Technological prospection of Diminazene Aceturate , an Angiotensin II Converting Enzyme activator , in front of diarrheic disorders

Diarrhea, which is a gastrointestinal disease, has as its main characteristic the rapid passage of gastric contents through the intestine, which leads to the loss of water and electrolytes and consequent dehydration. The most common fluid replacement is the use of oral rehydration solution (ORS) together with the use of the drug loperamide. However, the use of this medication can cause severe bacteremia followed by sepsis and even death. Currently, there is no effective pharmacological treatment for diarrhea, therefore, it is noted the importance of seeking new therapeutic targets for the treatment of this disease. Thus, the aim of the present study was to conduct a research on the biological activities already described for Diminazene Aceturate with a special focus on antidiarrheal agents. For this, a survey was carried out, through patent filing searches, in the USPTO, EPO, WIPO and INPI databases, using keywords and Boolean operators. Thus, it was found in the international patent databases the number of documents referring to the use of Diminazene Aceturate in several areas, mainly in the pharmaceutical industry, but with a relatively low number of documents regarding the description of possible antidiarrheal action of the compound under study , which reinforces the innovative character of research involving the use of Diminazene Aceturate as an antidiarrheal agent.


Introduction
Diminazene Aceturate (DIZE) has been used as a treatment for animal trypanosomiasis. The drug was first introduced to the market as a trypanosomicide and babesicide for cattle. Because of its high therapeutic index and low incidence of resistance compared to other compounds, it has become the most used therapeutic agent for trypanosomiasis in cattle. Its chemical composition is basically formed by an aromatic diamidine with two aminophenyl moieties attached by a triazene bridge (Peregrine;Mamman, 1993).
For over 60 years, Diminazene Aceturate has been used as a treatment for animal trypanosomiasis. The drug was first introduced to the market as a trypanosomicide and babesicide for cattle. Because of its high therapeutic index and low incidence of resistance compared to other compounds, it has become the most used therapeutic agent for trypanosomiasis in cattle. Its chemical composition is basically formed by an aromatic diamidine with two aminophenyl moieties attached by a triazene bridge (Peregrine;Mamman, 1993;Da Silva Oliveira, 2015).
Recently, several studies have shown that Diminazene is responsible for interfering with various physiological processes in the rodent organism. The use of this compound is linked to the activation of Angiotensin II Converting Enzyme (ACE II). ACE II metabolizes Research, Society and Development, v. 9, n. 12, e1691210755, 2020 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v9i12.10755 deleterious effects of the Ang II / AT1 pathway. (Velkoska et al., 2015) Studies research has shown that administration of Diminazene Aceturate prevents chronic bouts of pulmonary hypertension in experimental models (Shenoy et al., 2013). In addition, DIZE has also been shown to have protective effects under different physiological conditions, including stroke, ischemia, glaucoma and heart disease and diabetic nephropathy. (Colafella et al., 2019;Malek et al., 2019;Velkoska et al., 2016) in the gastrointestinal tract its protective effect has been described in models of gastric ulcers induced by ethanol and acetylic acid (Kuriakose; Uzonna, 2014) gastric ulcer (Souza et al.,2016).
Thus, considering the modulatory effects of DIZE already described in the literature and focusing on its possible protective potential of the gastrointestinal tract, its use as an antidiarrheal agent is pending, but still pending scientific confirmation. In this sense, studies that seek to assert such antidiarrheal property of this compound would be contributing to the field of science in general and public health, considering that diarrhea, for many decades, has been recognized as one of the main causes of death, especially among women.
Among the most frequent clinical manifestations related to gastrointestinal diseases is diarrhea (Major;Gunn, 2019). This is a gastrointestinal disease that has as its main feature a rapid passage of gastric contents through the intestine, thus generating an increase in the number of bowel movements three or more times a day. As well as increased stool fluidity, possibly having the presence of blood and mucus, besides being accompanied by increased secretion and decreased absorption of intestinal fluid which leads to the loss of water and electrolytes and consequent dehydration (Das et al., 2018). Many factors may be related to the onset of diarrhea, including infectious agents, toxins, intestinal functional disorders, nutrient malabsorption, inflammatory bowel disease, and medications (Riddle et al., 2017).
One of the most severe is secretory diarrhea that can lead the patient to death (Brandt et al., 2017). Among them are those caused by the strains Vibrio cholerae O1 and O1.39 and enterotoxigenic Escherichia coli (ETEC), in which there is extensive fluid loss, with minimal or fecal mass formation, being called "rice water" (Hurst, 2019). Cholera caused by the bacterium Vibrio cholerae is still one of the major causes of morbidity and mortality in tropical regions (Di John et al., 2017).
Cholera toxin seems to work by stimulating the transepithelial secretion of chlorine by crypt cells, thereby increasing fluid secretion by its osmotic effect (Yamasaki et al., 2017.). preparations, treatment for bowel syndrome. irritable, enteritis and colitis were also in the results, in addition to other pharmacological applications. In this search, it is still possible to point out that no patent deposits were found when the term "Diminazene Aceturate" was used. The search performed for the combination of the terms "Diminazene Aceturate" and "Diarrhea" returned no results.

Conclusion
Based on the analysis of the data presented, it is noted that in recent years there has been a growing patent filing for the use of Diminazene Aceturate in several thematic areas, especially the pharmaceutical industry. Such data represent the technological advance achieved in the last decade. As is the interest of the pharmaceutical industry in therapeutic alternatives for the treatment of diarrhea. However, the associated terms in patent searches have yielded scant results, which reinforces the innovative character of research involving the use of Diminazene Aceturate as an antidiarrheal agent.