Arkansas emergency medicine study at UAMS includes a Pennsylvania university
UAMS officials said the study is to determine if early intervention in patients with traumatic injury with blood loss by using calcium and vasopressin can improve outcomes. They added that the study will include approximately 1,050 people aged 18 to 90 years old.
UAMS receives $1.9 million from Department of Justice to help Little Rock schools with emergency response
Metropolitan Emergency Medical Services (MEMS) will have participating emergency response crews applying the therapy. The therapy can also be applied after a patient arrives at UAMS.
Officials said the trials, labeled CAVALIER for CAlcium and VAsopressin following Injury Early Resuscitation, are a change from the standard procedure of blood transfusions & blood clotting medication and surgery to stop bleeding. UAMS officials said even with these treatments, up to 30% of patients suffering significant blood loss can die.
'We are committed at UAMS to helping improve survival rates of these severely injured patients,' trauma surgeon and the UAMS principal investigator on the study, Dr. Joseph Margolick, said. 'We think early treatment with calcium and vasopressin in trauma patients may improve outcomes.'
Officials said CAVALIER is an Exception from Informed Consent trial, meaning that the trial requires performing a potentially life-saving treatment on people who are too injured to give permission
UAMS launches pilot program for statewide initiative to support mothers, infants after childbirth
The study is supported by a Department of Defense contract and by the UAMS Translational Research Institute.
Copyright 2025 Nexstar Media, Inc. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
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National Geographic
2 days ago
- National Geographic
How human hibernation could revolutionize medicine and get us to Mars
Putting people into sleep mode is a sci-fi concept that's a lot closer to becoming real than you might think. Erin Belback is part of an ongoing human trial backed by NASA that aims to replicate the effects of hibernation in humans—a potential tool for overcoming some of the physiological problems of long-duration spaceflight. Scientists at the University of Pittsburgh plan to monitor her exhaled breath and body temperature to study her metabolic rate for their research. Photograph by Rebecca Hale, National Geographic Photographs by Corey Arnold The test subject had slipped into what physician Clifton Callaway describes as a 'twilight kind of sleep.' Eighteen hours after Callaway's team at the University of Pittsburgh's Applied Physiology Lab started the man on a sedative that suppressed his body's natural shivering response, his internal temperature had sunk from 98.6°F to 95°F. His heart rate and blood pressure had dropped. His metabolism—and, along with it, his need for food, oxygen, and carbon dioxide removal—had plunged 20 percent. Yet the subject could still rise from his bed, shuffle to the bathroom to empty his bladder, and, when hungry, ring a bell to ask for food or a drink—alleviating the need for a catheter or intravenous lines and ensuring he could still respond and react. The man was one of five exceedingly fit volunteers, ranging in age from 21 to 54, who quietly dozed in the semidarkness—pretend astronauts on a nine-month journey to Mars. NASA had tasked Callaway, an expert in cardiac care and induced hypothermia, with figuring out a simple way to put human beings into a state that mimics some of the key features of hibernation without the use of a ventilator or immobilizing drugs, and careful dosing of dexmedetomidine did the trick. His subject, Callaway says now, was woozy, dreamy, but still able to function in an emergency if required—'just like a bear.' Humans in hibernation mode are a classic staple of space travel in science fiction movies, whether it's HAL 9000 fatally unplugging a few of his passengers in 2001: A Space Odyssey or Chris Pratt waking up Jennifer Lawrence too soon because he's lonely in Passengers. But NASA has grand ambitions of sending astronauts to Mars, for real, as soon as the 2030s, and putting humans in hibernation mode, for real, could be the key to achieving it, which is why both NASA and the European Space Agency are supporting studies like Callaway's. A bearlike state of hibernation could, in theory, help astronauts snooze through the tedium of extended space travel and limit crewmate conflict. Their slowed metabolism could help reduce cargo: Missions would require less food and oxygen, and consequently less fuel. Space agency-funded research is even exploring whether slowing a person's metabolism weakens the health impact of harmful radiation. This would be an encouraging boost for the viability of extended travel through space, where radiation is as much as 200 times greater than on Earth. In fact, when it comes to achieving the dream of crew missions to Mars, says ESA's chief exploration scientist Angelique Van Ombergen, space radiation 'is a big showstopper.' Robert Foote, a volunteer in the NASA-supported trial in Pittsburgh, is monitored by scientists after being asleep for 20 hours. By achieving hibernation on demand, researchers could potentially unlock a wide range of medical benefits, including extending the time that doctors have to treat strokes and heart attacks. Photograph by Tim Betler, UPMC Scientists aren't studying hibernation just so we can ship astronauts ever deeper into space, though. Its physiological superpowers could save countless lives here on Earth, if we can unlock the secrets to the mysterious molecular-level changes that shift animals in and out of a state of hibernation, or 'torpor'—a miraculously reversible state of dormancy characterized by extreme lethargy, a lowered body temperature and metabolic rate, and a host of other remarkable changes. 