Topical Paromomycin Research Articles

Enhanced topical paromomycin delivery for cutaneous leishmaniasis treatment: Passive and iontophoretic approaches

Conventional treatments for cutaneous leishmaniasis, a neglected vector-borne infectious disease, can frequently lead to serious adverse effects. Paromomycin (PAR), an aminoglycoside antibiotic, has been suggested for the topical treatment of disease-related lesions, but even when formulated in high drug-loading dosage forms, presents controversial efficacy. The presence of five ionizable amino groups hinder its passive cutaneous penetration but make PAR an excellent candidate for iontophoretic delivery. The objective of this study was to verify the feasibility of using iontophoresis for cutaneous PAR delivery and to propose a topical passive drug delivery system that could be applied between iontophoretic treatments. For this, in vitro iontophoretic experiments evaluated different application durations (10, 30, and 360 min), current densities (0.1, 0.25, and 0.5 mA/cm2), PAR concentrations (0.5 and 1.0 %), and skin models (intact and impaired porcine skin). In addition, 1 % PAR hydrogel had its penetration profile compared to 15 % PAR ointment in passive transport. Results showed iontophoresis could deliver suitable PAR amounts to dermal layers, even in short times and with impaired skin. Biodistribution assays showed both iontophoretic transport and the proposed hydrogel delivered higher PAR amounts to deeper skin layers than conventional ointment, even though applying 15 times less drug. To our knowledge, this is the first report of PAR drug delivery enhancement by iontophoresis. In summary, the association of iontophoresis with a topical application of PAR gel seems appropriate for improving cutaneous leishmaniasis treatment.

The Effect of Oleuropein on The Mitochondrial Membrane Potential and Generation of Reactive Oxygen Species on Leishmania tropica Promastigotes

Leishmania parasites, which are reported to be endemic in 98 countries around the world, infect humans as well as wild and domestic carnivores and small mammals, and are transmitted by sand flies (Phlebotomus, dwarf sandflies). It is reported that 350 million people are at risk and two million new cases are seen in the world every year. It has been reported that different drugs (topical paromomycin, oral miltefosine, ketoconazole, rifampin, and zinc) have been tried in studies especially in endemic regions in the treatment of cutaneous leishmaniasis, and response to treatment has been obtained at different rates. Today, the search for alternative treatments continues and many studies have been carried out for this purpose. For centuries, olive leaf extracts have been used to maintain health. Oleuropein has numerous health benefits, including antioxidant, antimicrobial, anti-inflammatory, antiatherogenic, anticarcinogenic, antiviral activities, cardio- and neuroprotective, hepatoprotective effects. The aim of this study was to determine and understand the mode of action of oleuropein, the cell death mechanisms caused by oleuropein in L.tropica promastigotes. In this study, the phenolic and flavonoid content of oleuropein was determined by HPLC method. The antioxidant capacity and the amount of oleuropein were determined. Afterwards, morphological and physiological (mitochondrial membrane potential, formation of reactive oxygen species, Annexin V binding) changes triggered by oleuropein in L.tropica promastigotes were investigated using flow cytometry. Our studies revealed that apoptotic properties such as mitochondrial dysfunction, production of reactive oxygen species, flip-flop action of phosphatidylserine could induce cell death in L.tropica promastigotes. It has been observed that oleuropein induced typical apoptotic morphological features in L.tropica promastigotes. Total phenolic content and total flavonoid content values of oleuropein extract were determined as 33 mg/g and 229 mg/g. The radical removal method was used to investigate the antioxidant capacity of methanol extracts against free radicals. Total antioxidant content of oleuropein extract was determined as 87%. In addition, the amount of oleuropein in the oleuropein extract was determined as 21. 1% by HPLC. The oleuropein dose that killed 50% of L.tropica promastigotes, that is the IC50 value, was detected as 46.6 µg/mL after 24 hours. It was observed that the parasites in the control group preserved their typical morphological features with a single nucleus, flagella, kinetoplast and narrow cell body at both 24 and 48 hours. It was observed that as oleuropein concentrations increased, the and kinetoplasts of L.tropica promastigotes could not be distinguished from each other, they moved away from the narrow cell body structure, they lost their flagella and turned into a round form, and they moved away from the typical form of the parasite. The percentage of Annexin V+ apoptotic cells was found to be 2.9 ± 0.4% in the untreated control group, and 38.1 ± 6.9% in the oleuropein-treated group. Polarization in the mitochondrial membrane of healthy promastigotes caused an approximately 1.7-fold change in the direction of depolarization in oleuropein-treated promastigotes. According to these findings, oleuropein triggered mitochondria-related death in L.tropica promastigotes. Moreover, 1.4 ± 0.2 fold increase in reactive oxygen species production was detected in oleuropein-treated promastigotes compared to the untreated control group. Comparisons between groups were made using the independent sample t test method. In conclusion, phenolic compounds of olive leaf extract oleuropein induced apoptotic cell death in L.tropica promastigotes. Our results support that olive products such as oleuropein may have anti-parasitic effects.

