Case Report: Use of Liposomal Amphotericin B in Low Doses in Patients With Visceral Leishmaniasis.
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ABSTRACT:
SUBMITTER: Ren D
PROVIDER: S-EPMC8635719 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Liposomal amphotericin B (LAmB) is recommended for treatment of Indian visceral leishmaniasis (VL), with a cure rate of more than 95% in the Indian subcontinent. A prospective observational study of 1,143 subjects was performed with a longer follow-up than prior studies (12 months) to evaluate the long-term effectiveness and safety of LAmB for the treatment of VL. Patients received a single dose of 10 mg/kg LAmB and were evaluated for initial cure at day 30 and final cure at 6 and 12 months to see the response to the therapy. Furthermore, predictors of relapse were also calculated. At day 30, the initial cure rate was 100%; however, at 6 months and 12 months, cure rates were 97.0% and 94.2% by per-protocol analysis and 96.9% and 93.9% by intension-to-treat analysis, respectively. Fever was the most common adverse event (AE). There were no deaths and serious AEs. Male gender, weight less than 30 kg, and spleen size more than 4 cm at the start of the treatment were significant risk factors of relapse. Liposomal amphotericin B was found to be very effective and safe in the treatment of VL. A longer follow-up period of 12 months is recommended to pick up late relapses.
| S-EPMC6779195 | biostudies-literature
Project description:BackgroundThere is a continued need to develop effective and safe treatments for visceral leishmaniasis (VL). Preclinical studies on pharmacokinetics and pharmacodynamics of anti-infective agents, such as anti-bacterials and anti-fungals, have provided valuable information in the development and dosing of these agents. The aim of this study was to characterise the pharmacokinetic and pharmacodynamic properties of the anti-leishmanial drugs AmBisome and miltefosine in a preclinical disease model of VL.Methodology / principal findingsBALB/c mice were infected with L. donovani (MHOM/ET/67/HU3) amastigotes. Groups of mice were treated with miltefosine (orally, multi-dose regimen) or AmBisome (intravenously, single dose regimen) or left untreated as control groups. At set time points groups of mice were killed and plasma, livers and spleens harvested. For pharmacodynamics the hepatic parasite burden was determined microscopically from tissue impression smears. For pharmacokinetics drug concentrations were measured in plasma and whole tissue homogenates by LC-MS. Unbound drug concentrations were determined by rapid equilibrium dialysis. Doses exerting maximum anti-leishmanial effects were 40 mg/kg for AmBisome and 150 mg/kg (cumulatively) for miltefosine. AmBisome displayed a wider therapeutic range than miltefosine. Dose fractionation at a total dose of 2.5 mg/kg pointed towards concentration-dependent anti-leishmanial activity of AmBisome, favouring the administration of large doses infrequently. Protein binding was >99% for miltefosine and amphotericin B in plasma and tissue homogenates.Conclusion / significanceUsing a PK/PD approach we propose optimal dosing strategies for AmBisome. Additionally, we describe pharmacokinetic and pharmacodynamic properties of miltefosine and compare our findings in a preclinical disease model to available knowledge from studies in humans. This approach also presents a strategy for improved use of animal models in the drug development process for VL.
| S-EPMC7924795 | biostudies-literature
Project description:Visceral leishmaniasis is a neglected tropical disease that causes significant morbidity and mortality worldwide. Characterization of the pharmacokinetics and pharmacodynamics of antileishmanial drugs in preclinical models is important for drug development and use. Here we investigated the pharmacodynamics and drug distribution of liposomal amphotericin B (AmBisome) in Leishmania donovani-infected BALB/c mice at three different dose levels and two different time points after infection. We additionally compared drug levels in plasma, liver, and spleen in infected and uninfected BALB/c mice over time. At the highest administered dose of 10 mg/kg AmBisome, >90% parasite inhibition was observed within 2 days after drug administration, consistent with drug distribution from blood to tissue within 24 h and a fast rate of kill. Decreased drug potency was observed in the spleen when AmBisome was administered on day 35 after infection, compared to day 14 after infection. Amphotericin B concentrations and total drug amounts per organ were lower in liver and spleen when AmBisome was administered at the advanced stage of infection and compared to those in uninfected BALB/c mice. However, the magnitude of difference was lower when total drug amounts per organ were estimated. Differences were also noted in drug distribution to L. donovani-infected livers and spleens. Taken together, our data suggest that organ enlargement and other pathophysiological factors cause infection- and organ-specific drug distribution and elimination after administration of single-dose AmBisome to L. donovani-infected mice. Plasma drug levels were not reflective of changes in drug levels in tissues.
