deoxycholic-acid and Leishmaniasis--Visceral

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

Some 50% of patients with visceral leishmaniasis (kala-azar) worldwide live in the Indian state of Bihar. Liposomal amphotericin B is an effective treatment when administered in short courses. We wanted to determine whether the efficacy of a single infusion of liposomal amphotericin B was inferior to conventional parenteral therapy, consisting of 15 alternate-day infusions of amphotericin B deoxycholate.. In this open-label study, we randomly assigned 412 patients in a 3:1 ratio to receive either liposomal amphotericin B (liposomal-therapy group) or amphotericin B deoxycholate (conventional-therapy group). Liposomal amphotericin B (at a dose of 10 mg per kilogram of body weight) was given once, and patients were discharged home 24 hours later. Amphotericin B deoxycholate, which was administered in 15 infusions of 1 mg per kilogram, was given every other day during a 29-day hospitalization. We determined the cure rate 6 months after treatment.. A total of 410 patients--304 of 304 patients (100%) in the liposomal-therapy group and 106 of 108 patients (98%) in the conventional-therapy group--had apparent cure responses at day 30. Cure rates at 6 months were similar in the two groups: 95.7% (95% confidence interval [CI], 93.4 to 97.9) in the liposomal-therapy group and 96.3% (95% CI, 92.6 to 99.9) in the conventional-therapy group. Adverse events in the liposomal-therapy group were infusion-related fever or rigors (in 40%) and increased anemia or thrombocytopenia (in 2%); such events in the conventional-therapy group were fever or rigors (in 64%), increased anemia (in 19%), and hypokalemia (in 2%). Nephrotoxicity or hepatotoxicity developed in no more than 1% of patients in each group.. A single infusion of liposomal amphotericin B was not inferior to and was less expensive than conventional therapy with amphotericin B deoxycholate. (ClinicalTrials.gov number, NCT00628719.)

Topics: Adolescent; Adult; Aged; Amphotericin B; Antiprotozoal Agents; Child; Child, Preschool; Deoxycholic Acid; Drug Combinations; Female; Humans; India; Infusions, Intravenous; Intention to Treat Analysis; Leishmaniasis, Visceral; Male; Middle Aged; Young Adult

Amphotericin B (AB) deoxycholate is highly effective in antimony refractory cases for the treatment of visceral leishmaniasis (VL) in Bihar. But the need for prolonged hospitalisation and frequent, occasionally serious, adverse events are its major drawbacks. Lipid formulations of AB are devoid of these problems, but very expensive. We evaluated the safety and efficacy of a commercial standardised amphotericin B emulsion, a product of AB formulated in lipid emulsion vehicle (ABLE) in the treatment of Indian VL. In this open label, non-comparative study, 15 patients in each group were given three daily intravenous infusions each of 3, 4 or 5 mg/kg. All 45 patients (15 in each group) completed the treatment. The drug was tolerated well. Infusion reactions occurred in 5 (11%) patients and vomiting in 2 (4.4%). No nephrotoxicity or other organ toxicity was observed. At the end of treatment all patients of every group were clinically and parasitologically cured. However, during 6 months follow up, three patients from the 5 mg/kg group and one from the 4 mg/kg group tested positive for splenic aspirate. Thus 41 (91.1%; 95% CI 78-97) of 45 patients were cured with a total dose ranging between 9 and 15 mg/kg. There was no dose response linear correlation. In this preliminary study, AB formulated in a lipid emulsion vehicle was safe and effective for the treatment of VL in India.

