Chemotherapy

The first chemical solutions against Chagas’ disease with sufficient activity to justify clinical trials, the bisquinaldines, were not discovered until 1937 (Jensch 1937), and it was not until 1972 that the first drug to combat the disease, nifurtimox, was announced and launched by Bayer for use in some countries of Latin America in 1976 (Bock et al. 1972). (Bayer has discontinued producing the drug as of 1997). Nifurtimox is a 5‑nitrofuran derivative (synonyms: Bayer 2502, Lampit) with antiprotozoal activity, and it is also used to treat leishmaniasis and African trypanosomiasis (Reynolds 1986:673; see Figure 32).

^{Figure 32.}

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

Nifurtimox is administered as a yellow powder that a patient is to dissolve in water and drink three times a day after meals for sixty to ninety days at a daily dose of 8‑10 mg per kg for adults, 15‑20 mg per kg for children aged one to ten years, and 12.5‑15 mg per kg for children aged eleven to sixteen years. Dosages may be as large as 25 mg/kg for severe complications such as acute meningoencephalitis (WHO 1991). Children tolerate the drug better than do adults. Nifurtimox is readily absorbed and rapidly metabolized, with a peak plasma concentration at one to three hours, which declines to zero by twenty‑four hours. Some doctors prefer to stagger the treatment in two‑month intervals (Jáuregui, interview 6/22/91). Although the usual treatment extends for 120 days, it can be effective when given for sixty days (Macedo 1982).

The earlier the diagnosis is made and treatment initiated, the greater is the chance that the patient will be parasitologically cured (Cancado and Brener 1979). Drug therapy is highly recommended to minimize parasitic invasion of vital tissues (McGreevy and Marsden 1986:117). Good results are achieved early in treatment, as indicated by the disappearance of circulating trypanosomes, remission of disease signs and symptoms, and occasional reversion to a serologically negative condition. Serological tests tend to become negative from six to eight months after treatment, and the cure is considered successful when both parasitemia and serological tests become negative and remain so for at least a year after the end of treatment.

Nifurtimox does have side effects, including nausea, skin rashes, peripheral neuritis, bone‑marrow depression, loss of weight, loss of memory, and sleeping disorders, which may lead to depression and general malaise to such a degree that few patients actually complete the treatment period (Gutteridge 1985). When nifurtimox was given to animals in high doses, it produced cancer; but no such effects have been described in human patients (McGreevy and Marsden 1986:117). In one study using nifurtimox in Brazil, all treated patients had weight loss, 70 percent had anorexia, and 33 percent had peripheral neuritis during treatment at 7‑8 mg/kg per day for sixty days (McGreevy and Marsden 1986:117). Peripheral neuritis and psychosis depend on dosages of nifurtimox and usually occur at the end of high‑dose treatment (15‑20 mg/kg per day). Nifurtimox will cause hemolytic anemia in glucose 6‑phosphate dehydrogenase (G6PD)‑deficient individuals.

The efficacy of nifurtimox varies in different geographical areas. Cure rates appear to decrease going from south to north in Latin America, and this is probably due in part to variation in the sensitivity of different strains of T. cruzi (see Appendix 2: Strains of T. cruzi ). Studies of both acute and chronic Chagas’ disease show that patients from central Brazil are relatively unresponsive to nifurtimox as compared with patients from Argentina, Bolivia, and Chile (Cancado and Brener 1979, Brener 1979). The cure rate is about 92 percent in Argentina, Chile, Bolivia, and southern Brazil, and about 53 percent in central Brazil. Low concentrations of circulating parasites are difficult to detect, and monthly xenodiagnosis or blood culture is required.