| S-EPMC5571318 | biostudies-literature
Project description:India is home to 60% of the total global visceral leishmaniasis (VL) population. Use of long-term oral (e.g. miltefosine) and parenteral drugs, considered the mainstay for treatment of VL, is now faced with increased resistance, decreased efficacy, low compliance and safety issues. The authors evaluated the efficacy and safety of an alternate treatment option, i.e. single infusion of preformed amphotericin B (AmB) lipid emulsion (ABLE) in comparison with that of liposomal formulation (LAmB).In this multicentric, open-label study, 500 patients with VL were randomly assigned in a 3:1 ratio to receive 15 mg/kg single infusion of either ABLE (N = 376) or LAmB (N = 124). Initial cure (Day 30/45), clinical improvement (Day 30) and long term definitive cure (Day 180) were assessed.A total of 326 (86.7%) patients in the ABLE group and 122 (98.4%) patients in the LAmB group completed the study. Initial cure was achieved by 95.9% of patients in the ABLE group compared to 100% in the LAmB group (p = 0.028; 95% CI: -0.0663, -0.0150). Clinical improvement was comparable between treatments (ABLE: 98.9% vs. LAmB: 98.4%). Definitive cure was achieved in 85.9% with ABLE compared to 98.4% with LAmB. Infusion-related pyrexia (37.2% vs. 32.3%) and chills (18.4% vs. 18.5%) were comparable between ABLE and LAmB, respectively. Treatment-related serious adverse events were fewer in ABLE (0.3%) compared to LAmB (1.6%). Two deaths occurred in the ABLE group, of which one was probably related to the study drug. Nephrotoxicity and hepatotoxicity was not observed in either group.ABLE 15 mg/kg single infusion had favorable efficacy and was well tolerated. Considering the demographic profile of the population in this region, a single dose treatment offers advantages in terms of compliance, cost and applicability.www.clinicaltrials.gov NCT00876824.
| S-EPMC4169371 | biostudies-literature
Project description:Leishmaniasis is a parasitic disease transmitted by phlebotomine sandflies. Between 700,000 and 1.2 million cases of cutaneous leishmaniasis and between 200,000 and 400,000 cases of visceral leishmaniasis (VL), which is fatal if left untreated, occur annually worldwide. Liposomal amphotericin B (LAMB), alone or in combination with other drugs, has been extensively studied as VL treatment, but data on routine field use are limited, and several challenges to patients' access to this life-saving drug remain.This article provides a review of clinical studies on LAMB for VL and other forms of leishmaniasis. The current development of generic versions of LAMB and related challenges are also discussed.LAMB proved to be highly efficacious and safe in over 8000 VL patients treated by MÉdecins Sans Frontières in South Asia, and its use was feasible even at primary healthcare level. Despite requiring higher doses, LAMB is the drug of choice to treat vulnerable groups (e.g., pregnant or HIV positive) and relapsing VL patients in East Africa. LAMB should be included in national VL guidelines and registered in all VL endemic countries. Its cost should be further reduced and regulatory pathways to prove bioequivalence for generic LAMB products should be implemented.
