amphotericin-b--deoxycholate-drug-combination and miltefosine

Despite a historical association with poor tolerability, a comprehensive review on safety of antileishmanial chemotherapies is lacking. We carried out an update of a previous systematic review of all published clinical trials in visceral leishmaniasis (VL) from 1980 to 2019 to document any reported serious adverse events (SAEs).. For this updated systematic review, we searched the following databases from 1st Jan 2016 through 2nd of May 2019: PUBMED, Embase, Scopus, Web of Science, Cochrane, clinicaltrials.gov, WHO ICTRP, and the Global Index Medicus. We included randomised and non-randomised interventional studies aimed at assessing therapeutic efficacy and extracted the number of SAEs reported within the first 30 days of treatment initiation. The incidence rate of death (IRD) from individual treatment arms were combined in a meta-analysis using random effects Poisson regression.. We identified 157 published studies enrolling 35,376 patients in 347 treatment arms. Pentavalent antimony was administered in 74 (21.3%), multiple-dose liposomal amphotericin B (L-AmB) in 52 (15.0%), amphotericin b deoxycholate in 51 (14.7%), miltefosine in 33 (9.5%), amphotericin b fat/lipid/colloid/cholesterol in 31 (8.9%), and single-dose L-AmB in 17 (4.9%) arms. There was a total of 804 SAEs reported of which 793 (including 428 deaths) were extracted at study arm level (11 SAEs were reported at study level only). During the first 30 days, there were 285 (66.6%) deaths with the overall IRD estimated at 0.068 [95% confidence interval (CI): 0.041-0.114; I2 = 81.4%; 95% prediction interval (PI): 0.001-2.779] per 1,000 person-days at risk; the rate was 0.628 [95% CI: 0.368-1.021; I2 = 82.5%] in Eastern Africa, and 0.041 [95% CI: 0.021-0.081; I2 = 68.1%] in the Indian Subcontinent. In 21 study arms which clearly indicated allowing the inclusion of patients with HIV co-infections the IRD was 0.575 [95% CI: 0.244-1.355; I2 = 91.9%] compared to 0.043 [95% CI: 0.020-0.090; I2 = 62.5%] in 160 arms which excluded HIV co-infections.. Mortality within the first 30 days of VL treatment initiation was a rarely reported event in clinical trials with an overall estimated rate of 0.068 deaths per 1,000 person-days at risk, though it varied across regions and patient populations. These estimates may serve as a benchmark for future trials against which mortality data from prospective and pharmacovigilance studies can be compared. The methodological limitations exposed by our review support the need to assemble individual patient data (IPD) to conduct robust IPD meta-analyses and generate stronger evidence from existing trials to support treatment guidelines and guide future research.

Topics: Amphotericin B; Antimony; Antiprotozoal Agents; Deoxycholic Acid; Drug Combinations; Humans; Leishmaniasis, Visceral; Phosphorylcholine

To evaluate the evidence for use of different formulations of amphotericin B (AmB), minimum effective dose for each formulation and its comparative efficacy against other drugs in achieving definitive cure of visceral leishmaniasis.. This systematic review and meta-analysis included following data sources: PubMed, Embase, Scopus, Web of Science and CINAHL. Controlled prospective clinical trials (randomized or nonrandomized, including dose-ranging studies) conducted between 1996 and 2017 with at least one treatment group receiving AmB were included (published data only). The primary outcome was definitive cure at 6 months. Adverse events and mortality were assessed as secondary outcomes. The PROSPERO registration number for this review is CRD42017067488.. Thirty-one studies (26 from India) that enrolled 6903 patients into 84 study groups met the selection criteria. In India, liposomal AmB was not inferior to AmB deoxycholate (relative risk 1.00, 95% confidence interval (CI) 0.96-1.03, two randomized controlled trials (RCTs), 514 participants, high-quality evidence), and a single dose of the earlier formulation as low as 3.75 mg/kg achieved a cure rate of over 89% (95% CI 70.6-97.2). AmB deoxycholate was as effective as miltefosine (relative risk 0.99, 95% CI 0.95-1.03, two trials, 523 participants, high-quality evidence) and may be better than paromomycin (relative risk 1.04, 95% CI 1.02-1.07, one trial, 667 participants, low-quality evidence) in achieving definitive cure.. AmB is an efficacious drug in the Indian subcontinent. Further evidence is needed from prospective clinical trials in other endemic geographical regions.