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 Köberle 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, Schumuñis 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‑named D0870 to be effective against both short‑ and long‑term Chagas’ disease. It is an inhibitor of sterol biosynthesis and as such was identified first as an anti‑fungal agent. Inhibitors of sterol biosynthesis also affect T. cruzi, which has similar steroid metabolism to fungi. Earlier in vitro studies showed that D0870 causes the parasite’s natural sterols to be replaced by 14 a‑methyl sterols. The new compound is able to cure a large percentage of both acute and chronic T. cruzi infections in miceblocking parasite growth and reproduction and penetrating cells infected by parasites in chronic infections. D0870 has been found to be effective against six different strains of T. cruzi in mice as well as T. brucei (responsible for African trypanosomiasis) in vitro. These results provide a sound basis for further pre‑clinical development of D0870 as an anti‑T. cruzi compound (toxicology and pharmacokinetics studies). After that, clinical studies using this compound for treating Chagas’ disease may be initiated. But the compound is in its early phases and it will be years before Zeneca Pharmaceutical makes it available for human treatment (TDRnews 1996:4‑4).

[1]1. This research is summarized in the following articles and books: concerning Aymara rituals (Bastien 1989), Kallawaya herbal curing (Bastien 1982, 1983a, 1983b), ethnophysiology (Bastien 1985), Kallawaya herbalists (Bastien 1987), cultural perceptions of neonatal tetanus and programming implications (Bastien 1988), integration of ethnomedicine and biomedicine (Bastien 1992), and training of community health workers (Bastien 1990).

[2]2. Some of these positions were coordinator with Project Concern for community health workers and biomedical personnel of the Department of Oruro, Bolivia, (Bastien 1987b, 1990a); educator with Project Concern for diarrhea control and oral rehydration therapy (Bastien 1987a: 81‑84); researcher with Resources for Child Health concerning prevention of neonatal tetanus (Bastien 1988); anthropologist working with Bolivian radio schools (1990); and ethnologist advisor to USAID projects: Community and Child Health (1987a, 1991), Bolivian Forestation Project (1995), and Chagas Control Project, Bolivia (1991).

[3]3. The acronym in Spanish is SNS/CCH, Programa Piloto de Control de Chagas; in English it is SOH/CCH, Chagas Control Pilot Project.

[4]1. For the medical history of Chagas’ disease see Chagas 1909, 1911, 1921, 1922, 1988; Chagas Filho 1959, 1968, 1988, 1993; Kean 1977; and Lewinsohn 1979, 1981.

[5]2. “La vinchuca incommode beaucoup ceux qui voyagent de Mendoza á BuenosAyres… C’est un escarbot ou scarabée, dont le corps est ovale e très‑aplati, et qui devient gros comme un grain de raisin, du sang qu’il suce… Cet insect ne sort que de nuit; les individus ailés peuvent avoir cinq lignes de long, et volent; ce qui n’arrive pas aux petit.”

[6]3. Concerning the debate whether Darwin had Chagas’ disease see Browne 1995:280; Keynes 1988:315; Goldstein 1989:586‑601; and Woodruff 1965.

[7]1. Castor oil is a fixed oil expressed from the seed of the croton plant, Croton tiglium. Although commonly used fifty years ago in biomedicine, Taber’s Cyclopedic Medical Dictionary (1985:400) says, “Action: Drastic cathartic, externally as a rubefacient. This chemical has no place in medicine and should not be used.”

[8]2. Biomedical ethics in Bolivia at the time treated lightly the fact that doctors used Indians as trial subjects. The most noted transgression was a La Paz oculist’s experiments on Aymara Indians, who were noted for their excellent vision, in the early development stages of radial kerometry. In other Latin American countries, prisoners have been experimentally infected with T. cruzi and treated with potential remedies (G. Stewart, interview, 1993).

[9]3. This name is purposely withheld for legal reasons. One of Bolivia’s most reputed naturalists, Jaime Zalles, claims that the patented formula from Regenerator has had millions of dollars in drug sales. I have been unable to verify this.

[10]4. As one example: “Fifth Case.‑ Margarita Vidaurre. First analysis from Laboratorio de Salud Pública on October 24, 1966. Complement Fixation: positive. Second analysis from Laboratorio de Salud Pública on July 12, 1970, negative.”

[11]5. Scientists discussed below discount floripondio as an insecticide.

[12]6. Leading this research are Dr. Gonzalo Tapia, director, and biologist Jose Luis Alcázar, both ofProyecto Chagas of the Universidad Mayor San Simon, Cochabamba; Dr. Gene Bourdy of Instituto Boliviano de Biología de Altura (IBBA); and botanist Suzanna Arrazola of the Herbario, Cochabamba.

