Pentoxifylline as an immunoregulatory and antioxidant therapy in chronic Chagas disease: from preclinical models to clinical trial

Chagas disease (CD), a neglected tropical illness caused by infection with the protozoan parasite Trypanosoma cruzi, afflicts more than 7 million people, mainly in endemic countries in Latin America. New scenarios of CD may emerge due to human migration to non-endemic countries, and global warming which may contribute to the spread of triatomine vectors of T. cruzi. The acute phase of the infection is usually asymptomatic; therefore, the timing for effective etiological treatment is missed. Although most CD patients show no clinical signs and symptoms (60-70%), the disease progresses at an average of 1.9% per year to cardiac (20-30%), digestive, and cardiodigestive (5-10%) forms. The chronic nervous form of CD remains under debate; nevertheless, behavioral changes (anxiety, depression) and cognitive deficits affect 20-40% of patients. Mostly, treatments of chronic CD only mitigate clinical signs and symptoms. It is proposed that the pathogenesis of chronic CD is underpinned by parasite persistence, intrinsic tissue processes, and systemic inflammatory profile. Currently, clinical trials and protocols for chronic CD are based on reducing the dose of available etiological drugs, mainly benznidazole, and on new antiparasitic drugs. Moreover, most new therapeutic approaches for CD tested in preclinical models fail to overcome the “valley of death” and proceed to clinical trials. Here, we discuss preclinical tests and a clinical trial using the nonselective phosphodiesterase inhibitor pentoxifylline (PTX) as an immunoregulatory and antioxidant drug, primarily targeting tissue damage and systemic inflammatory profiles. In preclinical models of mild and severe cardiac forms, PTX emerges as a monotherapy or an adjunctive medication, reducing or even reversing cardiac, behavioral, and cognitive changes, mitigating tissue damage, and revealing molecular pathways underlying CD pathogenesis. Crucially, the first clinical trial evaluating PTX in CD confirmed its immunoregulatory potential and opened a new avenue for exploration, aiming to improve patients' quality of life.