Pharmacological Approaches to Antitrypanosomal Chemotherapy

Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 94(2): 215-220, Mar./Apr. 1999 215 Pharmacological Approaches to Antitrypanosomal Chemotherapy Simon L Croft Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK There is an urgent need for new drugs for the chemotherapy of human African trypanosomiasis, Chagas disease and leishmaniasis. Progress has been made in the identification and characterization of novel drug targets for rational chemotherapy and inhibitors of trypanosomatid glycosomal enzymes, trypanothione reductase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, cysteine proteases and of the purine and sterol biosynthetic pathways. However, less attention has been paid to the pharmacological aspects of drug design or to the use of drug delivery systems in the chemotherapy of African trypanosomiasis and Chagas disease. A review of research on pharmacology and drug delivery systems shows that there are new opportunities for improving the chemotherapy of these diseases. Key words: Trypanosoma brucei - Trypanosoma cruzi - drug delivery systems - liposomes - blood brain barrier Arsenical and antimonial drugs were amongst lecular targets. Rational approaches to chemo- the first synthetic drugs to be introduced for infec- therapy have investigated several targets in detail tious diseases in the first two decades of this cen- including the sterol biosynthetic pathway in Try- tury. It is remarkable that organic derivatives of panosoma cruzi, ornithine decarboxylase in the T. these heavy metals remain the recommended drugs brucei complex, trypanothione reductase in Try- for the treatment of, respectively, human African panosoma and Leishmania spp., nucleoside trypanosomiasis (sleeping sickness or HAT) and phosphotransferases in Trypanosoma and Leish- leishmaniasis. No drugs became available for the mania spp., glycosomal enzymes in the T. brucei treatment of Chagas disease until the 1970’s when complex, cysteine proteases in T. cruzi and Leish- two nitroheterocyclic drugs, nifurtimox and mania, folate metabolism and DNA topoiso- benznidazole, were introduced. All the drugs rec- merases (see Hunter 1997, Wang 1997 and other ommended for the treatment of the trypanosomi- references in Coombs & Croft 1997). Several tar- ases and the leishmaniases have limitations, includ- gets have been characterised structurally and the ing either variable efficacy, toxicity, requirements design of specific inhibitors is well underway . for long courses of parenteral administration, re- In contrast the pharmacological aspects of drug sistance and problems of supply, or a combination design that include aspects to improve drug up- of these factors. Although there are several drugs take, activation by pathogen or host cells, absorp- on trial for the chemotherapy of human leishma- tion and distribution in the host (Gumbleton & niasis many are new formulations of old drugs. Sneader 1994, Navia & Chatuverdi 1996) have There are few drugs of promise for either HAT or received less attention. Most reported research in Chagas disease and the situation is precarious (De this area have focused on the chemotherapy of Castro 1993, Wang 1995, Croft et al. 1997). leishmaniasis and not the trypanosomiases, includ- A major focus for the discovery of novel ing studies on quantitative structure activity rela- antitrypanosomal and antileishmanial drugs dur- tionships to improve lipophilicity and activity ing the past two decades has been the identifica- (Booth et al. 1987), the lysosomotropic properties tion and characterization of biochemical and mo- of amino acid and dipeptide esters and bis (benzyl)polyamine analogues to enhance accumu- lation by the Leishmania infected phagosome (Rabinovitch 1989, Baumann et al. 1991), and carrier molecules to aid targetting of drug to parasite This work received financial support from the UNDP/ or parasite host cell, for example allopurinol- World Bank/WHO Special Programme for Research and glycosylated polymers to receptors on Leishma- Training in Tropical Diseases (TDR). nia infected macrophages (Negre et al. 1992). Drug Fax: +44-171-636.8739. E-mail: [email protected] delivery systems (cellular, particulate and vesicu- Received 12 November 1998 lar) designed to enhance drug targeting to infected Accepted 19 January 1999 tissues, reduce metabolism by the host or toxicity 216 Antitrypanosomal Chemotherapy Simon L Croft to the host, or enable sustained release of drug second stage disease, was suprisingly detected at within the host have also been explored for the 0.5-0.8% of plasma levels in the CSF (Bronner et treatment of leishmaniasis. The most successful al. 1991). This penetration of the CNS may be application of drug delivery systems has certainly due to a breakdown of the blood-brain barrier been the use of lipid amphotericin B formulations (BBB) resulting from the inflammatory response for visceral leishmaniasis both in experimental that accompanies the CNS infection. Eflornithine, models (Croft et al. 1991, Berman et al. 1992) and or DL-a-difluoromethylornithine (DFMO), the clinical trials (Berman et al. 1998); liposomes have only new drug to be developed for the treatment also proved effective in experimental cutaneous of late-stage HAT since the introduction of leishmaniasis (Yardley & Croft 1997). Alterna- melarsoprol in 1949, was registered for use in the tively, nanoparticles incorporating primaquine and early 1990s and has been used to treat many T. b. pentamidine have also shown to be useful drug gambiense cases including many melarsoprol-re- carriers in experimental visceral leishmaniasis fractory cases (Pepin & Milord 1994). Eflornithine (Rodrigues et al. 1994). So if these approaches can shows excellent penetration into the CNS and high benefit the chemotherapy of leishmaniasis, why not levels have been detected in CSF compared to also the chemotherapy of the trypanosomiases? plasma levels in adults, although lower levels were HUMAN AFRICAN TRYPANOSOMIASIS detected in the CSF of children (Milord et al. 1993). The inactivity of eflornithine against East African In the first stages of HAT parasites are restricted sleeping sickness is due to innate tolerance of T. b. to the haemolymphatic system and drugs, namely rhodesiense to the drug (Iten et al. 1995) and not pentamidine and suramin are available for the treat- CNS penetration. ment of early stage disease. The major problem in The BBB describes the continuous tight junc- treatment of HAT is the second stage, character- tions between the endothelial cells of the cerebral ized by the presence of trypanosomes in the Cen- capillaries that restrict the movement of polar sol- tral Nervous System (CNF) and the cerebrospinal utes into the brain and are important in controlling fluid (CSF). A re-appraisal of the pharmacokinet- the composition of the fluids that bathe the brain. ics of the only available drug for the treatment of Although fenestrated capillaries in the choroid both T. b. gambiense or T. b. rhodesiense second plexus allow a more direct exchange between blood stage disease, the trivalent arsenical melarsoprol â and brain fluids, this area constitutes only 1/5000 [Mel B ], may help to improve treatment. of the total area for exchange of the tight BBB cap- Melarsoprol, with a masked reactive arsenoxide illaries. This high level of control of access has group, is lipid soluble and should gain easy access clear implications for delivery of drugs to the brain. to the brain, although suprisingly low levels of drug However, the BBB is not an inert barrier; there are have been detected in the CNS, only 0.5 to 5% of special transport systems that enable access of plasma levels (Pepin & Milord 1994). Recom- amino acids, glucose and specific macromolecules mended treatment schedules are of three or four into the brain (Begley 1996). In addition passive courses spaced by an interval of at least one week. diffusion of low molecular weight lipophilic com- It has been suggested that these schedules may not pounds, for example melarsoprol, is possible. A be the most effective and may also be responsible vervet monkey model has recently been established in part for the frequently reported side effects, the to evaluate the capability of compounds to cross most severe being a reactive encephalopathy in up the BBB (Brun, pers. comm.). Some compounds to 10% of the treated patients with a mortality of found to be highly active in vitro or the acute ro- up to 5% (Pepin & Milord 1994). Bioassay and dent model of infection, for example the nucleo- Elisa techniques (Maes et al. 1988, Burri et al. side analogues S-HPMPA (Kaminsky et al. 1996) 1993) have been used to determine drug levels of and the diamidine trybizine hydrochloride (Bacchi, melarsoprol and active metabolites in serum and pers. comm., Kaminsky & Brun, pers. comm.) have CSF and an elimination half life time of 35 hr in not been pursued for further development because the blood (Burri et al. 1993). Since blood levels of their apparent inability to cross the BBB in this decreased to zero in between the courses, an alter- model (Brun, pers. comm.). native treatment protocol consisting of 10 consecu- A search for new treatments for other CNS dis- tive daily doses has been suggested and a prelimi- eases, for example Alzheimer’s and Parkinson’s nary clinical study in Zaire gave promising results diseases and viral infections has focused attention with the 10-day regime (Burri et al. 1995). A full on novel approaches to improve delivery of drugs clinical evaluation is now underway. A re-exami- across the BBB. Two such examples for HIV in- nation of the pharmacokinetics of pentamidine, a fections of the brain include the design of lipo- highly charged diamidine that should not cross the philic nucleoside derivatives (Ford et al. 1995) and blood-brain barrier (BBB) and is ineffective against the conjugation of zidothymidine to a lipophilic Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 94(2), Mar./Apr. 1999 217 carrier that crosses the BBB to become more hy- brain barrier has indicated receptor mediated drophilic and trapped in the brain (Brewster et al.

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