amphotericin-b and Neglected-Diseases

Recently, mycetoma was added to the World Health Organization's list of neglected tropical disease priorities. Fusarium as a genus has been reported to cause eumycetoma, but little is known about the species involved in this infection and their identification. In this study, molecular tools were applied to identify Fusarium agents from human eumycetoma cases. The partial translation elongation factor 1-alpha (TEF-1α) gene was used as diagnostic parameter. Two additional cases of eumycetoma, due to F. keratoplasticum and F. pseudensiforme, respectively, are presented. A systematic literature review was performed to assess general features, identification, treatment and outcome of eumycetoma infections due to Fusarium species. Of the 20 reviewed patients, the majority (75%) were male. Most agents belonged to the F. solani species complex, ie F. keratoplasticum, F. pseudensiforme, and an undescribed lineage of F. solani. In addition, F. thapsinum, a member of Fusarium fujikuroi species complex was encountered. The main antifungal drugs used were itraconazole, ketoconazole and amphotericin B, but cure rates were low (15%). Partial response or relapse was observed in some cases, and a case ended in amputation. Clinical management of eumycetoma due to Fusarium is complex and combination therapy might be required to increase cure rates.

Topics: Adult; Aged; Amphotericin B; Amputation, Surgical; Antifungal Agents; Female; Fusariosis; Fusarium; Humans; Itraconazole; Male; Microbial Sensitivity Tests; Middle Aged; Mycetoma; Neglected Diseases; Peptide Elongation Factor 1; Phylogeny; Recurrence; Sequence Analysis, DNA; Young Adult

Visceral leishmaniasis is a serious public health problem on the Indian subcontinent, causing high morbidity and mortality. The governments in the region launched a visceral leishmaniasis elimination initiative in 2005. We review knowledge gaps and research priorities. Key challenges include low coverage of health services for those most at risk, drug resistance, the absence of a vaccine, and the complex biology of the sandfly-human host transmission cycle. Vector control is an essential component, but innovation in this field is insufficient. Substantial progress has been made in the area of diagnostic, therapeutic, and vaccine development, but there are still many hurdles to overcome. For visceral leishmaniasis elimination to become a reality, effective deployment of these existing and new tools is essential. A strong commitment at community level is imperative, and appropriate diagnostic and treatment services as well as effective epidemiological surveillance need to be ensured.

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Health Services Accessibility; Humans; India; Insect Control; Insect Vectors; Leishmaniasis, Visceral; Neglected Diseases; Phosphorylcholine; Psychodidae; Public Health

Visceral leishmaniasis (VL) has been one of the most neglected tropical diseases in India. Concurrent and correct data on the burden of VL is vital to plan, allocate trained resources and to monitor the progress of the elimination program. More emphasis on integrated vector management can help in combating the disease spread. Effective surveillance, active and accurate diagnosis using rK39 strip test and use of an affordable, safe and efficient treatment option like liposomal amphotericin B remain the key components of VL control. Sustained advocacy, information, education and communication are needed in all the endemic areas. In this paper, we review the effectiveness of the strategies adopted in VL elimination in India.

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Communicable Disease Control; Government Programs; Humans; India; Insect Vectors; Insecticides; Leishmania donovani; Leishmaniasis, Visceral; Neglected Diseases; Preventive Health Services; Program Evaluation

Visceral leishmaniasis (VL) is a neglected tropical disease with more than 30,000 cases annually reported worldwide. In Brazil, about 3,700 cases are annually reported. The VL clinical presentation is variable, from asymptomatic to severe cases with a high risk of death. We reported three cases of VL with clinical sign similarities but distinct development. All cases had bone marrow hemophagocytosis and hemophagocytic lymphohistiocytosis (HLH) criteria. HLH is a rare condition that may have secondary causes, including infectious and parasitic diseases, like VL. The delayed recognition of the secondary HLH (sHLH) association to VL may cause unfavorable outcomes and death.