Topics: Adolescent; Adult; Amphotericin B; Animals; Antiprotozoal Agents; Child; Deoxycholic Acid; Drug Administration Schedule; Drug Combinations; Fat Emulsions, Intravenous; Female; Humans; India; Infusions, Intravenous; Leishmaniasis, Visceral; Male; Middle Aged; Treatment Outcome

In Bihar, India, where visceral leishmaniasis is hyperendemic, amphotericin B deoxycholate is now first-line parenteral treatment. To test the efficacy of amphotericin B deoxycholate versus that of its lipid formulations, Indian patients were randomized to receive treatment with amphotericin B deoxycholate (1 mg/kg on alternate days for 30 days; n=51), liposomal amphotericin B (2 mg/kg per day for 5 days; n=51), or amphotericin B lipid complex (2 mg/kg per day for 5 days; n=51). Infusion-associated reactions were frequent and persistent in subjects treated with amphotericin B deoxycholate. The illness of 3 patients failed to respond to treatment, and 5 patients experienced relapse. Final cure rates were similar. Estimated total treatment costs for a 25-kg patient-417 dollars for amphotericin B deoxycholate, 872 dollars for liposomal amphotericin B, and 947 dollars for amphotericin B lipid complex-differed as a result of drug cost. Substantial reductions (approximately 60%) in the price of liposomal amphotericin B and amphotericin B lipid complex would make treatment costs comparable to that of amphotericin B deoxycholate, permitting administration of short-course regimens in India.

Topics: Adolescent; Adult; Amphotericin B; Animals; Antiprotozoal Agents; Child; Child, Preschool; Deoxycholic Acid; Drug Combinations; Drug Costs; Female; Hospital Costs; Humans; India; Infant; Leishmaniasis, Visceral; Liposomes; Male; Middle Aged; Phosphatidylcholines; Phosphatidylglycerols; Treatment Outcome

A total of 288 parasitologically proved patients of kala-azar were randomly allocated to three treatment groups. Patients in groups A, B and C received amphotericin B (AMB) in a dose of 1 mg/kg body weight (bw)/day, 0.75 mg/kg bw/day and 0.5 mg/kg bw/day for 20 days respectively. Apparent cure (afebrile at the end of therapy) occurred in all patients and parasitological cure in 96 (100%), 92 (96%) and 84 (88%) patients respectively in groups A, B and C. Ultimate cure (no relapse in six months of follow up) occurred in 95 (99%), 87 (91%) and 79 (82%) patients in groups A, B and C respectively. The difference between the ultimate cure in the three groups was significant (P < 0.05). The incidence of adverse events (rise in serum creatinine and fall in serum potassium, loss of appetite and shivering, rigor and fever during infusion indicative of renal, GIT and infusion related toxicities respectively) was similar in the three groups. This study showed that amphotericin B should be given at a dosage of 1 mg/kg bw/day for 20 days for Indian kala-azar patients to minimise relapses and prevent development of drug unresponsiveness.

Topics: Adolescent; Adult; Amphotericin B; Anti-Bacterial Agents; Child; Child, Preschool; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Female; Humans; Leishmaniasis, Visceral; Male; Middle Aged; Treatment Outcome

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Deoxycholic Acid; Digitoxigenin; Drug Combinations; Drug Repositioning; Female; Leishmania infantum; Leishmaniasis, Visceral; Liver; Macrophages; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Micelles; Parasite Load; Poloxamer; Reactive Oxygen Species; Spleen

Fifteen VL patients recruited from Hospital Eduardo de Menezes (BH-MG) were grouped into relapsing (R-VL, n = 5) and non-relapsing (NR-VL, n = 10) and evaluated during active disease, immediately after treatment (post-treatment) and 6 months post-treatment (6mpt). Clinical and laboratory data obtained from medical records were correlated with CD4. During the active phase of VL, despite similarity in the clinical symptoms, the rates of thrombocytopenia, elevated transaminases (AST and ALT) and hyperbilirubinemia were higher in the NR-VL group compared to R-VL (p < 0.05), a profile reversed during the post-treatment phase. All patients had low CD4. During active phase of VL, the NR-VL patients presented more severe laboratorial abnormalities compared to R-VL, probably because the latter had already received previous treatment. On the other hand, R-VL exhibited greater impairment of immune reconstitution and a high degree of B lymphocyte activation, which must be a factor that favored relapses.

