Latest news with #AM404
Yahoo
13 hours ago
- Health
- Yahoo
Tylenol doesn't work the way we thought it does
When you buy through links on our articles, Future and its syndication partners may earn a commission. Acetaminophen is widely used to relieve pain, but exactly how it works has long been a mystery. Now, a new study suggests that a key byproduct of acetaminophen may block pain signals at the nerves — before they can reach the brain. Acetaminophen, also called paracetamol or Tylenol, is broken down by the liver into a compound called 4-aminophenol, which travels through the bloodstream to different organs. There, an enzyme links it with a fatty acid to produce AM404. Previous research found that AM404 can act in the central nervous system — the brain and spinal cord. But the new study, published June 4 in the journal PNAS, reveals that AM404 also affects the peripheral nervous system, where pain signals originate. "These results fundamentally change our understanding of paracetamol's mode of action," study co-authors Alexander Binshtok, a professor in pain research, and Avi Priel, a professor of pharmacy, both at the Hebrew University of Jerusalem, told Live Science in an email. Nial Wheate, a professor of pharmaceutical chemistry at Macquarie University in Australia, who wasn't involved in the study, agreed. "Even though we have been using paracetamol for the management of pain for more than 130 years, we still don't fully understand how the drug works," Wheate told Live Science. One widely held theory was that acetaminophen stopped the body from making. prostaglandins, which can trigger pain and inflammation, he said."If the results of this study are confirmed, then it significantly changes our understanding of the drug." However, the new study was in rats, so the findings may not apply in humans, he added. To test the effects of AM404, the scientists applied the compound to sensory neurons taken from newborn rats. They found that it blocks sodium channels — proteins that normally allow charged sodium particles to pass in and out of cells, which are essential for generating and transmitting pain signals. By blocking these channels, AM404 keeps the neurons from sending pain messages to the brain. Other byproducts of acetaminophen had no such effect. The researchers also injected AM404 into the paws of rats and tested their responses to painful stimuli. The treated paws became less sensitive to heat and pressure, with the strongest effect appearing about an hour after the injection. Importantly, the pain relief was limited to the site of the injection, leaving the other paw unaffected. While the findings may not change how acetaminophen is currently used to treat pain, they could influence the development of next-generation painkillers that are potentially safer, Wheate said. Acetaminophen overdoses can damage the liver and are responsible for 56,000 emergency visits a year in the U.S. RELATED STORIES —FDA approves 1st new class of opioid-free painkillers in over 20 years —Ozempic in a pill? New oral drug may work as well as Ozempic-style injectables —Acne vaccine: Experimental shot for common skin condition reaches clinical trials. Here's what you need to know. "Whole families of new drugs could be designed based around blocking sodium channels. These new drugs could be both more effective and safer than not just paracetamol, but other painkillers like ibuprofen or the opioids," Wheate said. Looking ahead, Binshtok and Priel hope to design improved versions of AM404 that are more chemically stable and optimized to work in the peripheral nervous system, they added. They also plan to test whether these compounds can help with chronic or nerve-related pain, where standard treatments often fall short. Another important next step is to assess the safety and therapeutic potential of AM404 in greater detail. This involves understanding how it is broken down and distributed in the body and whether it might affect any other organs.
Time of India
13-06-2025
- Health
- Time of India
Air pollution exposure alters fetal brain development
London: Brain development in the womb is affected by the mother's level of exposure to air pollution, researchers have found, although it's not clear whether the brain structure differences observed will cause any issues later. Researchers in Barcelona analyzed data collected between 2018 and 2021 from 754 mother-fetus pairs. During the third trimester of pregnancy, participants underwent transvaginal neurosonography, a specialized ultrasound that allows the analysis of fetal brain shape and structures. Higher prenatal exposure to nitrogen dioxide, particulate matter, and black carbon in pregnant women's homes, workplaces, and commuting routes was associated with an increase in the volumes of multiple brain regions that contain cerebrospinal fluid, the researchers reported in The Lancet Planetary Health. Higher exposure to black carbon was also linked with a reduction in the depth of a groove in the brain called the lateral sulcus, which the researchers said might suggest less maturation of the brain. All measurements of brain structures were within the range considered normal, however. "At this stage, we can only report having observed differences in the brains of fetuses with higher exposure to pollution compared to those with lower exposure," senior study author Jordi Sunyer of the Barcelona Institute for Global Health said in a statement. "Additional research is needed to determine whether these effects are reversible after birth or if they persist, and whether they have any implications for neurodevelopmental outcomes in later stages." SCIENTISTS DISCOVER HOW COMMON PAINKILLER REALLY WORKS Scientists have been wrong about how acetaminophen eases pain, a discovery that could lead to new pain management approaches, researchers reported in PNAS. For decades, scientists believed that acetaminophen, the main ingredient in Tylenol - known in some countries as paracetamol - relieved pain by working only in the brain and spinal cord. But researchers have discovered the drug also works outside the brain, in the nerves that first detect pain. After the drug is ingested, the body processes it into a metabolite called AM404. The new study found in laboratory experiments that AM404 is produced in