https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)67629-5.pdf

Advances in leishmaniasis.

Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.

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Drug Resistance in Leishmaniasis

Leishmaniasis– current chemotherapy and recent advances in the search for novel drugs

Visceral leishmaniasis is common in less developed countries, with an estimated 500000 new cases each year. Because of the diversity of epidemiological situations, no single diagnosis, treatment, or control will be suitable for all. Control measures through case finding, treatment, and vector control are seldom used, even where they could be useful. There is a place for a vaccine, and new imaginative approaches are needed. HIV co-infection is changing the epidemiology and presents problems for diagnosis and case management. Field diagnosis is difficult; simpler, less invasive tests are needed. Current treatments require long courses and parenteral administration, and most are expensive. Resistance is making the mainstay of treatment, agents based on pentavalent antimony, useless in northeastern India, where disease incidence is highest. Second-line drugs (pentamidine and amphotericin B) are limited by toxicity and availability, and newer formulations of amphotericin B are not affordable. The first effective oral drug, miltefosine, has been licensed in India, but the development of other drugs in clinical phases (paromomycin and sitamaquine) is slow. No novel compound is in the pipeline. Drug combinations must be developed to prevent drug resistance. Despite these urgent needs, research and development has been neglected, because a disease that mainly affects the poor ranks as a low priority in the private sector, and the public sector currently struggles to undertake the development of drugs and diagnostics in the absence of adequate funds and infrastructure. This article reviews the current situation and perspectives for diagnosis, treatment, and control of visceral leishmaniasis, and lists some priorities for research and development.

https://www.dndi.org/wp-content/uploads/2002/08/guerin_p_lancet_infec_disea.pdf

Visceral leishmaniasis : current status of control, diagnosis, and treatment, and a proposed research and development agenda

Background There are 500,000 cases per year of visceral leishmaniasis, which occurs primarily in the Indian subcontinent. Almost all untreated patients die, and all the effective agents have been parenteral. Miltefosine is an oral agent that has been shown in small numbers of patients to have a favorable therapeutic index for Indian visceral leishmaniasis. We performed a clinical trial in India comparing miltefosine with the most effective standard treatment, amphotericin B. Methods The study was a randomized, open-label comparison, in which 299 patients 12 years of age or older received orally administered miltefosine (50 or 100 mg [approximately 2.5 mg per kilogram of body weight] daily for 28 days) and 99 patients received intravenously administered amphotericin B (1 mg per kilogram every other day for a total of 15 injections). Results The groups were well matched in terms of age, weight, proportion with previous failure of treatment for leishmaniasis, parasitologic grade of splenic aspirate, and sple...

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Oral Miltefosine for Indian Visceral Leishmaniasis

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(98)04367-0.pdf

Trial of oral miltefosine for visceral leishmaniasis

# Treatment of Indian visceral leishmaniasis with single or daily infusions of low dose liposomal amphotericin B: randomised trial {#article-title-2}

Objective: To test short course, low dose liposomal amphotericin B as single or daily infusion treatment in Indian visceral leishmaniasis (kala-azar).

Design: Randomised, open label study.

Setting: Inpatient unit for leishmaniasis in Bihar, India.

Participants: 91 adults and children with splenic aspirate positive for infection.

Interventions: Total dose of 5 mg/kg of liposomal amphotericin B given as a single infusion (n=46) or as once daily infusions of 1 mg/kg for five days (n=45).

Main outcome measures: Clinical and parasitological cure assessed 14 days after treatment and long term definitive cure (healthy, no relapse) at six months.

Results: All but one person in each group had an initial apparent cure. During six months of follow up, three patients in the single dose group and two in the five dose group relapsed. Complete response (definitive cure) was therefore achieved in 84 of 91 subjects (92%): 42 of 46 patients in the single dose group (91%, 95% confidence interval 79% to 98%) and 42 of 45 in the five dose group (93%, 82% to 99%). Response rates in the two groups were not significantly different.

Conclusion: Low dose liposomal amphotericin B (5 mg/kg), given either as a five day course or as a single infusion, seems to be effective for visceral leishmaniasis and warrants further testing.

# Commentary: cost and resistance remain issues {#article-title-19}

Treatment of Indian visceral leishmaniasis with single or daily infusions of low dose liposomal amphotericin B: randomised trial.

One hundred fifty-six previously untreated Indian patients with visceral leishmaniasis were treated with pentavalent antimony (Sb) alone for 30 days (group A), Sb plus interferon-gamma (IFN-gamma) for 30 days (group B), or Sb plus IFN-gamma for 15 days (group C). The purpose was to show that IFN-gamma would increase the response to 30 days of Sb treatment and that short-course (15 days) combination therapy was as effective as 30 days of Sb alone. Six months after treatment, 36% of group A, 49% of group B, and 42% of group C patients were designated as definitively cured. The success rates for long-term responses to Sb alone (36%) and Sb plus IFN-gamma (49%) were unexpectedly low, and responses in groups A, B, and C were not significantly different. These results suggest that the beneficial effects of adjunctive IFN-gamma in visceral leishmaniasis may be limited in regions where this disseminated intracellular infection shows high-level resistance to Sb.

Response to interferon-γ plus pentavalent antimony in Indian visceral leishmaniasis

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Atovaquone alone or with fluconazole as oral therapy for Indian kala-azar.

The His-bundle has several locations from which conduction system pacing can be achieved. Some locations offer better sensing, thresholds and paced QRS durations. Existing techniques to aid repositioning of an already deployed, but sub-optimally placed lead, include either simple memory of the initial lead position combined with its observation on an x-ray review screen or utilizing an additional vascular access and pacing lead with the first lead serving as a real-time marker (Two-lead technique). We describe a novel, readily available, cost-efficient, imaging-based approach to assist in the re-positioning of a pacing lead for His-bundle pacing (the Image Overlay Technique).

Manoj K. Makharia

Papers

Trial of oral miltefosine for visceral leishmaniasis

Treatment of Indian visceral leishmaniasis with single or daily infusions of low dose liposomal amphotericin B: randomised trial.

Response to interferon-γ plus pentavalent antimony in Indian visceral leishmaniasis

Atovaquone alone or with fluconazole as oral therapy for Indian kala-azar.

Optimizing conduction system pacing lead placement utilizing the image overlay technique.