[13]7. There is hope that a novel compound code‑named D0870, which has been shown to cure both long‑term and short‑term Chagas’ disease in mice (Urbina et al. 1996), will do the same in humans; however, it is in the early phases of clinical development for other infections. (See Appendix 13.)

[14]1. Meningoencephalitis due to T. cruzi has been reported in pharmacologically immunodepressed patients and in patients with AIDS (Jost et al. 1977; Corona et al. 1988; Del Castillo et al. 1990). (See Appendix II.)

[15]2. In addition to these practical considerations, T. cruzi have unique properties that make them evasive targets for potential chemotherapeutic agents and therefore present formidable challenges to pharmacologists and medical chemists. T. cruzi are intracellular parasites, found in a variety of tissues. The effectiveness of a chemical compound depends on its capacity to cross the vascular endothelium and cell membranes into the cytoplasmic compartment of the parasite. T. cruzi is not a homogenous speciesthere are geographic strains which vary in tissue tropism and response to chemotherapy and biochemical parameters such as electrophoretic profiles of isoenzymes and peptides. The value of a particular drug depends on its effectiveness against both the amastigote and trypomastigote stages of all geographic strains (McGreevy and Marsden 1986:115‑27). (See Appendix 13.)

[16]3. In another study, Bryan and Tonn (1990:14) report higher rates of T. cruzi infection in captured (domestic) triatomines, with averages from 40 to 50 percent and infection rates of 70 to 90 percent in rural areas of the Cochabamba and Chuquisaca departments of Bolivia. (See Appendix 5.)

[17]4. A recent study analyzed hemotherapy and the problem of transfusional Chagas’ disease in 850 Brazilian municipalities from 1988 to 1989. It found that some type of hemotherapy was practiced in 68.8 percent of these municipalities (Moraes‑Souza et al. 1995). Prior screening of donors was carried out by 75.2 percent of the services for syphilis, 65.4 percent for hepatitis, 53.8 percent for AIDS, and 66.8 percent for Chagas’ disease. In the case of Chagas’ disease, only 10.3 percent of services used the chemoprophylaxis of gentian violet. Most services used only one serologic technique to screen donors, and the proportion of potential donors with positive serology for anti‑T. cruzi was around 1 percent. (See Appendix 13.)

[18]5. Although the potential problem of the blood supply in the United States has been recognized for some time (Schmuñis 1985), the recent diagnosis of Chagas’ disease acquired through blood transfusion in the United States (Grant et al. 1989) and Canada (Nickerson et al. 1989) has significantly highlighted the seriousness of this problem (Skolnick 1989, Kirchhoff 1989).

[19]6. In Brazil in 1911 Carlos Chagas considered the possibility of congenital transmission of T. cruzi when he found trypomastigotes in the blood‑smear of a two‑month‑old child whose mother was also infected (quoted in Howard and Rubio 1968). In Venezuela in 1949 Dao reported other cases of congenital Chagas’ disease in Latin America (quoted in Bittencourt 1976). In Chile, Howard (1962) observed that 0.5 percent of premature babies weighing less than 2,000 grams (4.4 pounds) suffered from congenital Chagas’ disease. In Salvador, Bahia, and Brazil, Bittencourt and colleagues (Bittencourt and Barbosa 1972, Bittencourt, Barbosa, et al. 1972) found that 2 percent of stillborn babies were infected with T. cruzi ; and, in Argentina, Salem and colleagues found slightly higher rates, 2.35 percent among stillborn infants (quoted in Bittencourt 1975). By 1979 the number of described cases had reached 100, giving the impression that congenital transmission of Chagas’ disease is infrequent. However, this impression is misleading, because the registered cases are only of fetuses and premature stillborns and do not include congenital Chagas’ disease in newborns delivered at term (Bittencourt et al. 1974). The varying degrees of fetal and neonatal pathology in such countries as Argentina, Brazil, and Chile may be related to inherent characteristics of the parasite (Moya 1994). The fact that the incidence of infection remains the same in each of these countries and geographic regions suggests that population‑related factors are not involved. Various factors having to do with the mother, the fetus, and the parasite are more likely implicated in transplacental transmission.

