Treatment of cutaneous leishmaniasis with a topical antileishmanial drug (WR279396): phase 2 pilot study.

Soto, Jaime; Toledo, Julia; Gutiérrez, Patrícia; Arboleda, Margarita; Nicholls, Rubén Santiago; Padilla, J.; Berman, Jonathan; English, Charles K; Grögl, Max

doi:10.4269/ajtmh.2002.66.147

Cited by 72 publications

(35 citation statements)

References 14 publications

(16 reference statements)

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“…Grogl et al (25) introduced a new topical formulation of PM which consisted of a complex cream containing 15% PM and 0.5% gentamicin. In clinical trials, there were no significant differences in the cure rates achieved with this formulation and those achieved with placebo (44).…”

Section: Vol 53 2009 Topical Liposomal Paromomycin For Leishmaniasimentioning

confidence: 99%

Effect of Topical Liposomes Containing Paromomycin Sulfate in the Course of Leishmania major Infection in Susceptible BALB/c Mice

Jaafari

Bavarsad

Bazzaz

et al. 2009

Antimicrob Agents Chemother

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The aim of this study was to evaluate the antileishmanial effects of topical liposomal paromomycin sulfate (PM) in Leishmania major-infected BALB/c mice. Liposomes containing 10 or 15% PM (Lip-PM-10 and Lip-PM-15, respectively) were prepared by the fusion method and were characterized for their size and encapsulation efficiency. The penetration of PM from the liposomal PM formulations (LPMFs) through and into skin was evaluated in vitro with Franz diffusion cells fitted with mouse skin at 37°C for 8 h. The in vitro permeation data showed that almost 15% of the LPMFs applied penetrated the mouse skin, and the amount retained in the skin was about 60% for both formulations. The 50% effective doses of Lip-PM-10 and Lip-PM-15 against L. major promastigotes in culture were 65.32 and 59.73 g/ml, respectively, and those against L. major amastigotes in macrophages were 24.64 and 26.44 g/ml, respectively. Lip-PM-10 or Lip-PM-15 was used topically twice a day for 4 weeks to treat L. major lesions on BALB/c mice, and the results showed a significantly (P < 0.001) smaller lesion size in the mice in the treated groups than in the mice in the control group, which received either empty liposomes or phosphate-buffered saline (PBS). Eight weeks after the beginning of the treatment, every mouse treated with LPMFs was completely cured. The spleen parasite burden was significantly (P < 0.001) lower in mice treated with Lip-PM-10 or Lip-PM-15 than in mice treated with PBS or control liposomes, but no significant difference was seen between the two groups treated with either Lip-PM-10 or Lip-PM-15. The results suggest that topical liposomal PM may be useful for the treatment of cutaneous leishmaniasis.Leishmaniasis, which has diverse clinical manifestations, is caused by different species of Leishmania and is endemic in many countries (49). Although cutaneous leishmaniasis (CL) is a self-healing disease, healing takes a long time, and healing times of even up to 2 years have been reported (37). Pentavalent antimonials, which are still the first-line treatment for CL, require multiple injections and are painful; as such, they are not tolerated by most of the patients and, moreover, are not always effective. In addition, resistance to pentavalent antimonials has been reported (12,13,33).Paromomycin sulfate (PM) was reported to show anti-Leishmania activity in the 1960s, and since then PM showed promising activity against both CL and visceral leishmaniasis (VL) in clinical trials (13, 31). Recently, the parenteral formulation of PM has been approved for use for the treatment of VL (27). Nevertheless, the systemic use of PM might cause nephrotoxicity. The conventional topical dosage forms of PM have been tested in clinical trials for their activities against CL and showed promising results, but acceptable efficacy was not always seen (2,3,5,13,18,23,28,43). The formidable barrier nature of the stratum corneum (SC) of the skin does not allow the penetration of drugs with high hydrophilicities and molecular weights, like PM (19). Furthermo...

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Section: Vol 53 2009 Topical Liposomal Paromomycin For Leishmaniasimentioning

confidence: 99%

Effect of Topical Liposomes Containing Paromomycin Sulfate in the Course of Leishmania major Infection in Susceptible BALB/c Mice

Jaafari

Bavarsad

Bazzaz

et al. 2009

Antimicrob Agents Chemother

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“…These include an amphotericin B liposome formulation registered in the United States and Europe (AmBisome) (14,105); oral miltefosine (142) which has been registered in India and is now in phase IV trial; a parenteral formulation of aminosidine (paromomycin) (150) currently completing phase III clinical trials in India (www.iowh.org) and on trial in East Africa (www.dndi .org); and oral sitamaquine (previously WR6026), which has completed phase II trials in India, Kenya, and Brazil (50,84,159) and is in development with GlaxoSmithKline (http://science.gsk.com/about/disease.htm). Treatment of CL has also improved through the introduction of topical formulations of paromomycin (8,55,138) and other drugs, including the immunomodulator imiquimod (6,67). Some forms of CL also respond to oral miltefosine and phase III trials have been reported in Central and South America (137).…”

Section: Introductionmentioning

confidence: 99%

Drug Resistance in Leishmaniasis

2006

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SUMMARY Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.

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“…Some topical dosage forms studied for CL topical treatment that should be mentioned are a paromomycin (PA) ointment (14), and a PA/urea ointment (15), but no significant cure of the lesions was observed with these treatments. In animals experimentally infected by Leishmania amazonensis or L.major, the activity of formulations containing only PA is usually low (16,17).…”

Section: Introductionmentioning

confidence: 99%

Study of In Vitro Drug Release and Percutaneous Absorption of Fluconazole from Topical Dosage Forms

2010

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Abstract. The present study aimed to evaluate different dosage forms, emulsions, emulgels, lipogels, and thickened microemulsion-based hydrogel, as fluconazole topical delivery systems with the purpose of determining a formulation with the capacity to deliver the whole active compound and maintain it within the skin so as to be considered a useful formulation either for topical mycosis treatment or as adjuvant in a combined therapy for Cutaneous Leishmaniasis. Propylene glycol and diethyleneglycol monoethyl ether were used for each dosage form as solvent for the drug and also as penetration enhancers. In vitro drug release after application of a clinically relevant dose of each formulation was evaluated and then microemulsions and lipogels were selected for the in vitro penetration and permeation study. Membranes of mixed cellulose esters and full-thickness pig ear skin were used for the in vitro studies. Candida albicans was used to test antifungal activity. A microemulsion containing diethyleneglycol monoethyl ether was found to be the optimum formulation as it was able to deliver the whole contained dose and enhance its skin penetration. Also this microemulsion showed the best performance in the antifungal activity test compared with the one containing propylene glycol. These results are according to previous reports of the advantages of microemulsions for topical administration and they are very promising for further clinical evaluation.

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Treatment of cutaneous leishmaniasis with a topical antileishmanial drug (WR279396): phase 2 pilot study.

Cited by 72 publications

References 14 publications

Effect of Topical Liposomes Containing Paromomycin Sulfate in the Course of Leishmania major Infection in Susceptible BALB/c Mice

Effect of Topical Liposomes Containing Paromomycin Sulfate in the Course of Leishmania major Infection in Susceptible BALB/c Mice

Drug Resistance in Leishmaniasis

Study of In Vitro Drug Release and Percutaneous Absorption of Fluconazole from Topical Dosage Forms

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