Topics: Amphotericin B; Antiprotozoal Agents; Clinical Trials as Topic; Deoxycholic Acid; Drug Combinations; Drug Compounding; Evidence-Based Medicine; Female; Humans; Leishmaniasis, Visceral; Male; Paromomycin; Phosphorylcholine; Survival Analysis; Treatment Outcome

Leishmaniasis is a parasitic infection endemic to more than 90 countries worldwide. As travel to endemic areas increases, dermatologists need to keep this entity in the differential for any chronic skin lesion in persons who may have had a possible exposure for any duration. It can be difficult to diagnose because manifestations are varied and sometimes subclinical. This article discusses the current state of epidemiology, pathogenesis, clinical presentation, diagnosis, and treatment options. A special focus is placed on cutaneous manifestations and their treatment.

Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Deoxycholic Acid; Drug Combinations; Humans; Incidence; Leishmania braziliensis; Leishmania donovani; Leishmania mexicana; Leishmania tropica; Leishmaniasis, Diffuse Cutaneous; Leishmaniasis, Mucocutaneous; Leishmaniasis, Visceral; Phosphorylcholine; Polymerase Chain Reaction; Travel

Visceral leishmaniasis (kala-azar) is a disseminated intracellular protozoal infection. Most cases (90%) occur in the rural regions of five countries: India, Sudan, Nepal, Bangladesh and Brazil. As with other infectious diseases embedded in high-level poverty, developing and/or delivering new treatments for visceral leishmaniasis had been painfully slow or nonexistent. However, despite persistent unresolved obstacles (e.g., drug affordability), renewed interest in visceral leishmaniasis and numerous successful treatment trials have combined to turn a therapeutic corner in the past 5 years, yielding new alternatives to conventional pentavalent antimony. Advances include the use of low-cost generic pentavalent antimony, rediscovery of amphotericin B, short-course regimens via lipid formulations of amphotericin B, retesting injectible paromyomycin and, of clear-cut importance, identifying miltefosine (Impavido, Zentaris) as the first effective oral therapy for this neglected disease.

Topics: Amphotericin B; Antimony; Antiprotozoal Agents; Clinical Trials as Topic; Deoxycholic Acid; Drug Combinations; Drug Costs; Humans; Leishmaniasis, Visceral; Paromomycin; Phosphatidylcholines; Phosphatidylglycerols; Phosphorylcholine; Practice Guidelines as Topic

A new series of pyrazolo[1,5-c]pyrimidines were synthesized by different hybridization strategies.. All structures were confirmed by IR,. The most active compounds 2a and 9a demonstrated superior potencies to miltefosine by ten- and six-fold, respectively, for the promastigote form, and by 5.5-fold for the amastigote form. Their binding scenario to Leishmania major pteridine reductase was rationalized by docking experiments. In addition, all compounds were safe for the experimental animals orally up to 150 mg/kg and parenterally up to 75 mg/kg.. This study provides novel chemotype class for antileishmanial activity. [Formula: see text].

Topics: Amphotericin B; Antiprotozoal Agents; Binding Sites; Deoxycholic Acid; Drug Combinations; Drug Design; Humans; Leishmania major; Molecular Docking Simulation; Molecular Structure; Phosphorylcholine; Protein Binding; Pyrazoles; Pyrimidines; Structure-Activity Relationship

Topics: Amino Acids; Amphotericin B; Antiprotozoal Agents; Deoxycholic Acid; Drug Combinations; Inhibitory Concentration 50; Isomerism; Leishmania; Magnetic Resonance Spectroscopy; Molecular Conformation; Phosphorylcholine; Quinazolines; Structure-Activity Relationship

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

Visceral leishmaniasis (VL) caused by parasites of Leishmania donovani complex is a severe human disease which often leads to death if left untreated. Domestic dogs are the main reservoir hosts for zoonotic human visceral infection caused by Leishmania infantum. In the absence of effective human and dog vaccines, the only feasible way to treat and control leishmaniasis is through the use of suitable medications. To know the drug susceptibility of human and canine Leishmania strains from Lisbon-Portugal, a study on a panel of strains was conducted by testing the susceptibility of promastigotes and intracellular amastigotes to the common drugs used in canine leishmaniasis (CanL) and human VL (meglumine antimoniate, amphotericin B, miltefosine and allopurinol). Although a high heterogeneity of susceptibilities was obtained to each drug on both axenic promastigote and intracellular amastigote assays, intracellular amastigotes system correlated better with treatment outcome. Parasites isolated from the refractory human case were the least susceptible to the drugs used highlighting that the emergence of cross-resistance to the drugs available for human therapy should not be neglected. Furthermore, parasites isolated from dogs showed low susceptibility to the main drugs used in CanL treatment. Our results focus the importance of reducing/avoiding the emergence and spread of resistant parasites in the canine and human populations, a factor that requires special consideration when dogs are treated using the same available anti-Leishmania drugs for human VL. In addition, efforts should be made in order to standardize the conditions used to test drug susceptibility (methodologies, drug formulations and media) in order to compare results between laboratories.

