| 1. |
- Banjara, Megha Raj, et al.
(författare)
-
Visceral leishmaniasis clinical management in endemic districts of India, Nepal, and Bangladesh
- 2012
-
Ingår i: Journal of Tropical Medicine. - : Hindawi Publishing Corporation. - 1687-9686 .- 1687-9694. ; 2012
-
Tidskriftsartikel (refereegranskat)abstract
- Background: National VL Elimination Programs in India, Nepal and Bangladesh face challenges as home-based Miltefosine treatment is introduced. Objectives. To study constraints of VL management in endemic districts within context of national elimination programs before and after intervention.Methods: Ninety-two and 41 newly diagnosed VL patients were interviewed for clinical and provider experience in 2009 before and in 2010 after intervention (district training and improved supply of diagnostics and drugs). Providers were assessed for adherence to treatment guidelines. Facilities and doctor-patient consultations were observed to assess quality of care.Results: Miltefosine use increased from 33% to 59% except in Nepal where amphotericin was better available. Incorrect dosage and treatment interruptions were rare. Advice on potential side effects was uncommon but improved significantly in 2010. Physicians did not rule out pregnancy prior to starting Miltefosine. Fever measurement or spleen palpation was infrequently done in Bangladesh but improved after intervention (from 23% to 47%). Physician awareness of renal or liver toxicity as Miltefosine side effects was lower in Bangladesh. Bio-chemical monitoring was uncommon. Patient satisfaction with services remained low for ease of access or time provider spent with patient. Health facilities were better stocked with rK39 kits and Miltefosine in 2010.
|
|
| 2. |
- Dorlo, Thomas P C, et al.
(författare)
-
Failure of miltefosine in visceral leishmaniasis is associated with low drug exposure.
- 2014
-
Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 210:1, s. 146-53
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recent reports indicated high miltefosine treatment failure rates for visceral leishmaniasis (VL) on the Indian subcontinent. To further explore the pharmacological factors associated with these treatment failures, a population pharmacokinetic-pharmacodynamic study was performed to examine the relationship between miltefosine drug exposure and treatment failure in a cohort of Nepalese patients with VL.METHODS: Miltefosine steady-state blood concentrations at the end of treatment were analyzed using liquid chromatography tandem mass spectrometry. A population pharmacokinetic-pharmacodynamic analysis was performed using nonlinear mixed-effects modeling and a logistic regression model. Individual estimates of miltefosine exposure were explored for their relationship with treatment failure.RESULTS: The overall probability of treatment failure was 21%. The time that the blood concentration was >10 times the half maximal effective concentration of miltefosine (median, 30.2 days) was significantly associated with treatment failure: each 1-day decrease in miltefosine exposure was associated with a 1.08-fold (95% confidence interval, 1.01-1.17) increased odds of treatment failure.CONCLUSIONS: Achieving a sufficient exposure to miltefosine is a significant and critical factor for VL treatment success, suggesting an urgent need to evaluate the recently proposed optimal allometric miltefosine dosing regimen. This study establishes the first evidence for a drug exposure-effect relationship for miltefosine in the treatment of VL.
|
|
| 3. |
- Dorlo, Thomas P C, et al.
(författare)
-
Reply to Arya and Agarwal.
- 2013
-
Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 57:6, s. 917-8
-
Tidskriftsartikel (refereegranskat)
|
|
| 4. |
- Huda, M Mamun, et al.