'It's a well-established principle,' Callaway explains, 'that at low temperatures, like in hibernating animals, you tolerate lack of oxygen, lack of blood flow better and longer.' But why? Why don't bears' muscles atrophy while they sleep? How come their blood doesn't clot? And what triggers the process to begin with? In their hunt for answers, scientists are now inching closer to their most ambitious discovery yet: a central switch in the brains of hibernating animals that activates the various beneficial phenomena of hibernation, all at once. Mimicking the colder body temperature of bears during hibernation, for instance, could lessen the severity of 'reperfusion injuries,' the often devastating damage that occurs after cardiac arrest when blood flow is restored to the oxygen-deprived tissues of the body, setting off massive inflammation, oxidative stress, and cell death. It could also help extend the narrow window of time that doctors have to provide critical care during strokes and heart attacks. A clearer understanding of how hibernating bears preserve muscle mass and turn on and off insulin resistance could have other benefits: It might help us treat chronic obesity and diabetes in humans. ICU patients can lose more than 10 percent of their muscle mass in seven days. Could an induced state of hibernation stall or even stop the decline? Scientists are searching beyond bears for the answers because, of course, bears aren't the only animals that hibernate. A team at Colorado State University is investigating how the 13-lined ground squirrel can rapidly fatten and then switch off its appetite before hibernation for clues to combating obesity. UCLA researchers examining the genes of yellow--bellied marmots have recently found that 'epigenetic aging' is 'essentially stalled' during the seven to eight months they hibernate each year. Experts in Germany are exploring how bats maintain blood circulation at low temperatures, with an eye to human hibernation applications. And biologists at the University of Alaska Fairbanks are studying a squirrel that can drop its body temperature by 70 degrees and heart rate down to five beats per minute and survive eight months in subzero temperatures. Their goal is to develop a 'hibernation mimetic' drug that might safely allow clinicians to place humans into an immediate state of hibernation—without a long prep time, in a rural hospital lacking advanced equipment, or even in an ambulance racing through the streets. It would instantly dial down cellular metabolism, slow cell death, and catalyze a whole host of other biological processes associated with hibernation. (New bat discovery could help humans hibernate during space travel.) To decode hibernation's mysteries, biologists like Heiko Jansen are carefully studying the world's most notorious hibernators: bears. The 11 grizzlies housed at the Washington State University Bear Center are onetime 'trouble' bears from Yellowstone National Park and their offspring. Today they are sleeping for the benefit of science. The center's grizzlies are monitored in camera-equipped dens as they snooze through the late stages of their hibernation. For the five months they rest, their metabolism slows dramatically, reducing their need for food and oxygen. Callaway's twilight sleep experiment provides a glimpse into what might be possible for humans, but what happens in the lab and in the wild are clearly two different things. Bears don't need drugs to settle in for the winter—they have a natural 'torpor switch,' he says, which is flipped through some process that we don't fully understand. And though they're unruly, bears still offer a good comparison for our own potential: They're at least closer to us in size than a rodent, and, perhaps most critically, their temperature drop during deep sleep is well within the range of human survivability. One bright afternoon in late March, biologist Heiko Jansen stood outside a fenced-in pasture at the Washington State University Bear Research, Education, and Conservation Center in Pullman and watched as a shaggy 300-pound female grizzly bear named Kio struggled to eat a marshmallow. Other than a serious case of bedhead and the glacial pace of Kio's chewing, there were few visible clues that the dangerous, disheveled giant with the four-inch claws was undergoing a profound metamorphosis. Looking from the outside, little about Kio's metabolic process seems applicable to humans. Ten days earlier, she rose from her bed of straw and began to slowly work through a feast of bear kibble, apples, and elk bones and leg meat. It was her first meal in five months. Her salivary glands were still sluggish. Then she pooped out a 'fecal plug' composed of plants, dried feces, dead cells, and hair lodged in her lower intestine. Those three key activities—rise, eat, poop out the plug—seem to have helped flip a series of microscopic genetic switches inside her cells, catalyzing the slow-motion reversal of a host of bizarre biological cycles her body had entered into over the winter. Kio's metabolism, which had been operating at one-quarter its normal speed, kicked into gear, more than doubling by the time she was struggling with the marshmallow. Her core body temperature, hovering about 12 degrees below normal, began to rise. Two of her heart's four chambers, which had all but shut down for the winter, reopened for business. Her fat cells, for months miraculously resistant to insulin, the hormone that tells the body when to absorb sugar, started to respond to it again. Her appetite, absent for months, rumbled to life. When the grizzlies begin to stir, in March, they are awake but drowsy—their bodies beginning the process of reversing their metabolic slowdown. This bear, Adak, will be rewarded