Topics: Adult; Amphotericin B; Antibodies, Protozoan; Brazil; CD4-Positive T-Lymphocytes; Deoxycholic Acid; Drug Combinations; Female; HIV Infections; Humans; Immunoglobulin G; Interleukin-6; Leishmania; Leishmaniasis, Visceral; Male; Middle Aged; Recurrence

Based on studies in India (as there was no studies from outside India) amphotericin B deoxycholate has been considered as a backup drug for treatment of visceral leishmaniasis. However, treatment response and adverse effect to anti-leishmanial drugs may vary across different populations and in Bangladesh the effect to amphotericin B deoxycholate for treatment of visceral leishmaniasis is still unknown. Therefore, there is a need to explore cure rate and adverse effects to amphotericin B deoxycholate to justify its use on visceral leishmaniasis patients in Bangladesh.. Here we report 34 visceral leishmaniasis patients who received treatment with amphotericin B deoxycholate in the Surya Kanta Kala-azar Research Centre from December 2011 to June 2015. The dose of the treatment was 1 mg/kg body weight for 15 days followed up until 12 months after treatment. Response to amphotericin B deoxycholate treatment was excellent as all 34 patients achieved a final cure. Hypokalaemia (47%), shivering (47%), vomiting (35%) and acidity (15%) were most common adverse events. However, we did not observe any serious adverse events. Amphotericin B deoxycholate for relapse visceral leishmaniasis was found to be highly effective and safe. Our study justified to include amphotericin B deoxycholate as a second line drug for visceral leishmaniasis in Bangladesh.

Topics: Adolescent; Adult; Amphotericin B; Anti-Infective Agents; Bangladesh; Child; Cross-Sectional Studies; Deoxycholic Acid; Drug Combinations; Female; Humans; Leishmaniasis, Visceral; Male; Recurrence; Treatment Outcome

Visceral leishmaniasis (VL) diagnosis is routinely performed by invasive liver, spleen, bone marrow, or lymph node biopsies, followed by microscopic identification of the parasites. Conventional serological tests cannot distinguish active disease from asymptomatic VL or from cured infection. Here, we report the initial validation of an enzyme-linked immunosorbent assay (ELISA) assembled to detect the Leishmania infantum/donovani antigens iron superoxide dismutase 1 (Li-isd1), tryparedoxin 1 (Li-trx1), and nuclear transport factor 2 (Li-ntf2) as a tool to monitor therapeutic efficacy of VL. The assembled ELISA detected the antigens in the urine samples from seven VL patients before initiation of therapy. Importantly, the antigens were no longer detected in all patients after completion of the treatment. These preliminary observations point to a promising tool to follow treatment efficacy of VL.

Topics: Amphotericin B; Animals; Antibodies, Protozoan; Antigens, Protozoan; Biomarkers; Chickens; Deoxycholic Acid; Drug Combinations; Enzyme-Linked Immunosorbent Assay; Humans; Leishmania infantum; Leishmaniasis, Visceral; Nucleocytoplasmic Transport Proteins; Protozoan Proteins; Rabbits; Recombinant Proteins; Sensitivity and Specificity; Superoxide Dismutase; Thioredoxins; Treatment Outcome

