NAC shown to help protect Osteoarthritis and Osteopenia
A protein involved in multiple cellular processes called ANP32A protects cartilage in the joints against degradation by damaging oxidation, preventing the development and progression of osteoarthritis, according to a new study by Frederique Cornelis and colleagues. Their findings suggest that some N-Acetyl Cysteine could be useful in preventing further cartilage damage and reducing the severity of osteoarthritis, and potentially other bone and brain disorders.
ANP32A regulates ATM expression and prevents oxidative stress in cartilage, brain, and bone
BY FREDERIQUE M. F. CORNELIS, SILVIA MONTEAGUDO, LAURA-AN K. A. GUNS, WOUTER DEN HOLLANDER, ROB G. H. H. NELISSEN, LIES STORMS, TINE PEETERS, ILSE JONKERS, INGRID MEULENBELT, RIK J. LORIES
Science Translational Medicine 12 Sep 2018: Vol. 10, Issue 458, eaar8426 DOI: 10.1126/scitranslmed.aar8426
NAC, N-Acetyl cysteine, osteoarthritis, osteopenia, ataxia, anp32a, atm, enzyme, brain disorders, bone loss, antioxidant
The systematic review involved eight independent clinical trials of nutrient supplementation in 457 young people. The review primarily covered ‘first-episode psychosis’ (FEP) as well as schizophrenia and a myriad of other ailments associated with the two.
Adjunctive nutrients in first-episode psychosis: A systematic review of efficacy, tolerability and neurobiological mechanisms. Early Intervention in Psychiatry, 2018; DOI: 10.1111/eip.12544
This press release is in support of a presentation by Professor Michael Berk on Monday Oct. 7 at the 26th ECNP Congress in Barcelona, Spain
BARCELONA, SPAIN (7 October 2013) – Improved understanding of the roles of inflammation and oxidative stress in psychiatric disorders has generated new leads in the search for novel therapies. One such investigative compound currently in clinical trials is an amino acid, N-Acetyl Cysteine (NAC), which appears to reduce the core symptoms of bipolar disorder, schizophrenia, depression, autism and cravings in addictions including cocaine, cannabis abuse and cigarette smoking.
At the start of the decade of the brain, in the early 1990s, there was great hope that a flurry of new treatment discoveries would eventuate. In contrast, today, most pharmaceutical companies have a drying psychiatry and neurology pipeline and many have exited the field entirely. “One of the factors has been an over reliance on typical monoamine pathways as targets for drug discovery,” said Professor Michael Berk, Chair in Psychiatry at Deakin University, Geelong, Australia.
Professor Berk pointed out that the situation regarding new drug development for psychiatric problems was best summarised by former National Institute for Mental Health Director, Steven Hyman: “drug discovery is at a near standstill for treating psychiatric disorders such as schizophrenia, bipolar disorder, depression and common forms of autism.”
Beyond the monoamine-based drugs, neuroscience has elucidated an array of other important pathways that are involved in most major psychiatric disorders, for example schizophrenia and both unipolar and bipolar depression. According to Professor Berk, there is now an incontrovertible evidence base that these disorders share inflammation and oxidative stress as part of their disease physiology. In addition, associated pathways including reduction in proteins that stimulate neuronal growth (neurotrophins), and increased cell death (apoptosis), as well as energy generation in organelles called mitochondria are intimately involved. “This understanding provides an entirely new set of treatment targets.”
The amino acid, NAC, seems to have multiple effects on all these pathways: it boosts glutathione, which is the body’s major antioxidant defence; has anti-inflammatory properties; enhances levels of nerve cell growth proteins and the growth of new neurons; and reduces cell death pathways. It also appears to reduce dysfunction of mitochondria.
These molecular effects of NAC have been investigated in a series of clinical trials, which show that NAC reduces the core symptoms of schizophrenia including negative symptoms such as improved apathy, social interaction and motivation. It also appears to reduce depression in people with bipolar disorder and at this meeting, new data on its role in unipolar major depression was presented. Furthermore, there is intriguing evidence that it reduces cravings in a number of addictions including cocaine, cannabis and cigarette smoking. “Apart from nausea, it appears to be relatively free of problematic side effects,” said Professor Berk.
In addition to NAC, a range of other compounds that target similar pathways, particularly inflammation, seem to have therapeutic potential. These include aspirin, cyclooxygenase (COX) inhibitors, statins, omega-3 fatty acids and even some anti-diabetic agents such as pioglitazone. “Capitalising on our understanding of inflammation and oxidative stress in major psychiatric disorders appears to give us an entirely new range of potential treatments for these common, severe and disabling conditions,” said Professor Berk.
Michael Berk Chair in Psychiatry at Deakin University Geelong, Australia Email: MIKEBE@BarwonHealth.org.au
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The European College of Neuropsychopharmacology (ECNP) is an independent scientific association dedicated to translating advances in the understanding of brain function and human behaviour into better treatments and enhanced public health. ECNP organises a wide range of scientific and educational activities, programmes and events across Europe, promoting exchange of high-quality experimental and clinical research and fostering young scientists and clinicians in the field. The annual ECNP Congress attracts around 4,000-7,000 scientists and clinicians from across the world to discuss the latest advances in brain research in Europe’s largest meeting on brain science.
