C. S. Lal

Phase 4 Trial of Miltefosine for the Treatment of Indian Visceral Leishmaniasis

BACKGROUND Visceral leishmaniasis (VL) is a major public health problem in Bihar, accounting for 90% of all cases in India. Development of high levels of resistance to various existing drugs necessitated the search for alternative orally administered drugs. Hospital-based studies have shown that oral miltefosine is a highly effective treatment for VL both in adults and in children. METHODS An open, single-arm trial was designed to investigate the feasibility of treatment of VL patients with miltefosine in field conditions in 13 centers in Bihar. RESULTS The phase 4 study was conducted among 1132 adult and pediatric VL patients. Compliance was good, with 1084 (95.5%) patients completing the full 28-day treatment course. Nine hundred and seventy-one (85.8%) patients returned for the final cure assessment at 6 months after treatment. The final cure rate was 82% by intention to treat analysis and 95% by per protocol analysis (similar to the 94% cure rate in hospitalized patients). Treatment-related adverse events of common toxicity criteria grade 3 occurred in ~3% of patients, including gastrointestinal toxicity and rise in aspertate amino transferase, alanine amino transferase, or serum creatinine levels, similar to previous clinical experience. CONCLUSION This study supports the use of miltefosine in an outpatient setting in an area where VL is endemic.

Designing Therapies against Experimental Visceral Leishmaniasis by Modulating the Membrane Fluidity of Antigen-Presenting Cells

ABSTRACT The membrane fluidity of antigen-presenting cells (APCs) has a significant bearing on T-cell-stimulating ability and is dependent on the cholesterol content of the membrane. The relationship, if any, between membrane fluidity and defective cell-mediated immunity in visceral leishmaniasis has been investigated. Systemic administration of cholesterol by liposome delivery (cholesterol liposomes) in Leishmania donovani-infected hamsters was found to cure the infection. Splenic macrophages as a prototype of APCs in infected hamsters had decreased membrane cholesterol and an inability to drive T cells, which was corrected by cholesterol liposome treatment. The effect was cholesterol specific because liposomes made up of the analogue 4-cholesten-3-one provided almost no protection. Infection led to increases in interleukin-10 (IL-10), transforming growth factor beta, and IL-4 signals and concomitant decreases in gamma interferon (IFN-γ), tumor necrosis factor alpha, and inducible NO synthase signals, which reverted upon cholesterol liposome treatment. The antileishmanial T-cell repertoire, whose expansion appeared to be associated with protection, was presumably type Th1, as shown by enhanced IFN-γ signals and the predominance of the immunoglobulin G2 isotype. The protected group produced significantly more reactive oxygen species and NO than the infected groups, which culminated in killing of L. donovani parasites. Therefore, cholesterol liposome treatment may be yet another simple strategy to enhance the cell-mediated immune response to L. donovani infection. To our knowledge, this is the first report on the therapeutic effect of cholesterol liposomes in any form of the disease.

Post-Kala-Azar Dermal Leishmaniasis in a Patient Treated with Injectable Paromomycin for Visceral Leishmaniasis in India

ABSTRACT Post kala-azar dermal leishmaniasis (PKDL) is a skin manifestation that usually develops after treatment of visceral leishmaniasis (VL), a major public health problem in India. The diagnosis and management of PKDL is complex. This is the first case report from India in which PKDL occurred after paromomycin treatment for VL in an Indian patient.

Evaluation of cholinesterase level in an endemic population exposed to malathion suspension formulation as a vector control measure

The manuscript describes a study on the blood cholinesterase (ChE) level in an exposed population at different interval of time after spraying with malathion suspension (SRES) use for kala-azar vector control in an endemic area of Bihar, India. The toxicity of a 5% malathion formulation in the form of a slow release emulsified suspension (SRES) was assessed by measuring serum ChE levels in spraymen and in the exposed population. The study showed a significant decrease in ChE levels in the spraymen (p < 0.01) after one week of spraying and in exposed population one week and one month after of spraying (p < 0.01), but was still within the normal range of ChE concentration, one year after spraying, the ChE concentration in the exposed population was the same as prior to spraying (p > 0.01). On no occasion was the decrease in ChE level alarming. A parallel examination of the clinical status also showed the absence of any over toxicity or any behavioural changes in the exposed population. Hence, it may be concluded that 5% malathion slow release formulation, SRES, is a safe insecticide for use as a vector control measure in endemic areas of kala-azar in Bihar, India so long as good personal protection for spraymen is provided to minimize absorption and it can substitute the presently used traditional DDT spray.

Milk of Cow (Bos taurus), Buffalo (Bubalus bubalis), and Goat (Capra hircus): a Better Alternative than Fetal Bovine Serum in Media for Primary Isolation, In Vitro Cultivation, and Maintenance of Leishmania donovani Promastigotes

ABSTRACT Tyndalized milk of goat, cow, and buffalo was found to be a potential substitute for fetal bovine serum (FBS) in the medium for the cultivation of Leishmania donovani promastigotes. The numbers (means) of promastigotes reached 2.6 × 107, 2.3 × 107, and 2.1 × 107/ml, respectively, in the medium supplemented with 10% milk of goat, cow, and buffalo, in comparison to 1.9 × 107/ml in the control with 10% FBS. In primary isolation, the milk-supplemented medium showed that 22 out of 26 samples were positive for promastigotes (84.6%) and the cells were maintained successfully during the observed period of 6 months.

HIV, visceral leishmaniasis and Parkinsonism combined with diabetes mellitus and hyperuricaemia: A case report

BackgroundVisceral leishmaniasis is caused by a protozoan parasite, Leishmania donovani and transmitted by the bite of female sandflies. India is endemic for this disease. On the other hand, India contributes to the largest number of cases of HIV as well.Case presentationWe hereby report an unusual case presentation of Visceral leishmaniasis/HIV co-infection with additional features of Parkinsonism and hyperuriciemia in an Indian male patient aged about 50 years.ConclusionThe increasing incidence of HIV/VL co-infection in India is of utmost importance. The diagnostic and management aspects of these cases are very difficult to handle particularly in an underdeveloped country like India.

Safety and efficacy of a combination of paromomycin and miltefosine for two vs. three courses in patients with post-kala-azar dermal leishmaniasis: an observational pilot study

PKDL is a dermal form of leishmaniasis caused by protozoal parasite Leishmania donovani. It is characterized by macular, popular and nodular lesions or a mixture of these1. It is mainly seen in Sudan and India, where it follows treatment of visceral leishmaniasis (VL) in 50% and 5-10% of cases respectively2. A phase III study on miltefosine-paromomycin combination for 10 days for treatment of Indian visceral leishmaniasis (n=157) revealed high cure rate (98.7%) with minimal toxicity, good compliance, lesser treatment duration and non-inferiority to standard amphotericin B3. We, therefore, aimed to assess the efficacy and safety of miltefosine plus paromomycin combination in thirty PKDL patients. This article is protected by copyright. All rights reserved.