Skip to main content
SpringerLink
Log in

Antileishmanial efficacy of fluconazole and miltefosine in combination with an immunomodulator—picroliv

  • Original Paper
  • Published:
Parasitology Research Aims and scope Submit manuscript

Abstract

The chemotherapy of visceral leishmaniasis (VL) has several limitations including resistance and toxicity of the existing drugs. Downregulation of immune system further aggravates the problems. To combat this situation, leishmanicidal efficacy of already marketed standard antifungal drug, fluconazole under the approach of “therapeutic switching” in combination with standard antileishmanial drug, miltefosine, and a potent immunomodulator agent, picroliv, were evaluated in hamsters infected with Leishmania donovani. Animals treated with fluconazole (50 mg/kg × 5 days, oral (p.o.)) + miltefosine (5 mg/kg × 5 days, p.o.) showed enhancement in antileishmanial efficacy (77%), reactive nitrogen species, reactive oxygen species, hydrogen peroxide, and phagocytosis index as compared to those treated with individual drugs. Addition of picroliv to this combination further increased the antileishmanial efficacy from 77% to 88%. Upregulation of cell-mediated immunity was also observed in animals of this group which strengthens the immunomodulatory role of picroliv. These findings suggest a new option for antileishmanial chemotherapy at lower cost and toxicity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Alrajhi AA, Ibrahim EA, De Vol EB, Khairat M, Faris RM, Maguire JH (2002) A six-week course of oral fluconazole, in a dose of 200 mg daily for 6 weeks, is a safe and useful treatment for cutaneous leishmaniasis caused by L. major. N Engl J Med 346:891–895

    Article  PubMed  CAS  Google Scholar 

  • Arevalo I, Ward B, Miller R (2001) Successful treatment of drug-resistant cutaneous leishmaniasis in humans by use of imiquimod, an immunomodulator. Clin Infect Dis 33:1847–1851

    Article  PubMed  CAS  Google Scholar 

  • Ashutosh GS, Ramesh SS, Goyal N (2005) Use of L. donovani field isolates expressing luciferase reporter gene in in vitro drug screening. Antimicrob Agents Chemother 49:3776–3783

    Article  PubMed  CAS  Google Scholar 

  • Bhatnagar S, Guru PY, Katiyar JC, Srivastava R, Mukherjee A, Akhtar MS, Seth M, Bhaduri AP (1989) Exploration of antileishmanial activity in heterocycles; results of their in vivo and in vitro bioevaluations. Indian J Med Res 89:439–444

    PubMed  CAS  Google Scholar 

  • Buates S, Matlashewski G (1999) Treatment of experimental leishmaniasis with the immunomodulators imiquimod and S-28463: efficacy and mode of action. J Infect Dis 179:1485–1494

    Article  PubMed  CAS  Google Scholar 

  • Colakoglu M, Yaylali G, Colakoglu NY, Yalmaz M (2006) Successful treatment of visceral leishmaniasis with fluconazole and allopurinol in a patient with renal failure. Scand J Infect Dis 38:208–210

    Article  PubMed  CAS  Google Scholar 

  • Croft SL, Yardley V (2002) Chemotherapy of leishmaniasis. Curr Pharmaceutic Des 8:319–342

    Article  CAS  Google Scholar 

  • Dalton JE, Kaye PM (2010) Immunomodulators: use in combined therapy against leishmaniasis. Expert Rev Anti Infect Ther 8:739–742

    Article  PubMed  Google Scholar 

  • Dwivedi Y, Rastogi R, Garg NK, Dhawan BN (1992) Picroliv and its components kutkoside and picroside I protect liver against galactosamine induced damage in rats. Pharmacol Toxicol 71:383–387

    Article  PubMed  CAS  Google Scholar 

  • Griensven J, Balasegaram M, Meheus F, Alvar J, Lynen L, Boelaert M (2010) Combination therapy for visceral leishmaniasis. Lancet Infect Dis 10:184–94

    Article  PubMed  Google Scholar 

  • Gupta S, Ramesh SSC, Shrivastava VML (2005) Efficacy of picroliv combination with miltefosine, an orally effective antileishmanial drug against experimental visceral leishmaniasis. Acta Trop 94:41–47

    Article  PubMed  CAS  Google Scholar 

  • Gupta L, Talwar A, Nishi PS, Gupta S, Chauhan PMS (2007) Synthesis of marine alkaloid 8,9 dihydrocoscinamide B and its analogues as a novel class of antileishmanial agents. Bioorg Med Chem Lett 17:4075–4079

    Article  PubMed  CAS  Google Scholar 

  • Jha BB (1998) Fluconazole in visceral leishmaniasis. Indian Pediatr 35:268–269

    PubMed  CAS  Google Scholar 

  • Murray HW, Berman JD, Wright SD (1988) Immunotherapy for intracellular L. donovani infection: gamma interferon plus pentavalent antimony. J Infect Dis 157:973–978

