharififar F, Rahmat MS et al. Evaluation of antileishmanial activity and cytotoxicity of the extracts of Berberis vulgaris and Nigellasativa against Leishmania tropica. J Vector Borne Dis. 2014; 51(4):294–99.

Mahmoudvand H, Saedi Dezaki E, Ezatpour B et al. In vitro and in vivo antileishmanial activities of Pistacia vera essential oil. Planta Med. 2016;82(4): 279–84.

Croft SL, Sundar S, Fairlamb AH. Drug resistance in leishmaniasis. Clin Microbiol Rev. 2006; 19(1):111–26.

Hadighi R, Mohebali M, Boucher P et al. Unresponsiveness to Glucantime Meglumine antimoniaate treatment in Iranian cutaneous leishmaniasis due to drug-resistant Leishmania tropica parasites. PLoS Med. 2006; 3(5):e162.

Hadighi R, Boucher P, Khamesipour A et al. Glucantime Meglumine antimoniaate-resistant Leishmania tropica isolated from Iranian patients with cutaneous leishmaniasis are sensitive to alternative antileishmania drugs. Parasitol Res. 2007; 101(5):1319-22.

Mohebali M, Fotouhi A, Hooshmand B et al. Comparison of miltefosine and meglumine antimoniate for the treatment of zoonotic cutaneous leishmaniasis (ZCL) by a randomized clinical trial in Iran. Acta Trop. 2007; 103(1):33–40.

Lira R, Sundar S, Makharia A et al. Evidence that the high incidence of treatment failure in Indian Kala azar is due the emergence of antimony resistant strains of Leishmania donovani. J Infect Dis. 1999; 180(2):564–7.

Raheem JM, Ayad QM. In vitro study of Methotrexate- polypeptide effect on Leishmania donovani replication rate. J College Education. 2012; 2(3):32-39.

Cronstein BN. Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev. 2005; 57(2):163-72.


Refbacks

  • There are currently no refbacks.


Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.