PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. Neglected diseases - Anti-trypanosomal drug discovery and delivery by Willias Masocha, Ph.D. Department of Neuroscience, Karolinska Institutet Stockholm, Sweden Introduction Trypanosomiasis (sleeping sickness) is categorized as an intractable disease. Other diseases in this category include malaria and tuberculosis. Trypanosomiasis and leishmaniasis could be considered among the �most neglected diseases.� The common features of these diseases are that they exclusively affect marginalized people in developing countries where the population is too poor to afford treatment and that there is a scarcity of therapeutic agents. In this perspective, I will focus on sleeping sickness or human African trypanosomiasis (HAT). However, the problems faced in developing therapeutics for HAT are also shared with the other neglected diseases. Description of the Disease HAT is a re-emerging zoonosis, caused by subspecies of Trypanosoma brucei (Tb) transmitted by infected tsetse flies during a blood meal. There are approximately 250 endemic foci in 36 sub-Saharan African countries. It is estimated that there are 300,000-500,000 new cases of HAT each year, causing more than 60,000 deaths per year. The disease is estimated to be a daily threat to about 60 million people. The subspecies Tb rhodesiense, which is found in East and Southern Africa, causes an acute form of HAT resulting in death within a few weeks or months, whereas Tb gambiense, which occurs in West and Central Africa, causes a chronic form of the disease, which lasts several months or years and is hallmarked by disturbances in sleep patterns from which the disease gets the name �sleeping sickness.� The disease progresses in two clinically distinguishable stages: in the first stage, the parasites are in the hemolymphatic system. In the second stage, the parasites invade the central nervous system (CNS) and either the parasites, an increased number of white blood cells (WBC), or both are found in the cerebrospinal fluid (CSF). Current Treatments The disease is fatal if untreated and the prognosis is grave when the CNS is invaded. There are only four drugs for treating this disease. Two of these drugs have poor penetration of the blood-brain barrier (BBB). These drugs are suramin, introduced in 1916, for Tb rhodesiense, and pentamidine (1937) for Tb gambiense. These two drugs are used to treat the first stage of the disease. The other two drugs -- used to treat the second stage -- cross the BBB better. These drugs are eflornithine, introduced in 1977 to treat Tb gambiense, and melarsoprol, introduced in 1949 for treatment of both sub-species. The drugs in the latter group are highly toxic. The arsenic compound in melarsoprol results in the deaths of four to eight percent of the patients treated with it. Resistance is also developing against these drugs, with a reported failure rate of 30% in some instances for melarsoprol. There is only one drug under development for the hemolymphatic stage of HAT, DB-289 (an oral prodrug) which is in Phase III clinical trials. Possible Solutions There is a dire need for new therapeutic agents to treat African trypanosomiasis. These agents need to be readily accessible to the population in affected areas. Even though HAT is among the most-studied parasites from the biological point of view and a number of drug targets have been highlighted in basic research, no new drugs have been developed in recent decades. There is a dearth of interest on the part of the pharmaceutical industry in developing therapeutic agents against HAT. The production of eflornithine was rescued by the intervention of the World Health Organization (WHO) and the discovery of its usefulness in cosmetics for removing unwanted facial hair. Now the drug is manufactured and donated by Sanofi-Aventis in association with WHO and M�decins Sans Fronti�res (MSF). The lack of interest is essentially financial; while there is certainly a need for anti-trypanosomal drugs, there is no money for them. The populations primarily affected by these diseases are some of the poorest people in developing countries, who live in remote rural areas and do not have buying power. Against this background, it is difficult to envision new drugs being developed and available in the near future to replace or supplement the compounds currently used. Therefore, the major question is how to provide these much-needed therapeutic agents. A number of solutions seem to be still available. The first is to optimize the therapeutic use of the available drugs. All four of the drugs currently used to treat sleeping sickness are administered parenterally with difficult treatment regimens. Treatment is challenging because patients have to be hospitalized or visit the health center several times during the treatment, not to mention the discomfort of parenteral administration and the complications associated with it. Therefore, the development of oral formulations of the available drugs is one option which would result in an increase in the use of the drugs. Patients would not need to be hospitalized or have frequent visits to the healthcare centers to obtain treatment. This regimen could potentially improve effectiveness due to increased compliance. Presently there is a joint effort by Sanofi-Aventis and WHO to produce an oral formulation of eflornithine. This drug is currently administered in a cumbersome procedure that requires it to be given intravenously four times a day for a fourteen-day period. Another possibility for increasing the effectiveness of the available drugs is through combination chemotherapy. This approach could increase cure rates, reduce toxicity due to lower dosages, and possibly shorten treatment periods. A number of combinations of the available drugs have been proposed and some are already being assessed. A third possibility being explored is to shorten the treatment period of the available drugs. Current trials are underway to compare the three-day course for pentamidine against the standard five-day period and to compare ten daily injections of melarsoprol against the established three series of three injections separated by 1-week intervals. Some researchers are already advocating for the use of the shorter regimens. Plants and Natural Products Besides the alternatives outlined above to maximize the therapeutic usage and effectiveness of the existing drugs, there are several other viable options that deserve to be explored to combat this disease. Plants and natural products have been used as medicine or sources of medicine for thousands of years. According to WHO, countries in Africa, Asia and Latin America use traditional medicine (incorporating plant, animal and mineral-based medicines) to meet their primary healthcare needs, whereas in the industrialized countries it is used as complementary medicine. The global market for herbal medicines currently stands at over $60 billion U.S. annually. WHO estimates that up to 80% of the African population relies on traditional medicine as their primary source of healthcare. The pharmacological and chemical study of traditional medicine has been the basis of many therapeutic agents used today, including aspirin, digitoxin, morphine, quinine, atropine, pilocarpine, and antibiotics, such as penicillin, to name a few. There is a large volume of literature showing that plants have been used in Africa to treat trypanosomiasis in humans as well as in domestic animals. Various researchers in the ethnopharmacology field have done research on extracts from these plants and have demonstrated trypanocidal effects in some of them and a reduction in parasitemia in animals treated with these extracts. Further research on the plants and extraction of the active components might produce some potential therapeutic agents for trypanosomiasis. I would expect that this research would be done at the academic level without the limitations of going through drug development within the pharmaceutical industry. �Educated or Informed Scavenging� �Educated or informed scavenging� is the study of drugs used to treat other disease conditions or infections and evaluating their trypanotoxic effects. For example, eflornithine, the most recent therapeutic agent, which is used for treating the second stage of HAT caused by Tb gambiense, was first synthesized as an anti-cancer drug and then for cosmetic formulations. Thus, studying some anti-cancer drugs with possible targets in the parasites could produce quick alternatives compared to the normal drug discovery and development (DDD) process. Several research groups have embarked on this course with promising results. This strategy has the advantage of discovering anti-trypanosomal drugs with an already known pharmacokinetic and toxicological profile in humans that are already being produced for other maladies. One of the limitations might be the cost of these drugs, since the targeted population has low purchasing power. Hence, the drugs should be relatively cheap (for example chloroquine, which costs $0.05 to $0.20 per treatment). The drugs should also be presented as oral formulations, which can cross the BBB efficiently. Other possible sites to scavenge are the anti-protozoal and anti-microbial drugs. The protozoa have enzymes, metabolic and transport pathways with similarities to trypanosomes that could be exploited as therapeutic targets. Examples of drugs that are effective against various infectious agents are pentamidine which has therapeutic use against Tb gambiense, Leishmania donovani and Pneumocystis carinii; and metronidazole which is used for treating infections with protozoans such as Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis and several other anaerobic bacteria. Some of the anti-infective agents may have anti-trypanosomal activity but are not curative as single agents. To get around this problem, one might have to resort to combination therapy with compounds that have a synergistic effect and thus eventually result in a cure. Combination chemotherapy with agents which are not curative in monotherapy has been used against cancer, HIV and some infectious diseases such as malaria, tuberculosis and leprosy. Thus, I would advocate for research in the area of combination therapy against trypanosomiasis with two or three anti-parasitic or anti-microbial agents with trypanotoxic effects. It is indisputable that drugs with curative effects in monotherapy would be the best option. However, considering that the disease is fatal and treatment is difficult to administer and involves toxic therapeutic agents, combination therapy may well be one of the best options available � especially because it is unlikely that new drugs will be developed in the foreseeable future. Another Avenue for Progress I end this perspective by briefly discussing another possibility of increasing the available therapeutic agents � through DDD by pharmaceutical companies. Private-public partnerships (PPP) could allow or enhance the funding of research and DDD for the treatment of HAT and other neglected diseases. A substantial number of reviews have been written on the potential of these partnerships for DDD for neglected diseases in general. To some extent private-pubic partnerships have reshaped drug research and development for neglected diseases, producing better results than either the public sector or the pharmaceutical industry alone. For example, eflornithine was developed for HAT treatment through collaboration between Marion Merrell Dow, now Sanofi-Aventis, and The Special Programme for Research and Training in Tropical Diseases (TDR), an independent global programme of scientific collaboration. TDR was established in 1975 and was co-sponsored by the United Nations Children's Fund (UNICEF), the United Nations Development Programme (UNDP), the World Bank, and the World Health Organization (WHO). As mentioned above, TDR and Aventis are collaborating to develop an oral formulation of eflornithine. Sanofi-Aventis also produces and donates three of the four drugs used for the treatment of HAT � pentamidine, melarsoprol and eflornithine � since 2001. These drugs are distributed by MSF under the direction of WHO. Thus, it is possible for international organizations, governments, development and aid agencies, academia, and other arms of the public sector to collaborate with committed pharmaceutical companies and other private-sector groups to salvage the development and delivery of drugs for neglected diseases. This type of collaboration is already happening to some extent, but there is a need to increase the awareness of these possibilities and to increase the number of active participants in order to provide these much-needed drugs. There is also a need for increased participation of the communities in affected countries through education, building research institutes, and funding on the part of the public sector and the private sector. Healthcare systems, including local pharmaceutical companies,should collaborate in manufacturing and drug development with already existing and established PPPs. A recent survey observed that about a quarter of ongoing PPP projects involve a pharmaceutical company from a developing country as a partner. Beside drug delivery and development, these efforts would encourage knowledge and technology transfer, which in the long run should reduce dependence on the benevolence of charity organizations and governments of other countries. There are many challenges to be faced; many strings to pull and threads to untangle. ### << Previous Next >> [ View All Perspectives ] |
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