(författare)
-
Active case detection in national visceral leishmaniasis elimination programs in Bangladesh, India, and Nepal : feasibility, performance and costs
- 2012
-
Ingår i: BMC Public Health. - : Springer Science and Business Media LLC. - 1471-2458. ; 12, s. 1001-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Active case detection (ACD) significantly contributes to early detection and treatment of visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL) cases and is cost effective. This paper evaluates the performance and feasibility of adapting ACD strategies into national programs for VL elimination in Bangladesh, India and Nepal.Methods: The camp search and index case search strategies were piloted in 2010-11 by national programs in high and moderate endemic districts / sub-districts respectively. Researchers independently assessed the performance and feasibility of these strategies through direct observation of activities and review of records. Program costs were estimated using an ingredients costing method.Results: Altogether 48 camps (Bangladesh-27, India-19, Nepal-2) and 81 index case searches (India-36, Nepal-45) were conducted by the health services across 50 health center areas (Bangladesh-4 Upazillas, India-9 PHCs, Nepal-37 VDCs). The mean number of new case detected per camp was 1.3 and it varied from 0.32 in India to 2.0 in Bangladesh. The cost (excluding training costs) of detecting one new VL case per camp varied from USD 22 in Bangladesh, USD 199 in Nepal to USD 320 in India. The camp search strategy detected a substantive number of new PKDL cases. The major challenges faced by the programs were inadequate preparation, time and resources spent on promoting camp awareness through IEC activities in the community. Incorrectly diagnosed splenic enlargement at camps probably due to poor clinical examination skills resulted in a high proportion of patients being subjected to rK39 testing.Conclusion: National programs can adapt ACD strategies for detection of new VL/PKDL cases. However adequate time and resources are required for training, planning and strengthening referral services to overcome challenges faced by the programs in conducting ACD.
|
|
| 5. |
- Ostyn, Bart, et al.
(författare)
-
Failure of miltefosine treatment for visceral leishmaniasis in children and men in South-East Asia.
- 2014
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e100220-
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: High frequency of relapse in miltefosine-treated visceral leishmaniasis (VL) patients in India and Nepal followed up for twelve months.OBJECTIVE: To identify epidemiological and clinical risk factors for relapse of VL in patients recently treated with standard dosing of miltefosine in India and Nepal.DESIGN: Prospective observational study in three Primary Health Centers and one reference center in Muzaffarpur district, Bihar, India; and two zonal hospitals and a university hospital in South-east Nepal; records of all consenting patients diagnosed with VL and treated with miltefosine according to the current treatment guidelines of the Kala azar elimination program between 2009 and 2011.RESULTS: We compared the clinical records of 78 cases of relapse with those of 775 patients who had no record of subsequent relapse. Relapse was 2 times more common amongst male patients (IRR 2.14, 95% CI 1.27-3.61), and 2 to 3 times more frequent in the age groups below 15 compared to the over 25 year olds (age 10 to 14: IRR 2.53; 95% CI 1.37-4.65 and Age 2 to 9: IRR 3.19; 95% CI 1.77-5.77). History of earlier VL episodes, or specific clinical features at time of diagnosis such as duration of symptoms or spleen size were no predictors of relapse.CONCLUSIONS: Young age and male gender were associated with increased risk of VL relapse after miltefosine, suggesting that the mechanism of relapse is mainly host-related i.e. immunological factors and/or drug exposure (pharmacokinetics). The observed decrease in efficacy of miltefosine may be explained by the inclusion of younger patients compared to the earlier clinical trials, rather than by a decreased susceptibility of the parasite to miltefosine. Our findings highlight the importance of proper clinical trials in children, including pharmacokinetics, to determine the safety, efficacy, drug exposure and therapeutic response of new drugs in this age group.
|
|
| 6. |
- Palic, Semra, et al.
(författare)
-
Skin pharmacokinetics of miltefosine in the treatment of post-kala-azar dermal leishmaniasis in South Asia
- 2024
-
Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 79:7, s. 1547-1554
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Post-kala-azar dermal leishmaniasis (PKDL) arises as a dermal complication following a visceral leishmaniasis (VL) infection. Current treatment options for PKDL are unsatisfactory, and there is a knowledge gap regarding the distribution of antileishmanial compounds within human skin. The present study investigated the skin distribution of miltefosine in PKDL patients, with the aim to improve the understanding of the pharmacokinetics at the skin target site in PKDL.Methods: Fifty-two PKDL patients underwent treatment with liposomal amphotericin B (20mg/kg) plus miltefosine (allometric dosing) for 21 days. Plasma concentrations of miltefosine were measured on study days 8, 15, 22 and 30, while a punch skin biopsy was taken on day 22. A physiologically based pharmacokinetic (PBPK) model was developed to evaluate the distribution of miltefosine into the skin.Results: Following the allometric weight-based dosing regimen, median miltefosine concentrations on day 22 were 43.73 mu g/g (IQR: 21.94-60.65 mu g/g) in skin and 33.29 mu g/mL (IQR: 25.9-42.58 mu g/mL) in plasma. The median individual concentration ratio of skin to plasma was 1.19 (IQR: 0.79-1.9). In 87% (45/52) of patients, skin exposure was above the suggested EC90 PK target of 10.6mg/L associated with in vitro susceptibility. Simulations indicated that the residence time of miltefosine in the skin would be more than 2-fold longer than in plasma, estimated by a mean residence time of 604 versus 266 hours, respectively.Conclusion: This study provides the first accurate measurements of miltefosine penetration into the skin, demonstrating substantial exposure and prolonged retention of miltefosine within the skin. These findings support the use of miltefosine in cutaneous manifestations of leishmaniasis. In combination with parasitological and clinical data, these results are critical for the future optimization of combination therapies with miltefosine in the treatment of PKDL.
