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Alternative Treatment for Leishmaniasis

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Renata Mondêgo de Oliveira, Solange de Araújo Melo, Tatiane Aranha da Penha-Silva, Fernando Almeida-Souza and Ana Lucia Abreu-Silva

Submitted: September 26th, 2017 Reviewed: February 23rd, 2018 Published: October 10th, 2018

DOI: 10.5772/intechopen.75895

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Leishmaniasis remains as one of the most important neglected diseases in the world and, after all these years, its treatment is still a problem, mainly because of the side effects caused by the first- and second-line drugs and the indiscriminate treatment, which leads to increasing cases of parasite resistance. The search for alternative therapies for the treatment of leishmaniasis is extremely important. In this context, the use of natural products arises as a promising alternative, combining the empirical knowledge disseminated in the population with researches that aim to scientifically prove the therapeutic effects of plants. Based on this, the use of medicinal plants is considered a desirable and accessible tool in the treatment of these diseases and considered by pharmacognosy as a valuable source for the development of new drugs and as adjuvant for conventional therapies.


  • herbal medicine
  • Leishmania spp.
  • natural products
  • visceral leishmaniasis
  • traditional medicine

1. Introduction

Protozoa of the genus Leishmaniacause a broad spectrum of diseases collectively called Leishmaniasis, which represent a serious public health problem worldwide. Its clinical forms vary from cutaneous leishmaniasis (CL), characterized by tegumentary lesions that can heal and regress spontaneously, to visceral leishmaniasis (VL), more severe and potentially fatal, if not treated [1].

VL is an important zoonosis caused by parasites of the Leishmania donovanicomplex (L. donovaniin India and Central Africa and L. infantumin America, Middle East, Central Asia, China, and the Mediterranean Basin) [2, 3]. It is present in 98 countries but, although widely distributed, more than 90% of cases are restricted to India, Bangladesh, Sudan, South Sudan, Ethiopia, and Brazil [4, 5]. In the Americas, dogs are considered the main reservoir of the parasites, as well as an important link for the maintenance of the infection in the urban environment [6] (Figure 1).

Figure 1.

Status of endemicity of visceral leishmaniasis worldwide, 2015. Source: Adapted from WHO (2015) [7].

Leishmaniaspecies have a complex life cycle, alternating between a permissive insect vector and a susceptible vertebrate host [8]. The transmission of the parasite occurs through the bite of an infected female sandfly, belonging to the genus Phlebotomus, in the Old World, or Lutzomyia, in the New World [9]. Once inside the vertebrate host, the promastigote forms inoculated by the insect will be phagocytosed by macrophages, transforming into amastigotes. After extensive multiplication, the amastigotes increase in quantity until the cell ruptures, leading to infection of other phagocytic cells, continuing the cycle [10].

Other forms of transmission have already been reported, such as vertical and/or sexual transmission [11], non-vector hematogenous [12, 13], and through other vectors, such as Rhipicephalus sanguineus[14], but their role in the maintenance of the disease is not totally clear yet.

In epidemiological terms, the dynamics of disease transmission is very complex and depends on several factors, such as the socioeconomic status of the population (poor living conditions, malnutrition), climate and environmental changes (which leads to sandfly adaptation and spread), host–parasite relationship (immunocompromised individuals, evasion mechanisms employed by the parasite), and population mobility (international travels and/or migration from non-endemic areas to endemic areas), which means that there may be differences in the pattern of disease spread, depending on the place [8, 15, 16, 17, 18].


2. Therapeutic modalities for VL

2.1. Chemotherapy

Despite its importance for both human and animal health, there are few therapeutic options for VL treatment. The bases of therapeutic protocols in humans are the pentavalent antimonials (sodium stibogluconate and meglumine antimoniate), but the need of hospitalization and the severe side effects caused by its administration leads to high dropout rates among the patients, which contributes for parasite resistance in case of disease relapse. Although widely used, the mechanism of action of antimonials is still poorly understood [19, 20].

As a second-line drug, amphotericin B was initially recommended for patients who did not respond to the treatment with pentavalent antimonials. It presents high cure rates, efficacy, and safety, but, once again, needs prolonged hospitalization, for close monitoring of renal functions, and has some adverse effects, such as fever and chills [21, 22].

Miltefosine was the first oral drug used for VL cases, which simplified the treatment in several aspects. It was originally designed for breast cancer and other solid tumors, but the gastrointestinal side effects limited its use [23, 24]. In vitro and in vivo evidences of the antileishmanial activity of miltefosine [25, 26, 27] conducted in clinical trials in humans and its release for the treatment of human VL in many countries [28, 29, 30]. However, it should not be used in pregnant women due to its teratogenic effect [23]. Besides that, its indiscriminate use, incomplete treatment, and the long half-life of the drug has increased the cases of parasitic resistance, which represents a serious concern [31].

Other drugs are commonly used as therapeutic alternatives for VL, such as paromomycin, pentamidine, and sitamaquine. However, all have variable side effects or cure rates lower than the reference drugs [22, 32, 33, 34, 35, 36].

In general, all available drugs have problems related to toxicity and high costs, which hinders the treatment of Leishmaniasis, especially in poor and developing countries, where the great majority of the cases are concentrated [8]. For this reason, it is of great importance the adoption of strategies for the search and development of new candidate drugs. In this context, we emphasize the emergence of phytotherapy as a promising therapeutic alternative, since the use of natural products is widely disseminated in the population [37]. Therefore, it is necessary to combine the empirical knowledge with researches, with the aim to scientifically prove the therapeutic effects of plants—crude extracts, fractions or isolated substances—against Leishmaniaspecies, especially the causative agents of VL.

2.2. Phytotherapy

Medicinal plants are defined as those administered to man or animals, by any routes, that exert some therapeutical activity [38]. Plants are used as sources of new compounds throughout the history of mankind and, even today, serve as basis of many products used in the medical routine [39].

The use of medicinal plants has become, especially in developing countries, an alternative to traditional health services, both in rural areas, deprived of public health resources, as in urban areas, as an option or as a complement to allopathic medication [40]. This tradition has been passed on to the populations in every generation, and is configured as a new science, the phytotherapy [41].

