Good news!
"Japanese scientists have developed ADRIANA, a non-opioid painkiller that could provide powerful relief without the dangers of addiction. With successful trials already completed, large U.S. studies are now underway, raising hopes for a safer future in pain treatment. ...
The research team was first inspired by substances that mimic noradrenaline, which is released in life-threatening situations andactivates α2A-adrenoceptors to suppress pain. However, these pose a high risk of cardiovascular instability. After observing noradrenaline levels and α2B-adrenoceptors, the team hypothesized that selectively blocking α2B-adrenoceptors could elevate noradrenaline levels, leading to activation of α2A-adrenoceptors and resulting in pain relief without causing cardiovascular instability.
To identify selective inhibitors of α2B-adrenoceptors and measure the activity of individual α2-adrenoceptor subtypes, the researchers employed a novel technology known as the TGFα shedding assay and conducted compound screening leading to their discovery of the world's first selective α2B-adrenoceptor antagonist.
After success in administering the compound to mice and conducting non-clinical studies to assess its safety, physician-led clinical trials were conducted at Kyoto University Hospital. Both the Phase I trial in healthy volunteers and the Phase II trial in patients with postoperative pain following lung cancer surgery yielded highly promising results. ..."
From the significance and abstract:
"Significance
Control of pain is a global social health issue because severe pain strongly affects patients’ quality of life. Although opioids are the strongest painkillers, continuous use of opioids often leads to addiction with numerous adverse effects, including respiratory depression, constipation, and hyperalgesia.
An emerging alternative to opioid-based analgesics is dexmedetomidine, an α2-adrenergic receptor agonist. We found that administration of an α2B-specific antagonist, adrenergic inducer of analgesia (ADRIANA), induced noradrenaline release in the spinal dorsal horn and suppressed pain through an α2A-dependent pathway without causing hemodynamic instability. ADRIANA did not cause addiction or any behavioral change in mice and monkeys. A phase I/II clinical trial of the ADRIANA oral tablet is underway to test its effectiveness in reducing postoperative pain.
Abstract
Noradrenaline is a major monoaminergic neurotransmitter involved in pain modulation through an α2A-adrenergic receptor. Hence, α2-adrenergic agonists such as clonidine and dexmedetomidine exhibit analgesic and opioid-sparing effects. However, their use is restricted to hospital settings due to potential risks of acute hypertension/hypotension and bradycardia.
Here, we report that (Z)-1-(3-ethyl-5-fluorobenzo[d] thiazol-2(3H)-ylidene)propan-2-one [adrenergic inducer of analgesia (ADRIANA)], a newly identified α2B subtype-specific antagonist, specifically promotes noradrenaline release in the murine spinal dorsal horn and produces analgesic effects by stimulating the α2A-dependent pain inhibitory pathway.
Orally administered ADRIANA has potent analgesic effects in several nociceptive pain models of mice and nonhuman primates without cardiovascular effects.
Mice with genetic loss of the α2B adrenoceptor showed normal responses to mechanical pain, but the analgesic effect of ADRIANA was not significantly detected.
These findings reveal that the α2B adrenoceptor is a promising target for nonopioid analgesics through the activation of the α2A-dependent descending pathway."
A new alternative to opioids (original news release)
Mechanism of pain relief by ADRIANA
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