Body Weight Response With Disulfiram in Humans. Concept Testing Study

BACKGROUND Overweight and obesity due to food that exceeds the requirements is an increasingly common global problem. It is considered one of the great public health challenges because it leads to the so-called "metabolic syndrome" and its associates such as diabetes mellitus, hypertension and non-alcoholic steatohepatitis. In 2016, more than 1.9 billion adults aged 18 and over were overweight, of which more than 650 million were obese. It is estimated that if nothing is done, by 2030 about half of the world's adult population will have obesity.

Multiple paths have been taken to reverse overweight and obesity, with poor results. Lifestyle intervention and anorectic drugs result in minimal weight loss, which tends to be easily regained. In addition, drugs tend to have too many side effects and have had to be withdrawn from management schemes and even from the market. In Mexico, for example, there are aberrant commercial presentations of drugs that include anorectics, benzodiazepines, thyroid hormones, and atropinic drugs in a single capsule. Bariatric surgery is more effective, but it is an extreme solution that is reserved for patients with morbid obesity and it is associated with its own postoperative morbidity and mortality. Therefore, it is urgent to have new therapeutic elements that help to lose weight effectively and permanently; otherwise, there is no way out of this global problem.

One of the most attractive study targets for developing anti-overweight drugs is the dynamics of body fat. Adipose tissue is not inert, but participates in the control of appetite, glucose homeostasis, insulin sensitivity, and body temperature. White adipose tissue (WAT) stores important energy reserves. Brown adipose tissue (BAT) is an important site of thermo genesis, essential for maintaining body temperature regulated by mitochondrial uncoupling protein 1 (UCP-1), which is activated by exposure to cold. The WAT can acquire characteristics of the BAT thanks to a "browning", which is the appearance of brown fat within deposits of white fat; this improves thermo genesis, increases energy expenditure, and potentially reduces obesity. This browning and its metabolic changes have been achieved in mice with the use of digoxin, thanks to the inhibition of the Interleukin-17 (IL-17) axis.

Disulfiram (Antabuse®) is approved by the Food and Drug Administration against chronic alcohol addiction. In a mouse study, disulfiram prevented body weight gain and prevented the adverse impact of an obesogenic diet on insulin; furthermore, it reverted established diet-induced obesity and metabolic dysfunctions, apparently due to a reduction in feeding efficiency and an increase in energy expenditure; Also in mice treated with disulfiram, loss of fatty tissue, reduction of steatohepatitis and reduction of hyperplasia of the pancreatic islets have been observed, apparently due to the promotion of autophagy. Given the potent anti-obesogenic effects in rodents, clinical reassignment of disulfiram could represent a new strategy to treat obesity and its metabolic comorbidities. In the present study, the investigators proposed a proof-of-concept design to observe the safety of the use of disulfiram in adults with a body mass index greater than 22, as well as the eventual response of body weight and serum metabolic indicators.

JUSTIFICATION