[20]7. The newborns were delivered at the Percy Boland Maternity Hospital in the city of Santa Cruz and observed from August 1979 until July 1980. Blood samples from newborns and mothers were used to investigate the presence of T. cruzi by means of the modified Strout concentration, which has the highest sensitivity (95.2 percent; but only for acute cases) when compared to other direct parasitological testing methods (Flores et al. 1966; Cerisola 1972:97‑100). (See Appendix 12.)

[21]8. Fetal infection can occur when the mother is in acute, indeterminate, and chronic phases of infection. Most infected pregnant women experience the chronic, or inapparent, form of the disease during their pregnancy, although cases of acute infection have been reported (Moya 1994). The fetus of an infected pregnant woman is usually unaffected, with no observed alterations in the growth or viability of the fetus, nor is the newborn predisposed to exhibit specific disorders. Chagas’ disease in the mother poses little risk to the baby during the perinatal period, which is after the twenty‑eighth week of pregnancy through twenty‑eight days following birth (Moya 1977, 1994; Moya and Barousse 1984; Castilho and Da Silva 1976).the fetus is infected, the outcome of pregnancy may be spontaneous abortion, fetal death, premature birth, low birth weight for gestational age, and even full‑term delivery (Moya 1994). Congenitally infected infants present a broad spectrum of clinical manifestationsfrom grave illness with multisystem compromise (usually in premature neonates) to a total absence of symptoms at birth. Some infants remain asymptomatic; others present manifestations of the disease several weeks or months later. Clinical manifestations are encephalitis, meningoencephalitis, lesions in the retina or choroid, and elevated protein levels and cell counts in cerebrospinal fluid (Mufioz and Acevedo 1994).

[22]9. Another route for T. cruzi is through the blood, by hematogenous spread, and through crossing of the placenta, with multiplication of the parasite in the Hofbauer cells (Bittencourt 1975). The amniotic fluid may provide another vehicle for T. cruzi to travel to fetuses as well as to obstetricians and gynecologists (Apt, Tejada, and Atrozz 1968; Bittencourt et al. 1981; Nattan‑Larrier 1921). Contact of the skin with infected amniotic fluid could allow penetration of the skin, and T. cruzi has been found in the skin (Bittencourt 1976). Research is needed to evaluate the exact mechanisms of congenital transmission.

[23]10. In laboratory experiments, animals have been infected by eating infected triatomines or mammals, but this has not been documented in experiments with humans (WHO 1991:34).

[24]1. Volvulus is found among Andeans at high altitudes (13,500 feet) and its predisposing cause is a prolapsed mesentery intestine, which may be caused by T. cruzi within this organ.

[25]2. This doctor’s behavior represents an elitist attitude that some Bolivian doctors exhibit in their treatment of peasants. There has been a considerable change within the 1990s with other Bolivian doctors who are able to communicate cross‑culturally with the peasants (see Bastien 1992: 173‑91).

[26]3. See Marcondes de Rezende and Ostermayer 1994; Teixeira et al. 1980; Ribeiro dos Santos and L. Hudson 1980; Petry and Eisen 1989.

[27]4. Dr. Mario Barragan Vargas conducted a five‑year study of megacolon in Viacha, elevation 13,123 feet, located twenty miles from La Paz on the Altiplano. He found many cases of megacolon, which he attributed to altitudinal and genetic dispositions, not to Chagas’ disease.

[28]5. See MacSweeney, Shankar, and Theodorous 1995; Cutait and Cutait 1991; and Da Silveira 1976 for a discussion of current procedures.

[29]6. See Rezende and Rassi 1958; Godoy and Haddad 1961; Vieira and Godoy 1963; Morales Rojas et al. 1961; and Ifiiguez‑Montenegro 1961.