with honey and other treats after presenting his legs for a blood draw. Five months earlier, back in November, when Kio lay down and packed it in for the winter, she stopped eating, her gut entered 'stasis,' her saliva glands shut down, and she began living on her own body fat. Over the following months, she burned roughly 20 percent, or 70 pounds, of her body weight. To facilitate this, her body became resistant to insulin, a good thing for hibernators. Humans who become insulin resistant often develop diabetes—clearly a bad thing. Bears can switch that resistance on and off, depending on the season, without health consequences. If we could understand how, maybe we could figure out a way for humans to do it too? (Hibernating bears could hold a clue to treating diabetes.) The notion got a boost of confidence in 2018, when a Canadian group published the first complete grizzly bear DNA sequence. A year later, Jansen headed up a team that used a technique known as RNA sequencing to identify which genes are activated in bear muscle, fat, and liver tissue samples before, during, and after hibernation. They found seasonal changes in more than 10,000 of a grizzly's 30,723 genes. Now, in order to decode how bears switch insulin resistance on and off, Jansen has been extracting stem cells from blood samples collected from Pullman's bears at different times of year, methodically eliminating individual genes and then growing colonies of fat cells in petri dishes to see what happens. 'We're not saying that we'll find something that can reverse diabetes,' Jansen offers. 'But at least by looking at a model system, the cells that change their sensitivity, we can begin to develop some clues as to what's going on.' Kio's cardiac function might also yield insights that help treat human blood--clotting disorders. While Kio was hibernating, her heart rate slowed from 80 to 100 beats per minute to about 10. Normally this would cause her blood to clot into dangerous blockages and induce a stroke—'if that happened to us,' says Jansen, 'we'd be dead'—but hibernating bears also experience a remarkable drop in their blood-clotting platelets. It was Kio's ability to maintain muscle tone, however, that particularly transfixed some of her researchers. Unlike humans, who begin to lose muscle mass within a week of inactivity, Kio rose from her hibernation bed as fit as if she'd spent the winter chasing chipmunks. Up in Alaska, researchers Vadim Fedorov and Anna Goropashnaya are trying to unlock the mystery of how bears do this—and test the hypothesis that humans might be able to as well. The Russian-born husband-and-wife team specialize in evolutionary genetics at the University of Alaska's Institute of Arctic Biology (IAB), in Fairbanks. When they began analyzing gene expression patterns in tissue samples collected from captive black bears nearly 20 years ago, the results shocked them. Seeing as how bears stop eating and slow their metabolism during hibernation, Fedorov and Goropashnaya assumed the gene activity involved in building new muscles would be dialed down to preserve energy. Instead, the genes were just as active and even appeared to ramp up. 'We checked it several times,' says Goropashnaya. 'We couldn't believe it.' At the university's Institute for Arctic Biology, Anna Goropashnaya and Vadim Fedorov are investigating how muscle tissue of squirrels and bears (squirrel tissue is projected on their lab wall for this image) is preserved in hibernation when the animals don't eat and barely move. The findings were 'illogical' but somehow correct. Scores of genes known to be part of muscle protein biosynthesis were turned up in what appeared to be a coordinated—and metabolically costly—frenzy of activity. The two presented their first paper on the phenomenon in 2011. Now, with the aid of newer DNA sequencing technologies, they're able to study twice as many genes and with far more specificity, which is what led them to the mTOR pathway, a well-known cellular 'dial' that also plays a key role in controlling the rate of cell division. Typically, when mammals are starved of nutrients, their bodies dial mTOR down to suppress cell regeneration and steer energy to protect existing cells. But in the muscles of hibernating bears, the researchers confirmed what they'd first observed years earlier: mTOR increased instead. Fedorov and Goropashnaya were stumped. If hibernating bears are building new muscle, where are they getting the nutrients to make it? Researchers at the Universities of Wisconsin and Montreal have explored one possibility: microbes. Early findings in other hibernators indicate that instead of producing urine when hibernating, animals recycle the nitrogen in urea, and microbes in their guts could be ingesting and metabolizing it into amino acids, which make new muscles. If Fedorov and Goropashnaya can identify a single, extra-powerful 'upstream' gene responsible for switching on this muscle regeneration, it could have profound medical implications. The muscles of bedbound ICU patients wouldn't melt away within weeks, and astronauts could build muscles while resting. But what if all the disparate and remarkable processes of hibernation could be globally activated all at once—with a drug? To find out, scientists are looking deeper into the animal kingdom to unlock the secrets of the most extreme hibernator of all. (It's not just bears: These hibernating animals may surprise you.) The arctic ground squirrel, a diminutive rodent with gold-tinted fur, a button nose, and a tiny pair of Bugs Bunny-like front incisors, can drastically drop its body temperature and heart rate, slow to one breath per minute, and survive months in subzero conditions. The squirrels are also, for the most part, far easier to study than bears. An arctic ground squirrel remains in hibernation in a lab at the Institute of Arctic Biology at the University of Alaska Fairbanks. 