In countries with a great diversity of flora, such as Brazil, there is a great potential for the rational exploitation of plant resources and for the diffusion of herbal practices. Such practices are able to generate benefits both in the cultural point of view such as contributions to the scientific validation of the use of plant species [42, 43], since many of these are consumed without their pharmacological properties are, in fact, known [44].

The scientific community reveals a growing interest in this field, recognizing the true health benefit that plants provide [45]. The World Health Organization itself recognizes that the solution to combating numerous diseases, especially the so-called “neglected diseases,” lies in the traditional knowledge and in the development of new drugs derived from biodiversity products [46].

Historically, experiments with the use of plants in medicine with therapeutical and healing purposes have been reported, which demonstrates that man began to use plants not only as food but also as a therapeutic resource for many diseases. Currently, many plant drugs are pointed out and described as viable alternatives in the treatment of many diseases [47], progressively abandoning empirical use based on experiments, starting for rational use based on iatrochemistry [48], based on the evident undesirable effects of some synthetic drugs [49].

Tagboto and Townson [50] describe as challenging the path of validation of the use of natural drugs and this includes not only the discovery of new drugs, but also the certification of products already used, culminating in the preservation of biodiversity. These authors report that, due to the widespread use of natural drugs being used, especially in underdeveloped countries, there was a need for certification of these products, and that due to these reasons, in 2000, the World Health Organization created a demand in order to qualify and regulate with scientific bases some medicines whose principles are already known, as well as empirical ones, in order to identify new possibilities within pharmacognosy.


3. Alternate therapies—mechanism of action

3.1. Immunomodulation by antileishmanial plant products

The immunological condition of a patient infected with Leishmaniarepresents a determinant point for a favorable treatment. In visceral leishmaniasis, the immune system is markedly shaken by secondary infections and other opportunistic infections associated with the clinical picture of the disease, which emphasizes the need for drugs that not only favor immune recovery but also present a leishmanicidal action [51]. The modern medicine has changed the focus regarding the treatment of several diseases, such as neoplasms and infectious diseases. Traditionally, the drugs were developed to act directly on the microorganisms or neoplastic cells, but now, the main goal is to strengthen the body’s defenses. Plants have several secondary metabolites, for example, flavonoids, polysaccharides, lactones, alkaloids, diterpenoids, and glycosides that may activate the immunological system [52]. Regarding leishmaniosis treatment, Chouhan et al. [53] describe the use of medicinal plants as an alternative for modulating the patient’s immune response as an effective device in therapy. A combination of miltefosine and nanoparticles of curcumin displayed lymphocyte proliferation and increased the phagocytic capacity of peritoneal macrophages. This effect was attributed to curcumin [54]. A substance isolated of Casearia arborea, tricin, was able to modulate the respiratory burst, which favors the parasite elimination [55].

Awareness of the importance of modulating the immune system has been a crucial point in the prevention and treatment of various diseases, and for this reason, the immunomodulatory properties of plants have been extensively explored so that researchers seek not only to affect the permanence of the pathogen but also have sought to boost both the patient’s natural and adaptive defenses [56, 57]. This fact was observed by Almeida-Souza et al. [58], demonstrating a hypothesis that determines compounds obtained by different extraction methods can favor the increase of mediators such as nitric oxide (NO), increasing the functions and abilities of macrophages in the elimination of amastigote forms.

3.2. Reactive oxygen species generation

Against obligate intracellular parasite, macrophages use various mechanisms of action to control infection, as the induction of reactive oxygen and nitrogen species. Hydrogen peroxide is a major source of hydroxyl radicals and other reactive oxygen species, which macrophages produce in greater quantities [59, 60]. Among reactive nitrogen species, nitric oxide (NO) has a potent microbicide effect against intracellular parasites, such as Leishmania[61]. NO is a freely diffusible gas produced by the activity of inducible NO synthase (iNOS) enzyme by the conversion of L-arginine to L-citrulline. iNOS is induced by various pro-inflammatory factors such as cytokines or endotoxins [62]. In its short life, NO acts directly on pathogens by inhibition of proliferation, DNA mutagenesis, disruption of [FeS] clusters, metabolic blockade, and inactivation of virulence factors or molecules associated with infectious pathogens [63]. The functions of NO also include immunostimulatory (pro-inflammatory) effects that together with antimicrobial activity contribute to the killing of intracellular Leishmaniaas previous reported [58].

3.3. Apoptosis-inducing potential

The mechanism of action of leishmanicidal drugs is not well elucidated. It has been reported that both conventional drugs and some plants extracts used in the treatment of visceral leishmaniasis may induce a phenomenon like apoptosis in the parasite. The ethanolic extract of seeds and leaves of Azadiracta indica[64] and essentials oils of Artemisia campestrisand Artemisia herba-alba[65] act as an apoptosis inductor in promastigotes of L. donovaniand L. infantum,respectively.


4. Plants with antileishmanial properties

The available drugs against leishmaniasis do not always present a satisfactory result and have been shown as an expressive challenge for current treatment protocols [66]. Many plants that present anti-infectious characteristics have been studied for the careful detection of new active compounds isolated [67] of antiparasitic action and also as immunomodulators, so that they are shown as a collection of bioactive compounds for the optimization of the treatment of leishmaniasis [68], as well as the presence of active compounds belonging to several chemical groups [69, 70, 71], such as flavonoids, isoflavonoids, saponins, alkaloids, sesquiterpenes, polysaccharides, tannins, indoles, and glucans [72].

Much information about plants and formulations employed in popular medicine is contained in the literature, and based on this information, new constituents have been successfully perfected and clinically tested, correlating traditional and modern medicine, combining science and empiricism (Table 1). Traditional medicine is based primarily on personal experience, with the use of compounds not yet fully validated, requiring complementary evidence to become safe and effective [106].