pain-sensing nerve endings, where it shuts off specific channels that help transmit pain signals to the brain. By blocking these sodium channels, AM404 stops the pain message before it even starts, the researchers said. "This is the first time we've shown that AM404 works directly on the nerves outside the brain," study leader Alexander Binshtok of Hebrew University in Israel said in a statement. "It changes our entire understanding of how paracetamol fights pain." The discovery could lead to new types of painkillers that mimic the effects of AM404, the researchers suggested. Because AM404 targets only the nerves that carry pain, such drugs may avoid some of the side effects of traditional painkillers, they said. RARE APPENDIX CANCERS SPIKE AMONG GEN X, MILLENNIALS U.S. appendix cancer rates, while still low, have been climbing dramatically in younger adults, according to a report published in Annals of Internal Medicine. Appendix cancer rates were three times higher among people born between 1975 and 1985, and four times higher among those born between 1981 and 1989, than among people born in the 1940s, based on national U.S. population data. The conclusions are drawn from the nearly 4,900 adults who were diagnosed with appendix cancer in the United States between 1975 and 2019. The pattern of increasing cancer rates held true, to varying degrees, for all tumor types, including nonmucinous, mucinous, goblet cell, or signet ring cell carcinoma, the researchers said. Rates of colon cancers and other gastrointestinal malignancies have also been rising in younger adults, for reasons that remain unclear, the researchers noted. "It really struck our curiosity... Would we observe similar patterns in rare appendiceal cancers?" said study leader Dr. Andreana Holowatyj of Vanderbilt University Medical Center in Nashville, Tennessee. "And certainly the answer was yes," "The big question remains as to why is this happening," she added. "But what's most important is that as these higher-risk birth cohorts continue to age, it's likely these rates will continue to increase." (To receive the full newsletter in your inbox for free sign up here)
Arabian Post
11-06-2025
- Health
- Arabian Post
Breakthrough Reveals Tylenol Blocks Pain at Its Source
A landmark study from the Hebrew University of Jerusalem challenges long-held beliefs about acetaminophen's mode of action, showing that its metabolite, AM404, halts pain signals in peripheral nerves by inhibiting specific sodium channels. This discovery, published in PNAS on 10 June 2025, marks a pivotal shift in pain management science. Historically, acetaminophen was thought to work primarily in the brain and spinal cord. The new research uncovers a peripheral mechanism: AM404 is generated in pain-sensing nerve endings and blocks voltage-gated sodium channels — specifically NaV1.7 and NaV1.8 — preventing pain signals from ever firing. The study was led by Professor Alexander Binshtok and Professor Avi Priel, combining expertise from the Faculty of Medicine and School of Pharmacy. Their team demonstrated that AM404 is synthesised locally in nociceptors and directly inhibits sodium currents, significantly reducing pain behaviours in both normal and inflamed rat models. ADVERTISEMENT This peripheral action mirrors the effect of local anaesthetics but targets only the nerves responsible for pain perception. As a result, AM404-based interventions could preserve motor and sensory functions, avoiding numbness or weakness commonly associated with traditional local anaesthetics. Prof. Binshtok stated, 'This is the first time we've shown that AM404 works directly on the nerves outside the brain. It changes our entire understanding of how acetaminophen fights pain'. Prof. Priel added that exploiting AM404's selectivity could lead to safer, more precise analgesics that bypass the side effects of existing medications. Published on 10 June 2025, the paper titled 'The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels' identifies the compound's mechanism as state-dependent binding to the local anaesthetic site on NaV1.7 and NaV1.8 channels. These findings correct the incomplete understanding of acetaminophen as primarily a central nervous system agent and highlight a dual mechanism involving both central and peripheral pathways. Other experts in neuroscience are welcoming the breakthrough. Commentary in Medical Xpress noted that this 'ends a longstanding mystery' about how acetaminophen relieves pain. IFL Science emphasises the therapeutic promise: AM404's ability to selectively silence pain neurons could inspire local anaesthetics without typical side effects. From a pharmacological perspective, this discovery aligns with earlier theories by researchers like Stephen Waxman, who posited that peripheral sodium channels are viable targets for analgesia. NaV1.7 and NaV1.8 are central to pain signalling in peripheral neurons, a fact that has spurred generations of drug discovery efforts. Beyond academic significance, this insight opens a new paradigm for drug development. AM404's specific action suggests that chemists could design molecules that mimic or enhance its peripheral blocking properties, potentially offering pain relief without impairing motor function or causing dependency. The clinical implications are substantial. Opioids and traditional local anaesthetics carry risks of addiction, motor impairment, and systemic side effects. AM404-inspired drugs could provide non-addictive, nerve-targeted alternatives with fewer adverse effects, particularly in postoperative and chronic pain management. Next steps centre on translating these findings into human studies. Researchers must investigate whether AM404 concentrations in human peripheral tissues reach effective levels and evaluate long-term safety, metabolism, and efficacy across diverse patient populations. As Prof. Binshtok and Prof. Priel note, the journey has begun but much work remains to assess clinical potential. The discovery adds to a growing trend of re-evaluating old medications with modern techniques, uncovering their hidden benefits. It comes one month after Indiana University researchers pointed to acetaminophen's influence on endocannabinoid metabolism — another central mechanism — suggesting that the drug's effects may be multifaceted.
