Editorial - Drug Development to Protozoan Diseases



Lianet Monzote*, 1, Afshan Siddiq 2
1 Parasitology Department, Institute of Medicine Tropical “Pedro Kourí”, Havana City, Cuba
2 Department of Pharmacology, University of Karachi, Karachi, Pakistan


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© Monzote and Siddiq; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the Departamento de Parasitología, Instituto de Medicina Tropical “Pedro Kourí”, Apartado Postal No. 601, Marianao 13. Ciudad Habana, Cuba; Tel: +53 7 2020650; Fax: +53 7 2046051; E-mail: monzote@ipk.sld.cu


Abstract

The diseases caused by protozoan parasite are responsible for considerable mortality and morbidity, affecting more than 500 million of people in the world. The epidemiological control of protozoan is unsatisfactory due to difficulties of vector and reservoir control; while the progress in the development of vaccine tends to be slow and arduous. Currently, the chemotherapy remains essential component of both clinical management and disease control programmer in endemic areas. The drugs in use as anti-protozoan agents were discovered over 50 years and a number of factors limit their utility such as: high cost, poor compliance, drug resistance, low efficacy and poor safety. In the recent years, the searches about the development of new drugs against protozoa parasite have been increased. This special issue of The Open Medicinal Chemistry Journal will present some of developments in this field with the aim to shown the significant advances in the discovery of new anti-protozoan drugs

Keywords: Anti-infective, anti-protozoan, drugs.



INTRODUCTION

Protozoa parasites are composed by a very diverse group of unicellular eukaryotic organism from Protista kingdom, which present nuclei and other structures similar to animals. The main infections in human are due to protozoan of Plasmodium, Trypanosoma and Leishmania genus. Others agents with medical importance exist, such as intestinal protozoa, Toxoplasma gondii and Trichomonas vaginalis. The protozoan have been characterized as a diverse polyphyletic group that present a wide range of epidemiology characteristics and clinic manifestation in different geographic zones, particularly in tropics and subtropics from developing countries (Table 1) [1-4].

Table 1.

General Features of Main Protozoan Parasitic Diseases that Affect the Human Health


Disease Some Representative Etiological Agents Geographical Localization Clinical Features
Malaria Plasmodium falciparum, P. vivax Over 100 countries in the tropic and subtropics Fever, shivering, cough, respiratory distress, pain in the joints, headache, watery diarrhea, vomiting, convulsions severe anemia
African trypanosomiasis Trypanosoma brucei 36 countries in sub-Sahara Africa Initial haemolytic phase (fever, joint pains followed by neurological disorder, somnolence
Chagas disease Trypanosoma cruzi From northem Mexico to South Argentina Acute phase (fever and splenomegaly)
Chronic phase (irreversible damage to heart, esophagus and colon)
Leishmaniasis Leishmania donovani, L. major, L. mexicana, L. braziliensis Over 88 countries in tropic and subtropics Skin ulcers, mucocutaneous complications and visceral diseases (hepatosplenomegaly)
Toxoplasmosis Toxoplasma gondii Worldwide Blindness and mental retardation can result in congenitally infected children.
Immunosuppressed patients can present more severe symptoms: splenomegaly, polymyositis, dermatomyositis, chorioretinitis, myocarditis, pneumonitis, hepatitis, encephalitis, and multisystem organ failure.
Trichomoniasis Trichomonas vaginalis Worldwide Vaginal discharge, odor and edema or erythema.
Intestinal protozoan Giardia lamblia, Entamoeba histolytica, Cryptosporidium parvum, Cyclospora cayetanensis Worldwide Hematuria, anemia, impaired growth. Renal, hepatic and spleen failure

The diseases caused by protozoan parasite are responsible for considerable mortality and morbidity, affecting more than 500 million of people in the world (Table 2). The history of protozoa infections in humans teaches us that improved nutrition, economic development and public health measures are probably the deciding factors in increasing diseases in the tropics [4, 5].

Table 2.

Summary of Statistics for Damage Caused by Main Parasitic Diseases


Disease Population at Risk (x106) Number of People Infected (x106) Number of Death (x103)
Malaria ~ 2 000 ~ 300 ~1000-2000
African trypanosomiasis ~ 60 ~ 0.3-0.5 ~ 50
Chagas disease ~ 40 ~ 17 ~ 21
Leishmaniasis ~ 350 ~ 2 ~ 59
Intestinal protozoans > 1000 ~ 450 ~ 40-100

The study of protozoa biology has attracted the attention not only because they are fascinating organism, but also due to the need of finding tools and developing strategies to decrease the remarkable social and economic burden they cause on human societies [6]. The control of protozoan disease requires a complex interplay of activities in the fields of public health, education political will and medical science. However, the epidemiological control of protozoan is unsatisfactory due to difficulties of vector and reservoir control; while the progress in the development of vaccine tends to be slow and arduous. Currently, the chemotherapy remains essential component of both clinical management and disease control programmer in endemic areas [4].

CURRENT DRUGS TO PROTOZOAN DISEASES

Since the decade of 1930 was discoveries the conventional drugs against protozoa disease, which presents general characteristics such as: (a) the compounds are formed by a low number of elements that including carbon, oxygen and nitrogen; while other elements are only present in specific structures, per example the sulphur; (b) the inorganic compounds are scare, although can be used the arsenic and antimonies; (c) the annular structure are very common and the benzene are present in a high percent of compounds or have nitrogen; (d) the methyl, hydroxyl and amine group are very frequently; while the sulphydryl radical is absent [7]. Current drugs in use as anti-protozoan agents were discovered over 50 years. A number of factors limit the utility of existing drugs (Table 3) in resource-poor setting, such as high cost, poor compliance, drug resistance, low efficacy and poor safety [1, 2, 5].

Table 3.

Limitations of Currently Used Drugs for Main Protozoan Diseases


Disease Some Current Used Drugs Limitations
Malaria Chloroquine, 1945 Resistance
Artemisin, 1994 Compliance, cost, manufacture
African trypanosomiasis Suramin, 1920 Safety, not effective in late-stage diseases, injectable
Pentamidine, 1939 Safety, resistance, not effective in late-stage diseases, injectable
Melarsoprol, 1949 Safety, resistance, injectable
Eflornithine, 1991 Cost, injectable, only effective against T. gambiense
Chagas disease Nifurtimox, 1970 Safety, long treatment, compliance, activity limited to acute stage of disease
Benznidazole, 1974 Safety
Leishmaniasis Pentamidine, 1939 Safety, resistance, injectable
Antimonials, 1950 Safety, resistance, injectable
Liposomal amphotericin B, 1990 Cost, injectable
Miltefosine, 2002 Contraindicated in pregnancy
Toxoplasmosis Sulfonamides, 1932 Safety, only in combined therapy
Pyrimethamine, 1951 Safety, Contraindicated in pregnancy
Trichomoniasis Metronidazole, 1955 Resistance
Intestinal protozoan Metronidazole, 1955 Resistance
Diloxanide, 1956 Resistance

DRUG DEVELOPMENT TO PROTOZOAN DISEASES

There is still a great need for drug development against protozoan diseases. The past 20 years has seen a significant increase in our basic knowledge of protozoa parasite. The currently search to develop new drugs have been facilitated by advances in sciences, especially in the field of parasite genomics (identification of unique metabolic pathways and key enzyme of the protozoa), chemistry methodologies (high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) and mass spectrometry) and bioinformatics tools (quantitative structure-activity relation ship (QSAR) modeling techniques) [8-12]. In parallel, recent development have been increased thanks to dedicated academic, public initiatives, private-public partnerships, pharmaceutical industry and the experience of public health care organizations that focus on various aspects of drug discovery for infectious diseases, including the injection of new funds into this research area [13, 14]. Different strategies have been defined to develop new anti-protozoan drugs in short/medium time (optimization of therapy with existing drugs, development of analogs of current drugs, combination therapy with conventional drugs and identification of agents to use against other indications) and in large time (search new targets and rational drug design and natural products) [15].

This special issue of The Open Medicinal Chemistry Journal will present some of developments in this field with the aim to shown the significant advances in the discovery of new anti-protozoan drugs

REFERENCES

[1] Fennell BJ, Naughton JA, Barlow J, et al. Microtubules as antiparasitic drug targets Expert Opin Drug Discov 2008; 3: 501-18.
[2] Pink R, Hudson A, Mouriés MA, Bendig M. Opportunities and challenges in antiparasitic drug discovery Nat Rev Drug Discov 2005; 4: 727-40.
[3] Tekwani BL, Walker LA. 8-Aminoquinolines: future role as antiprotozoal drugs Curr Opin Infect Dis 2006; 19: 623-31.
[4] Watkins BM. Drugs for the control of parasitic diseases: current status and development Trends Parasitol 2003; 19: 477-8.
[5] Dupouy-Camet J. New drugs for the treatment of human parasitic protozoa Parasitologia 2004; 46: 81-4.
[6] Cooper RA, Carucci DJ. Proteomic approaches to studying drug targets and resistance in Plasmodium Curr Drug Targets Infect Disord 2004; 4: 41-51.
[7] Aparicio P, Rodríguez E, Gárate T, Molina R, Soto A, Alvar J. Terapêutica antiparasitária Enferm Infecc Microbiol Clin 2003; 21: 579-94.
[8] Cowman AF, Crabb BS. Functional genomics: identifying drug targets for parasitic diseases Trends Parasitol 2003; 19: 538-43.
[9] Bleicher KH, Bohm HJ, Muller K, Alanine AI. Hit and lead generation: beyond high-throughput screening Nat Rev Drug Discov 2003; 2: 369-78.
[10] Kissinger JC. A tale of three genomes: the kinetoplastids have arrived Trends Parasitol 2006; 22: 240-3.
[11] Morales A, Rodríguez-Borgues JE, García-Mera X, Fernández F, Cordeiro MN. Probing the anticancer activity of nucleoside analogues: a QSAR model approach using an internally consistent training set J Med Chem 2007; 50: 1537-45.
[12] Kozikowski AP, Roth B, Tropsha A. Why academic drug discovery makes sense Science 2006; 313: 1235-6.
[13] Nwaka S, Hudson A. Innovative lead discovery strategies for tropical diseases Nat Rev 2006; 5: 941-54.
[14] Nwaka S, Ridley RG. Virtual drug discovery and development for neglected diseases through public-private partnerships Nature Rev Drug Dis 2003; 2: 919-28.
[15] Na- Bangchang K, Karbwang J. Current status of malaria chemotherapy and the role of pharmacology in antimalarial drug research and development Fund Clin Pharmacol 2009; 23: 387-409.