Topics: Adult; Amphotericin B; Antiprotozoal Agents; Brazil; Fatal Outcome; Female; Humans; Immunoglobulins; Leishmaniasis, Visceral; Lymphohistiocytosis, Hemophagocytic; Male; Methylprednisolone; Neglected Diseases; Treatment Outcome; Young Adult

Therapeutic options for the treatment of leishmaniasis are insufficient and need improvements owing to their low efficiency and high toxicity as well as the emergence of resistant strains. The limited number of new drugs for neglected diseases and lack of innovation in your development are still challenges. In this context, the process of discovery and development of biological assays play a pivotal role for the identification of bioactive compounds. The assays currently used for screening of drugs with cytotoxic activity against Leishmania parasites, include different processes that utilize intact parasite (free or intracellular) or specific enzymes of metabolism as a target cell. These assays allow the screening of large numbers of samples followed by more detailed secondary confirmatory assays to confirm the observed activity and assess their toxicity. In the present study, we described the development of a new functional and more complete assay that enables simultaneous assessment of potential anti-Leishmania compounds through evaluation of internalization of fluorescein-labeled L. braziliensis promastigotes by human peripheral blood monocytes and their cytotoxicity by flow cytometry. We standardized the conditions for parasite labeling to achieve better phagocytosis analysis by setting the ratio of number of parasites per cell as 1 to 2, at incubation time of 6h. The cytotoxicity assessment was performed by the quantification of cells undergoing early/late apoptosis and necrosis using a double labelling platform employing 7AAD for late apoptosis and necrosis analysis and Annexin-V for early apoptosis evaluation. Hemolysis analysis was an additional parameter to test cytotoxicity. Two drugs used on clinic (Amphotericin B and Glucantime®) were used to validate the proposed methodology, and the assay was able to detect their known leishmanicidal activity and immunotoxicity properties. This new predictive assay will contribute to the development of translational medicine strategies in drug discovery for neglected diseases such as leishmaniasis.

Topics: Adult; Amphotericin B; Animal Testing Alternatives; Animals; Antiprotozoal Agents; Drug Discovery; Drug Evaluation, Preclinical; Flow Cytometry; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Humans; Leishmania; Leishmania braziliensis; Leishmaniasis; Leukocytes; Meglumine Antimoniate; Microscopy, Confocal; Middle Aged; Monocytes; Neglected Diseases; Time Factors; Young Adult

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Bangladesh; Disease Vectors; Drug Therapy, Combination; Epidemiological Monitoring; Humans; India; International Cooperation; Leishmaniasis, Visceral; Neglected Diseases; Nepal; Paromomycin; Phosphorylcholine; Program Development; Program Evaluation

Topics: Amphotericin B; Bone Marrow Examination; Child; Diagnosis, Differential; Female; Hepatomegaly; Humans; Hyperpigmentation; Leishmania; Leishmaniasis; Neglected Diseases; Splenomegaly

Post kala-azar dermal leishmaniasis (PKDL) is a neglected parasitic disease that occurs after apparent cure from visceral leishmaniasis (VL) and poses a challenge for elimination of VL, being its proposed reservoir. Several epidemiological studies have proposed that sex hormones may account for the increased susceptibility of males towards infectious diseases, including leishmaniasis; however, the role of testosterone and sex bias, if any, in PKDL has not been evaluated.. The study population included 87 patients with PKDL and 39 with VL; levels of testosterone were measured by competitive enzyme-linked immunosorbent assay along with their levels of antileishmanial immunoglobulin and IgG. The association of testosterone, if any, was then correlated with age, gender, humoral response, lesional profile, disease duration, and lag period.. A male predominance was evident in PKDL, not in VL; importantly, this male bias was predominant postpubertal, strongly indicative of an association between sex hormone and disease progression. Male patients with PKDL had significantly higher levels of testosterone, which regressed significantly with miltefosine, not with sodium antimony gluconate. Additionally, a significant correlation was found between plasma testosterone and antileishmanial IgG.. Taken together, our study has established a male dominance in PKDL, which showed a strong association with testosterone. This information should be taken into consideration for disease monitoring and control.

Topics: Adolescent; Adult; Amphotericin B; Antibodies, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Disease Progression; Female; Humans; Immunoglobulin G; India; Leishmania donovani; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Neglected Diseases; Phosphorylcholine; Sex Factors; Testosterone; Young Adult

Topics: Aged; Amphotericin B; Antiprotozoal Agents; Bone Marrow; Female; Humans; Leishmania donovani; Leishmaniasis, Visceral; Neglected Diseases