'Until they open their eyes,' says Kelly Drew, the affable, silver-haired neuroscientist who directs the Center for Transformative Research in Metabolism at the IAB, after digging through a nest of cotton and wood shavings to pull out a frozen, furry snowball. 'Then they can bite.' In the early 2000s, Drew persuaded the U.S. military to fund a search for the brain chemicals that trigger hibernation in the squirrels. If she could identify those chemicals, she suggested, she could then test them on humans, in hopes of developing new ways to cool wounded soldiers on the battlefield. Drew's first breakthrough with the squirrels arrived in 2005 when an undergraduate research assistant chanced upon a paper from a Japanese lab while combing through scientific literature. The Japanese group had actually achieved the opposite of what Drew hoped to do. They'd found a drug that woke hibernating hamsters by blocking their brain cells' response to a specific chemical called adenosine. Drew assigned a graduate student to inject a synthetic version of adenosine, a drug called 6-Cyclohexyladenosine, or CHA, directly into the brains of her squirrels. Rather than blocking adenosine, which is how the caffeine in your coffee works its magic, CHA replicates its effects. When the graduate student dosed a squirrel's brain in the summer, outside of hibernation season, nothing happened. But when he repeated it closer to hibernation season, the CHA put the animal into such a deep state of torpor, the student initially thought he had killed it. 'He was super sad because that's a big deal,' Drew recalls. 'He takes the animal out for the vet to do the necropsy. The vet gets the tools out, he's going to start cutting open this dead animal, and it starts to move.' Her lab had done it. They'd found a way to put a squirrel in hibernation mode, like flipping a switch. Temporarily removed from its refrigerated hibernation den and settled on a bed of wood shavings, this arctic ground squirrel remained in a state of torpor for over an hour before beginning to stir. The squirrels survive their long hibernation by warming up for short periods every few weeks. On the opposite side of the world, at the University of Bologna in Italy, around the same time Drew's grad student stumbled on that Japanese paper about adenosine, another grad student named Domenico Tupone was charting a similar path. The focus of his laboratory research wasn't hibernation per se but a component of it: identifying the brain circuits that regulate body temperature during sleep. His team suspected that a small patch of neurons at the base of an ordinary rat's brain helped convey temperature-control signals to the periphery of the body. They temporarily immobilized those neurons with an injection, then placed the rat in a cold, dark cage. The experiment validated their hypothesis. As Tupone and his colleagues watched, the rat sank into a state of hypothermia so extreme it should have proved fatal. That's when things got weird. Six hours and four injections later, the hypothermic rat was still alive. And when the team finally removed it from its cage and warmed it up, the rat behaved, at least outwardly, as if nothing had happened. Afterward, as Tupone and his colleagues examined the brain waves picked up by a web of electrodes attached to the rodent's skull, scientist Matteo Cerri made an observation that altered the course of Tupone's future research. The peaks and valleys of the brain waves looked familiar. Cerri had seen the same patterns in hibernating animals. But there was one crucial difference. Unlike arctic ground squirrels, rats do not naturally hibernate. Tupone had to know: If a non-hibernating animal could be safely induced into hibernation, then maybe humans could do it too? In the years that followed, Tupone obsessed over scraps of paper in dimly lit bars, sketching out what a brain circuit capable of triggering hibernation in humans might look like. In bed, he tossed and turned, fantasizing about a 'revolutionary' IV-administered drug akin to Drew's 'hibernation mimetic' that paramedics could use to slow cell death on the way to the hospital. He became convinced that if it could be accomplished safely, inducing natural torpor in humans would upend basic science. The next step for both researchers, though—human trials—presented their stiffest obstacle yet. In order to administer Drew's 'hibernation mimetic' to ground squirrels, her team often had to perform invasive brain surgeries. For humans, the drug would need to be delivered via IV. The trouble is, adenosine receptors are present throughout the body, and activating them globally can trigger unwanted side effects, including cardiac arrest. After four more years of frustrating trial and error, Drew paired the drug with a compound that fixed the heart attack problem, and she's currently trying to solve the additional obstacle of fluctuating blood glucose levels, which in extreme cases can cause seizures in lab animals and even death. 'It works; it definitely cools them,' Drew says. 