With widespread resistance to pentavalent antimonial in the endemic eastern terai belt of Nepal and Bihar, India, Amphotericin B deoxycholate is now the first-line antileishmanial drug for the treatment of visceral leishmaniasis (VL). However, universal occurrence of infusion-related fever and rigors with amphotericin B (AmB), occasional serious life-threatening toxicities like cardiotoxicity, anaphylaxis, hypokalemia, and nephrotoxicity are major barriers to its use in areas with limited medical facilities. Liposomal amphotericins, however, are devoid of adverse effects, high cost makes it unaffordable. We had formulated nanoparticles (10-20 nm) from amphotericin B deoxycholate (1-2 μm) applying high pressure (150 atm) milling homogenization in argon atmosphere and tested its ex vivo efficacy in Leishmania infected J774A cell line and peritoneal macrophage. The ex vivo ED50 for intracellular amastigotes in peritoneal macrophage by nano-amphotericin was 0.0027 ± 0.001 μg/mL which was significantly less (p = 0.0029) than the required dose of amphotericin B (0.0426 ± 0.003 μg/mL). Similarly, in J774A cell line, 50 % of intracellular amastigotes were cleared by 0.0038 ± 0.001 μg/mL of nano-amphotericin while the dose was a bit more for AmB (0.0196 ± 0.001 μg/mL) illustrating the significant difference (p value, 0.0122). The nanoformulation has also shown high efficacy (ED50, 0.0028-0.0035 μg/mL) in inhibition of infected macrophage count. The new formulation accumulated to spleen, the targeted organ, 7 days after inoculation of drug to the infected hamster as traced in vivo by TEM convincing it as potential drug. Given a favorable safety profile and very low cost of production contemplated, it may prove to be a feasible alternative for conventional amphotericin B.

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Cell Line; Cricetinae; Deoxycholic Acid; Drug Combinations; Drug Dosage Calculations; Humans; Inhibitory Concentration 50; Leishmania donovani; Leishmaniasis, Visceral; Life Cycle Stages; Macrophages, Peritoneal; Mice; Nanoparticles; Spleen

Visceral leishmaniasis or kala-azar is an endemic parasitic disease in some parts of the world which is characterized by fever, splenomegaly, and pancytopenia in most of the cases. Herein we report an 11 month-old male infant with diagnosis of kala-azar who presented with pallor, hepatosplenomegaly, failure to gain weight, and no history of fever. Surprisingly, fever started after beginning of meglumine antimoniate treatment in this patient. As far as we are aware of, this is a rare presentation of visceral leishmaniasis. Therefore, clinicians especially in endemic areas are highly recommended to include kala-azar among differential diagnosis of unexplained anemia without fever to prevent misdiagnosis of this potentially fatal, but treatable condition.

Topics: Amphotericin B; Anemia; Antiprotozoal Agents; Deoxycholic Acid; Diagnosis, Differential; Drug Combinations; Endemic Diseases; Fever; Humans; Infant; Iran; Leishmania infantum; Leishmaniasis, Visceral; Male; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Splenomegaly

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

Because of the large number of cases of visceral leishmaniasis (VL) recorded in Brazil over the last few years, this disease has been showing characteristics different from previously known ones. We report cases of pregnant women treated for VL, describing their course and outcome and the chemotherapeutic medication used according to the clinical signs and symptoms of each patient.. We report five cases of pregnant women treated for VL in a central-western region of Brazil.. No case of vertical transmission was observed, even in patients who were treated after delivery. One of the patients with a late diagnosis made after the onset of symptoms died. Thus, the treatment of VL during pregnancy reduces maternal mortality and the rate of vertical transmission of the disease, being safe and effective as long as the disease is diagnosed early.. At present, amphotericin B and its derivatives appear to be the best therapeutic option for the mother-child binomial.

Topics: Adult; Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Brazil; Deoxycholic Acid; Drug Combinations; Female; Fever; Hepatomegaly; Humans; Leishmaniasis, Visceral; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Splenomegaly