PlantPart of plantPreparationSpeciesReference
Withania somniferaLeaves; whole plantAlcoholic fractions F5 and F6; tablets; methanolic extract (fraction A6)L. donovaniChandrasekaran et al. [68]
Kaur et al. [73]
Sharma et al. [74]
Inula chritmoidesNot citedAcetone and dichloromethane extractsL. infantumOliveira et al. [75]
Casearia arboreaLeavesMethanolic extractL. infantumSantos et al. [55]
Curcuma longaRhizomeOral formulation based on nanoparticlesL. donovaniTiwari et al. [54]
Spergularia rubraNot citedAcetone and dichloromethane extractsL. infantumOliveira et al. [75]
Ocimum sanctumLeavesEthanolic extractL. donovaniBhalla et al. [76];
Kaur et al. [73]
Cocos nuciferaHusk fiberAqueous extractL. donovaniBhalla et al. [76]
Sterculia villosaBarkMethanolic extractL. donovaniDas et al. [77]
Coccinia grandisLeavesExtractL. donovaiPramanik et al. [78]
Das et al. [79]
Morinda citrifoliaFruitsAqueous extract
Fruit juice
L. chagasiAlmeida-Souza et al. [80]
Solanum tuberosumTuberSodium bisulphite extractionL. donovaniPaik et al. [81]
Paik et al. [82]
Moringa oleiferaFlowerEthyl acetate fractionL. donovaniSingh et al. [83]
Azadirachta indicaLeaves and seedsEthanolic fraction and ethyl acetate fractionL. donovaniChouhan et al. [84]; Dayakar et al. [85]
Croton caudatusLeavesHexanic extractL. donovaniDey et al. [86]
Artemisia annuaLeaves and seedsn-hexane fractionsL. donovaniIslamuddin et al. [87] Islamuddin et al. [88]
Asparagus racemosusWhole plantTabletsL. donovaniKaur et al. [89]
Sachdeva et al. [90]
Syzygium aromaticumFlowerEssential oilL. donovaniIslamuddin et al. [91]
Croton cajucaraLeavesEssential oilL. chagasiRodrigues et al. [7]
Solanocia manniiLeavesExtractL. donovaniHubert et al. [92]
Solanum torvumLeavesExtractL. donovaniHubert et al. [92]
Coriandrum sativumSeedsOleoresinL. chagasiRondon et al. [93]
Lippia sidoidesNot citedEssential oilL. chagasiRondon et al. [93]
Copaifera reticulataSeedsEssential oilL. chagasiRondon et al. [93]
Spondias mombinAerial partsEthanolic extract (Sm3 fraction)L. chagasiAccioly et al. [94]
Annona squamosaLeavesAlkaloid and acetogenic extractL. chagasiVila-Nova et al. [95]
Annona muricataSeedsAlkaloid and acetogenic extractL. chagasiVila-Nova et al. [95]
Aloe veraLeavesExtractL. infantumRondon et al. [96]
Coriandrum sativumSeedsExtractL. infantumRondon et al. [96]
Ricinus communisLeavesExtractL. infantumRondon et al. [96]
Valeriana wallichiiRootMethanol and chloroform extractsL. donovaniGhosh et al. [97]
Momordica charantiaFruitCrude extractL. donovaniGupta et al. [98]
Kalanchoe pinnataLeavesAqueous extractL. chagasiGomes et al. [99]
Allium sativumBulbMethanolic extract (fraction G3)L. donovaniSharma et al. [74]
Piper betleLeavesMethanolic extract and essential oilL. donovaniMisra et al. [100]
Nyctanthes arbor-tristisLeavesMethanolic extract (fraction calceolariosidea)L. donovaniPoddar et al. [101]
Aloe veraLeavesExudateL. donovaniDutta et al. [102]
Tinospora sinensisPowdered stemEthanolic extractL. donovaniSingh et al. [103]
Chenopodium ambrosioidesAerial partsEssential oilL. donovaniManzote et al. [104]
Annona crassifloraStem barkExanolic and ethanolic extractL. donovaniMesquita et al. [105]
Himatanthus obovatusRoot woodExanolic and ethanolic extractL. donovaniMesquita et al. [105]
Guarea kunthianaRootsExanolic and ethanolic extractL. donovaniMesquita et al. [105]
Cupania vernalisLeavesExanolic and ethanolic extractL. donovaniMesquita et al. [105]
Serjania lethalisRoot barkExanolic and ethanolic extractL. donovaniMesquita et al. [105]

Table 1.

Antileishmanial activity of plants against visceral leishmaniasis.


5. Conclusion

The drugs available for the treatment of visceral leishmaniasis have adverse effects, a high cost, and, in addition, parasitic resistance is frequent. These facts are a challenge for modern science, which uses traditional medicine as a research source to find a compound that is effective and has minimal side effects. Many studies have been carried out, but the results obtained are not very encouraging. Most of the plants studied did not present leishmanicidal effect but the immunomodulatory effect has often been emphasized. Summarizing, data in the literature show that the substances obtained from the study of plants may be excellent allies in the treatment of leishmaniasis because they have immunomodulatory effects, but none has a direct effect against the parasite.



This work was supported by Fundação de Amparo à Pesquisa e Desenvolvimento Científico e Tecnológico do Maranhão – FAPEMA [grant numbers APP-00844/09, Pronex-241709/2014 to Abreu-Silva AL; DCR03438/16 to Almeida-Souza F]; Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq [grant numbers 309885/2017-5 to Abreu-Silva AL; 312765/2016-9 to Almeida-Souza F]; Secretaria da Ciência Tecnologia e Inovação do Estado do Maranhão [grant number DCR03438/16 to Almeida-Souza F]; and CAPES PNPD program [grant to Penha-Silva TA].


Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this chapter.