'We're just trying to tweak it so it's as safe as possible.' Clinicians have lots of devices to regulate temperature, 'but the human body typically fights it. By avoiding that cold defense response, which is what our hibernation mimetic does, then the clinician has the ability to dial in whatever temperature they want.' In minutes, not hours. Tupone, meanwhile, was working on parallel tracks at Portland's Oregon Health & Science University under Shaun Morrison, one of the world's experts on the brain circuits that control body temperature. Tupone's primary focus was on extending the map of temperature--related circuits into new parts of the brain, but in his spare time, he continued to hunt for the elusive hibernation switch. Around 2016, he stumbled upon a curious biological phenomenon that convinced him he was getting close. He and Morrison were attempting to confirm their map of the brain's thermoregulatory control system, in an experiment similar to the one in which the unexpected survival of those hypothermic Italian rats had blown his mind. This time, Tupone used a small knife to sever the bundle of nerves running to the rat's brain stem, cutting off the pathway that relays temperature--control signals down to the body's periphery. Once again, though, Tupone's results seemed to flip the expected rule of mammalian physiology. Rather than disabling the ability of the rat to respond to heat or cold, Tupone's incision somehow enhanced it. When Tupone wrapped the rat in a plastic blanket and ran hot water over it, its body began generating even more heat. When he used freezing cold water, the rat's brain seemed to allow its body temperature to fall even faster. An arctic ground squirrel emerges from a burrow in the foothills of Alaska's Brooks Range shortly after its eight-month hibernation. Each fall, Colorado State University scientists working at the nearby Toolik Field Station collar squirrels with devices to track body temperature data and light, which tells them if a squirrel is in or out of its burrow. In the spring, new squirrels are ear-tagged and weighed before their summer of foraging begins. The long-term study is revealing how climate change is affecting the biology of these important hibernators. Tupone and Morrison quickly concluded they had discovered something profound. The results suggested that a second, previously undiscovered brain circuit capable of modulating body temperature existed—one that facilitated the transition in and out of hibernation. They named the phenomenon 'thermoregulatory inversion' (TI). But where exactly was this circuit, and how could it be activated? After eight years of trial and error, Tupone and Morrison published a paper this past January announcing they'd found a small patch of neurons in the rat's hypothalamus—the ventromedial periventricular area (VMPeA)—that, when activated, not only seems to slow metabolism, lower body temperature, and induce brain waves and cardiac patterns unique to hibernation but also sets in motion phenomena that flip the body's normal temperature-control system on its head, facilitating the transition into and out of the torpor state. They'd found it: the elusive 'torpor switch.' Tupone believes the switch is connected to an incomplete version of the hibernation circuitry that still exists in many animals. To disable it, he hypothesizes, evolution did the most efficient thing. It simply removed the connection between the circuitry and the switch that would flip it on automatically. 'It is like you have all the cables inside your walls to turn on a light,' he says, but you've removed the connection to the switch that controls that light. 'We think humans have all the circuitry.' Our switch, he believes, just isn't connected anymore. To back up his findings, Tupone is now collaborating with Kelly Drew's lab to find the analogous circuitry—and the switch—in arctic ground squirrels. And he's laying the groundwork for a drug of his own that can flip the switch in his rats without invasive brain surgery. Each advance, though, generates more mysteries. To flip their switch on and off in the study they published in January, Tupone and Morrison had to use invasive brain surgery and manually apply a drug to the general area where it was located. Even that infinitesimally small patch of the brain still contained millions of neurons, including an entire neighborhood of unrelated neurons surrounding it. To find a drug specific enough to give to humans without immense side effects, Tupone will need to identify the precise neurons around the switch and design a drug that will target only those involved in hibernation. That's just the tip of the iceberg, though. To suppress the shivering response in humans, anesthesiologists typically administer muscle relaxants or paralyzing drugs, which suppress breathing, so doctors have to intubate patients … which requires putting them into a medically induced coma. This is why induced hypothermia is not available outside hospitals. It's also not currently an option for stroke patients, because of the dangerous drop in blood pressure that often occurs during the gap between administering anesthesia and intubating a patient, which can deprive the brain of even more oxygen at a moment when dangerous blockages are already suffocating its cells. Rats don't hibernate. But what if they could? Neurologist Domenico Tupone and fellow researchers from the University of Oregon say they've identified a 'torpor switch' in rat brain neurons (projected on the wall) that can be activated to send the rodents into a deep state of hibernation. Identifying this circuitry in non-hibernators could be a breakthrough in the human hibernation effort. 'It can actually worsen a stroke,' says researcher Cal-laway, from the University of Pittsburgh. 'But boy, it sure would be nice to lower your body temperature and let your brain tolerate the stroke longer until I can get you to the cath lab and take that blood clot out.' As an emergency physician, Callaway understands better than most the potential applications for humans, as well as the challenges presented by making the leap from bears and squirrels to humans. He's been researching and refining the techniques used to induce hypothermia in cardiac and brain-injured patients since the 1990s, and he's also a former chair of the American Heart Association's Emergency Cardiovascular Care Committee, which is why NASA awarded him a grant through the Translational Research Institute for Space Health to explore whether his techniques can be applied to the metabolic needs of astronauts. So far, there are problems. The drop in blood pressure and heart rate in his five healthy volunteers was so extreme that those with cardiovascular or other medical conditions might not be able to tolerate it. And within days, all five of the 'pretend astronauts' had developed a tolerance to his sedative, suggesting, among other things, that its effectiveness would fade over time. Those are solvable problems, Callaway says. 