Visceral leishmaniasis is a neglected parasitic disease that has a high fatality rate in the absence of treatment. New drugs that are inexpensive, orally active, and effective could be useful tools in the fight against this disease. We previously showed that N(2),N(4)-disubstituted quinazoline-2,4-diamines displayed low- to sub-micromolar potency against intracellular Leishmania, and lead compound N(4)-(furan-2-ylmethyl)-N(2)-isopropyl-7-methylquinazoline-2,4-diamine (4) exhibited modest efficacy in an acute murine model of visceral leishmaniasis. In the present work, thirty-one N(2),N(4)-disubstituted quinazoline-2,4-diamines that had not previously been examined for their antileishmanial activity were evaluated for their potency and selectivity against Leishmania donovani, the causative parasite of visceral leishmaniasis. Quinazoline-2,4-diamines with aromatic substituents at both N(2) and N(4) exhibited potent in vitro antileishmanial activity but relatively low selectivity, while compounds substituted with small alkyl groups at either N(2) or N(4) generally showed lower antileishmanial potency but were less toxic to a murine macrophage cell line. Based on their in vitro antileishmanial potency, N(4)-benzyl-N(2)-(4-chlorobenzyl)quinazoline-2,4-diamine (15) and N(2)-benzyl-N(4)-isopropylquinazoline-2,4-diamine (40) were selected for in vivo evaluation of their pharmacokinetic and antileishmanial properties. While 15 displayed a longer plasma half-life and a greater area under the curve than 40, both compounds showed low efficacy in an acute murine visceral leishmaniasis model. Although the present study did not identify new quinazoline-2,4-diamines with promising in vivo efficacy, the reduced in vitro toxicity of derivatives bearing small alkyl groups at either N(2) or N(4) may provide clues for the design of safe and effective antileishmanial quinazolines.

Topics: Animals; Antiprotozoal Agents; Diamines; Humans; Leishmania donovani; Leishmaniasis, Visceral; Mice; Mice, Inbred BALB C; Neglected Diseases; Quinazolines; Structure-Activity Relationship

Polyalthic acid is a naturally occurring diterpene found in copaiba oil, one of the most popular natural medicines in the Amazon. Based on the reported antileishmanial activity of copaiba oil, a series of amides and diols derivatives of polyalthic acid were synthesized and tested against Leishmania donovani and Trypanosoma brucei. Polyalthic acid was active in both assays with IC50 ranging from 3.87 to 8.68 μg/mL. The compound with best antileishmanial activity was 2 h (IC50=3.84 μg/mL) and compound 2c showed the best antitrypanosomal activity with an IC50 of 2.54 μg/mL.

Topics: Antiparasitic Agents; Diterpenes; Inhibitory Concentration 50; Leishmania donovani; Molecular Structure; Neglected Diseases; Trypanocidal Agents; Trypanosoma brucei brucei

Despite recent advances in the treatment of some forms of leishmaniasis, the available drugs are still far from ideal due to inefficacy, parasite resistance, toxicity and cost. The wide-spectrum antimicrobial activity of 2-nitrovinylfuran compounds has been described, as has their activity against Trichomonas vaginalis and other protozoa. Thus, the aim of this study was to test the antileishmanial activities of six 2-nitrovinylfurans in vitro and in a murine model of leishmaniasis. Minimum parasiticide concentration (MPC) and 50% inhibitory concentration (IC50) values for these compounds against the promastigotes of Leishmania amazonensis, Leishmania infantum and Leishmania braziliensis were determined, as were the efficacies of two selected compounds in an experimental model of cutaneous leishmaniasis (CL) caused by L. amazonensis in BALB/c mice. All of the compounds were active against the promastigotes of the three Leishmania species tested. IC50 and MPC values were in the ranges of 0.8-4.7 µM and 1.7-32 µM, respectively. The compounds 2-bromo-5-(2-bromo-2-nitrovinyl)-furan (furvina) and 2-bromo-5-(2-methyl-2-nitrovinyl)-furan (UC245) also reduced lesion growth in vivo at a magnitude comparable to or higher than that achieved by amphotericin B treatment. The results demonstrate the potential of this class of compounds as antileishmanial agents and support the clinical testing of Dermofural(r) (a furvina-containing antifungal ointment) for the treatment of CL.

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Cell Proliferation; Clinical Trials as Topic; Disease Models, Animal; Female; Furans; Humans; In Vitro Techniques; Inhibitory Concentration 50; KB Cells; Leishmania; Leishmaniasis, Cutaneous; Mice, Inbred BALB C; Neglected Diseases; Time Factors; Vinyl Compounds