| S-EPMC3518293 | biostudies-other
Project description:BACKGROUND: The skin disorder Post Kala-Azar Dermal Leishmaniasis (PKDL) occurs in up to 10% of patients treated for visceral leishmaniasis (VL) in India. The pathogenesis of PKDL is not yet fully understood. Cases have been reported in India following therapy with most available treatments, but rarely in those treated with liposomal amphotericin B (Ambisome). Between July 2007 and August 2012 with the support of the Rajendra Memorial Research Institute (RMRI), Médecins Sans Frontières (MSF) supported a VL treatment programme in Bihar, India-an area highly endemic for Leishmania donovani-in which 8749 patients received 20 mg/kg intravenous Ambisome as first-line treatment. This study describes the characteristics of patients who returned to the MSF supported treatment programme with PKDL. METHODS AND PRINCIPAL FINDINGS: Over a 5-year period, Ambisome was administered to 8749 patients with laboratory-confirmed VL (clinical signs, rK39 positive, with/without parasite confirmation) in four intravenous doses of 5 mg/kg to a total of 20 mg/kg, with a high initial-cure rate (99.3%) and low default rate (0.3%). All patients received health education highlighting the possibility and symptoms of developing PKDL, and advice to return to the MSF programme if these symptoms developed. This is an observational retrospective cohort study of the programme outcomes. Of the 8311 patients completing treatment for their first episode of VL, 24 (0.3%) returned passively to the programme complaining of symptoms subsequently confirmed as PKDL, diagnosed from clinical history, appearance consistent with PKDL, and slit-skin smear examination. Of the 24 patients, 89% had macular lesions, with a median time (interquartile range) to development of 1.2 (0.8-2.2) years following treatment. Comparison of the demographic and clinical characteristics of the VL patients treated with Ambisome who later developed PKDL, with those of the remaining cohort did not identify any significant risk factors for PKDL. However, the time to developing PKDL was significantly shorter with Ambisome than in a subset of patients presenting to the programme with PKDL following previous sodium stibogluconate treatment for VL. CONCLUSIONS: In this large cohort of patients with VL in Bihar who were treated with 20 mg/kg Ambisome, PKDL following treatment appears to be infrequent with no predictive risk factors. The shorter median time to developing symptoms of PKDL compared with that after conventional VL treatments should be taken into account when counseling patients treated with regimens including Ambisome.
| S-EPMC3879248 | biostudies-literature
Project description:BACKGROUND: A proportion of all immunocompetent patients treated for visceral leishmaniasis (VL) are known to relapse; however, the risk factors for relapse are not well understood. With the support of the Rajendra Memorial Research Institute (RMRI), Médecins Sans Frontières (MSF) implemented a program in Bihar, India, using intravenous liposomal amphotericin B (Ambisome) as a first-line treatment for VL. The aim of this study was to identify risk factors for VL relapse by examining the characteristics of immunocompetent patients who relapsed following this regimen. METHODS AND PRINCIPAL FINDINGS: This is an observational retrospective cohort study of all VL patients treated by the MSF program from July 2007 to August 2012. Intravenous Ambisome was administered to 8749 patients with VL in four doses of 5 mg/kg (for a total dose of 20 mg/kg) over 4-10 days, depending on the severity of disease. Out of 8588 patients not known to be HIV-positive, 8537 (99.4%) were discharged as initial cures, 24 (0.3%) defaulted, and 27 (0.3%) died during or immediately after treatment. In total, 1.4% (n?=?119) of the initial cured patients re-attended the programme with parasitologically confirmed VL relapse, with a median time to relapse of 10.1 months. Male sex, age <5 years and ?45 years, a decrease in spleen size at time of discharge of ?0.5 cm/day, and a shorter duration of symptoms prior to seeking treatment were significantly associated with relapse. Spleen size at admission, hemoglobin level, nutritional status, and previous history of relapse were not associated with relapse. CONCLUSIONS: This is the largest cohort of VL patients treated with Ambisome worldwide. The risk factors for relapse included male sex, age <5 and ?45 years, a smaller decrease in splenomegaly at discharge, and a shorter duration of symptoms prior to seeking treatment. The majority of relapses in this cohort occurred 6-12 months following treatment, suggesting that a 1-year follow-up is appropriate in future studies.
| S-EPMC3879206 | biostudies-literature
Project description:BACKGROUND:Bangladesh is one of the endemic countries for Visceral Leishmaniasis (VL). Médecins Sans Frontières (MSF) ran a VL treatment clinic in the most endemic district (Fulbaria) between 2010 and 2013 using a semi-ambulatory regimen for primary VL of 15 mg/kg Liposomal Amphotericin-B (AmBisome) in three equal doses of 5 mg/kg. The main objective of this study was to analyze the effectiveness and safety of this regimen after a 12 month follow-up period by retrospective analysis of routinely collected program data. A secondary objective was to explore risk factors for relapse. METHODS AND PRINCIPAL FINDINGS:Our analysis included 1521 patients who were initially cured, of whom 1278 (84%) and 1179 (77.5%) were followed-up at 6 and 12 months, respectively. Cure rates at 6 and 12 months were 98.7% (1262/1278) and 96.4% (1137/1179), respectively. Most relapses (26/39) occurred between 6 and 12 months after treatment. Serious adverse events (SAE) were recorded for 7 patients (0.5%). Odds of relapse at 12 months were highest in the youngest and oldest age groups. There was some evidence that spleen size measured on discharge (one month after initiation of treatment) was associated with risk of relapse: OR=1.25 (95% CI 1.01 to 1.55) per cm below lower costal margin (P=0.04). CONCLUSIONS:Our study demonstrates that 15 mg/kg AmBisome in three doses of 5 mg/kg is an effective (>95% cure rate) and safe (<1% SAE) treatment for primary VL in Bangladesh. The majority of relapses occurred between 6 and 12 months, justifying the use of a longer follow-up period when feasible. Assessment of risk of relapse based on easily measured clinical parameters such as spleen size could be incorporated in VL treatment protocols in resource-poor settings where test-of-cure is not always feasible.