'This is just the first step' in a process that he believes will take 10 to 15 years—a mere nap for Rip Van Winkle. 'There's a lot of science to be done,' he says. But he's excited by the progress: 'I don't think it's pie-in-the-sky anymore.' To keep the pretend astronauts inspired during the human trial, Callaway's team had plastered the walls of their lab with posters: a satellite floating in space above the swirling blues and whites of Earth; the cratered, gleaming surface of a moonlike planet; the rainbow-hued burst of starlight, radiating from a distant galaxy. For now, such destinations are accessible only in our dreams. But someday in the not too distant future, a real astronaut might awaken from a hibernation-like slumber to gaze on the real thing.
Business Wire
11-08-2025
- Business Wire
Community Health Systems, Inc. Announces Consideration for Tender Offer for Its 5.625% Senior Secured Notes Due 2027
FRANKLIN, Tenn.--(BUSINESS WIRE)--Community Health Systems, Inc. (the 'Company') (NYSE: CYH) announced today the consideration payable in respect of the previously announced cash tender offer (the 'Tender Offer') by its wholly owned subsidiary, CHS/Community Health Systems, Inc. (the 'Issuer'), to purchase any and all of the Issuer's outstanding 5.625% Senior Secured Notes due 2027 (the '2027 Notes'), on the terms and subject to the conditions set forth in the Offer to Purchase, dated July 28, 2025, as amended (the 'Offer to Purchase'). The consideration (the 'Early Tender Consideration') of $1,002.65 per $1,000 principal amount of 2027 Notes that were validly tendered at or prior to the Early Tender Deadline (as defined below) and are accepted for purchase pursuant to the Tender Offer was determined in the manner described in the Offer to Purchase by reference to the fixed spread specified in the table below plus the yield of 4.293%, which is based on the bid-side price of the U.S. Treasury security specified in the table below, as quoted on the Bloomberg Reference Page specified in the Offer to Purchase, calculated as of 10:00 a.m., New York City time, on August 11, 2025, and includes an early tender premium of $30 per $1,000 principal amount of 2027 Notes (the 'Early Tender Payment'). Only holders of 2027 Notes who validly tendered their 2027 Notes at or prior to the Early Tender Deadline, and whose 2027 Notes have been accepted for purchase, will receive the Early Tender Consideration (which includes the Early Tender Payment). Holders of 2027 Notes tendered following the Early Tender Deadline, but on or prior to the Expiration Time (as defined below) and accepted for purchase will receive an amount equal to the Early Tender Consideration minus the Early Tender Payment (the 'Late Tender Consideration'). The settlement date for 2027 Notes validly tendered as of the Early Tender Deadline and accepted for purchase is expected to occur on August 12, 2025. In addition to the Early Tender Consideration or the Late Tender Consideration, as applicable, holders whose 2027 Notes are purchased in the Tender Offer will receive accrued and unpaid interest on such 2027 Notes from and including the last interest payment date for the 2027 Notes up to, but not including, the applicable settlement date for such 2027 Notes accepted for purchase. The Tender Offer is scheduled to expire at 5:00 p.m., New York City time, on August 25, 2025 (the 'Expiration Time'), unless extended or earlier terminated by the Issuer. The Tender Offer is subject to the satisfaction or waiver of certain conditions as described in the Offer to Purchase. The complete terms and conditions of the Tender Offer are set forth in the Offer to Purchase and remain unchanged. The Issuer has retained Citigroup Global Markets Inc. to act as dealer manager in connection with the Tender Offer. Questions about the Tender Offer may be directed to Citigroup Global Markets Inc. at (800) 558-3745 (toll free) or (212) 723-6106 (collect). Copies of the Tender Offer documents and other related documents may be obtained from Global Bondholder Services Corporation, the depositary and information agent for the Tender Offer, at (855) 654-2015 (toll free) or (212) 430-3774 (collect), or by email at contact@ This press release shall not constitute an offer to buy or sell, or the solicitation of any offer to buy or sell, any securities. Any offer or solicitation with respect to the Tender Offer will be made only by means of the Offer to Purchase, and the information in this press release is qualified by reference to the Offer to Purchase. The Tender Offer is not being made to holders of 2027 Notes in any jurisdiction in which the making or acceptance thereof would not be in compliance with the securities, blue sky or other laws of such jurisdiction. In addition, nothing contained herein constitutes a notice of redemption of the 2027 Notes. Holders must make their own decision as to whether to tender any of their 2027 Notes, and, if so, the principal amount of 2027 Notes to tender. Forward-Looking Statements This press release may include information that could constitute forward-looking statements. These statements involve risk and uncertainties. The Company undertakes no obligation to revise or update any forward-looking statements, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise, except as otherwise required by law.