|
|
| 7. |
- Rijal, Suman, et al.
(författare)
-
Increasing failure of miltefosine in the treatment of Kala-azar in Nepal and the potential role of parasite drug resistance, reinfection, or noncompliance.
- 2013
-
Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 56:11, s. 1530-8
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Miltefosine (MIL), the only oral drug for visceral leishmaniasis (VL), is currently the first-line therapy in the VL elimination program of the Indian subcontinent. Given the paucity of anti-VL drugs and the looming threat of resistance, there is an obvious need for close monitoring of clinical efficacy of MIL.METHODS: In a cohort study of 120 VL patients treated with MIL in Nepal, we monitored the clinical outcomes up to 12 months after completion of therapy and explored the potential role of drug compliance, parasite drug resistance, and reinfection.RESULTS: The initial cure rate was 95.8% (95% confidence interval [CI], 92.2-99.4) and the relapse rate at 6 and 12 months was 10.8% (95% CI, 5.2-16.4) and 20.0% (95% CI, 12.8-27.2) , respectively. No significant clinical risk factors of relapse apart from age <12 years were found. Parasite fingerprints of pretreatment and relapse bone marrow isolates within 8 patients were similar, suggesting that clinical relapses were not due to reinfection with a new strain. The mean promastigote MIL susceptibility (50% inhibitory concentration) of isolates from definite cures was similar to that of relapses. Although more tolerant strains were observed, parasite resistance, as currently measured, is thus not likely involved in MIL treatment failure. Moreover, MIL blood levels at the end of treatment were similar in cured and relapsed patients.CONCLUSIONS: Relapse in one-fifth of the MIL-treated patients observed in our study is an alarming signal for the VL elimination campaign, urging for further review and cohort monitoring.
|
|
| 8. |
- Uranw, Surendra, et al.
(författare)
-
Adherence to miltefosine treatment for visceral leishmaniasis under routine conditions in Nepal.
- 2013
-
Ingår i: Tropical medicine & international health. - : Wiley. - 1360-2276 .- 1365-3156. ; 18:2, s. 179-87
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess patient adherence to unsupervised single-drug miltefosine treatment for visceral leishmaniasis and to identify the factors influencing adherence.METHODS: This is a prospective cohort study of 171 patients with Visceral leishmaniasis (VL) in three healthcare settings in Nepal. Adherence was assessed through pill count, checking of treatment cards and adherence questionnaires, as well as miltefosine concentration measurements at the end of treatment. Poor adherence was defined as less than 90% of required capsules taken.RESULTS: Patient adherence to miltefosine was 83%. Predictors of adherence were being the male sex (OR = 2.60, 95% CI 1.02-6.67) and knowing the duration of treatment (OR = 3.05, 95% CI 1.16-8.04). Adherence was also better for patients who were literate and knew the side effects of treatment. Gastrointestinal side effects and negligence after the resolution of clinical symptoms of VL were the main reasons for poor adherence. Poor adherence was associated (though not statistically significant) with future relapse.CONCLUSION: Effective counselling during the treatment, a short take-home message on VL and on side effects and action of miltefosine, and follow-up visits are the best way to prevent poor adherence. Single end-of-treatment measurements of miltefosine concentrations as objective assessment of adherence would only be useful in addition to the subjective assessments when substantial doses of miltefosine have been missed.
|
|