  1. 1. Stanley AC, Engwerda CR. Balancing immunity and pathology in visceral leishmaniasis. Immunology Cell Biology. 2007;85:138-147. DOI: 10.1038/sj.icb7100011
  2. 2. Baneth G, Koutinas AF, Solano-Gallego L, Bourdeau P, Ferrer L. Canine leishmaniosis – new concepts and insights on an expanding zoonosis: Part one. Trends in Parasitology. 2008;24:324-330. DOI: 10.1016/
  3. 3. CB1 P-d-S, Day MJ. One health: The global challenge of epidemic and endemic leishmaniasis. Parasites & Vectors. 2011;4:197. DOI: 10.1186/1756-3305-4-197
  4. 4. Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, Jannin J, den Boer M, WHO Leishmaniasis Control Team. Leishmaniasis worldwide and global estimates of its incidence. PLoS One. 2012;7(5):e35671. DOI: 10.1371/journal.pone.0035671
  5. 5. Singh S. Changing trends in the epidemiology, clinical presentation, and diagnosis ofLeishmania-HIV co-infection in India. International Journal of Infectious Diseases. 2014;29:103-112. DOI: 10.1016/j.ijid.2014.07.011
  6. 6. Dantas-Torres F, Brandão-Filho SP. Visceral leishmaniasis in Brazil: Revisiting paradigms of epidemiology and control. Revista do Instituto de Medicina Tropical de São Paulo. 2006;48:151-156. DOI: /S0036-46652006000300007
  7. 7. Rodrigues IA, Azevedo MM, Chaves FC, Bizzo HR, Corte-Real S, Alviano DS, Alviano CS, Rosa MS, Vermelho AB. In vitro cytocidal effects of the essential oil from Croton cajucara (red sacaca) and its major constituent 7-hydroxycalamenene against Leishmania chagasi. BMC Complementary and Alternative Medicine. 2013 Oct 2;13:249. DOI: 10.1186/1472-6882-13-249
  8. 8. Savoia D. Recent updates and perspectives on leishmaniasis. Journal of Infection in Developing Countries. 2015;9:588-596. DOI: 10.3855/jidc.6833
  9. 9. Murray HW, Berman JD, Davies CR, Saravia NG. Advances in leishmaniasis. The Lancet. 2005;366:1561-1577. DOI: 10.1016/S0140-6736(05)67629-5
  10. 10. Bañuls AL, Hide M, Prugnolle F.Leishmaniaand the Leishmaniases: A parasite genetic update and advances in taxonomy, epidemiology and pathogenicity in humans. Advances in Parasitology. 2007;64:1-109. DOI: 10.1016/S0065-308X(06)64001-3
  11. 11. Turchetti AP, Souza TD, Paixão TA, Santos RL. Sexual and vertical transmission of visceral leishmaniasis. Journal of Infection in Developing Countries. 2014;8:403-407. DOI: 10.3855/jidc.4108
  12. 12. Owens SD, Oakley DA, Marryott K, Hatchett W, Walton R, Nolan TJ, Newton A, Steurer F, Schantz P, Giger U. Transmission of visceral leishmaniasis through blood transfusions from infected English foxhounds to anemic dogs. Journal of the American Veterinary Medical Association. 2001;219:1076-1083. DOI: 10.2460/javma.2001.219.1076
  13. 13. Tabar MD, Roura X, Francino O, Altet L, Ruiz de Gopegui R. Detection ofLeishmania infantumby real-time PCR in a canine blood bank. Journal of Small Animal Practice. 2008;49:325-328. DOI: 10.1111/j.1748-5827.2008.00542.x
  14. 14. Viol MA, Guerrero FD, de Oliveira BC, de Aquino MC, Loiola SH, de Melo GD, de Souza Gomes AH, Kanamura CT, Garcia MV, Andreotti R, de Lima VM, Bresciani KD. Identification ofLeishmaniaspp. promastigotes in the intestines, ovaries, and salivary glands ofRhipicephalus sanguineusactively infesting dogs. Parasitology Research. 2016;115:3479-3484. DOI: 10.1007/s00436-016-5111-5
  15. 15. Alvar J, Yactayo S, Bern C. Leishmaniasis and poverty. Trends in Parasitology. 2006;22:552-557. DOI: 10.1016/
  16. 16. Cardenas R, Sandoval CM, Rodriguez-Morales AJ, Vivas P. Zoonoses and climate variability. Annals of the New York Academy of Sciences. 2008;1149:326-330. DOI: 10.1196/annals.1428.094
  17. 17. Cecilio P, Perez-Cabezas B, Santarem N, Maciel J, Rodrigues V, Cordeiro da Silva A. Deception and manipulation: The arms ofLeishmania, a successful parasite. Frontiers in Immunology. 2014;5:480. DOI: 10.3389/fimmu.2014.00480
  18. 18. Leta S, Dao TH, Mesele F, Alemayehu G. Visceral leishmaniasis in Ethiopia: An evolving disease. PLoS Neglected Tropical Diseases. 2014;8:e3131. DOI: 10.1371/journal.pntd.0003131
  19. 19. Frézard F, Demicheli C, Ribeiro RR. Pentavalent antimonials: New perspectives for old drugs. Molecules. 2009;14:2317-2336. DOI: 10.3390/molecules14072317
  20. 20. Sundar S, Chakravarty J. An update on pharmacotherapy for leishmaniasis. Expert Opinion on Pharmacotherapy. 2015;16:237-252. DOI: 10.1517/14656566.2015.973850
  21. 21. Chattopadhyay A, Jafurulla M. A novel mechanism for an old drug: Amphotericin B in the treatment of visceral leishmaniasis. Biochemical and Biophysical Research Communications. 2011;416:7-12. DOI: 10.1016/j.bbrc.2011.11.023
  22. 22. Singh OP. Current challenges in treatment options for visceral leishmaniasis in India: A public health perspective. Infectious Diseases of Poverty. 2016;5:19. DOI: 10.1186/s40249-016-0112-2
  23. 23. Sundar S, Olliaro PL. Miltefosine in the treatment of leishmaniasis: Clinical evidence for informed clinical risk management. Therapeutics and Clinical Risk Management. 2007;3:733-740