Treatment of Cutaneous Leishmaniasis in a Nonendemic Country: A Case Series of Children in Australia.

We describe 4 cases of cutaneous leishmaniasis in children in Australia. Treatment is challenging given lack of firm guidelines and limited access to conventional modalities used in endemic countries. Topical paromomycin or oral fluconazole were effective outpatient-based first-line treatments, however, topical paromomycin use was limited by expense to import or compound locally.

Refractory facial cutaneous leishmaniasis in a child

Cutaneous leishmanasis (CL) is the most common form of leishmaniasis. The lesions are typically painless and can self-resolve. Chronic cases occur, particularly in immunocompromised patients. This report describes the treatment of a paediatric patient with refractory cutaneous leishmaniasis. Treatment of CL in children requires consideration of drug dosing, palatability, ethics of utilising treatments with limited supporting evidence and the potential long-term side effects. An immunocompetent 13-year-old girl presented with non-healing ulcer on her face following migration from Pakistan in 2018. The lesion had persisted despite previous empiric treatment with intra-lesional sodium stibogluconate. Biopsy was performed and Leishmaniasis tropica identified by PCR. Response to topical paromomycin was poor. There was partial resolution with oral miltefosine 50 mg BD for 28 days. Re-ulceration occurred within 6 weeks of cessation. The use of liposomal amphotericin was precluded by initial anaphylaxis; desensitisation was unsuccessful. Miltefosine was restarted at a higher dose of 50 mg TDS combined with fluconazole 300 mg daily. Again there was partial response but diminished compared to previous. After 3 months, fluconazole was replaced with allopurinol 200 mg TDS for 30 days. The lesion remained static. Topical GM-CSF was subsequently added for 3 weeks, with marginal improvement. Finally, photodynamic therapy was initiated in December 2019.

Successful Treatment of Cutaneous Leishmaniasis with Topical Paramomycin in a Child After Treatment Failure with Systemic Fluconazole

It is challenging to find safe, nonscarring and noninvasive treatment of facial cutaneous leishmaniasis (CL) in children. Herein, we report a child with CL from a region endemic for Leishmania tropica, whose lesion persisted after treatment with oral fluconazole but responded to topical paromomycin. Paromomycin should be considered early for treatment of Old World CL and is a well-tolerated and effective mode of therapy for facial lesions.

Combined suboptimal schedules of topical paromomycin, meglumine antimoniate and miltefosine to treat experimental infection caused by Leishmania (Viannia) braziliensis.

This study aimed to evaluate the efficacy of binary combinations of suboptimal schedules of drugs with different administration routes (topical paromomycin, intramuscular meglumine antimoniate and oral miltefosine) to treat animals infected with Leishmania (Viannia) braziliensis. Hamsters were inoculated with L. (V.) braziliensis and after ulceration of lesions, divided into seven groups: untreated control, paromomycin, miltefosine, meglumine antimoniate, meglumine antimoniate + paromomycin, miltefosine + paromomycin and meglumine antimoniate + miltefosine. Meglumine antimoniate and miltefosine were administered at low doses and topical paromomycin at a single daily application regimen. The animals were treated for 20 consecutive days (meglumine antimoniate and/or paromomycin) and/or 10 alternate days (miltefosine). Lesion sizes were determined weekly. Upon completion of treatment, parasites were recovered from skin lesions and spleens and evaluated by limiting dilution assay. The combinations of a once daily application of paromomycin with low doses of miltefosine or meglumine antimoniate yielded higher efficacies in reducing the parasite load as well as lesion size when compared with any of these drugs administered as monotherapy regimens at the same suboptimal schedules. Considering the parameters evaluated, the combinations of a systemic therapy with topical treatment were more effective than monotherapy with each of these drugs. These combinations may represent an alternative combination strategy for the treatment of leishmaniasis caused by L. (V.) braziliensis.

