Abstract Current developments in experimental chemo- therapy of Chagas’ disease are reviewed, in particular the demonstration that fourth-generation azole derivatives (in- hibitors of sterol C14α demethylase), with particular se- lectivity against Trypanosoma cruzi and special pharmaco- kinetic properties, are capable of inducing radical parasitological cures in murine models of both acute and chronic disease. These are the first reports of parasitologi- cal cure of this disease in its chronic phase. We also dis- cuss the relevance of etiological treatment in the clinical outcome of patients with chronic Chagas’ disease. Al- though previous studies have suggested an important au- toimmune component in the pathogenesis of this disease, recent results obtained using highly sensitive polymerase chain reaction based detection methods and detailed im- munological characterization of the inflammatory process associated with chagasic cardiomyopathy indicate a posi- tive correlation between tissue parasitism and the severity of cardiac pathological findings. Effective antiparasitic treatment can lead to regression of the inflammatory heart lesions and fibrosis in experimental animals and to stop the progression of the disease in humans. Taken together, these findings support the notion that the presence of the parasite is a necessary and sufficient condition for cha- gasic cardiomyopathy and confirm the importance of spe- cific etiological treatment in the management of chronic chagasic patients. Key words Chagas' disease · Trypanosoma cruzi · chemotherapy · sterol biosynthesis inhibitors · nitrofurans · nitroimidazoles · autoimmunity Abbreviations PCR Polymerase chain-reaction · SBI Sterol biosynthesis inhibitors Julio A. Urbina Laboratorio de Química Biológica, Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Apartado 21827, Caracas 1020A, Venezuela e-mail: jaurbina@cbb.ivic.ve J Mol Med (1999) 77: 332–338 © Springer-Verlag 1999 REVIEW Julio A. Urbina Chemotherapy of Chagas’ disease: the how and the why Received: 30 March 1998 / Accepted: 6 November 1998 Introduction Chagas’ disease (American trypanosomiasis) is a parasitic disease caused by the kinetoplastid protozoon Trypanoso- ma (Schizotrypanum) cruzi. It is formally a zoonosis, widespread in North and South America from the southern United States to southern Argentina, and afflicts a large variety of small autochthonous mammals; the parasite is transmitted among its hosts by hematophagous reduviid vectors [1]. As with other kinetoplastid parasites, T. cruzi has a complex life cycle, with specialized stages for sur- vival in both the vector and vertebrate hosts (Fig. 1). In the insect vector the parasite proliferates in the lumen of the gastrointestinal tract as the noninfective epimastigote JULIO A. URBINA received a Ph.D. in physical chemistry from the Massachu- setts Institute of Technology in Cambridge, Massachusetts, USA. He is presently Head of the Biological Chemistry Labo- ratory at the Instituto Venezol- ano de Investigaciones Científ- icas (Venezuelan Institute for Scientific Research, IVIC) and Associate Professor at the Uni- versidad Central de Venezuela, both in Caracas, Venezuela. He has been Visiting Professor of the University of Illinois at Ur- bana-Champaign, The Johns Hopkins University in Balti- more, Maryland, the Universidade Federal do Rio de Janeiro, Brazil, and the Uni- versidad de Granada, Spain. His research interests include molecular biophysics of biolog- ical membranes, physical chemistry of enzyme catalysis, and the development of rational chemotherapeutic approaches to parasitic diseases.