  24. 24. Dummer R, Krasovec M, Röger J, Sindermann H, Burg G. Topical administration of hexadecylphosphocholine in patients with cutaneous lymphomas: Results of a phase I/II study. Journal of the American Academy of Dermatology. 1993;29:963-970. DOI: 10.1016/0190-9622(93)70275-X
  25. 25. Croft SL, Neal RA, Pendergast W, Chan JH. The activity of alkyl phosphorylcholines and related derivatives againstLeishmania donovani. Biochemical Pharmacology. 1987;36:2633-2636. DOI: 10.1016/0006-2952(87)90543-0
  26. 26. Croft SL, Snowdon D, Yardley V. The activities of four anticancer alkyllysophospholipids againstLeishmania donovani,Trypanosoma cruziandTrypanosoma brucei. Journal of Antimicrobial Chemotherapy. 1996;38:1041-1047
  27. 27. Kuhlencord A, Maniera T, Eibl H, Unger C. Hexadecylphosphocholine: Oral treatment of visceral leishmaniasis in mice. Antimicrobial Agents and Chemotherapy. 1992;36:1630-1634. DOI: 0066-4804/92/081630-05$02.00/0
  28. 28. Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, Fischer C, Junge K, Bryceson A, Berman J. Oral miltefosine for Indian visceral leishmaniasis. The New England Journal of Medicine. 2002;347:1739-1746. DOI: 10.1056/NEJMoa021556
  29. 29. Berman J. Miltefosine to treat leishmaniasis. Expert Opinion on Pharmacotherapy. 2005;6:1381-1388. DOI: 10.1517/14656566.6.8.1381
  30. 30. Sindermann H, Engel J. Development of miltefosine as an oral treatment for leishmaniasis. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2006;100(Suppl 1):S17-S20. DOI: 10.1016/j.trstmh.2006.02.010
  31. 31. Bhandari V, Kulshrestha A, Deep DK, Stark O, Prajapati VK, Ramesh V, Sundar S, Schonian G, Dujardin JC, Salotra P. Drug susceptibility inLeishmaniaisolates following miltefosine treatment in cases of visceral leishmaniasis and post kala-azar dermal leishmaniasis. PLoS Neglected Tropical Diseases. 2012;6:e1657. DOI: 10.1371/journal.pntd.0001657
  32. 32. Neal RA, Allen S, McCoy N, Olliaro P, Croft SL. The sensitivity ofLeishmaniaspecies to aminosidine. Journal of Antimicrobial Chemotherapy. 1995;35:577-584. DOI: 10.1093/jac/35.5.577
  33. 33. Das VN, Ranjan A, Sinha AN, Verma N, Lal CS, Gupta AK, Siddiqui NA, Kar SK. A randomized clinical trial of low dosage combination of pentamidine and allopurinol in the treatment of antimony unresponsive cases of visceral leishmaniasis. The Journal of the Association of Physicians of India. 2001;49:609-613
  34. 34. Dietze R, Carvalho SF, Valli LC, Berman J, Brewer T, Milhous W, Sanchez J, Schuster B, Grogl M. Phase 2 trial of WR6026, an orally administered 8-aminoquinoline, in the treatment of visceral leishmaniasis caused byLeishmania chagasi. American Journal of Tropical Medicine and Hygiene. 2001;65:685-689
  35. 35. Jha TK, Sundar S, Thakur CP, Felton JM, Sabin AJ, Horton J. A phase II dose-ranging study of sitamaquine for the treatment of visceral leishmaniasis in India. American Journal of Tropical Medicine and Hygiene. 2005;73:1005-1011
  36. 36. Wasunna MK, Rashid JR, Mbui J, Kirigi G, Kinoti D, Lodenyo H, Felton JM, Sabin AJ, Albert MJ, Horton J. A phase II dose-increasing study of sitamaquine for the treatment of visceral leishmaniasis in Kenya. American Journal of Tropical Medicine and Hygiene. 2005;73:871-876
  37. 37. Harvey AL. Natural products in drug discovery. Drug Discovery Today. 2008;13:894-901. DOI: 10.1016/j.drudis.2008.07.004
  38. 38. Almassy AA Jr et al. Folhas de chá: Plantas medicinais na terapêutica humana. Viçosa: UFV; 2005. p. 233
  39. 39. Cragg GM, Grothaus PG, Newman DJ. Impact of natural products on developing new anti-cancer agents. Chemical Reviews. 2009;109:3012-3043. DOI: 10.1021/cr900019j
  40. 40. Formagio AS, Kassuya CA, Neto FF, Volobuff CR, Iriguchi EK, Vieira Mdo C, Foglio MA. The flavonoid content and antiproliferative, hypoglycaemic, anti-inflammatory and free radical scavenging activities of Annona dioica St. Hill. BMC Complement Altern Med. 2013 Jan 11;13:14. DOI: 10.1186/1472-6882-13-14
  41. 41. Lima JFJ, Dimesntein M. A fitoterapia na saúde pública: visão do odontólogo. Saúde em Revista. 2006;8:37-44
  42. 42. Külkamp IC, Burin GD, de Souza MHM, da Silva P, Piovezan AP. Aceitação de práticas não-convencionais em saúde por estudantes de medicina da Universidade do Sul de Santa Catarina. Revista Brasileira de Educação Médica. 2007;31:229-235. DOI: 10.1590/S0100-55022007000300005
  43. 43. Menezes VA, dos Anjos AGP, Pereira MRD, Leite AF, Granville-Garcia AF. Terapêutica com plantas medicinais: percepção de profissionais da estratégia de saúde da família de um município do agreste pernambucano. Odonto. 2012;20:111-122
  44. 44. Santos OJ, Torres OJM. Phytotherapy evolution in the healing process in surgery. Arquivos Brasileiros de Cirurgia Digestiva. 2012;25:139. DOI: 10.1590/S0102-67202012000300001
  45. 45. Miguel MD, Miguel OG. Desenvolvimento de fitoterápicos. Ribeirão Preto: Tecmed. 2004;115p
