University of São Paulo: New mediator can potentiate anti-inflammatory drugs without risk of gastrointestinal damage

New mediator can potentiate anti-inflammatory drugs without risk of gastrointestinal damage
Very effective against pain and inflammation and without side effects, compound can be a good candidate to replace classic non-steroidal anti-inflammatory drugs and opioid analgesics

In an experiment, a compound showed a more efficient analgesic action than ketoprofen, with a low dose, in addition to a reduction in gastrointestinal toxicity- Photo: Freepik
UA compound studied by researchers at the Institute of Biomedical Sciences (ICB) at USP showed better performance than classic non-steroidal anti-inflammatory drugs and without gastrointestinal effects. This is ATB352, a derivative of the anti-inflammatory ketoprofen, which contains a portion of the molecule capable of donating hydrogen sulfide (H2S). The study was on the cover of the magazine Antioxidants & Redox Signaling and by professors Soraia KP Costa and Marcelo Muscará, in partnership with researcher John L. Wallace of Antibe Therapeutics (Canada). It also counted on the participation of other members of the ICB, such as professor Gilberto de Nucci and the graduate students in Pharmacology, Larissa Gonzaga Santos and Jorge Luiz Dallazen.
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Learn how anti-inflammatories act in the body
Despite being a potent anti-inflammatory and analgesic, ketoprofen can cause injuries and even bleeding in the gastrointestinal tract, even when used for a short period. The scientists tested ATB352 on animals in the postoperative pain model, which causes the phenomenon of hyperalgesia – increased sensitivity in nerve endings, generating a painful response to stimuli that normally do not cause pain. The result was a more efficient analgesic action than ketoprofen, with a low dose, in addition to a reduction in gastrointestinal toxicity, revealing the beneficial aspects of the H2S releasing portion both in the treatment of pain and in the protection of the gastric mucosa.

As an explanation for these effects, the researchers identified a new route of action for the compound: the potentiation of endocannabinoids by inhibiting their enzymatic degradation. Endocannabinoids are molecules of the nervous system that bind to cannabinoid receptors, performing important functions in the body, such as regulating sleep, metabolism, mood, pain, etc.

To confirm the involvement of these mediators, the scientists administered ATB352 in conjunction with a CB1 antagonist to block the cannabinoid receptor. As a result, the benefits were lost. “We observed not only a local pain blocking effect, but also a systemic effect related to endocannabinoids. Our hypothesis is that ATB352 would be a good substitute for opioid analgesics, because it could act at other levels, including the central nervous system ”, says Marcelo Muscará.

Opioids: a public health problem

The search for therapeutic solutions that can replace opioid drugs is justified by the public health crisis related to its indiscriminate use, especially in the United States. Although opioids are very effective in treating pain, as they act on central nervous system receptors, they can also cause addiction. “As repeated doses are administered, the therapeutic effect is lost, making it necessary to increase the dose”, explains Soraia Costa.

Another important application of ATB352 would be in the control of postoperative pain. Often, this treatment is done with classic non-steroidal anti-inflammatory drugs, such as ketoprofen. “What happens is that the patient ends up stopping taking the medication ahead of time due to gastrointestinal discomfort. If the pain is not treated correctly, it can become chronic ”, he adds.

Next steps

The researchers are testing the molecule in other animal models of pain, such as orofacial and visceral pain. Until then, the group has observed the same results. Another molecule being studied by Antibe Therapeutics partners is already being tested on patients and the expectation is that ATB352 will follow the same path.

Antibe Therapeutics is a Canadian biotechnology company that seeks new drugs to treat pain and inflammation based on H2S gaseous mediator release technology. At USP’s Institute of Biomedical Sciences (ICB), professors Soraia KP Costa and Marcelo Muscará work with inflammation and have already tested different H2S donor molecules in models such as arthritis, psoriasis, dermatitis, asthma and inflammatory diseases in general.

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