Can a simple outpatient-based treatment be used to treat cutaneous leishmaniasis in young children? A Critically Appraised Topic

A 5-year-old boy from rural Afghanistan presented with a 1-year history of a skin lesion on his left knee, confirmed by polymerase chain reaction to be cutaneous leishmaniasis (Leishmania tropica). Conventional treatment of cutaneous leishmaniasis involves intravenous or intralesional pentavalent antimonials. The aim of this Critically Appraised Topic (CAT) is therefore to determine what alternative effective but less painful treatments (such as oral or topical therapies) can be used to treat cutaneous leishmaniasis in children. Embase and PubMed were searched for 'cutaneous leishmania*' AND 'treatment' AND 'children' in August 2014. All abstracts from April 2008 to August 2014 were reviewed. This search period was chosen to follow on from the Cochrane reviews on Old World and American leishmaniasis. Five randomized controlled trials met our inclusion criteria and have been included in this CAT. The study design and reporting quality in most of the trials included in both Cochrane reviews was found to be poor, and neither Cochrane review investigated the effect of patient age on response to treatment. This CAT identified two nonpainful treatments, topical paromomycin and oral miltefosine, whose effective use in children is supported in the literature. However, both of these treatments are currently unlicensed in the U.K. Our patient was successfully treated with miltefosine 20mg twice daily for 4weeks, leading to good resolution of the leishmaniasis plaque but with residual scarring.

Editorial Commentary: Local Treatments for Cutaneous Leishmaniasis

Cutaneous leishmaniasis (CL) is an infection caused by various species of Leishmania protozoa, which are usually transmitted by the bite of various species of phlebotomine sandflies [1]. It is a “neglected tropical disease” that causes significant morbidity and social stigmatization and also occurs in subtropical regions such as southern Europe and the southern United States. Its clinical presentations and natural history vary considerably, and although nearly all cases will eventually heal spontaneously, this can take more than a year and be complicated by secondary bacterial infections, lymphatic involvement, local recurrences, and mucosal leishmaniasis due to Leishmania (Viannia) braziliensis complex infections in certain New World countries. Laboratory diagnosis requires specialist parasitology and molecular biology techniques, and numerous local and systemic treatment options are available. Recent studies [2, 3] offer a timely reminder of the value of local (topical or intralesional) treatments for CL, when most research is focused on systemic (oral or parenteral) treatments instead. Morizot et al [2] show how national treatment guidelines and expert advice can optimize the use of simple wound care only or local treatment for a wide range of CL infections in travelers with impressive results. Overall, 62% of cases were treated this way and cure rates within 60 days of starting treatment were 92% for wound care only and 79% for cryotherapy plus intralesional antimony, compared to 60% for systemic treatments. The majority of cases had a good prognosis and were suitable for nonsystemic treatment according to the national guidelines, whereas those with a worse prognosis were more likely to be given systemic treatment, and so there is obvious selection bias. However, some centers would have treated all of these cases with systemic treatments at higher cost and with more adverse effects and so the results remain valuable. Interestingly, no patients seem to have withdrawn due to the transient but severe pain sometimes caused by intralesional treatment (or other forms of cryotherapy) that may dissuade physicians from using such techniques. Systemic treatments for CL are often preferred for several reasons, including the fact that most new therapies for CL are derived from those used for visceral leishmaniasis, which are inevitably systemic in nature. Local treatments are also more difficult to evaluate due to problems in standardizing the dose given during administration of a topical or intralesional drug. Even when local treatments are known to be effective, there may be problems in the provision of therapies such as intralesional pentavalent antimonial (SbV) drugs (sodium stibogluconate or meglumine antimoniate), cryotherapy, topical paromomycin (aminosidine), and thermotherapy. Overall, our healthcare systems often make it