  46. 46. WHO. World Health Organization. WHO police perspectives on medicines; 2010. Available from:[Accessed: February 06, 2018]
  47. 47. Petrovska BB. Historical review of medicinal plants’ usage. Pharmacognosy Reviews. 2012;6(11):1-5. DOI: 10.4103/0973-7847.95849
  48. 48. Stojanoski N. Development of health culture in Veles and its region from the past to the end of the 20th century. Veles: Society of science and Art; 1999. pp. 13-34
  49. 49. Kelly K. History of Medicine. New York: Facts on File; 2009. pp. 29-50
  50. 50. Tagboto S, Townson S. Antiparasitic properties of medicinal plants and other naturally occurring products. Advances in Parasitology. 2001;50:199-295. DOI: 10.1016/S0065-308X(01)50032-9
  51. 51. Berger BJ, Fairlamb AH. Interactions between immunity and chemotherapy in the treatment of the trypanosomiases and leishmaniases. Parasitology. 1992;105:S71-S78. DOI: 10.1017/S0031182000075375
  52. 52. Jantan I, Ahmad W, Bukhari SN. Plant-derived immunomodulators: An insight on their preclinical evaluation and clinical trials Ibrahim. Frontiers in Plant Science. 2015;6. DOI: 10.3389/fpls.2015.00655
  53. 53. Chouhan G, Islamuddin M, Sahal D, Afrin F. Exploring the role of medicinal plant-based immunomodulators for effective therapy of leishmaniasis. Frontiers in Immunology. 2014;5(193):29-35. DOI: 10.3389/fimmu.2014.00193
  54. 54. Tiwari B, Pahuja R, Kumar P, Rath SK, Gupta KC, Goyala N. Nanotized curcumin and miltefosine, a potential combination for treatment of experimental visceral Leishmaniasis. Antimicrobial Agents and Chemotherapy. 2017;61:e01169-e01116. DOI: 10.1128/AAC.01169-16
  55. 55. Santos AL, Yamamoto ES, Passero LFD, Laurenti MD, Martins LF, Lima ML, Uemi M, Soares MG, Lago JHG, Tempone AG, Sartorelli P. Antileishmanial activity and immunomodulatory effects of tricin isolated from leaves of Caseariaarborea(Salicaceae). Chemistry and Biodiversity. 2017;14(5). DOI: 10.1002/cbdv.201600458
  56. 56. Ali N, Nakhasi HL, Valenzuela JG, Reis AB. Targeted immunology for prevention and cure of VL. Frontiers in Immunology. 2014;5(193):29-35. DOI: 10.3389/fimmu.2014.00660
  57. 57. Shukla S, Bajpai VK, Kim M. Plants as potential sources of natural immunomodulators. Reviews in Environmental Science and Bio/Technology. 2014;13(1):17-33. DOI: 10.1007/s11157-012-9303-x
  58. 58. Almeida-Souza F, de Souza Cda S, Taniwaki NN, Silva JJ, de Oliveira RM, Abreu-Silva AL, Calabrese Kda S. Morinda citrifolia Linn. Fruit (noni) juice induces an increase in NO production and death of Leishmania amazonensis amastigotes in peritoneal macrophages from BALB/c. Nitric Oxide. 2016;58:51-58. DOI: 10.1016/j.niox.2016.06.004 a
  59. 59. Nathan C, Shiloh MU. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proceedings of the National Academy of Sciences of the United States of America. 2000;97:8841-8848
  60. 60. Horta MF, Mendes BP, Roma EH, Noronha FS, Macêdo JP, Oliveira LS, Duarte MM, Vieira LQ. Reactive oxygen species and nitric oxide in cutaneous leishmaniasis. J Parasitol Res. 2012;2012:203818. DOI: 10.1155/2012/203818. Epub 2012 Apr 12
  61. 61. Bogdan C. Nitric oxide synthase in innate and adaptive immunity: An update. Trends in Immunology. 2015;36:161-178. DOI: 10.1016/
  62. 62. Bredt DS. Endogenous nitric oxide synthesis: Biological functions and pathophysiology. Free Radical Research. 1999;31:577-596
  63. 63. Fang FC. Antimicrobial reactive oxygen and nitrogen species: Concepts and controversies. Nature Reviews Microbiology. 2004;2:820-832
  64. 64. Chouhan G, Islamuddin M, Want MY, Abdin MZ, Ozbak HA, Hemeg HA, Sahal D, Afrin F. Apoptosis mediated leishmanicidal activity ofAzadirachta indicabioactive fractions is accompanied by Th1 immunostimulatory potential and therapeutic cure in vivo. Parasites & Vectors. 2015;8(183):1-24
  65. 65. Aloui Z, Messaoud C, Haoues M, Neffati N, Bassoumi Jamoussi I, Essafi-Benkhadir K, Boussaid M, Guizani I, Karoui H. Asteraceae Artemisia campestris and Artemisia herba-alba essential oils trigger apoptosis and cell cycle arrest inLeishmania infantumPromastigotes. Evidence-Based Complementary and Alternative Medicine. 2016;9147096:1-15
  66. 66. Tiuman TS, Santos AO, Ueda-Nakamura T, Filho BPD, Nakamura CV. Recent advances in leishmaniasis treatment. International Journal of Infectious Diseases. 2001;15(8):525-532. DOI: 10.1016/j.ijid.2011.03.021
  67. 67. Rates SM. Plants as source of drugs. Toxicon. 2001;39:603-613. DOI: 10.1016/S0041-0101(00)00154-9
  68. 68. Chandrasekaran S, Veronica J, Sundar S, Maurya R. Alcoholic fractions F5 and F6 from Withania somnifera leaves show a potent antileishmanial and immunomodulatory activities to control experimental visceral leishmaniasis. Frontiers in Medicine (Lausanne). 2017;12(4):55. DOI: 10.3389/fmed.2017.00055
  69. 69. Adebayo OL, Suleman D, Samson AA. Natural products in antileishmanial drug discovery: A review. Journal of Asian Scientific Research. 2013;3(2):157-173