The aim of the present study was to compare the efficacy of a nano form of amphotericin B deoxycholate with that of conventional amphotericin B deoxycholate for the treatment of visceral leishmaniasis.. We have formulated nanoparticles (10-20 nM) from amphotericin B deoxycholate (1-2 microM) by applying high-pressure (150 argon) milling homogenization and have tested their efficacy in a J774A cell line and in hamsters. Parasite survival and tissue burden in spleen were evaluated for nano-amphotericin B and conventional amphotericin B. Both nano-amphotericin B and conventional amphotericin B were injected intraperitoneally at 5 mg/kg per day for 5 days.. The inhibition of amastigotes in the splenic tissue with nano-amphotericin B was significantly more than with conventional amphotericin B (92.18% versus 74.57%, P = 0.005). Similarly, the suppression of parasite replication in the spleen was also found to be significant (99.18% versus 97.17%, P = 0.05). In a cytotoxicity test, nano-amphotericin B against the J774A cell line had a CC(50) of 12.67 mg/L in comparison with 10.61 mg/L for amphotericin B, far higher than the doses used for ED(50).. Nanoparticles of amphotericin B had significantly greater efficacy than conventional amphotericin B. This formulation may have a favourable safety profile, and if production costs are low, it may prove to be a feasible alternative to conventional amphotericin B.

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Cell Line; Cricetinae; Deoxycholic Acid; Drug Combinations; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Mesocricetus; Mice; Nanoparticles; Spleen

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

Amphotericin B (AmB) was formulated in trilaurin-based emulsomes (nanosize lipid particles) stabilized by soya phosphatidylcholine (PC), as a new delivery system for macrophage targeting for the treatment of visceral leishmaniasis (VL). Emulsomes were modified by coating them with macrophage-specific ligand (O-palmitoyl mannan, OPM). The antileishmanial activity of AmB-deoxycholate (AmB-Doc) and emulsome entrapped AmB was tested in vitro in Leishmania donovani infected macrophage-amastigote system (J774A.1 cells), which showed higher efficacy of OPM grafted AmB emulsomes (TLEs-OPM) over plain AmB emulsomes (TLEs) and AmB-Doc. The in vivo antileishmanial activity of the AmB (0.5 mg/kg) was tested in AmB-Doc, TLEs and TLEs-OPM forms against VL in L. donovani infected hamsters. Formulation TLEs-OPM eliminated intracellular amastigotes of L. donovani within splenic macrophages more efficiently (73.7 +/- 6.7% parasite inhibition) than the formulation TLEs (51.7 +/- 5.4% parasite inhibition) (P < 0.01) or AmB-Doc (30.4 +/- 4.8% parasite inhibition) (P < 0.001). Our results suggest that these newer formulations (plain and ligand appended emulsomes) are a promising alternative to the conventional AmB-Doc formulation for the treatment of VL.

Topics: Amphotericin B; Animals; Cricetinae; Deoxycholic Acid; Disease Models, Animal; Drug Carriers; Drug Combinations; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Male; Mesocricetus; Mice; Nanoparticles; Trypanocidal Agents

To identify and quantify the direct and indirect economic cost of treatment for visceral leishmaniasis (VL) with conventional Amphotericin B deoxycholate, currently the first-line treatment in Muzaffarpur.. Costs of patient management for VL were estimated from a societal and household perspective by means of a questionnaire designed for this study, interviews and financial reports.. The total cost of care per episode of VL from the societal perspective was estimated at US$355, equivalent to 58% of annual household income. The largest cost category was medical costs (55%), followed by indirect costs (36%) and non-medical costs (9%). The cost from the household perspective was equivalent to US$217. The largest cost category was indirect costs (59%), followed by medical costs (27%) and non-medical costs (15%). Loss of income because of illness and hospitalization and expenses for drugs were the largest cost components.. The economic costs related to VL are substantial, both to society and the patient. Public health authorities in Bihar should focus on policies that detect VL in the early stage and implement interventions that minimize the burden to households affected by VL.

Topics: Adolescent; Adult; Amphotericin B; Antiprotozoal Agents; Child; Child, Preschool; Cost of Illness; Deoxycholic Acid; Drug Combinations; Female; Health Care Costs; Humans; Income; India; Leishmaniasis, Visceral; Male; Middle Aged; Patient Acceptance of Health Care; Socioeconomic Factors