| S-EPMC4383421 | biostudies-literature
Project description:Background. For the treatment of visceral leishmaniasis in Bangladesh, single dose liposomal amphotericin B (ambisome) is supposed to be the safest and most effective treatment. Specific needs for application and storage raise questions about feasibility of its implementation and acceptance by patients and health staff. Methods. The study was carried out in the most endemic district of Bangladesh. Study population includes patients treated with ambisome or miltefosine, hospital staff, and a director of the national visceral leishmaniasis program. Study methods include direct observation (subdistrict hospitals), open interviews (heath staff and program personnel), structured questionnaires, and focus group discussions (patients). Results. Politicalcommitment for ambisome is strong; the general hospital infrastructure favours implementation but further strengthening is required, particularly for drug storage below 25°C (refrigerators), back-up energy (fuel for generators), and supplies for ambisome administration (like 5% dextrose solution). Ambisome created high satisfaction in patients and hospital staff, less adverse events, and less income loss for patients compared to miltefosine. Conclusions. High political commitment, general capacities of subdistrict hospitals, and high acceptability favour the implementation of ambisome treatment in Bangladesh. However, strengthening of the infrastructure and uninterrupted supplies of essential accessories is mandatory before introducing sLAB in Bangladesh.
| S-EPMC3918353 | biostudies-literature
Project description:BACKGROUND:Visceral Leishmaniasis (VL; also known as kala-azar) is an ultimately fatal disease endemic in the Indian state of Bihar, while HIV/AIDS is an emerging disease in this region. A 2011 observational cohort study conducted in Bihar involving 55 VL/HIV co-infected patients treated with 20-25 mg/kg intravenous liposomal amphotericin B (AmBisome) estimated an 85.5% probability of survival and a 26.5% probability of VL relapse within 2 years. Here we report the long-term field outcomes of a larger cohort of co-infected patients treated with this regimen between 2007 and 2012. METHODS AND PRINCIPAL FINDINGS:Intravenous AmBisome (20-25 mg/kg) was administered to 159 VL/HIV co-infected patients (both primary infections and relapses) in four or five doses of 5 mg/kg over 4-10 days. Initial cure of VL at discharge was defined as improved symptoms, cessation of fever, improvement of appetite and recession of spleen enlargement. Test of cure was not routinely performed. Antiretroviral treatment (ART) was initiated in 23 (14.5%), 39 (24.5%) and 61 (38.4%) before, during and after admission respectively. Initial cure was achieved in all discharged patients. A total of 36 patients died during follow-up, including six who died shortly after admission. Death occurred at a median of 11 weeks (IQR 4-51) after starting VL treatment. Estimated mortality risk was 14.3% at six months, 22.4% at two years and 29.7% at four years after treatment. Among the 153 patients discharged from the hospital, 26 cases of VL relapse were diagnosed during follow-up, occurring at a median of 10 months (IQR 7-14) after discharge. After accounting for competing risks, the estimated risk of relapse was 16.1% at one year, 20.4% at two years and 25.9% at four years. Low hemoglobin level and concurrent infection with tuberculosis were independent risk factors for mortality, while ART initiated shortly after admission for VL treatment was associated with a 64-66% reduced risk of mortality and 75% reduced risk of relapse. SIGNIFICANCE:This is the largest cohort of HIV-VL co-infected patients reported from the Indian subcontinent. Even after initial cure following treatment with AmBisome, these patients appear to have much higher rates of VL relapse and mortality than patients not known to be HIV-positive, although relapse rates appear to stabilize after 2 years. These results extend the earlier findings that co-infected patients are at increased risk of death and require a multidisciplinary approach for long-term management.
| S-EPMC4125300 | biostudies-other