[30]7. In Brazil, chagasic esophageal problems are well known to the people, who refer to it in Portuguese as Mal de Engasgo (“Sickness of Choking”), Entalo (“Stuck”), and Embuchamento (“Engorgement”). The most frequent symptoms expressed are difficulty in swallowing, 99 percent; regurgitation, 57 percent; painful swallowing, 52 percent; belching, 41 percent; hiccups, 38 percent; sensation of plenitude, 32 percent; and coughing, 26 percent (Köberle 1968:90‑91). Loss of weight, heartburn, and sour eructations are also very frequent, occurring in 70 percent of the cases. Advanced cases show elongation of esophagus muscles that can reach twenty‑six times their normal weight. Advanced cases also have a predisposition to carcinoma, which may occur in 10 percent of the cases (Camara‑Lopes 1962).

[31]8. Nerve cells are decreased along the whole extension of the esophagus, resulting in loss of the coordinated peristalsis and sensitivity of the denervated musculature. This phenomenon, which occurs in the denervated hollow muscular organ, is called “aperistalsis” and describes the absence of esophageal motility (Brasil 1956). The denervated structure becomes supersensitive to any stimulus, inducing diffuse and severe spasms of the esophagus, which occasionally needs an urgent application of atropine.

[32]9. The consistency of what is ingested is very important, because the transport of solids requires a more coordinated peristalsis than does the movement of liquids; also, excessive solid transport can cause a high overload to the damaged organ. In addition, increased consistency (reduced liquidity) of the contents of the esophagus favors the development of megaesophagus. Patients often drink large quantities of liquids to aid the passage of solids through the organ. Generally either very hot or very cold food intensifies difficulties in swallowing, and perhaps the associated abundant salivation constitutes a type of auxiliary mechanism for the deficient deglutition.

[33]1. This center began in 1984 with assistance from Banco InterAmericano Desarrollo (BID) and a contract with the Universidad El Salvador de Buenos Aires, Ministerio de Previsión Social y Salud Pública, and La Universidad de Sucre.

[34]2. Figures have been adjusted to the 1992 census.

[35]3. Such pathologies include cardiac enlargement, mitral and tricuspid valve insufficiency, and pulmonary embolization. An abnormal left ventricular impulse may reflect the frequent apical aneurysm formation. Right‑bundle‑branch block is frequent. Complete heart block, high‑grade ventricular ectopy, and atrial fibrillation have a grave prognostic significance, both aggravating the congestive heart failure and enhancing predisposition for sudden cardiac death (see Iosa 1994). (See Appendix 10.)

[36]4. Ventricular arrhythmias are a prominent feature of chronic Chagas’ disease. Ventricular premature depolarization, often with multiple morphologies, is seen frequently. Bouts of ventricular tachycardia and arterial hypertension may occur as well as bradycardia and arterial hypotension (Braunwald 1988:1447; Iosa 1994).

[37]5. See Brener (1994) and Appendix II for an overview of current theories on pathogenesis.

[38]6. Investigators have found autoantibody and self‑reactive T‑cell formation in human and experimental T. cruzi infections (Teixeira, Teixeira, and Santos‑Buch 1975; Cossio et al. 1974). Cross‑reactive autoantibodies were mainly directed toward ubiquitous and evolutionary conservative molecules (Levin et al. 1989, Kerner et al. 1991, Van Voorhis et al. 1991) which lack clinical and biological significance for the different clinical forms of chronic Chagas’ disease.

[39]7. The presence of an antibody against cardiac myosin is correlated with the development of chronic inflammatory cardiopathy in T. cruzi‑infected mice (Tibbetts et al. 1994). Immunization with cardiac myosin HC induces aggressive myocarditis (Neu et al. 1987b). Cunha‑Neto and colleagues (1995) have recognized a heart‑specific T. cruzi cross‑reactive epitope, with chronic heart lesions further indicating the involvement of cross‑reactions of myosin and B13 in the pathogenesis of chronic Chagas’ disease.

[40]8. See Voltarelli, Donadi, and Falcao 1987; Cunningham, Grogl, and Kuhn 1980; Mosca, Briceño, and Hernández 1991.

[41]9. These antigens include many stress proteins with sequence homology to those of living organisms (Young, Lathigra, and Hendrix 1988).