    PubMed  CAS  Google Scholar 

  • Mussi SV, Fernandes AP, Ferreira LAM (2007) Comparative study of the efficacy of formulations containing fluconazole or paromomycin for topical treatment of infections by Leishmania (Leishmania) major and Leishmania (Leishmania) amazonensis. Parasitol Res 100:1221–1226

    Article  PubMed  Google Scholar 

  • Puri A, Saxena RP, Guru PY, Kulshreshtha DK, Saxena KC, Dhawan BN (1992) Immunostimulant activity of Picroliv, the iridoid glycoside fraction of P. kurroa and its protective action against L. donovani infection in hamsters. Planta Med 58:528–532

    Article  CAS  Google Scholar 

  • Rajeshkumar NV, Kuttan R (2000) Inhibition of N-nitrosodiethylamine-induced hepatocarcinogenesis by picroliv. J Exp Clin Cancer Res 19:459–465

    PubMed  CAS  Google Scholar 

  • Ray A, Chaudhuri SR, Majumdar B, Bandyopadhyay SK (2002) Antioxidant activity of ethanol extract of rhizome of P. kurroa on indomethacin-induced gastric ulcer during healing. Ind J Clin Biochem 17:44–51

    Article  Google Scholar 

  • Sane SA, Shakya N, Haq W, Gupta S (2010) CpG oligodeoxynucleotide augments the antileishmanial activity of miltefosine against experimental visceral leishmaniasis. J Antimicro Chemother 65:1448–1454

    Article  CAS  Google Scholar 

  • Seifert K, Croft SL (2006) In vitro and in vivo interactions between miltefosine and other antileishmanial drugs. Antimicrob Agents Chemother 50:73–79

    Article  PubMed  CAS  Google Scholar 

  • Sharma P, Raghavan SAV, Saini R, Dikshit M (2004) Ascorbate-mediated enhancement of reactive oxygen species generation from polymorphonuclear leukocyte: modulatory effect of nitric oxide. J Leukocyte Biol 75:1070–1078

    Article  PubMed  CAS  Google Scholar 

  • Shrivastava JK, Misra A, Sharma P, Srivastava B, Naik S, Dube A (2003) Prophylactic potential of autoclaved L. donovani with BCG against experimental visceral leishmaniasis. Parasitol 127:107–114

    Article  Google Scholar 

  • Srinivas N, Palne S, Nishi GS, Bhandari K (2009) Aryloxy cyclohexyl imidazoles: a novel class of antileishmanial agents. Bioorg Med Chem 19(324):327

    Google Scholar 

  • Sundar S, Singh VP, Agrawal NK, Gibbs DL, Murray HW (1996) Treatment of kala-azar with oral fluconazole. Lancet 348(9027):614

    Article  PubMed  CAS  Google Scholar 

  • Torrus D, Boix V, Massa B, Portilla J, Perez-Mateo M (1996) Fluconazole plus allopurinol in treatment of visceral leishmaniasis. J Antimicrob Chemother 37:1042–1043

    Article  PubMed  CAS  Google Scholar 

  • Verma PC, Vaishali B, Gupta V, Saxena G, Rahman LU (2009) Pharmacology and chemistry of a potent hepatoprotective compound picroliv isolated from the roots and rhizomes of Picrorhiza kurroa Royle ex Benth. (Kutki). Curr Pharmaceut Biotec 10:641–649

    Article  CAS  Google Scholar 

  • Walrand S, Valeix S, Rodriguez C, Ligot P, Chassagne J, Vasson MP (2003) Flow cytometry study of polymorphonuclear neutrophiloxidative burst: a comparison of three fluorescent probes. Clin Chem Acta 331:103–110

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. TK Chakraborty, Director, CDRI, Lucknow, India for providing his facilities and encouragement. Thanks are also due to Mr. AL Vishwakarma, Flow Cytometry Lab, for FACS analysis. Financial support in the form of Senior Research Fellowship received from the Council of Scientific and Industrial Research (CSIR), New Delhi, India to Nishi Shakya and Shraddha A. Sane is also gratefully acknowledged. This paper has CDRI communication number 7966.

Author information

Authors and Affiliations

  1. Division of Parasitology, Central Drug Research Institute (CSIR), Chattar Manzil Palace, M.G. Road, Lucknow, 226001, Uttar Pradesh, India

    Nishi Shakya, Shraddha A. Sane & Suman Gupta

Authors
  1. Nishi Shakya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shraddha A. Sane
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suman Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suman Gupta.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shakya, N., Sane, S.A. & Gupta, S. Antileishmanial efficacy of fluconazole and miltefosine in combination with an immunomodulator—picroliv. Parasitol Res 108, 793–800 (2011). https://doi.org/10.1007/s00436-010-2230-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00436-010-2230-2

Keywords

Search

Navigation