Topics: Allopurinol; Amphotericin B; Animals; Antiprotozoal Agents; Deoxycholic Acid; Disease Reservoirs; Dog Diseases; Dogs; Drug Combinations; Humans; Immunocompetence; Immunocompromised Host; Inhibitory Concentration 50; Leishmania infantum; Leishmaniasis, Visceral; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Parasitic Sensitivity Tests; Phosphorylcholine

Miltefosine is an alkyl phosphocholine with good oral bioavailability and in vitro activity against Cryptococcus species that has gained interest as an additional agent for cryptococcal infections. Our objective was to further evaluate the in vivo efficacy of miltefosine in experimental in vivo models of cryptococcal meningoencephalitis and disseminated cryptococcosis. Mice were infected intracranially or intravenously with either C. neoformans USC1597 or H99. Miltefosine treatment (1.8 to 45 mg/kg of body weight orally once daily) began at either 1 h or 1 day postinoculation. Fluconazole (10 mg/kg orally twice daily) or amphotericin B deoxycholate (3 mg/kg intraperitoneally once daily) served as positive controls. In our standard models, miltefosine did not result in significant improvements in survival or reductions in fungal burden against either C. neoformans isolate. There was a trend toward improved survival with miltefosine at 7.2 mg/kg against disseminated cryptococcosis with the H99 strain but only at a low infecting inoculum. In contrast, both fluconazole and amphotericin B significantly improved survival in mice with cryptococcal meningoencephalitis and disseminated cryptococcosis due to USC1597. Amphotericin B also improved survival against both cryptococcal infections caused by H99. Combination therapy with miltefosine demonstrated neither synergy nor antagonism in both models. These results demonstrate limited efficacy of miltefosine and suggest caution with the potential use of this agent for the treatment of C. neoformans infections.

Topics: Amphotericin B; Animals; Antifungal Agents; Cryptococcosis; Cryptococcus neoformans; Deoxycholic Acid; Drug Combinations; Fluconazole; Meningitis, Cryptococcal; Meningoencephalitis; Mice; Microbial Sensitivity Tests; Phosphorylcholine; Survival

To facilitate the choice of the best visceral leishmaniasis (VL) treatment strategy for first-line health services in (VL)-endemic areas, we compared in a formal decision analysis the cost and the cost-effectiveness of the different available options.. We selected four drug regimens for VL on the basis of frequency of use, feasibility and reported efficacy studies. The point estimates and the range of plausible values of effectiveness and cost were retrieved from a literature review. A decision tree was constructed and the strategy minimizing the cost per death averted was selected.. Treatment with amphotericin B deoxycholate was the most effective approach in the baseline analysis and averted 87.2% of all deaths attributable to VL. The least expensive and the most cost-effective treatment was the miltefosine regimen, and the most expensive and the least cost-effective was AmBisome treatment. The cost of drug and medical care are the main determinants of the cost-effectiveness ranking of the alternative schemes. Sensitivity analysis showed that antimonial was competitive with miltefosine in the low-resistance regions.. In areas with >94% response rates to antimonials, generic sodium stibogluconate remains the most cost-effective option for VL treatment, mainly due to low drug cost. In other regions, miltefosine is the most cost-effective option of treatment, but its use as a first-line drug is limited by its teratogenicity and rapid resistance development. AmBisome in mono- or combination therapy is too expensive to compete in cost-effectiveness with the other regimens.

Topics: Amphotericin B; Antimony; Antiprotozoal Agents; Cost-Benefit Analysis; Decision Trees; Deoxycholic Acid; Drug Combinations; Endemic Diseases; Health Care Costs; Humans; Leishmaniasis, Visceral; Phosphorylcholine; Treatment Outcome