[42]1. An appropriate technology for chagasic control is to teach peasants how to prevent vinchuca infestation by means of readily available materials, such as the use of cow dung in plastering and the use of bottle caps with nails through them to secure roofing and sheeting. For an excellent study on housing in La Paz, see Köster 1995.

[43]2. Bolivia has traditionally had authoritarian governments, a carryover from colonial times. Presidents enjoyed power akin to the concept of the “divine right of kings.” By 1985, Bolivians had suffered a series of military dictators, the most brutal being Luis Garcia Meza, presently serving thirty years in prison for his crimes. In 1997, Bolivians voted for another “old time” military leader, General Hugo Banzer.

[44]1. Another acronym for the organization is PSBB, which refers to Proyecto Social Boliviano‑Británico “Cardenal Maurer .” By 1994, the British government no longer partially financed this project, so it was shortened to the Cardenal Maurer Project (CM).

[45]2. The Proyecto Británico Cardenal Maurer project in Chuquisaca was included in 1991 as one of three pilot projects sponsored by the Bolivian Secretariat of Health (SOH) and Community and Child Health (CCH), with assistance from the United States Agency for International Development (USAID) and the Centers for Disease Control (CDC). The SOH/CCH Chagas Control Program ended on December 31, 1994.

[46]3. Other successful health projects in Bolivia support this conclusion. Enthusiastic leaders include Gregory Rake with the CHW program in Oruro, Oscar Velasco with Project Concern in Potosí, Evaristo Mayda with ethnomedicinal practitioners in Cochabamba, Irene Vance with Pro‑Habitat in La Paz, and José Beltrán with Plan International in Tarija.

[47]4. These nongovernmental organizations (NGOs) include Pro‑Habitat (Tarija), Plan‑International (Tarija), and Proyecto Chagas (Cochabamba).

[48]5. As authorities on the control of Chagas’ disease in Bolivia, Bryan and Tonn (1990) wrote: “PBCM in Sucre is the best project of Chagas’ disease control. It is a small project but well organized, with emphasis on community participation, health education, fumigation, and improvement of housing. It serves as a model for other chagasic control projects.”

[49]6. See WHO and UNICEF 1978:2‑3; Coreil and Mull 1990; Phillips 1990:150‑77.

[50]7. USAID in Bolivia subcontracts many of its projects to nongovernmental organizations such as Project Concern, Save the Children, Operation Hope, Caritas. These organizations have their own goals underlying proposed humanitarian objectives of the project. As one measure, PROCOSI was formed in Bolivia in the 1980s and serves as a coordinating board of NGOs in Bolivia through which USAID‑Bolivia channels developmental monies.

[51]8. Paulo Freire initiated concientización in Brazil, and spread it throughout Latin America by his writings, most notably, Pedagogy of the Oppressed (1970) and Education for Critical Consciousness (1973). See Luft (1983) and Hope and Timmel (1987) for detailed descriptions of concientización pedagogy. Although concientización has been identified with Karl Marx’s analyses of the contradictions inherent in matter and the exploitation of the peasant by the capitalist classes, it also reflects the teachings of Jesus. Freire’s 1970 book became a “Marxist’s bible,” as some saw it, for liberation‑theology priests forming base communities. Severe military repression, both by Latin American and U.S. military forces, has extinguished these priests and their base communities. For a different interpretation see Berryman (1987:34‑38, 71, 73, 130).

[52]9. These pilot projects modified the role of community health workers (CHWs). A plan was adopted where each CHW was responsible for forty to ninety (average sixty) houses, and their fundamental role was to visit each family weekly to provide motivation and technical education (SOH/CCH 1994:16). This required too much time from CHWs, however, who were required to spend from thirty to sixty hours a week visiting families, considering that they have other responsibilities and are unpaid. In contrast, PBCM’s practice of having traveling teams and CHWs meet together with the community members was more effective. Community leaders were motivated to assume responsibility for seeing that every family carried out its assigned task. The community accepted responsibility to carry out the project and CHWs served as liaison between the house improvement committees and PBCM personnel.