Topical Paromomycin with or without Gentamicin for Cutaneous Leishmaniasis

BackgroundThere is a need for a simple and efficacious treatment for cutaneous leishmaniasis with an acceptable side-effect profile.MethodsWe conducted a randomized, vehicle-controlled phase 3 trial of topical treatments containing 15% paromomycin, with and without 0.5% gentamicin, for cutaneous leishmaniasis caused by Leishmania major in Tunisia. We randomly assigned 375 patients with one to five ulcerative lesions from cutaneous leishmaniasis to receive a cream containing 15% paromomycin–0.5% gentamicin (called WR 279,396), 15% paromomycin alone, or vehicle control (with the same base as the other two creams but containing neither paromomycin nor gentamicin). Each lesion was treated once daily for 20 days. The primary end point was the cure of the index lesion. Cure was defined as at least 50% reduction in the size of the index lesion by 42 days, complete reepithelialization by 98 days, and absence of relapse by the end of the trial (168 days). Any withdrawal from the trial was considered a treatment failure.ResultsThe rate of cure of the index lesion was 81% (95% confidence interval [CI], 73 to 87) for paromomycin–gentamicin, 82% (95% CI, 74 to 87) for paromomycin alone, and 58% (95% CI, 50 to 67) for vehicle control (P<0.001 for each treatment group vs. the vehicle-control group). Cure of the index lesion was accompanied by cure of all other lesions except in five patients, one in each of the paromomycin groups and three in the vehicle-control group. Mild-to-moderate application-site reactions were more frequent in the paromomycin groups than in the vehicle-control group.ConclusionsThis trial provides evidence of the efficacy of paromomycin–gentamicin and paromomycin alone for ulcerative L. major disease. (Funded by the Department of the Army; ClinicalTrials.gov number, NCT00606580.)

Editorial introductions

Current Opinion in Infectious Diseases was launched in 1988. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of infectious diseases is divided into 11 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Monica A. SlavinMonica A. SlavinDr Monica Slavin has been Head of the Department of Infectious Diseases at the Peter MacCallum Cancer Centre in Melbourne, Australia since 2000. She is a Professor in the Department of Medicine at the University of Melbourne, Australia and a Research Associate at the Macfarlane Burnet Centre for Medical Research and Public Health, Australia. She received her medical degree from the University of Melbourne and after completing training in infectious diseases in Melbourne, worked for 3 years in the Program in Infectious Diseases at Fred Hutchison Cancer Research Center in Seattle, USA. She has been an infectious diseases physician since 1993 with a major interest in infections in the immunocompromised, especially patients with cancer and undergoing stem cell transplantation. Her current research focus is prevention and early treatment of invasive fungal infections in haematology patients. She has served on national steering committees for the development of antifungal and fever and neutropenia treatment guidelines and for the conduct of Australia-wide studies of the epidemiology of fungal infection. Simon L. CroftSimon L. CroftSimon Croft is Professor of Parasitology and Head of the Faculty of Infectious and Tropical Diseases at the London School of Hygiene & Tropical Medicine, London, UK. He trained as a parasitologist at the Liverpool School of Tropical Medicine, UK, and, after post-doctoral periods in the laboratory researching anti-parasite drug mechanisms and in disease endemic countries working on the transmission of African trypanosomiasis, he moved to research on drug discovery and development. His expertise and knowledge on anti-parasitic and antimicrobial chemotherapy was developed while working for 5 years with the Wellcome Research Laboratories, Beckenham, UK in the 1980 s. Following his return to academia, Simon focused his research on the identification and evaluation of novel drugs and formulations for the treatment of leishmaniasis, malaria, human African trypanosomiasis (sleeping sickness) and American trypanosomiasis (Chagas disease). This research included projects on miltefosine, AmBisome and topical paromomycin, all of which reached clinical trials for the treatment of leishmaniasis, and many others with academic and private sector partners. From 2004 to 2007 Simon was the first R & D Director of the Drugs for Neglected Diseases Initiative (DNDi), Geneva. Current research interests include drug – immune response interactions, pharmacokinetic/pharmacodynamic (PK PD) relationships in leishmaniasis and trypanosomiasis and development of pharmaceutical formulations for parasitic diseases. Deenan PillayDeenan PillayFollowing a PhD in Biochemistry, Professor Pillay studied Medicine in Newcastle upon Tyne, UK, and undertook postgraduate training in medical virology at St Thomas's Hospital and Royal Free Hospital, London, UK, followed by an National Institute of Health (NIH) fellowship in the laboratory of Dr Doug Richman, University of California, San Diego, USA, where he developed an interest in HIV drug resistance. On his return to the UK, Professor Pillay took up the post of Consultant Medical Virologist, Birmingham Public Health Laboratory, UK, and in 1996 became Director of the National PHLS Reference Laboratory for antiviral drug resistance. Currently Deenan Pillay is Professor of Virology at University College London (UCL), UK, Head of the Research Department of Infection and Honorary Consultant Virologist at University College London Hospital (UCLH). He is Programme Director for Infection, Immunology and Inflammation at the National Institute for Health Research (NIHR) UCLH/UCL Biomedical Research Centre, UK and Programme Director for Infectious Diseases for UCL Partners. He is also a Senior Investigator for the NIHR. His research focuses on the biological and clinical implications of HIV drug resistance, and the molecular epidemiology of HIV. In addition, he works on international studies of HIV treatment rollout, and is Director of one of the five World Health Organization Specialist Reference Laboratories for HIV drug resistance.

