Development Of Antileishmanial Drugs Research Articles

Mode of Action of Fenarimol Against Leishmania Spp.

This paper evaluates the effects of certain herbicides on Leishmania spp., their mechanism of action, and the evolutionary origin of the relevant susceptible leishmanial targets. We demonstrated that a relatively nontoxic herbicide, fenarimol, successfully interferes with a leishmanial target, which is probably a relic of an ancient ancestor. Fenarimol impairs the function of leishmanial 14alpha-sterol demethylase, a key enzyme in the sterol biosynthetic pathway. Therefore, fenarimol or its derivatives may be candidates for development of anti-leishmanial drugs. Of the herbicides that have the capability to act as potential inhibitors of the metabolism of Leishmania spp., fenarimol was found as the most active substance against both promastigotes and amastigotes in culture. In addition, it ameliorated lesions caused by Leishmania major in mice. Light microscopy demonstrated rounding of the parasite shape. Increase of osmophilic vacuoles and autophagosomal structures were observed by transmission electron microscopy. Biochemical studies demonstrated that fenarimol inhibited sterol biosynthesis. Docking of fenarimol to the modeled catalytic binding site of 14alpha-lanosterol demethylase of L. major showed a geometrical fit. Fenarimol is stabilized via hydrophobic interactions with the residues that surround it and interactions with the heme ring. These results provide support to the hypothesis that fenarimol inhibits leishmanial sterol biosynthesis. Overall, the findings suggest an additional source of substances for development of anti-leishmanial drugs.

Development of new antileishmanial drugs – current knowledge and future prospects

Leishmaniasis is a protozoan vector borne disease prevalent throughout the world and present in at least 88 countries. The parasite is transmitted by infected phlebotomine sandfly bites. While conventional therapies i.e. pentavalent antimonials, amphotericin B and pentamidine continue to play a major role, it is evident that new drugs or strategies must circumvent the limitations, such as a long-term parenteral administration, toxicity, the high cost in endemic countries and the emergence of resistance, that prevail. One of the most promising drugs is miltefosine, a new oral, approved alkylphospholipid for visceral leishmaniasis with only slight adverse effects. Although we have now this recent and encouraging advance, there is still a need to develop safe, efficient and affordable new treatments for the different clinical forms that exist. This review summarises conventional therapy and the current efforts in the discovery of drugs to treat leishmaniasis with the emphasis on drug combinations to enhance efficiency and prevent the emergence of resistance, the investigation of natural products with the objective of offering new bioactive chemical structures and the development of novel antileishmanial targets.

Costs of patient management of visceral leishmaniasis in Muzaffarpur, Bihar, India

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.

Treatment of leishmaniasis in HIV-positive patients.

Although, in southern Europe, there has been considerable experience in the treatment of visceral leishmaniasis (VL) in HIV-positive patients, the optimal therapy has yet to be established. Pentavalent antimony salts, free amphotericin B deoxycholate (ABD) and lipidic formulations of amphotericin B are the drugs most commonly used. Treatment with pentavalent antimonials requires daily injections for 28 days, is not well tolerated and leads to initial clinical cure in only 66% of the co-infected cases. Free ABD has to be given, intravenously, for just as long, has significant toxicity and leads to initial clinical cure in even fewer cases (62%). In a prospective, comparative trial, treatment of co-infected cases with a pentavalent antimonial was found to have similar efficacy and toxicity to treatment with free ABD. The duration of treatment and the associated toxicity may both be reduced by the use of lipidic formulations of amphotericin B. Anecdotal evidence and the results of non-randomized trials indicate that treatment with liposomal amphotericin B is highly effective. In a comparative trial, amphotericin B lipid complex was found to be not only as effective as a pentavalent antimonial but also better tolerated. At the moment, however, such lipidic formulations have only been tested against VL/HIV cases in Europe, not elsewhere in the world, and they remain very expensive. However successful the treatment in terms of initial clinical cure, almost all VL/HIV cases develop VL relapses. Although the data available on secondary prophylaxis are limited and often inconclusive, it appears that regular treatment with a pentavalent antimonial drug, liposomal amphothericin B or amphotericin B lipid complex can reduce the incidence of leishmanial relapses in HIV-positive patients with VL. The development of new regimens, use of new oral drugs (such as miltefosine) and the development of new antileishmanial drugs could all improve the treatment of HIV-related VL in the future.

