Scientists study the use of the same drug for more than one treatment

To try to shorten and cheapen the complicated process that leads to the approval of a new drug, capable of consuming hundreds of millions of dollars, some scientists have bet on the discovery of new uses for drugs that are already on the market. The so-called drug repositioning already has some success stories, but the approach still comes up against the fact that relatively little is known about the interaction between drugs and the body.

Some of the most well-known drugs in the world fall into this category. This is the case with sildenafil (better known as Viagra), which revolutionized the treatment for erectile dysfunction, but was originally tested to treat high blood pressure and chest pain caused by heart problems — the effects on erection were noticed during the first clinical trials to the original purposes of the remedy. Aspirin, used for decades against pain and fever, can be used as a preventive medicine against strokes and blood clots.

“But the fact is that the market is not yet full of examples like these”, ponders Helder Nakaya, a researcher at the Hospital Israelita Albert Einstein and at the Faculty of Pharmaceutical Sciences at USP.

“This probably has more to do with the fact that we still don’t understand how many drugs work. Curing diseases is a difficult thing because, often, you don’t know exactly the source of the problem, and this is directly linked to the target. with which the drug interacts in the body.”

Despite this, drug repositioning has been explored because it has the potential to skip some steps in the drug development process.

If a certain substance is already considered safe for use in humans and is on the market, for example, the initial tests with patients could be seen as something already resolved.

This is not always the case, as the ideal or safe dose for an illness may be quite different from that used for the original health problem. Even so, the repositioning can facilitate previous phases, such as toxicity studies (basically aimed at knowing which doses of the substance are toxic, and how) or in vitro and animal tests.

“A strategy widely used is the so-called ‘target-based’ [baseada em alvos]”, explains pharmacist Thiago Mattar Cunha, a professor at USP in Ribeirão Preto.

Roughly speaking, in these cases, researchers use libraries of drugs already approved for use and check whether the molecules in the organism with which they interact in their known use are also important in other diseases. If this “match” happens, other tests can follow.

Even in these cases, subsequent work often ends up revealing that the initial understanding of the drug’s action was wrong — which isn’t always a problem, as long as it works, of course.

“An interesting case is that of pregabalin, originally used against seizures”, says Mattar Cunha. “The idea is that it increased concentrations of Gaba [um neurotransmissor, ou seja, mensageiro químico do cérebro] in the central nervous system. It turned out to be a great pain reliever for chronic pain, and its mechanism of action was quite different.”

According to Helder Nakaya, another intriguing clue for drug repositioning came from the study of the brains of babies who had died from congenital Zika syndrome, that is, from brain lesions triggered by the disease virus.

“The analyzes indicated a possible involvement of glutamate, a substance that can act as a neurotransmitter and that is toxic in high concentrations.”

The next step was to try to use a drug against Alzheimer’s, whose function is precisely to block the “conversation” of glutamate with neurons, in pregnant mice infected with Zika. Apparently, it works — and, as far as we know, the drug is safe for use in pregnant women. “Each step of these gives greater excitement that the idea can work, although the process is long”, says the expert.

To make this process faster, scientists are increasingly relying on artificial intelligence, using software capable of automatically scanning huge databases on the diseases they want to study, the drugs used for them, and genes (roughly speaking, functional snippets of DNA) with which these substances interact.

That’s what Nakaya and his colleagues recently did, conducting an analysis of millions of articles in the scientific literature on psychiatric conditions such as Alzheimer’s, depression and schizophrenia, finding correlations between 722 drugs and 1,588 genes.

“The idea was to assemble maps of knowledge involving genes, drugs and diseases. That is, if there is a drug used to treat a certain disease, affecting a certain gene, could this same drug be used against another problem in which the same genes are activated? ?”, he explains.

One sign that the results made sense was the fact that the researchers, after the initial analysis, looked at databases on clinical trials (ie, trials of drugs in people, still in progress).

They found that the drugs pointed out as promising, in several cases, were in fact already being tested, although there was no direct mention of their use in the scientific literature.

Another approach that has grown, says Mattar Cunha, are the so-called in vivo phenotypic tests. Despite the complicated name, the idea is simple: to test the repositioning of drugs in laboratory animals that belong to a strain that is already used to study certain diseases (because of their natural characteristics or because they are genetically modified for that purpose).

“In these cases, you leave out specific targets, since in complex diseases it is difficult to isolate them, and you simply give more weight to what works, without necessarily having any idea how it works,” he says, citing as an example cannabidiol, a derivative of marijuana, whose experimental has expanded a lot.

Another important issue in repositioning work is how to get pharmaceutical companies interested in putting old drugs to new uses. It is something that, for the industry, may be less advantageous than profiting from patents on a new drug.

“You cannot obtain a new patent for a new use, but this is possible if a different mechanism of action is demonstrated”, says the researcher at USP from Ribeirão Preto. In cases where this is not feasible, public investment is essential, he says.