The aim of this study was to report the patient profile and treatment outcomes, including relapses, of patients with visceral leishmaniasis (VL) treated with liposomal amphotericin B (AmBisome) in Gedaref, Sudan.. AmBisome was offered to two groups of patients: primary VL patients with specific criteria (age ≤2 or ≥45 years, advanced clinical disease, pregnancy, HIV co-infection and contraindications for antimonials) and VL relapses. AmBisome was given at a total dose of 30 mg/kg, over 10 days. Slow responders received up to 50 mg/kg. Treatment failure was confirmed parasitologically. Standardised treatment outcomes were assessed.. Between March 2010 and June 2012, a total of 281 (74%) patients with primary VL and 98 (26%) patients with VL relapses received AmBisome (54% male, median age = 11 years, interquartile range 2-30). End-of-treatment outcomes for primary VL were 260 (92%) initial cure including three (1%) slow responders, three (1%) treatment failures, 14 (5%) deaths and four (1%) unknown outcomes. Outcomes for VL relapses were 92 (94%) initial cure with five (5%) slow responders, four (4%) treatment failures, one (1%) death and one (1%) unknown outcome. At 6 months, there were 19 (7%) relapses amongst primary VL and 10 (10%) VL relapses had a new relapse. Loss to follow-up in both groups was 38%. None of the deaths that occurred during the study period was attributed to AmBisome.. AmBisome appears to be effective for initial cure of VL and the drug seems safe, but is expensive (400 USD/treatment). Sustained mechanisms to allow improved access of this expensive drug particularly in East Africa are urgently needed. Relapses and losses to follow-up require specific investigation.

Topics: Adolescent; Adult; Amphotericin B; Child; Child, Preschool; Female; HIV Infections; Humans; Infant; Leishmania donovani; Leishmaniasis, Visceral; Lost to Follow-Up; Male; Middle Aged; Neglected Diseases; Pregnancy; Pregnancy Complications, Parasitic; Recurrence; Sudan; Treatment Failure; Treatment Outcome; Trypanocidal Agents; Young Adult

Neglected diseases represent a major health problem. It is estimated that one third of the world population is infected with tuberculosis and additionally Leishmaniosis and Chagas disease affect approximately 30 million people. N-Acylhydrazone moiety is a repeated functional group present in several prototypes and drug candidates for these neglected diseases. On the other hand, furoxan system has been studied as pharmacophore for Leishmaniosis and Chagas diseases. Here we report on the design and preparation of forty hybrid furoxanyl N-acylhydrazones and on their activity on Mycobacterium tuberculosis, H37Rv and MDR strains, Trypanosoma cruzi, and Leishmania amazonensis. Among them, four derivatives displayed excellent to good selectivity indexes against the three different microorganisms. Hybrid compound N'-(4-phenyl-3-furoxanylmethylidene)isoniazide 9 showed the best antibacterial profile with MIC value 4.5 lesser than the value for the reference isoniazid against MDR strain. Furoxanyl N-acylhydrazone (E)-2-methyl-N'-(4-phenyl-3-furoxanylmethylidene)-4H-imidazo[1,2-a]pyridine-3-carbohydrazide 15 was ten-fold more potent against T. cruzi Amastigotes than the standard drug nifurtimox. On the other hand, derivatives (E)-N'-(5-benzofuroxanylmethylidene)benzo[d][1,3]dioxole-5-carbohydrazide 25 and (E)-N'-(4-hydroxy-3-methoxyphenylmethylidene)-3-methylfuroxan-4-carbohydrazide 37 emerged as leads for the development of new leishmanicidal agents. The adequate stability, in simulated biological system and plasma, and the lack of mutagenicity of these derivatives allow us to propose them as candidates for further pre-clinical studies.

Topics: Anti-Infective Agents; Drug Design; Drug Stability; Hydrazones; Inhibitory Concentration 50; Leishmania; Mycobacterium tuberculosis; Neglected Diseases; Oxadiazoles; Trypanosoma cruzi

We report a case of laryngeal leishmaniasis in a United Kingdom (UK) resident who lived in Spain for 5 years.. The patient presented with a history of hoarseness. He had returned to the UK after spending 5 years in Spain as a retiree. His past medical history includes chronic obstructive pulmonary disease (COPD). Histology of a vocal cord biopsy was suggestive of leishmaniasis and polymerase chain reaction (PCR) test was positive for Leishmania donovani. His use of steroid inhaler probably contributed to his acquiring this extremely unusual infection. He was successfully treated with intravenous amphotericin.. Laryngeal leishmaniasis is an extremely rare infection and is rarely reported in the UK. The ease of travel ensures that many tropical infections may present to UK clinicians.

Topics: Aged, 80 and over; Amphotericin B; Antiprotozoal Agents; DNA, Protozoan; Humans; Laryngeal Diseases; Leishmania donovani; Leishmaniasis, Visceral; Male; Neglected Diseases; Polymerase Chain Reaction; Travel