Role of Imiquimod and Parenteral Meglumine Antimoniate in the Initial Treatment of Cutaneous Leishmaniasis

Arevalo, Iracema; Tulliano, Gianfranco; Quispe, Ana; Späth, Gérald F.; Matlashewski, Greg; Llanos-Cuentas, Alejandro; Pollack, Henry

doi:10.1086/518172

Cited by 90 publications

(55 citation statements)

References 10 publications

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“…Following the resolution of infection, people are immune for life, demonstrating that protective immunity can be achieved by delivering Leishmania antigen to the skin. Second, we have shown that the treatment of human cutaneous leishmaniasis with topical imiquimod is safe and, in combination with intravenously administered antimony, can enhance the rate of cure of established infections (1,2,14). The adjuvant properties of topical imiquimod together with the Leishmania antigen released by antimony killing of the parasite may have enhanced the immunological clearance of infection in these trials.…”

Section: Discussionmentioning

confidence: 97%

Immunization with a Toll-Like Receptor 7 and/or 8 Agonist Vaccine Adjuvant Increases Protective Immunity againstLeishmania majorin BALB/c Mice

Zhang

Matlashewski

2008

Infect Immun

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Activation of Toll-like receptors (TLRs) on antigen-presenting cells of the innate immune system initiates, amplifies, and directs the antigen-specific acquired immune response. Ligands that stimulate TLRs therefore represent potential vaccine adjuvants. In the present study, we determined whether imiquimod and its related compound R848, which are TLR7 and/or TLR8 agonists, represent potential vaccine adjuvants when delivered topically, subcutaneously, or intramuscularly. Using the Leishmania major infection model in BALB/c mice, vaccination with crude Leishmania antigen was not protective against subsequent challenge infection unless it was administered with R848 or a topical application of imiquimod containing cream on the skin. Subcutaneous vaccination with these adjuvants mediated a TH1 response against L. major antigen, which appeared to suppress the TH2 response following a challenge infection. Protective immunity was generated following subcutaneous vaccination but not intramuscular vaccination. These observations suggest that topically administered imiquimod or subcutaneously injected R848 represent potential vaccine adjuvants to enhance the TH1 response, which can be used with existing or new vaccine formulations.

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Section: Discussionmentioning

confidence: 97%

Immunization with a Toll-Like Receptor 7 and/or 8 Agonist Vaccine Adjuvant Increases Protective Immunity againstLeishmania majorin BALB/c Mice

Zhang

Matlashewski

2008

Infect Immun

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“…Reduced sensitivity of Leishmania parasites to antimonials has also been reported. [5][6][7][8][9][10][11][12][13][14] All of these factors have driven the search for therapeutic alternatives for the treatment of leishmaniasis. 2 Various oral medications have been evaluated in the search for therapeutic alternatives to antimonials, including dapsone, 15 ketoconazol, 16,17 mefloquine, 18 allopurinol, 19 and others, 2 but none were shown to be effective.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Miltefosine for the Treatment of American Cutaneous Leishmaniasis

Vélez

López²,

Sánchez³

et al. 2010

The American Society of Tropical Medicine and Hygiene

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Miltefosine is an oral agent used for cutaneous leishmaniasis treatment. An open-label, randomized, phase III clinical trial was carried out in the Colombian army population. Miltefosine, 50 mg capsule was taken orally three times per day for 28 days (N = 145) or meglumine antimoniate, 20 mg/kg body weight per day for 20 days by intramuscular injection (N = 143). The efficacy of miltefosine by protocol was 69.8% (85/122 patients) and 58.6% (85/145 patients) by intention to treat. For meglumine antimoniate, the efficacy by protocol was 85.1% (103/121 patients) and 72% (103/143 patients) by intention to treat. No association was found between drug efficacy and L. (V.) braziliensis or L. (V.) panamensis species of Leishmania responsible for infection. Adverse gastrointestinal events were associated with the use of miltefosine, the meglumine antimoniate treatment was associated with adverse effects on the skeletal musculature, fever, cephalea, and higher toxicity in kidney, liver, pancreas, and hematological system.

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“…Human trials of topical imiquimod in CL patients, in combination with pentavalent antimony, demonstrated modest improvements over antimony treatment alone (15)(16)(17)(18). These studies have focused exclusively on cutaneous disease to which imiquimod could be directly applied, however.…”

Section: Discussionmentioning

confidence: 99%

Topical Resiquimod Protects against Visceral Infection with Leishmania infantum chagasi in Mice

Craft¹,

Birnbaum²,

Quanquin³

et al. 2014

Clin. Vaccine Immunol.

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New prevention and treatment strategies are needed for visceral leishmaniasis, particularly ones that can be deployed simply and inexpensively in areas where leishmaniasis is endemic. Synthetic molecules that activate Toll-like receptor 7 and 8 (TLR7/8) pathways have previously been demonstrated to enhance protection against cutaneous leishmaniasis. We initially sought to determine whether the TLR7/8-activating molecule resiquimod might serve as an effective vaccine adjuvant targeting visceral leishmaniasis caused by infection with Leishmania infantum chagasi. Resiquimod was topically applied to the skin of mice either prior to or after systemic infection with L. infantum chagasi, and parasite burdens were assessed. Surprisingly, topical resiquimod application alone, in the absence of vaccination, conferred robust resistance to mice against future intravenous challenge with virulent L. infantum chagasi. This protection against L. infantum chagasi infection persisted as long as 8 weeks after the final topical resiquimod treatment. In addition, in mice with existing infections, therapeutic treatment with topical resiquimod led to significantly lower visceral parasite loads. Resiquimod increased trafficking of leukocytes, including B cells, CD4؉ and CD8 ؉ T cells, dendritic cells, macrophages, and granulocytes, in livers and spleens, which are the key target organs of visceralizing infection. We conclude that topical resiquimod leads to systemic immune modulation and confers durable protection against visceralizing L. infantum chagasi infection, in both prophylactic and therapeutic settings. These studies support continued studies of TLR-modulating agents to determine mechanisms of protection and also provide a rationale for translational development of a critically needed, novel class of topical, preventative, and therapeutic agents for these lethal infections.

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Role of Imiquimod and Parenteral Meglumine Antimoniate in the Initial Treatment of Cutaneous Leishmaniasis

Abstract: Combination therapy with imiquimod and meglumine antimoniate is a promising regimen for the initial treatment of cutaneous leishmaniasis that warrants additional larger studies.

Cited by 90 publications

References 10 publications

Immunization with a Toll-Like Receptor 7 and/or 8 Agonist Vaccine Adjuvant Increases Protective Immunity againstLeishmania majorin BALB/c Mice

Immunization with a Toll-Like Receptor 7 and/or 8 Agonist Vaccine Adjuvant Increases Protective Immunity againstLeishmania majorin BALB/c Mice

Efficacy of Miltefosine for the Treatment of American Cutaneous Leishmaniasis

Topical Resiquimod Protects against Visceral Infection with Leishmania infantum chagasi in Mice

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