Plants with anti-Leishmania activity: Integrative review from 2000 to 2011.

The search for more effective new drugs to treat Leishmaniasis is undoubtedly relevant. Our objective in this study was to investigate research publications addressing plants with anti-Leishmaniasis activity. An integrative review of the literature from 2000 to 2011 was carried out in the databases such as Latin-American and Caribbean Health Sciences (LILACS), Scientific Electronic Library Online (SciELO), and Medical Literature Analysis and Retrieval System Online (MEDLINE). In the initial search, 150 articles were found, with 25 based in LILACS, 68 in SciELO, and 46 in MEDLINE. From these data, after reading the abstracts that were available online, we excluded 12 from LILACS, 39 from SciELO, and 28 from MEDLINE for presenting article duplications. This left 61 articles to be read; however, only 18 of them answered the research questions and determined the final sample of this review. The results showed that research involving the search for new drugs against Leishmaniasis should be intensified, especially for the amastigote form, and studies with in vivo tests could become a great strategy for successfully finding new treatments for Leishmaniasis. It is believed that it is extremely important and urgent to conduct more trials in search of new effective drugs against Leishmaniasis that possess minimal adverse effects and that are easily accessible to the public.

INTRODUCTION

Leishmaniasis caused by protozoan parasites of the genus Leishmania is endemic in 88 countries, including Europe and mainly the underdeveloped or developing countries. This potentially fatal tropical disease, whose study is currently being neglected,[1] is considered by the World Health Organization (WHO) as the second most important protozoan in regard to public health.

The main carriers of the parasite referred to above are domestic animals such as dogs, as well as wild animals, with the disease transmitted by the bite of female insects of the genus Lutzomyia; during the bite, the parasites are inoculated into the epidermis and dermis of their vertebrate hosts, including humans.[2] In the insect, the parasites are in the infective promastigote form, whereas in their vertebrate hosts, they are found in the amastigote form.[3]

The treatment for Leishmaniasis is complicated, since, in humans, the protozoan Leishmania is an obligate intracellular parasite of macrophages in the amastigote form.[4]

There is no vaccine available for the disease and the medications of first choice, the pentavalent antimonials, are toxic and administered exclusively by the parenteral route.[4] Moreover, resistance to these medications has been reported, a fact increasing for all forms of Leishmaniasis and especially in areas endemic for these threats to human health.[5]

Seifert and Croft,[6] studying the region of Bihar, India, where the PRevalence of Leishmaniasis is quite pronounced, reported rates over 65% of non-responsiveness to treatment with pentavalent antimonials, which now-a-days are no longer used in these locations.

As second-line treatment in cases of resistance or intolerance to antimonials, amphotericin B is used in the lyophilized form of sodium deoxycholate – amphotericin B and pentamidine. However, due to the numerous adverse effects frequently developed by amphotericin B in the form of deoxycholate, new formulations have been produced and are currently commercially available. One of these formulations is liposomal amphotericin B. Its high cost, however, does not allow its routine use by health services in developing countries like Brazil.[7]

As for pentamidine, it belongs to the chemical group of diamidines and has been particularly useful in cases that do not respond to antimonials or in cases of individuals suffering from Leishmaniasis hypersensitive to antimony; however, its high toxicity becomes a limiting factor, leading to hypoglycemia, hypotension, cardiac abnormalities, nephrotoxicity, and even sudden death, as reported by some users.[8]

Another drug that has proven effective against visceral Leishmaniasis is paromomycin, considered an aminoglycoside and administered via parenteral route. It has shown a cure rate of 79% but has not been successful against cutaneous Leishmaniasis, besides having high renal toxicity.[9]

In the year 2002, miltefosine, originally developed as an anti-cancer substance, was registered in India to treat visceral Leishmaniasis, becoming the first oral treatment and the last leishmanicidal medication placed on the market.[10] In 2007, the medication mentioned above was also registered in Colombia for the treatment of cutaneous Leishmaniasis.[11] Since coming into clinical use, no cases of resistance to the treatment of Leishmaniasis with miltefosine have been reported. Studies indicate, however, the ease with which this resistance can occur, especially when the medication is used continuously.[12]

Azoles and allopurinol are two of many oral medications that are weakly active against Leishmania. These drugs are not useful as a single agent, and there are reports that they can interfere in the efficacy of the treatment of immunocompromised patients when the drugs are used in combination, although clinical trials to test this combination have not yet been performed.[13]

For Oliveira et al.,[9] the incidence of millions of new cases of Leishmaniasis per year worldwide and deficiencies in current treatment point to an urgent need for new medications to combat the parasitic diseases mentioned above.

According to the WHO, plants are the best and largest source of drugs for humanity, and Brazil has 60.7% of its territory in natural and planted forests, representing the second largest forest area in the world, only behind Russia.[14]

Thus, the purpose of this study was to perform an integrative literature review that consists of one of the research methods used in Evidence-Based Practice in Health and permits the consolidation of findings in care practice. This method can be directed to the definition of concepts, review of theories, or the methodological analysis of studies on a determined subject, helping to improve the knowledge of the research topic.[15]

With this in view, it can be understood that the search for new compounds that offer treatment options for Leishmaniasis is imminent. This study, then, asks the following research question: What findings discovered between 2000 and 2011 referred to the use of active ingredients from plants against Leishmaniasis?

In this scenario, it is believed that extracts or compounds of plant origin can be incorporated into a valuable starting point for the search of new therapeutic agents, since natural products and their derivatives, according to Basso et al.,[16] are the sources of 30% of the global pharmaceutical market. In an attempt to improve that knowledge related to the search for new molecules against Leishmaniasis, this study aimed to address research carried out with plants from 2000 to 2011 and published in databases, consolidated in the form of documents or articles that present promising anti-Leishmania results.