Business Wire
11-08-2025
- Business Wire
Newron Notes the Publication of New Preclinical Research Suggesting Evenamide Ameliorates Schizophrenia-Related Dysfunction
MILAN & MORRISTOWN, N.J.--(BUSINESS WIRE)-- Newron Pharmaceuticals S.p.A. ('Newron') (SIX: NWRN, XETRA: NP5), a biopharmaceutical company focused on the development of novel therapies for diseases of the central and peripheral nervous system, notes the publication of new preclinical research in the peer-reviewed journal Neuropsychopharmacology on the unique mechanism and site of action of evenamide as a potential treatment for schizophrenia. 1 The findings by researchers at the University of Pittsburgh, using the neurodevelopmental methylazoxymethanol acetate (MAM) animal model, indicated that evenamide, Newron's first-in-class glutamate modulator, could offer a novel therapeutic strategy capable of addressing positive, cognitive, and negative symptoms of schizophrenia. The study findings suggest that evenamide has high therapeutic potential for treating multiple symptom domains of schizophrenia. Evenamide is a unique NCE acting at the site of the deficit in schizophrenia by reducing hippocampal hyperexcitability. Share Schizophrenia is a neurodevelopmental disorder affecting approximately 1% of the world's population, and is characterized by positive, negative, and cognitive symptoms. However, current dopamine D2 antagonist-based antipsychotic drugs only address primarily positive symptoms. It is known that limbic hippocampus hyperexcitability is a key pathological state of schizophrenia and therefore represents an ideal therapeutic target. This newly published research shows how evenamide, a selective voltage-gated sodium channel blocker, uniquely targets hippocampal hyperexcitability and selectively inhibits hyperactive neurons. Additionally, time-course analysis indicates effects of a single dose of evenamide last long after its elimination, suggesting evenamide may have an effect on neuronal plasticity. Studies to date suggest evenamide is devoid of activity at any other central nervous system target, and it normalizes excessive synaptic glutamate induced by NMDA hypofunction. 'The study examined the effect of acute evenamide treatment on the hyperdopaminergic state, hippocampal hyperexcitability, social deficits, and recognition memory in the methylazoxymethanol acetate (MAM) neurodevelopmental model,' explained Daniela L. Uliana, first author of the study, from the Departments of Neuroscience, Psychiatry and Psychology of the University of Pittsburgh. 'The MAM model consists of injecting MAM during gestational day 17 into pregnant rats at a time that approximates the human second trimester; a period of vulnerability in pregnancy during which prenatal disruptions can result in increased schizophrenia incidence in adults. The MAM-treated rats show multiple anatomical, behavioral, neurochemical, and physiological changes consistent with schizophrenia.' 'The study findings suggest that evenamide has high therapeutic potential for treating multiple symptom domains of schizophrenia,' said Senior study author Dr. Anthony A. Grace of the University of Pittsburgh. 'Evenamide is a unique NCE agent in acting at the site of the deficit in schizophrenia by reducing hippocampal hyperexcitability. This represents a significant advancement in treatment, as evenamide can downregulate the hyperdopaminergic state without producing D2 blockade-related side effects while also improving behavioral deficits that are not properly treated by D2 blocking antipsychotic agents.' 'The recognition memory improvement induced by evenamide in the study's MAM model may indicate that it may also enhance cognitive function in patients with schizophrenia and ultimately lead to a better functional outcome,' continued Grace. 'Current D2-based antipsychotic agents do not effectively address cognitive symptoms, which limits their overall efficacy and produces a significant functional burden on patients. Therefore, evenamide would offer advantages over existing antipsychotic drugs by targeting positive symptoms, cognitive deficits and social isolation.' 'This study provides important learnings, which explain the results of our earlier Phase II and Phase III trials in patients with chronic schizophrenia. The prolonged effect in the MAM model explains the continuing improvement in symptoms even one year after starting treatment with evenamide in TRS patients in our phase 2 trial. In the Phase 3 trial in patients who were not responding to their current 2 nd -generation antipsychotic drugs, including clozapine, the addition of evenamide led to significant improvements on the primary efficacy measure (PANSS total) as well as a clinically and statistically significant increases in responder rates,' said Ravi Anand, Newron's CMO. 