  70. 70. Rocha LG, Almeida JR, Macêdo RO, Barbosa-Filho JM. A review of natural products with antileishmanial activity. Phytomedicine. 2005;12:514-535. DOI: 10.1016/j.phymed.2003.10.006
  71. 71. Wang J, Peng Q, Li G. New compounds of natural resources in 2008. African Journal of Biotechnology. 2009;8:4299-4307
  72. 72. Patwardhan B, Gautam M. Botanical immunodrugs: Scope and opportunities. Drug Discovery Today. 2005;10:495-502. DOI: 10.1016/S1359-6446(04)03357-4
  73. 73. Kaur S, Bhardwaj K, Sachdeva H. Antileishmanial efficacy of Boerhaavia diffusa L. and Ocimum sanctum L. against experimental visceral leishmaniasis. Indian Journal of Experimental Biology. 2015 Aug;53(8):522-529
  74. 74. Sharma U, Velpandian T, Sharma P, Singh S. Evaluation of anti-leishmanial activity of selected Indian plants known to have antimicrobial properties. Parasitology Research. 2009 Oct;105(5):1287-1293. DOI: 10.1007/s00436-009-1554-2
  75. 75. Oliveira M, João Rodrigues M, Pereira C, Neto RLDM, Junior PAS, Neng NDR, Nogueira JMF, Varela J, Barreira L, Custódio L. First report of the in vitro antileishmanial properties of extremophile plants from the Algarve coast. Natural Product Research. 2017 May;11:1-5. DOI: 10.1080/14786419.2017.1326489
  76. 76. Bhalla G, Kaur S, Kaur J, Kaur R, Raina P. Antileishmanial and immunomodulatory potential of Ocimum sanctum Linn. and Cocos nucifera Linn. In murine visceral leishmaniasis. Journal of Parasitic Disease. 2017 Mar;41(1):76-85. DOI: 10.1007/s12639-016-0753-x
  77. 77. Das A, Das MC, Das N, Bhattacharjee S. Evaluation of the antileishmanial potency, toxicity and phytochemical constituents of methanol bark extract of Sterculia villosa. Pharmaceutical Biology. 2017 Dec;55(1):998-1009. DOI: 10.1080/13880209.2017.1285946
  78. 78. Pramanik A, Paik D, Naskar K, Chakraborti T. Coccinia grandis (L.) Voigt leaf extract exhibits antileishmanial effect through pro-inflammatory response: An in vitro study. Current Microbiology. 2017 Jan;74(1):59-67. DOI: 10.1007/s00284-016-1151-4
  79. 79. Das P, Paik D, Pramanik A, De T, Chakraborti T. Antiproteolytic and leishmanicidal activity of Coccinia grandis (L.) Voigt leaf extract against Leishmania donovani promastigotes. Indian Journal Experimental Biology. 2015;53(11):740-746
  80. 80. Almeida-Souza F, Taniwaki NN, Amaral AC, de Souza Cda S, Calabrese Kda S, Abreu-Silva A. Ultrastructural changes and death ofLeishmania infantumpromastigotes induced byMorinda citrifoliaLinn. Fruit (noni) juice treatment. Evidence-Based Complementary and Alternative Medicine. 2016;2016:5063540. DOI: 10.1155/2016/5063540 b
  81. 81. Paik D, Das P, Naskar K, Pramanik PK, Chakraborti T. Protective inflammatory response against visceral leishmaniasis with potato tuber extract: A new approach of successful therapy. Biomedicine & Pharmacotherapy. 2016 Oct;83:1295-1302. DOI: 10.1016/j.biopha.2016.08.046
  82. 82. Paik D, Das P, De T, Chakraborti T. In vitro anti-leishmanial efficacy of potato tuber extract (PTEx): Leishmanial serine protease(s) as putative target. Experimental Parasitolology. 2014 Nov;146:11-19. DOI: 10.1016/j.exppara.2014.08.009
  83. 83. Singh MK, Paul J, De T, Chakraborti T. Bioactivity guided fractionation of Moringa oleífera lam. Flower targeting Leishmania donovani. Indian Journal of Experimental Biology. 2015;53:747-752
  84. 84. Chouhan G, Islamuddin M, Want MY, Abdin MZ, Ozbak HA, Hemeg HA, Sahal D, Afrin F. Apoptosis mediated leishmanicidal activity of Azadirachta indica bioactive fractions is accompanied by Th1 immunostimulatory potential and therapeutic cure in vivo. Parasites and Vectors. 2015 Mar 26;8:183. DOI: 10.1186/s13071-015-0788-3
  85. 85. Dayakar A, Chandrasekaran S, Veronica J, Sundar S, Maurya R. In vitro and in vivo evaluation of anti-leishmanial and immunomodulatory activity of Neem leaf extract in Leishmania donovani infection. Experimental Parasitology. 2015 Jun;153:45-54. DOI: 10.1016/j.exppara.2015.02.011
  86. 86. Dey S, Mukherjee D, Chakraborty S, Mallick S, Dutta A, Ghosh J, Swapana N, Maiti S, Ghorai N, Singh CB, Pal C. Protective effect of Croton caudatus Geisel leaf extract against experimental visceral leishmaniasis induces proinflammatory cytokines in vitro and in vivo. Experimental Parasitology. 2015 Apr-May;151-152:84-95. DOI: 10.1016/j.exppara.2015.01.012
  87. 87. Islamuddin M, Chouhan G, Farooque A, Dwarakanath BS, Sahal D, Afrin F. Th1-biased immunomodulation and therapeutic potential of Artemisia annua in murine visceral leishmaniasis. PLoS Neglected Tropical Disease. 2015 Jan 8;9(1):e3321. DOI: 10.1371/journal.pntd.0003321
  88. 88. Islamuddin M, Farooque A, Dwarakanath BS, Sahal D, Afrin F. Extracts of Artemisia annua leaves and seeds mediate programmed cell death in Leishmania donovani. Journal of Medical Microbiology. 2012 Dec;61(Pt 12):1709-1718. DOI: 10.1099/jmm.0.049387-0
