The Kiss of Death

Regarding acute patients in central Brazil, xenodiagnosis is usually negative during nifurtimox treatment, but it converts to positive in 60-70 percent of the patients over a four-year period. Post-treatment serodiagnosis usually remains positive in chronic patients, suggesting that parasites persist even when xenodiagnosis is negative.

Nifurtimox’s action has been explained by two hypotheses. The first implicates biosynthetic reactions, especially nucleic and protein synthesis (see Sims and Gutteridge 1978, 1979), as a consequence of interaction with nucleic acids, especially DNA, in which single- and double-strand breaks occur (Gugliotta et al. 1980). This mechanism is similar to that suggested for the antibacterial action of similarly acting drugs and also explains the known mutagenicity and carcinogenicity of many 5-nitrofurans (Gutteridge 1985). The second hypothesis explains the lysing of the parasites as a result of drug metabolism, of superoxide anions and hence hydrogen peroxide, which accumulates to cytotoxic levels in T. cruzi because of the absence of catalase (Docampo and Stoppani 1979, Docampo and Moreno 1984). This hypothesis explains the ultrastructural lesions that these drugs produce (Sims and Gutteridge 1979), and T. cruzi does indeed generate free radical metabolites from nifurtimox at physiological drug concentrations (Docampo and Moreno 1984). Neither hypothesis is mutually exclusive-drug metabolism produces both types of activity. Research on the effects of nifurtimox on intact T. cruzi is required to resolve this debate.

^{Figure 33.}

^{Benznidazole. (From W.E. Gutteridge, Existing Chemotherapy and Its Limitations, 1985.)}

Benznidazole was announced in 1974 and released by the Roche pharmaceutical company in Latin America in late 1978 (Barclay et al. 1978; see Figure 33). Benznidazole’s synonyms are R07-1051, Radanil, and Rochagan. It is a 2-nitroimidazole derivative with antiprotozoal activity (Reynolds 1986:660). Also a yellow powder, it is taken in water and is rapidly absorbed and distributed through the body tissues (Macedo 1982). Recommended dosage is 5 mg/kg/day (10mg/kg/day for children) for sixty days (Gutteridge 1985). It is claimed to be effective in curing more than 80 percent of both acute and chronic Chagas’ disease patients. There is no clear evidence that it has any advantage over nifurtimox, and the efficacy of the two drugs is similar, though it has been claimed that benznidazole has less geographic variation in cure rates (Ribeiro-dos-Santos, Rassi, and Koberle 1980).

Initial clinical studies with benznidazole used higher doses, and serious side effects such as polyneuropathy and progressive purpuric dermatitis occurred. Adverse effects of benznidazole include nausea, vomiting, abdominal pain, peripheral neuropathy, and severe skin reactions (Reynolds 1986:660). It causes erythematous light-sensitive skin rashes, which can be severe, in half of the patients (Boainain 1979). A study involving twenty patients with chronic Chagas’ disease who were given benznidazole in a dosage of 5 mg per kg of body weight daily had to be stopped because of the high incidence of skin rashes and neurological symptoms (Apt 1986:1010). Benznidazole also causes a marked thrombocytopenia in humans and depresses thymusdependent immune functions in rabbits (Teixeira et al. 1983).

^{Figure 34.}

^{Gentian violet. (From W.E. Gutteridge, Existing Chemotherapy and Its Limitations, 1985.)}

As possible new drug leads, another nitroimidazole (2-amino-5-[methyl-5nitro-2-imidazolyl]-1,3,4 thiadiazole) has shown remarkable efficacy in mice, curing 89 percent of cases with a single dose (Filardi and Brener 1982). It is also active against parasite strains that are resistant to nifurtimox and 2-nitroimkidaxole derivatives. Trypomastigotes are cleared from the bloodstream in six hours, and destruction of amastigotes occurs in eighteen to thirty-six hours (Almeida et al. 1984). This drug is presently being tested on humans (McGreevy and Marsden 1986:118).

Another promising drug, allopurinol, is presently being researched, with initial studies indicating trypanosomicidal action at daily doses of 600 mg given for thirty to sixty days. Research is still being conducted concerning its efficacy and toxicity.