[53]10. The total cost for 400 houses was $83,256, out of which villagers provided $37,642 in work and materials, and collaborators in the project provided $45,614, of which PBCM gave $10,814, Catholic Relief Services $5,000, the British embassy $5,000, and PROCOSI $24,800. PROCOSI (Programa de Coordinación en Supervivencia Infantil) is funded by USAID and the Bolivia Child Survival program. It is a supervisory and administrative organization for many nongovernmental health agencies and projects in Bolivia.

[54]11. Volunteer labor is figured in to the cost of each house to indicate to providers of funds that what they contribute is matched. However, this gives the impression that house improvement is much more costly to the taxpayer or contributor.

[55]12. The addition of vermifuge plants to wall plaster is another possibility, and insecticide paints are now being used effectively in Brazil (Pinchin et al. 1978a, 1978b).

[56]13. Slow‑release insecticide paints used during house building have shown lasting properties of killing 100 percent of 5th instar T. infestans after a ten‑minute period of contact more than five years after being applied and subsequently exposed to environmental conditions in Brazil (Oliveira Filho, Deus, and Brasil 1987). Structures of a house were painted with black bitumen paint containing 9.7 percent clorpyrifos‑ethyl (Dursban) before covering them with mud. This technique could be used in areas where houses are being built or restored. Using Dursban insecticide for painting walls presents problems of toxicity for humans, however.

[57]14. An alternative low‑cost roofing for tropical areas of Latin America involves the conversion of fibrous agricultural residues, such as bagasse from sugar cane, into a corrugated fiber roofing panel, which requires a relatively low capital investment and is labor intensive (Bryant 1978). Cost per square foot is about fifteen cents in U.S. money (1978).

[58]15. Because of its clay content, walls built of unstabilized soil will swell on taking up water and shrink on drying (Briceño‑León 1987:384). This results in cracking, which provides nesting areas for vinchucas. Soil stabilization is achieved by increasing the strength and cohesion of the soil, reducing the movement of moisture in the soil, and by making the soil more waterproof. Strength of a soil can be increased by the addition ofcementious materials, such as Portland cement or other materials that include hydrated lime and lime‑pozzolana mixes. A pozzolanic reaction is the reaction between lime and certain clay minerals to form various cementlike compounds. Lime also reduces the extent to which clay absorbs water, thus making the soil less sensitive to changes in moisture.

[59]16. In Venezuela and Brazil, workers use metal presses to compact the mud within the cane to assure greater durability for cloth coverings or cement later placed on the walls (Schofield et al. 1990 and Bricefio‑León 1990:137). All these devices produce low‑cost building blocks of about 12 x 6 x 4 inches, similar in size to traditional handmade adobe blocks (Bricefio‑Leon 1987:384).

[60]17. Marco Antonio Prieto, director of Centro por Estudios por Desarollo Chuquisaca (CEDEC), provided this critique.

[61]1. See Victor Varas Reyes’ study El Castellano Popular en Tarija and Ananias Barreto’s work Costumbresy Creencias del Campo Taijeño for more examples.

[62]2. A number of institutions, including Caritas (Catholic Relief), Pro‑Habitat (UNICEF), SOH/CCH (Secretaria Nacional de Salud and USAID), and Plan International, have been involved in several projects in the Department of Tarija to improve houses. Each institution has contributed to solving the problem: Caritas (formation of CHWs), Pro‑Habitat (educational material), SOH/CCH (evaluation studies and financial support), and Plan International (a micro‑credit system). The projects have had different sponsoring organizations through their tenure.

[63]3. I first met José Beltrán in 1991 and admired his teaching skills. During our last visit in 1997, he was even more proficient using the colorful charts and posters that he had helped design for other projects sponsored by SOH/CCH.

[64]4. U.S. Public Law 480, according to which funds in host‑country national currency derived from the sale of U.S. agricultural products are retained in the host country for use in development‑assistance projects.

[65]5. The five‑year, $20 million Community and Child Health Project from 1989 until 1994 was funded by USAID, whose objectives were maternal and child health, primary health care, improvement of water and sanitation facilities, agricultural sustainability, and family planning. In 1991, Chagas’ disease control was added, mostly through the efforts of Dr. Joel Kuritsky and President Jaime Paz, who during his inaugural visit to Washington, D.C., asked President George Bush for additional monies to combat Chagas’ disease.