Editorial introductions

Current Opinion in Infectious Diseases was launched in 1988. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of infectious diseases is divided into 11 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. Section Editors Monica SlavinMonica SlavinDr Monica Slavin has been Head of the Department of Infectious Diseases at the Peter MacCallum Cancer Centre in Melbourne, Australia since 2000. She is an Associate Professor in the Department of Medicine at the University of Melbourne and a Research Associate at the Macfarlane Burnet Centre for Medical Research and Public Health. She received her medical degree from the University of Melbourne and after completing training in Infectious Diseases in Melbourne, worked for 3 years in the Program in Infectious Diseases at Fred Hutchison Cancer Research Center in Seattle, USA. She has been an Infectious Diseases physician since 1993 with a major interest in infections in immunocompromised especially patients with cancer and undergoing stem cell transplantation. Her current research focus is prevention and early treatment of invasive fungal infections in haematology patients. She has served on national steering committees for the development of antifungal and fever and neutropenia treatment guidelines and for the conduct of Australia-wide studies of the epidemiology of fungal infection. Simon CroftSimon CroftSimon Croft is Professor of Parasitology in the Faculty of Infectious and Tropical Diseases at the London School of Hygiene & Tropical Medicine, London, UK. He gained a PhD at the Liverpool School of Tropical Medicine and, after post-doctoral periods working in the laboratory on parasite ultrastructure and biochemistry and overseas on the transmission of African trypanosomiasis, he moved to research on anti-protozoal chemotherapy. His expertise and knowledge on anti-protozoal chemotherapy was developed while working with the Wellcome Research Laboratories, Beckenham, UK in the 1980 s. Following his return to academia, Simon focused his research on the identification and evaluation of novel drugs and formulations for the treatment of leishmaniasis, malaria, human African trypanosomiasis (sleeping sickness) and South American trypanosomiasis (Chagas disease). This work included projects on miltefosine, AmBisome and topical paromomycin, all of which reached clinical trials for the treatment of leishmaniasis. Other current research interests include the drug – immune response interaction and pharmacokinetics and drug delivery of antiprotozols. From 2004 to 2007 he was the Research and Development Director at the Drugs for Neglected Diseases Initiative (DNDi), Geneva. Deenan PillayDeenan PillayFollowing a PhD in Biochemistry, Dr Pillay studied Medicine in Newcastle upon Tyne and undertook postgraduate training in medical virology at St Thomas's Hospital and Royal Free Hospital, London. He was then a visiting NIH Fellow in the laboratory of Dr Doug Richman, University of California, San Diego, where he developed an interest in HIV Drug Resistance. On his return to the UK, Dr Pillay took up the post of Consultant Medical Virologist, Birmingham Public Health Laboratory and in 1996 became Director of the National PHLS Reference Laboratory for antiviral drug resistance. In 2003 he moved to University College London, with a joint appointment at the Central Public Health Laboratory, Colindale, where he is pursuing academic and epidemiological studies on drug resistance, with particular reference to HIV. Dr Pillay's main areas of interest are the treatment of viral infections and laboratory monitoring of such treatment. His current research is focused on clinical correlates of antiviral drug resistance, viral informatic approaches to antiviral drug resistance data, and epidemiology of drug resistance.

Liposomal amphotericin B treatment of cutaneous leishmaniasis due to Leishmania tropica

Cutaneous leishmaniasis (CL) is endemic in Israel, and in the past, has been attributed almost exclusively to Leishmania major. Over the last decade or so, an increase in Leishmania tropica (L. tropica) infections has occurred in several regions of Israel. Topical treatment of Old World CL is usually the rule, however, in some cases systemic treatment is indicated. Liposomal amphotericin B (L-AmB) is efficacious and safe for treating visceral leishmaniasis but its role in treating various forms of CL is yet to be defined. In this study, we summarize the efficacy and safety of L-AmB treatment in a series of Israeli patients with L. tropica infection. Cases of PCR-proven CL caused by L. tropica were treated in an outpatient setting. Treatment schedule consisted of five consecutive days of 3 mg/kg L-AmB, followed by a sixth dose on day 10. Thirteen consecutive patients (11 men, two women), received L-AmB. Mean age was 15.3 years; of the 13 patients, 85% had facial lesions. Six had previously failed intralesional sodium stibogluconate treatment and four had failed topical paromomycin treatment. Eleven of 13 patients (84%) achieved complete clinical cure within 2 months. Mean follow-up of 11 months revealed no relapses. Side effects were mild and none terminated treatment prematurely. A non-randomized study, with a small number of patients. Liposomal amphotericin B treatment for L. tropica is effective, well tolerated and cost beneficial in countries where cost of hospital-care is significant.

Reductions in Skin and Systemic Parasite Burdens as a Combined Effect of Topical Paromomycin and Oral Miltefosine Treatment of Mice Experimentally Infected with Leishmania ( Leishmania ) amazonensis

This study aimed to investigate the activity of a combination of topical paromomycin gel and oral miltefosine for the treatment of experimental cutaneous leishmaniasis caused by Leishmania (Leishmania) amazonensis. The efficacy of the combination, evaluated by measuring lesion size and parasite burden in the skin and spleen, was assessed in BALB/c mice infected by L. (L.) amazonensis. The miltefosine was administered orally at 10 mg/kg of body weight/day for 10 days, while 10% paromomycin gel was applied topically twice a day for 20 days. Treatment of the experimentally infected animals with a topical paromomycin-oral miltefosine combination induced a statistically significant reduction in lesion size and parasite burden in the skin and spleen, with complete healing of ulcers, compared with those treated with a placebo group. A combination of topical paromomycin gel and oral miltefosine provided enhanced efficacy in the treatment of L. (L.) amazonensis-infected mice, showing activity higher than that observed for the monotherapeutic regimens.

Kutane Leishmaniase der Alten Welt nach Spanienaufenthalt

Die kutane Leishmaniase der Alten Welt kommt endemisch im Mittelmeerraum vor und weist eine steigende Inzidenz auf. Oft kommt es durch diagnostisch schwierige Verläufe zu einer Therapieverschleppung. Wir berichten über einen 27-jährigen Patienten mit kutaner Leishmaniase der Nase nach Spanienaufenthalt. Nach langwieriger Diagnostik konnte die Therapie mit intraläsionalen Injektionen von Meglumin-Animonat in Kombination mit topischem Paromomycin erfolgreich durchgeführt werden.

Cutaneous and mucocutaneous leishmaniasis: emerging therapies and progress in disease management

Importance of the field: Cutaneous leishmaniasis (CL) is a major tropical skin disease. Its incidence continues to increase, and disease control and management are challenging. Available therapies remain inadequate and are associated with low efficacy, toxicity, difficulties with administration, or are expensive.Areas covered in this review: This article describes progress in the therapeutics of CL since 2006. Clinical trials have provided further evidence for the use of alternative systemic agents to first-line antimonials, an enhanced topical paromomycin preparation, the efficacy of thermotherapy, photodynamic therapy as an emerging physical therapy, and the role of immunotherapy and immunomodulators as adjuncts to chemotherapy. In addition, in vitro studies have demonstrated the anti-leishmanial effects of several drugs, which might represent potential future therapeutic agents for CL.What the reader will gain: An overview of the magnitude and complexity of this heterogenous disease, and an update on recent advances in therapeutics and future directions for new drug development.Take home message: Drug therapy for CL must be tailored according to infective species, endemic region, and host responses; a range of different therapies and modalities is therefore required. The impetus for new drug development must continue, combination therapies need to be evaluated, and robust and comparative trials of existing agents are required to adequately assess their efficacy and tolerability.

Combined topical paromomycin and oral miltefosine treatment of mice experimentally infected with Leishmania (Leishmania) major leads to reduction in both lesion size and systemic parasite burdens

This study aimed to investigate the activity of the combination of topical paromomycin gel and oral miltefosine for the treatment of experimental cutaneous leishmaniasis caused by Leishmania (Leishmania) major. The efficacy of the combination, evaluated by measuring lesion size and parasite burden in the skin and spleen, was assessed in BALB/c mice infected by L. (L.) major. Miltefosine was administered orally at 25 mg/kg/day for 10 days, while 10% paromomycin gel was applied topically twice a day for 10 days. Treatment of the experimentally infected animals with topical paromomycin + oral miltefosine combination induced a statistically significant reduction in lesion size and parasite burden in the skin, with complete healing of ulcers, as compared with those treated with oral miltefosine or placebo. Furthermore, topical paromomycin + oral miltefosine combination was as effective as topical paromomycin alone to reduce the lesion size and parasite load in lesions. However, the efficacy of the combination was significantly higher than that observed for the other treatments, including topical paromomycin alone, in reducing the parasite burden in spleen. The combination of topical paromomycin gel and oral miltefosine provides an enhanced efficacy in the treatment of L. (L.) major-infected mice, thus presenting a significantly higher activity than that observed for the monotherapeutic regimens.

Is Paromomycin an Effective and Safe Treatment against Cutaneous Leishmaniasis? A Meta-Analysis of 14 Randomized Controlled Trials

BackgroundHigh cost, poor compliance, and systemic toxicity have limited the use of pentavalent antimony compounds (SbV), the treatment of choice for cutaneous leishmaniasis (CL). Paromomycin (PR) has been developed as an alternative to SbV, but existing data are conflicting.Methodology/Principal FindingsWe searched PubMed, Scopus, and Cochrane Central Register of Controlled Trials, without language restriction, through August 2007, to identify randomized controlled trials that compared the efficacy or safety between PR and placebo or SbV. Primary outcome was clinical cure, defined as complete healing, disappearance, or reepithelialization of all lesions. Data were extracted independently by two investigators, and pooled using a random-effects model. Fourteen trials including 1,221 patients were included. In placebo-controlled trials, topical PR appeared to have therapeutic activity against the old world and new world CL, with increased local reactions, when used with methylbenzethonium chloride (MBCL) compared to when used alone (risk ratio [RR] for clinical cure, 2.58 versus 1.01: RR for local reactions, 1.60 versus 1.07). In SbV-controlled trials, the efficacy of topical PR was not significantly different from that of intralesional SbV in the old world CL (RR, 0.70; 95% confidence interval, 0.26–1.89), whereas topical PR was inferior to parenteral SbV in treating the new world CL (0.67; 0.54–0.82). No significant difference in efficacy was found between parenteral PR and parenteral SbV in the new world CL (0.88; 0.56–1.38). Systemic side effects were fewer with topical or parenteral PR than parenteral SbV.Conclusions/SignificanceTopical PR with MBCL could be a therapeutic alternative to SbV in selected cases of the old world CL. Development of new formulations with better efficacy and tolerability remains to be an area of future research.

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

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 degrees 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 microg/ml, respectively, and those against L. major amastigotes in macrophages were 24.64 and 26.44 microg/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.

Efeito de uma formulação hidrofílica de paromomicina tópica na leishmaniose cutânea em pacientes com contra-indicações de tratamento com antimonial pentavalente

The therapeutic effect of and adverse events associated with topical use of 10% paromomycin gel on cutaneous leishmaniasis are described. Fifteen patients with cutaneous leishmaniasis fulfilled the following inclusion criteria: contraindication for the use of meglumine antimoniate, positive Montenegro skin test and up to four ulcerated lesions. The formula was prescribed twice a day for 20 days. Fourteen patients were available for the therapeutic outcome evaluation. The cure rate was 21.4% (3/14); 50% improved as far as complete epithelialization; and the failure rate was 28.6%. Nine patients who did not initially present cure were retreated. Eight received a new series of topical paromomycin and one was treated with meglumine antimoniate. Two patients did not receive any new treatment and had continuous slow improvement. Five out of the eight patients retreated with topical paromomycin achieved clinical cure, and three presented failure, including one patient who had shown any improvement with the first treatment. For 53.3% of the patients, the adverse events were mild and local and never led to treatment suspension.

Failure of Nitazoxanide to Cure Trichomoniasis in Three Women

Failure of Nitazoxanide to Cure Trichomoniasis in Three Women