  89. 89. Kaur S, Chauhan K, Sachdeva H. Protection against experimental visceral leishmaniasis by immunostimulation with herbal drugs derived from Withania somnifera andAsparagus racemosus. Journal of Medical Microbiology. 2014 Oct;63(Pt 10):1328-1338. DOI: 10.1099/jmm.0.072694-0
  90. 90. Sachdeva H, Sehgal R, Kaur S. Asparagus racemosus ameliorates cisplatin induced toxicities and augments its antileishmanial activity by immunomodulation in vivo. Parasitology International. 2014 Feb;63(1):21-30. DOI: 10.1016/j.parint.2013.09.016
  91. 91. Islamuddin M, Sahal D, Afrin F. Apoptosis-like death in Leishmania donovani promastigotes induced by eugenol-rich oil of Syzygium aromaticum. Journal of Medical Microbiology. 2014 Jan;63(Pt 1):74-85. DOI: 10.1099/jmm.0.064709-0
  92. 92. Hubert DJ, Céline N, Michel N, Gogulamudi VR, Florence NT, Johnson BN, Bonaventure NT, Singh IP, Sehgal R. In vitro leishmanicidal activity of some Cameroonian medicinal plants. Experimental Parasitology. 2013 Jul;134(3):304-308. DOI: 10.1016/j.exppara.2013.03.023
  93. 93. Rondon FC, Bevilaqua CM, Accioly MP, de Morais SM, de Andrade-Júnior HF, de Carvalho CA, Lima JC, Magalhães HC. In vitro efficacy of Coriandrum sativum, Lippia sidoides and Copaifera reticulata against Leishmania chagasi. Revista Brasileira de Parasitologia Veterinária. 2012 July–Sep;21(3):185-191
  94. 94. Accioly MP, Bevilaqua CM, Rondon FC, de Morais SM, Machado LK, Almeida CA, de Andrade HF Jr, Cardoso RP. Leishmanicidal activity in vitro of Musa paradisiaca L. and Spondias mombin L. fractions. Veterinary Parasitology. 2012 Jun 8;187(1-2):79-84. DOI: 10.1016/j.vetpar.2011.12.029
  95. 95. Vila-Nova NS, Morais SM, Falcão MJ, Machado LK, Beviláqua CM, Costa IR, Brasil NV, Andrade Júnior HF. Leishmanicidal activity and cytotoxicity of compounds from two Annonacea species cultivated in northeastern Brazil. Revista da Sociedade Brasileira de Medicina Tropical. 2011 Oct;44(5):567-571
  96. 96. Rondon FC, Bevilaqua CM, Accioly MP, Morais SM, Andrade-Junior HF, Machado LK, Cardoso RP, Almeida CA, Queiroz-Junior EM, Rodrigues AC. In vitro effect of Aloe vera, Coriandrum sativum and Ricinus communis fractions on Leishmania infantum and on murine monocytic cells. Veterinary Parasitolology. 2011 June 10;178(3-4):235-240. DOI: 10.1016/j.vetpar.2011.01.007
  97. 97. Ghosh S, Debnath S, Hazra S, Hartung A, Thomale K, Schultheis M, Kapkova P, Schurigt U, Moll H, Holzgrabe U, Hazra B. Valeriana wallichii root extracts and fractions with activity against Leishmania spp. Parasitology Research. 2011 Apr;108(4):861-871. DOI: 10.1007/s00436-010-2127-0
  98. 98. Gupta S, Raychaudhuri B, Banerjee S, Das B, Mukhopadhaya S, Datta SC. Momordicatin purified from fruits ofMomordica charantiais effective to act as a potent antileishmania agent. Parasitology International. 2010 June;59(2):192-197. DOI: 10.1016/j.parint.2010.01.004
  99. 99. Gomes DC, Muzitano MF, Costa SS, Rossi-Bergmann B. Effectiveness of the immunomodulatory extract of Kalanchoe pinnata against murine visceral leishmaniasis. Parasitology. 2010 Apr;137(4):613-618. DOI: 10.1017/S0031182009991405
  100. 100. Misra P, Kumar A, Khare P, Gupta S, Kumar N, Dube A. Pro-apoptotic effect of the landrace Bangla Mahoba of Piper betle on Leishmania donovani may be due to the high content of eugenol. Journal of Medical Microbiology. 2009 Aug;58:1058-1066. DOI: 10.1099/jmm.0.009290-0
  101. 101. Poddar A, Banerjee A, Ghanta S, Chattopadhyay S. In vivo efficacy of calceolarioside a against experimental visceral leishmaniasis. Planta Medica. 2008 Apr;74(5):503-508. DOI: 10.1055/s-2008-1034373
  102. 102. Dutta A, Sarkar D, Gurib-Fakim A, Mandal C, Chatterjee M. In vitro and in vivo activity of Aloe vera leaf exudate in experimental visceral leishmaniasis. Parasitology Research. 2008;102:1235-1242. DOI: 10.1007/s00436-008-0899-2
  103. 103. Singh N, Kumar A, Gupta P, Chand K, Samant M, Maurya R, Dube A. Evaluation of antileishmanial potential of Tinospora sinensis against experimental visceral leishmaniasis. Parasitology Research. 2008 Feb;102(3):561-565. DOI: 10.1007/s00436-007-0822-2
  104. 104. Manzote L, García M, Montalvo AM, Scull R, Miranda M, Abreu J. In vitro activity of an essential oil against Leishmania donovani. Phytotherapy Research. 2007 Nov;21(11):1055-1058
  105. 105. Mesquita ML, Desrivot J, Bories C, Fournet A, Paula JE, Grellier P, Espindola LS. Antileishmanial and trypanocidal activity of Brazilian Cerrado plants. Memórias do Instituto Oswaldo Cruz. 2005;(7). DOI: 10.1590/S0074-02762005000700019
  106. 106. World Health Organization. A Report of the Consultation Meeting on Traditional and Modern Medicine: Harmonizing two Approaches; November 22-26, 1999. Beijing: West Pacific Region; 2000

Written By

Renata Mondêgo de Oliveira, Solange de Araújo Melo, Tatiane Aranha da Penha-Silva, Fernando Almeida-Souza and Ana Lucia Abreu-Silva

Submitted: September 26th, 2017 Reviewed: February 23rd, 2018 Published: October 10th, 2018