[66]6. Project personnel are prone to criticize people doing other projects, although Beltrán’s remarks reflected the opinion of other observers. He is considered the foremost expert on Chagas’ control in Tarija.

[67]7. For an outline of procedures, see Table 2: Production of Educational Materials, and Table 3: Phases of Educational Process (SOH/CCH 1994:36‑37).

[68]1. Pilot projects were supported by the Bolivian Secretariat of Health (SOH) and the USAID Community and Child Health Project (CCH). The SOH/CCH Chagas’ Disease Control Program lasted from 1991 to 1994, cost U.S. $4 million, and sponsored housing‑improvement projects in Tarija, Cochabamba, and Chuquisaca, improving 3,135 houses (see SOH/CCH 1994).

[69]2. Dr. Oscar Velasco is mentioned in Chapter 5. He is a Bolivian medical anthropologist and is presently director of Project Concern in Potosí. Velasco and I also designed the CHWS program and the articulation of biomedicine and ethnomedicine in the Department of Oruro (see Bastien 1992).

[70]3. Marco Antonio Prieto is director of Centro por Estudios por Desarollo Chuquisaca (CEDEC). His criticism was primarily directed at the project in Chuquisaca, which, of the three pilot projects, attempted most to become integrated with the culture.

[71]4. Dr. Pablo Regalsky is director of Centro de Comunicación y Desarollo Andino (CENDA) in Cochabamba.

[72]5. Dr. Evaristo Mayda suggested the triangle diagram. Dr. Mayda is director of Project Concern Cochabamba and has been a leader in integrating ethnomedicine and biomedicine in the Department of Cochabamba.

[73]6. Melogno is director of Fundación de Programas de Asentamientos Humanos, a housing project in the Alto Beni. He was interviewed on May 13, 1997.

[74]7. SOH/CCH allocated a dollar amount to this volunteer activity as a form of cost‑sharing; thus, when a household matched the money donated, their share was calculated according to what they would have earned if they had been paid. Cost‑sharing was helpful in negotiating for matching funds from institutions.

[75]8. All are native Bolivians, except for Regalsky, who was born in Buenos Aires but who speaks the Quechua language fluently and has done fieldwork among the Quechua of Ragaypampa. Quechua leaders work with him on matters concerning the new laws and popular participation. He has been an advocate for Quechuans for ten years.

[76]1. The SOH/CCH projects were directed by biologists from Vector Biology Control and a medical doctor and epidemiologist from the Centers for Disease Control, with only token considerations from anthropologists, economists, and sociologists. As a result, these projects narrowly focused on house improvement and spraying as the immediate solution to control vinchucas. Afterwards, with the exception of some communities in the Chuquisaca project, infestation began anew because peasants improved their houses for reasons other than vinchuca control.

[77]1. Dr. George Stewart, professor of Biology at the University of Texas at Arlington, has done extensive and noted research on parasites and disease. Many of the ideas and facts in the appendices are from his lectures. Nonetheless, I am totally responsible for the content of the appendices.

[78]1. For a comparison of sampling techniques for domestic populations of triatomines see Schofield and Marsden (1982:356), who used another method for studying house infestation. Inspectors examined a house for bugs at approximately monthly intervals for two and a half years. Two men, each equipped with a flashlight and long forceps, searched the house for forty‑five minutes and collected all the live bugs they could find. These bugs were sorted, counted, and then destroyed. Bug population estimates were then made by the Zippin (1956:163‑89) withdrawal method. Within the house being studied 92 adults and 169 fifth instars were collected. The number of the other stages present could not be estimated, but life‑table studies indicate that these figures are consistent with a total bug population (including eggs) of approximately 2,200 individuals.údez et al. (1978) examined a henhouse in Gutiérrez, in a rural area of the Department of Santa Cruz, Bolivia, and found 1,524 triatomines; less than 1 percent were infected with T. cruzi. One explanation is that these T. infestans predominantly fed on chickens, which cannot become hosts for T. cruzi.