Antileishmanial drug development: exploitation of parasite heme dependency.

A rational approach in the search for new antiparasitic drugs is the exploitation of biochemical differences between the parasite and its mammalian host. One specific example in the case of Leishmania relates to the biosynthesis of heme, a critical prosthetic group for proteins involved in metabolism and electron transport. Like all Trypanosomatids, Leishmania parasites require heme or pre-formed porphyrins for survival because they lack several key enzymes in the heme biosynthetic pathway. Considering their specific nutritional requirements, we speculated that they would be particularly sensitive to the effects of heme-complexing xanthones. In this report, we document the antileishmanial activity of selected nitrogenated xanthones and correlate drug potency with heme affinity. In vitro tests demonstrated that 3,6-bis-omega-diethylaminoamyloxyxanthone, C5, was at least 100 times more active than pentamidine against intracellular amastigotes of Leishmania mexicana. Our findings provide practical guidance for optimizing the antileishmanial activity of the xanthone pharmacophore to better exploit parasite heme salvage processes.

Drug resistance in Indian visceral leishmaniasis.

Throughout the world, pentavalent antimonial compounds (Sb(v)) have been the mainstay of antileishmanial therapy for more than 50 years. Sb(v) has been highly effective in the treatment of Indian visceral leishmaniasis (VL: kala-azar) at a low dose (10 mg/kg) for short durations (6-10 days). But in the early 1980s reports of its ineffectiveness emerged, and the dose of Sb(v) was eventually raised to 20 mg/kg for 30-40 days. This regimen cures most patients with VL except in India, where the proportion of patients unresponsive to Sb(v) has steadily increased. In hyperendemic districts of north Bihar, 50-65% patients fail treatment with Sb(v). Important reasons are rampant use of subtherapeutic doses, incomplete duration of treatment and substandard drugs. In vitro experiments have established emergence of Sb(v) resistant strains of Leishmania donovani, as isolates from unresponsive patients require 3-5 times more Sb(v) to reach similarly effectiveness against the parasite as in Sb(v) responders. Anthroponotic transmission in India has been an important factor in rapid increase in the Sb(v) refractoriness. Pentamidine was the first drug to be used and cured 99% of these refractory patients, but over time even with double the amount of initial doses, it cures only 69-78% patients now and its use has largely been abandoned in India. Despite several disadvantages, amphotericin B is the only drug available for use in these areas and should be used as first-line drug instead of Sb(v). The new oral antileishmanial drug miltefosine is likely to be the first-line drug in future. Unfortunately, development of newer antileishmanial drugs is rare; two promising drugs, aminosidine and sitamaquine, may be developed for use in the treatment of VL. Lipid associated amphotericin B has an excellent safety and efficacy profile, but remains out of reach for most patients because of its high cost.

Treatment of visceral leishmaniasis.

Growing antimony resistance in patients with visceral leishmaniasis (VL) over last two decades, especially in Indian subcontinent, renders this cheap and easily available drug useless for a vast majority of patients. Use of the second line drug pentamidine isethionate, a toxic drug with declining efficacy, has largely been abandoned. Thus, in these areas amphotericin B remains the only drug; although it cures > 97% patients, infusion-related adverse events are common and occasionally serious toxicity, such as myocarditis, or death can occur. In recent years India has been the center for clinical development of new anti-leishmanial drugs like lipid formulations of amphotericin B, new drugs like parenterally administered aminosidine and oral miltefosine. The alkyl phospholipid compound miltefosine is the first effective oral compound for VL and is likely to be marketed soon. In addition to the monotherapy, efforts in development of combination chemotherapy are needed if the menace of drug resistance is to be contained.