'The preclinical and clinical results suggest high likelihood of success for our ongoing pivotal Phase III program and to potentially offering a completely new treatment paradigm to patients with schizophrenia.' About schizophrenia Approximately 25 million people worldwide are affected by schizophrenia. Despite more than 60 different types of atypical and typical antipsychotics used to treat schizophrenia globally, a considerable number of patients remain severely ill or resistant to treatment. Overall, 30-50% of patients do not respond to the available medications and are defined as treatment resistant. In addition to the patients with treatment-resistant schizophrenia (TRS), another 20-30% are described as 'poor responders to antipsychotic medication', even if not meeting the criteria for TRS. New findings indicate that patients with TRS have abnormalities in the glutamatergic system, but not in dopaminergic transmission, so there is a significant unmet medical need for treatments with a glutamatergic mechanism of action, efficacious both in TRS patients and in those who are poor responders to the current treatments. About evenamide Evenamide is the first new chemical entity that has demonstrated significant benefits in this difficult-to-treat patient population, as seen in the potentially pivotal Phase III study 008A trial, as an add-on treatment to second generation antipsychotics including clozapine, in 291 poorly responding patients with chronic schizophrenia. The primary endpoint, the Positive and Negative Syndrome Scale (PANSS) 2, and the key secondary endpoint, the Clinical Global Impressions Scale – Severity (CGI-S), were met and showed statistical significance compared to placebo. Importantly, evenamide treatment was associated with statistically significant increases in the proportion of patients who experienced 'clinically meaningful benefit' on the outcome variables. Evenamide was extremely well tolerated, without any of the usual side effects of available antipsychotics. About Newron Pharmaceuticals Newron (SIX: NWRN, XETRA: NP5) is a biopharmaceutical company focused on developing novel therapies for patients with diseases of the central and peripheral nervous system. Headquartered in Bresso, near Milan, Italy, Newron is advancing its lead compound, evenamide, a first-in-class glutamate modulator, which has the potential to be the first add-on therapy for treatment-resistant schizophrenia (TRS) and for poorly responding patients with schizophrenia. Evenamide is currently in Phase III development and clinical trial results to date demonstrate the benefits of this drug candidate in the TRS patient population, with significant improvements across key efficacy measures increasing over time, as well as a favourable safety profile, which is uncommon for available antipsychotic medications. Newron has signed development and commercialization agreements for evenamide with EA Pharma (a subsidiary of Eisai) for Japan and other Asian territories, as well as Myung In Pharm for South Korea. Newron has a proven track record in bringing CNS therapies to market. Its Parkinson's disease treatment, Xadago ® (safinamide), is approved in over 20 markets, including the USA, UK, EU, Switzerland, and Japan, and commercialized in partnerships with Zambon and Meiji Seika. For more information, please visit: Important Notices This document contains forward-looking statements, including (without limitation) about (1) Newron's ability to develop and expand its business, successfully complete development of its current product candidates, the timing of commencement of various clinical trials and receipt of data and current and future collaborations for the development and commercialization of its product candidates, (2) the market for drugs to treat CNS diseases and pain conditions, (3) Newron's financial resources, and (4) assumptions underlying any such statements. 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This document does not contain or constitute an offer or invitation to purchase or subscribe for any securities of Newron and no part of it shall form the basis of or be relied upon in connection with any contract or commitment whatsoever. 1 Uliana DL, Walsh RA, Fabris D and Grace AA. Evenamide reverses schizophrenia-related dysfunction in a neurodevelopmental animal model, Neuropsychopharmacology (2025); 2 Positive and Negative Syndrome Scale (PANSS) is widely used in clinical trials of schizophrenia and is considered the 'gold standard' for assessment of antipsychotic treatment efficacy (Innvo Clin Neurosci, 2017:
