deoxycholic-acid and Leishmaniasis--Cutaneous

Cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL) are endemic diseases in America, especially in some countries such as Colombia. Among the therapeutic options is amphotericin B (AB). Nevertheless, its lipid-associated formulations have better safety profiles and effectiveness in other diseases, so far with no comparative studies in CL or MCL. We conducted a retrospective descriptive study describing the effectiveness and adverse effects of AB deoxycholate (ABD), AB colloidal dispersion (ABCD), and liposomal AB (LAB) as third-line treatments for CL and MCL. The effectiveness of LAB (88.5%) was greater than those of ABCD (66.6%) and ABD (80.8%). There were also fewer adverse effects in the LAB group (46.2%) than in the ABD (96.1%) and ABCD (80.9%) groups. LAB is an alternative for the treatment of CL and MCL in patients with therapeutic failure to first- and second-line drugs; findings suggest it might be less toxic and more effective than ABD and ABCD.

Topics: Amphotericin B; Antiprotozoal Agents; Colloids; Colombia; Deoxycholic Acid; Drug Combinations; Humans; Leishmaniasis, Cutaneous; Leishmaniasis, Mucocutaneous; Retrospective Studies

Leishmaniasis is endemic in the Indian subcontinent with predominance of visceral leishmaniasis (VL) due to Leishmania donovani. Cutaneous leishmaniasis (CL) is uncommon, and mucocutaneous leishmaniasis (MCL) is rarely reported in this region. Recent reports reveal a changing epidemiology and atypical manifestations. A retrospective study of 52 suspected cases with cutaneous and mucosal involvement seen from January 2008 to December 2018 in a tertiary care setting in a non-endemic state in southern India is reported. Twelve patients were confirmed to have leishmaniasis; seven had MCL, two had CL, and three had post-kala-azar dermal leishmaniasis (PKDL). All cases were male, with a median age of 41.5 years (interquartile range, 30-55.5 years), and the median duration of the disease was 6 years (interquartile range, 1-9.5 years). Patients with MCL had mucosal involvement including destructive ulcero-proliferative lesions due to delayed diagnosis; none had a history of travel to countries endemic for MCL and all were attributable to L. donovani species. On the other hand, Leishmania major which was the causative species in both CL patients was associated with travel to the Middle East. Patients with PKDL presented with multiple plaques and hypopigmented patches; one had concomitant VL and all were from endemic areas. Hitherto uncommon MCL, caused by potentially atypical variants of L. donovani, has emerged as a new manifestation of leishmaniasis in this region. A high index of suspicion based on lesions seen and history of travel combined with PCR-based diagnostics are required to confirm diagnosis for the various skin manifestations of leishmaniasis.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Antimony Sodium Gluconate; Antiprotozoal Agents; Deoxycholic Acid; Drug Combinations; Humans; India; Itraconazole; Leishmania donovani; Leishmania major; Leishmaniasis, Cutaneous; Leishmaniasis, Mucocutaneous; Male; Middle Aged; Skin

The development of an effective amphotericin B (AmB) topical formulation to replace the systemically toxic injections currently used in cutaneous leishmaniasis (CL) treatment is challenging due to poor absorption through the skin. Aiming at an effective local chemotherapy, we designed PLGA (poly(lactide-co-glycolide acid) microparticles loaded with deoxycholate amphotericin B (d-AmB) for both macrophage intracellular targeting and sustained extracellular release. For that, d-AmB/PLGA microparticles with sizes ranging from 0.5 μm to 20 μm were synthesized and tested both in vitro and in vivo. In vitro, d-AmB/PLGA was more selectively active against intracellular amastigotes of Leishmania amazonensis than free d-AmB (selectivity index = 50 and 25, respectively). In vivo, the efficacy of a single intralesional (i.l) injection with d-AmB/PLGA was determined in early and established BALB/c mouse ear lesions. In early lesions, a single injection given on day 10 of infection was more effective in controlling parasite growth than eight i.l. injections with free d-AmB, as measured on day 120. Such d-AmB/PLGA injection was also effective in established lesions (day 30), leading to 97% parasite burden reduction, as compared with d-AmB or liposomal AmB (Ambisome®) i.l. injection containing the same AmB dose. Pharmacokinetic studies showed that following d-AmB/PLGA injection, AmB leaked slower from non-infected than infected ears, yet remaining in the ear tissue for as long as 30 days. Of interest, AmB was not detectable in the circulating plasma for at least two weeks of d-AmB/PLGA injection, contrasting with the rapid and durable (2 days) detection after free d-AmB injection. Despite the transient ear swelling and local cell infiltration, no alterations in AST, ALT and creatinine serum levels was induced by d-AmB/PLGA. For its approved components, local efficacy, and single-dose applicability, this novel and safe AmB microparticle depot formulation has strong potential as a new therapy for human CL.

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Deoxycholic Acid; Drug Combinations; Drug Delivery Systems; Ear; Leishmaniasis, Cutaneous; Male; Mice; Mice, Inbred BALB C; Nanoparticles; Polyglactin 910

Leishmania braziliensis is the most prevalent species isolated from patients displaying cutaneous and muco-cutaneous leishmaniasis in South America. However, there are difficulties for studying L. braziliensis pathogenesis or response to chemotherapy in vivo due to the natural resistance of most mouse strains to infection with these parasites. The aim of this work was to develop an experimental set up that could be used to assess drug efficacy against L. braziliensis. The model was tested using miltefosine.. A L. braziliensis line, originally isolated from a cutaneous leishmaniasis patient, was passaged repeatedly in laboratory rodents and further genetically manipulated to express luciferase. Once collected from a culture of parasites freshly transformed from amastigotes, 106 wild type or luciferase-expressing stationary phase promastigotes were inoculated subcutaneously in young BALB/c mice or golden hamsters. In both groups, sustained cutaneous lesions developed at the site of inoculation, no spontaneous self- healing being observed 4 months post-inoculation, if left untreated. Compared to the wild type line features, no difference was noted for the luciferase-transgenic line. Infected animals were treated with 5 or 15 mg/kg/day miltefosine orally for 15 days. At the end of treatment, lesions had regressed and parasites were not detected. However, relapses were observed in animals treated with both doses of miltefosine.. Here we described experimental settings for a late-healing model of cutaneous leishmaniasis upon inoculation of a luciferase-expressing L. braziliensis line that can be applied to drug development projects. These settings allowed the monitoring of the transient efficacy of a short-term miltefosine administration.

Topics: Amphotericin B; Animals; Antifungal Agents; Antiprotozoal Agents; Cricetinae; Deoxycholic Acid; Drug Combinations; Female; Gene Expression Regulation, Enzymologic; Leishmania braziliensis; Leishmaniasis, Cutaneous; Luciferases; Male; Mesocricetus; Mice; Mice, Inbred BALB C; Organisms, Genetically Modified; Phosphorylcholine; Time Factors

Cutaneous leishmaniasis is endemic in Salta, the northwestern province of Argentina. We describe an outbreak involving five recreational hunters whose exposure was limited to several hours in a residual patch of primary forest. All patients presented with typical cutaneous lesions after a mean incubation period of 59 days (range 15-78), and one developed simultaneous mucosal involvement. Polymerase chain reaction analysis of lesions confirmed Leishmania (V.) braziliensis as the etiologic agent in three cases. All patients were cured with anti-Leishmania treatment. Entomologic surveys in the transmission area revealed a predominance of Lutzomyia neivai. This outbreak report confirms a microfocal transmission pattern of tegumentary leishmaniasis in the Americas and based on a well-determined exposure, allows the determination of incubation times for leishmaniasis caused by Leishmania braziliensis.

Topics: Adult; Amphotericin B; Animals; Antiprotozoal Agents; Argentina; Deoxycholic Acid; Disease Outbreaks; Drug Combinations; Environmental Exposure; Humans; Insect Vectors; Leishmaniasis, Cutaneous; Psychodidae; Trees