Toxic Side Effects of Drugs Used to Treat Chagas’ Disease (American Trypanosomiasis)

Abstract

<jats:p> Chagas’ disease (American trypanosomiasis) is an endemic parasitic disease in some areas of Latin America. About 16-18 million persons are infected with the aetiological agent of the disease, Trypanosoma cruzi, and more than 100 million are living at risk of infection. There are different modes of infection: 1) via blood sucking vector insects infected with T. cruzi, accounting for 80-90% of transmission of the disease; 2) via blood transfusion or congenital transmission, accounting for0.5-8% of transmission; 3) other less common forms of infection, eg, from infected food or drinks or via infected organs used in transplants. The acute phase of the disease can last from weeks to months and typically is asymptomatic or associated with fever and other mild non-specific manifestations. However, life-threatening myocarditis or meningoencephalitis can occur during the acute phase. The death rate for persons in this phase is about 10%. Approximately 10-50% of the survivors develop chronic Chagas’ disease, which is characterized by potentially lethal cardiopathy and megacolon or megaoesophagus. There are two drugs available for the aetiological treatment of Chagas’ disease: nifurtimox (Nfx) and benznidazole (Bz). Nfx is a nitrofurane and Bz is a nitroimidazole compound. The use of these drugs to treat the acute phase of the disease is widely accepted. However, their use in the treatment of the chronic phase is controversial. The undesirable side effects of both drugs are a major drawback in their use, frequently forcing the physician to stop treatment. The most frequent adverse effects observed in the use of Nfx are: anorexia, loss of weight, psychic alterations, excitability, sleepiness, digestive manifestations such as nausea or vomiting, and occasionally intestinal colic and diarrhoea. In the case of Bz, skin manifestations are the most notorious (eg, hypersensitivity, dermatitis with cutaneous eruptions, generalized oedema, fever, lymphoadenopathy, articular and muscular pain), with depression of bone marrow, thrombocytopenic purpura and agranulocytosis being the more severe manifestations. Experimental toxicity studies with Nfx evidenced neurotoxicity, testicular damage, ovarian toxicity, and deleterious effects in adrenal, colon, oesophageal and mammary tissue. In the case of Bz, deleterious effects were observed in adrenals, colon and oesophagus. Bz also inhibits the metabolism of several xenobiotics biotransformed by the cytochrome P450 system and its reactive metabolites react with fetal components in vivo. Both drugs exhibited significant mutagenic effects and were shown to be tumorigenic or carcinogenic in some studies. The toxic side effects of both nitroheterocyclic derivatives require enzymatic reduction of their nitro group. Those processes are fundamentally mediated by cytochrome P450 reductase and cytochrome P450. Other enzymes such as xanthine oxidoreductase or aldehyde oxidase may also be involved. </jats:p>

Co-infection Trypanosoma cruzi/HIV: systematic review (1980 - 2010)

“…The count of CD4 + T cells was reported in 59 (20.3%) cases varying from 1 cell/mm 3 to 1,949 cells/mm 3 , with an average of 340 cell/mm 3 . In the reactivated cases, the count varied from 1 cell/mm 3 to 551 cells/mm 3 , with an average of 98 cells/mm 3 .…”

“…It is estimated that 14 million people are infected and that 60 million are at risk of infection whereby in Brazil 1.8 to 2.4 million individuals are in the chronic stage of the disease, 1/3 of them are in the cardiac and digestive form, generating a high morbimortality 2 . Despite its relevance there are still major challenges in understanding various aspects of the disease 3,4 . Due to the vectorial transmission control, especially of the main insect Triatoma infestans, combined with the transfusional transmission control, the acute phase of the disease is becoming increasingly rare 5 , determining that the attention is focused on the population with chronic infection, as well as other changes occurring in the epidemiology of the Chagas disease.…”

Medicinal Plants of Chile: Evaluation of their Anti-Trypanosoma cruzi Activity

“…Both drugs generate severe side effects, and nifurtimox is no longer used in several countries because of its toxicity (Castro et al, 2006;Croft et al, 2005). Consequently, the need for effective anti-Trypanosoma compounds with less toxicity stimulates the search for natural products as novel drug candidates with a potential clinical use (Hoffmann et al, 1992;González et al, 1990).…”

Photoinactivation of Trypanosoma cruzi in red cell suspensions with thiopyrylium

“…It is estimated that 50,000 infected individual die of Chagas' disease annually. Although the disease was primarily transmitted to humans by the excrement of the Reduviid bug in rural areas of Mexico, Central, and South America, transfusion of infected blood products accounts for a significant proportion of transmissions [1][2][3][4]. Since 1987, six cases of transfusion-transmitted T. cruzi and five cases of organtransmitted T. cruzi have been reported in North America [5,6].…”

“…Even with the availability of antibody screening, the proportion of seronegative donors who can still transmit the disease is unknown. Two drugs, nifurtimox and benznidazole, are considered effective in treating acutely infected individuals; however, their use is controversial in chronically infected patients and the toxicities of treatment are often a drawback to their use [2]. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.…”