This is particularly relevant in the case of Trypanosoma species, which are considered facultative anaerobes.Under anaerobic conditions, the nitro group of nitroimidazoles is believed to be reduced by the pyruvate:ferredoxin oxidoreductase complex to create a reactive nitro radical species. The nitro radical can then either engage in other redox reactions directly or spontaneously give rise to a nitrite ion and imidazole radical instead. The initial reduction takes place because nitroimidazoles are better electron acceptors for ferredoxin than the natural substrates. In mammals, the principal mediators of electron transport are NAD+/NADH and NADP+/NADPH, which have a more positive reduction potential and so will not reduce nitroimidazoles to the radical form. This limits the spectrum of activity of nitroimidazoles so that host cells and DNA are not also damaged. This mechanism has been well-established for 5-nitroimidazoles such as metronidazole, but it is unclear if the same mechanism can be expanded to 2-nitroimidazoles (including benznidazole).In the presence of oxygen, by contrast, any radical nitro compounds produced will be rapidly oxidized by molecular oxygen, yielding the original nitroimidazole compound and a superoxide anion in a process known as "futile cycling". In these cases, the generation of superoxide is believed to give rise to other reactive oxygen species. The degree of toxicity or mutagenicity produced by these oxygen radicals depends on cells ability to detoxify superoxide radicals and other reactive oxygen species. In mammals, these radicals can be converted safely to hydrogen peroxide, meaning benznidazole has very limited direct toxicity to human cells.
A further important advance was made in the early 1960s by Doniach with the recognition that pernicious anemia is an autoimmune disease. Pernicious anemia is eventually treated with either injections or large oral doses of B12, typically between 1 and 4 mg daily. A medical author takes the view that Mary Todd Lincoln, the wife of American President Abraham Lincoln, had pernicious anemia for decades and died from it in 1882. Research
Permeation enhancers
Treatment using oral drugs is an easier option in management but the bioavailabity of B12 is low. This is due to low absorption in the intestine, and breakdown by enzyme activity. Research continues to focus on the use of permeation enhancers or permeation absorbers in combination with the treatment. One of the better performing enhancers studied is salcoprozate sodium (SNAC). SNAC is able to form a noncovalent complex with cobalamin while preserving its chemical integrity and protect B12 from gastric acidity. This complex is much more lipophilic than the water-soluble vitamin B12, so is able to pass through cellular membranes with greater ease. Molecular dynamics are used in experiments to gain an understanding of the molecular interactions involved in the different molecules used and the degree of ease achieved in absorption across the gastric epithelium. References
External links
Pernicious anemia at Curlie