Another drug, gentian violet, is used to prevent transmission of the disease through blood transfusions. Although gentian violet is effective in destroying trypomastigotes in blood supplies, people dislike receiving a transfusion of violet-colored blood, and it is still being evaluated for safety. Gentian violet (crystal violet) is a cationic dye (see Figure 34) that demonstrates photodynamic action in visible light to produce hydrogen peroxide (Docampo et al. 1988). It is readily soluble in water. First used in 1953, it rapidly lyses trypomastigote forms of T. cruzi in whole blood and thus prevents the transmission of Chagas’ disease through blood transfusion (Nussenzweig et al. 1953). The dosage is 25 cc of solution gentian at 0.5 percent in glucoside isotonic solution for each 500 cc of blood for twenty-four hours, but blood is rarely, if ever, held long enough in Bolivia to be treated with gentian violet (Nussenzweig et al. 1953, Schumunis 1991). At the University of Brasilia in Brazil, this technique has been used to treat seropositive blood for many years without mishap (Marsden 1983:255). However, it does not work against all strains of T. cruzi (Brener 1979).

Gentian violet exhibits photodynamic action against parasites (Docampo et al. 1988). Visible light causes photoreduction of gentian violet to a carbon-centered radical, and under aerobic conditions this free radical autooxidizes generating anion whose dismutation yields hydrogen peroxide.

Side effects for patients who receive blood with gentian violet are being studied (see Ramirez et al. 1995 for alternative methods under research). Gentian violet causes microagglutination and rouleaux formation of erythrocytes in vitro, and it has never been subjected to current safety testing standards. The concern shown by patients towards the coloration (Gutteridge 1982, 1986) is a factor to be considered and discussed with patients receiving a transfusion, as they are likely to encounter this at a time when psychological disturbances should be kept to a minimum.

In highly endemic areas of Chagas’ disease where serology is occasionally unreliable and little screening is done, addition of gentian violet to all blood before transfusion has been recommended (Carrasco et al. 1990, Rassi and Rezende 1976).

Presently, nifurtimox and benznidazole are effective in controlling the acute stage of Chagas’ disease to prevent damage to vital organs. A cure rate of near 90 percent is claimed if these drugs are administered at an early stage and in prescribed dosages. Nifurtimox and benznidazole have effectively treated congenital Chagas’ disease in newborns and infants in Argentina, Bolivia, Brazil, Chile, and Uruguay. Severe side effects, questionable safety, and availability provide serious limitations that need to be resolved by research to provide more adequate drugs and more funds to provide these drugs to the impoverished in Latin America. In endemic areas with high risks of reinfection, it may be advisable to use these drugs in lesser dosages to limit the damage of T. cruzi rather than attempt to completely eradicate it.

None of these drugs, including gentian violet, is ideal (Gutteridge 1985, Ramirez et al. 1995), and our ability to control and treat, let alone eradicate, Chagas’ disease is severely curtailed. The obstacles are formidable on the scientific side and relate not only to finding trypanocides that lyse the parasites in their different stages and differing strains but also to getting the drug to the vicinity of the in vivo sites of trypanosomes without destroying human cells.

The cost of discovering a drug and developing it to product registration is on average about ten years and millions of dollars, with about one successful drug resulting from 10,000 tested compounds. The problem is further aggravated with Chagas’ disease because the human commercial market is small in comparison to the number of people infected, so pharmaceutical companies are unlikely to invest in drug development when the potential return on their investment is risky. However, as Chagas’ disease continues to become worldwide in scope through immigration, vertical transmission, and blood transfusions, the marketability of treatment drugs will increase. The discovery of the nematocidal and ectoparasiticidal activities of the avermectins, and the commercial success of Ivermec, ensure that increasing attention will be paid to trying to find similarly successful drugs for Chagas’ disease. Pharmaceutical companies, international agencies such as World Health Organization and the United Stages Agency for International Development, and governments of Andean countries are beginning to work together with scientists in the development and distribution of drugs to treat Chagas’ disease.

Very encouraging news has come from a group of scientists at the Instituto Venezolano de Investigaciones Cientificas, the London School of Hygiene and Tropical Medicine, Janssen Research Foundation, and the Swiss Tropical Institute (Urbina et al. 1996). They have screened hundreds of compounds and found a compound code-