5308381 Ammonia extraction of gold and silver from ores and other materials: Kenneth N Han, Xinghu Meng assigned to South Dakota School of Mines & Technology

Leishmaniasis is a vector-borne parasitic disease caused by protozoan parasites belonging to the family Trypanosomatidae and genus Leishmania. The disease prevails in 88 subtropical and tropical countries in five continents where about 350 million people live. Approximately two million incidences of new cases are recorded every year, causing high morbidity and mortality with a wide spectrum of clinical manifestations in humans. Treatment for leishmaniasis depends on pentavalent antimonials developed 50 years ago as first-line drugs, whereas a limited range of other drugs such as paromomycin, miltefosine, and amphotericin B exist to supplement them. However, potential toxicity, costs, and emergence of drug-resistant pathogens are the most serious obstacles for successful treatment of the disease in most endemic areas. This demands the development of new antileishmanial agents. In this regard, the search for new drugs from various synthetic products continues, and involves also compounds isolated from natural sources and drugs used for the treatment of other ailments (cancer, viral infections, TB, immunosuppression, etc.) in order to discover compounds with unknown chemical structures and with potential novel modes of action. Medicinal and aromatic plants are a major source of natural organic compounds which are widely used as medicine. The extensive ethnomedicinal knowledge, diversity of plant species, and the disease burden worldwide necessitates the status of natural products in treatments of leishmaniasis to be assessed. This chapter will review plant crude extracts and fractions/active principles obtained from medicinal plants which are used in or have potential for the treatment of leishmaniasis. Plant species are systematically presented by family, bioactive phytochemicals in various classes, and results obtained on specific organisms tested. Recent empirical and rationale approaches for antileishmanial drug targeting and development of novel drugs derived from natural products will be discussed.

The activity of 2-substituted quinoline alkaloids in BALB/c mice infected with Leishmania donovani.

Potent antileishmanial activity has recently been described in vivo when certain 2-substituted quinoline alkaloids are administered to mice with cutaneous leishmaniasis. We now report the antileishmanial activity of four 2-substituted quinoline alkaloids, namely chimanine D or 2-(1',2'-trans-epoxypropyl) quinoline (I), 2-n-propylquinoline (II), 2-styrylquinoline (III) and 2-(2'-hydroxypropyl) quinoline (IV), for experimental treatment of visceral leishmaniasis in infected BALB/c mice. Subcutaneous treatment with chimanine D for 10 days at 0.54 mmol/kg per day resulted in 86.6% parasite suppression in the liver. Oral administration of 0.54 mmol/kg of 2-n-propylquinoline once daily for 5 or 10 days to L. donovani-infected mice suppressed parasite burdens in liver by 87.8 and 99.9%, respectively. Cutaneous administration of meglumine antimonate for 10 days resulted in 97.4% parasite suppression in the liver. This study is, to our knowledge, the first to demonstrate the activity of 2-substituted quinoline alkaloids in experimental treatment of visceral leishmaniasis. Further biological and chemical studies of these products might yet prove helpful for the development of new antileishmanial drugs.

2-substituted quinoline alkaloids as potential antileishmanial drugs

Ten 2-substituted quinoline alkaloids isolated from a plant used for treatment of New World cutaneous leishmaniasis have antileishmanial in vitro activities against the extracellular forms of Leishmania spp. BALB/c mice infected with Leishmania amazonensis PH8 or H-142 or Leishmania venezuelensis were treated 1 day after the parasitic infection with a quinoline alkaloid (100 mg/kg of body weight per day) or with reference drug N-methylglucamine antimonate (Glucantime) (56 mg of pentavalent antimony [Sbv] per kg per day) for 14 days. Lesion development was the criterium used to assess disease severity. Two three-carbon chain quinolines [2-n-propylquinoline and 2-(1',2'-trans-epoxypropyl)quinoline (chimanine D)] were more potent than N-methylglucamine antimonate against L. amazonensis PH8, and five quinoline alkaloids [2-(3,4-methylenedioxyphenylethyl)quinoline, cusparine, 2-(3,4-dimethoxyphenylethyl)quinoline, 2-(E)-prop-1'-enylquinoline (chimanine B), and skimmianine] were as effective as the reference drug. Single treatment near the site of infection, 14 days after infection with L. amazonensis, with 2-n-propylquinoline or chimanine B reduced the severity of lesions but less notably than N-methylglucamine antimonate. 2-n-Propylquinoline exhibited significant activity against the virulent strain L. venezuelensis. The active products did not show any apparent toxicities during the experiment. This study is, to our knowledge, the first to show the activity of 2-substituted quinoline alkaloids for experimental treatment of New World cutaneous leishmaniasis. Further investigations of these compounds might yet prove helpful for the development of new antileishmanial drugs.