MATERIALS AND METHODS

In performing this review, we went through the following phases: Identification and selection of the theme of the research question; establishment of criteria for selection of the sampling; definition of information to be extracted from selected studies and ranking of the studies; assessment of the studies included in the integrative review; and finally, explanation of the results and presentation of the review.[17]

The bibliographic research was conducted from January 2012 to April 2012 in the following indexed databases: Scientific Electronic Library Online (SciELO), Latin-American and Caribbean Health Sciences (LILACS), and Medical Literature Analysis and Retrieval System Online (MEDLINE). As for the data search, we used terminologies registered in the descriptive sciences subject headings generated by the Virtual Health Library, standardized from the medical subject headings from the United States-National Library of Medicine, which allows the use of common terminology in English, Portuguese, and Spanish.

The groups of keywords used to search the databases were: Leishmania, medicinal plants, and natural products; Leishmania, anti-Leishmaniasis, and anti-Leishmania; leishmanicidal activity; visceral Leishmania, plants, and leishmanicidal activity; Leishmania amazonensis, anti-Leishmanial activity, and medicinal plants.

In the initial search, 150 articles were found, with 25 based in LILACS, 68 in SciELO, and 46 in MEDLINE. From these data, after reading the abstracts that were availab le online, we excluded 12 from LILACS, 39 from SciELO, and 28 from MEDLINE for presenting article duplications. This left 61 articles to be read; however, only 18 of them answered the research questions and determined the final sample of this review, as 38 articles studied active ingredients that were not of plant origin.

The selection of the information was based on an instrument that was completed for each article from the final sampling of the review. The tool referred to above presented the following information: Identification of the article and authors, source location, purpose, research design, methodology, results, and main conclusions of each study, in accordance with Mendes et al.[18]

The articles were numbered according to order of occurrence, and the data were organized according to the concept of information to be drawn from the chosen publications. Presentation of the results was in the form of a summary chart, two tables, and a descriptive discussion of the information.

RESULTS

Characterization of the studies analyzed

In regard to characterization, the findings from the 18 selected articles were published between 2003 and 2011. All studies had a quantitative approach and experimental character using analytes from plants [Tables 1-3].

Table 1

Studies included in the integrative review of trials on plants with anti-Leishmaniasis activity. Aracaju, SE, 2012

Table 3

Plants with anti-Leishmania activity

We need to understand that studies with the type of approach above are used when seeking answers, such as for new drugs to treat Leishmaniasis, because the resistance of these protozoa to the drugs in use has been increasing worldwide, justifying the relevance of these studies. The data in Table 1 represent the articles selected for this review.

Concerning the articles reviewed, it was noted that most had been published in journals specialized in the area of natural products research.

It was noted that the objectives of the studies were oriented toward testing the active ingredients (crude extract, essential oil, etc.) against the promastigote and amastigote forms of Leishmaniasis.

Regarding the origin of the publications, i.e., journal and year of publication, this information is detailed in Table 1. The observation of diverse publications can be justified due to Leishmaniasis’ presence in 88 countries, with reported cases of drug resistance already existing in all of them.

DISCUSSION

Based on the materials analyzed, we were able to come up with pertinent questions to be answered in relation to research on plants for treatment against Leishmaniasis.

In recent years, the reasoning for the search for new anti-Leishmania molecules has been developed through basic techniques, such as impeding the growth of promastigotes in vitro, according to Liu.[34]

Acestor et al.[35] stated that there has been a limited availability of studies on the amastigote form. However, Davis, Murray and Hadman[36] argued that one cannot help noticing that the mechanism of action and interaction of medications in humans are often discovered after their indication and use. These authors also stated that, during the search for new medications, compounds may have been discarded for not demonstrating results in vitro or for possibly being pro-drugs.

For Leandro and Campino,[37] the resistance of protozoa such as Leishmania to medications used for treatment is increasing in developed countries. These authors believe that, in many cases, resistance is due to the expression of the ABC efflux pump (Adenosine-5-triphosphate (ATP) - binding cassette), since there are several classes of ABC transporters of Leishmania spp. protozoa, resulting in different phenotypes in the resistance to medications.

Efforts to investigate new molecules that are effective in treating Leishmaniasis include the germicidal potential of compounds derived from plants, as seen by Napolitano et al.,[38] who reported that in several regions of the world, many people rely on traditional practices for primary health care, and plants are essential sources of remedies.

For Mendonça-Filho et al.[39] and Desjeux,[40] the search for active plant molecules can lead to new strategies for the control of Leishmaniasis.

We believe that the scientific community should be more daring and develop innovative, sustainable research projects on the amastigote form in vivo, and conduct pre-clinical trials, and not remain content to carry out experiments in vitro on the promastigote form.

Through such initiatives, perhaps more robust results can be obtained for the treatment of Leishmaniasis that lead to more consolidated expectations that stimulate greater financial investments in research on natural products, not only against Leishmaniasis but also to combat other protozoan infectious diseases such as malaria, which is considered the most lethal parasitic disease worldwide.

Final considerations

Through this integrative review, it was possible to note that several researchers are dedicated to the search for new molecules that have efficacy against Leishmaniasis; however, it was also evident that, under the conditions of this study, the majority of tests were performed with the promastigote form.

We believe that these studies are undoubtedly important because promastigotes are infective to man and other animals. However, it is urgent that other studies be conducted using more and more compounds derived from plants with the aim of finding anti-amastigote activity, since the morbimortality associated with Leishmania is caused by this form.

Although publications have been increasing in recent years with regard to studies on plants that are likely to treat Leishmaniasis, it is still necessary that research developers invest more resources in this area, and thus minimize the lack of attention that has been given to these parasitic diseases.

Table 2

Some botanical aspects of the plants in the present study