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Researchers from Italy have found that the antioxidant, N-acetylcysteine (NAC), when injected prior to harvesting of the liver, significantly improves graft survival following transplantation. Results published in the February issue of Liver Transplantation, a journal of the American Association for the Study of Liver Diseases (AASLD), suggest that the NAC effect on early graft function and survival is higher when suboptimal organs are used.
A 2010 World Health Organization (WHO) report estimates that 22,000 liver transplants were performed worldwide, with nearly 18,500 from deceased donors. According to the Organ Procurement and Transplantation Network (OPTN) close to 16,000 U.S. patients are currently on the waiting list for a liver. Nearly 18,500 deceased donor transplants were performed between January and October 2012 in the U.S. OPTN reports that roughly 7,000 livers were recovered from deceased donors during the same time period.
“Liver transplantation is the standard treatment for end-stage liver disease,” explains lead author Dr. Francesco D’Amico from Padova University in Italy. “Antioxidants such as NAC could potentially reduce damage to deceased donor livers, improving graft function.” Studies have shown that ischemia-reperfusion injury (IFI)—damage to the liver tissue when blood supply returns to the liver after lack of oxygen (ischemia)—often occurs during storage and preservation of donated livers, and impacts early graft function post-transplantation.
For the present study researchers assigned 140 organs to adult candidates with liver disease undergoing their first transplant. An NAC infusion of 30 mg/kg was administered to one hour prior to liver procurement and another infusion of 300 mg (150mg/kg liver weight) through the portal vein before cross-clamping. There were 69 transplant candidates who received an NAC infused organ and 71 patients who had a standard transplant without NAC.
Results indicate that graft survival rates at 3 and 12 months were 93% and 90%, respectively, for patients receiving NAC infused livers; rates were 82% and 70% in the control group. Post-transplant complication rates were 23% for the NAC group and 51% in the control group. Analysis of the 61 patients receiving suboptimal livers the incidence of organ dysfunction was lower in the NAC group compared to controls at 15% and 32%, respectively.
Dr. D’Amico concludes, “Our study was the first randomized trial to investigate the use of NAC antioxidant infusion during the liver procurement procedure. We propose that NAC be used during organ harvesting to improve liver transplantation outcomes, particularly with the increased use of suboptimal organs. NAC has a good safety profile and the very low cost per patient, make this protocol highly cost-effective in consideration of grafts survival, length of hospital stays and post operative complications. Moreover we are performing further analyses to determine beneficial effects on the other organ procured with NAC protocol.”
In a related editorial published this month in Liver Transplantation the authors from the University of California, San Francisco (UCSF) and OneLegacy (Organ Procurement Organization, Los Angeles) highlight the importance and rarity of deceased organ donor research, such as the study by D’Amico et al., despite the fact that randomized clinical trials are essential to evidence-based medicine. Dr. Claus Niemann from the Department of Anesthesia and the Department of Surgery, Division of Transplantation at UCSF said, “Well-controlled deceased donor research is crucial to uncovering superior clinical practices that improve organ utilization and transplant outcomes. However, researchers are currently operating in a regulatory and legal vacuum since no review and oversight policies are established.”
For a copy of the study and editoral, please email firstname.lastname@example.org.
Full citations: “Use of N-Acetylcysteine During Liver Procurement: A Prospective Randomized Controlled Study.” Francesco D’Amico, Alessandro Vitale, Anna Chiara Frigo, Donatella Piovan, Alessandra Bertacco, Domenico Bassi, Rafael Ramirez Morales, Pasquale Bonsignore, Enrico Gringeri, Michele Valmasoni, Greta Garbo, Enrico Lodo, Francesco Enrico D’Amico, Michele Scopelliti, Amedeo Carraro, Martina Gambato, Alberto Brolese, Giacomo Zanus, Daniele Neri and Prof. Umberto Cillo. Liver Transplantation; (DOI: 10.1002/lt.23527) Print Issue Date: February, 2013.
Editorial: “Deceased Organ Donor Research: The Last Research Frontier?” Thomas Mone, John Heldens and Claus U. Niemann. Liver Transplantation; (DOI: 10.1002/lt.23579) Print Issue Date: February, 2013.
About the Journal
Liver Transplantation is published by Wiley on behalf of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. Since the first application of liver transplantation in a clinical situation was reported more than twenty years ago, there has been a great deal of growth in this field and more is anticipated. As an official publication of the AASLD and the ILTS, Liver Transplantation delivers current, peer-reviewed articles on surgical techniques, clinical investigations and drug research — the information necessary to keep abreast of this evolving specialty. For more information, please visit http://wileyonlinelibrary.com/journal/livertransplantation.
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2009 study posted for filing
Patients with the disorder, known as trichotillomania, reported feeling much improved after taking the supplement
MINNEAPOLIS/ ST. PAUL (July 6, 2009) – University of Minnesota Medical School researchers have discovered that a common anti-oxidant, widely available as a health food supplement, may help stop the urges of those with trichotillomania, a disorder characterized by compulsive hair-pulling.
Fifty people enrolled in a double-blind 12 week study; half were given N-Acetylcysteine, an amino acid commonly found in health food supplements. The average age of patients who enrolled was about 34, and most started pulling hair compulsively by the age of 12. Patients were given 1,200 mg of N-Acetylcysteine every day for six weeks. For the following six weeks, the dosage was increased to 2,400 mg per day. After nine weeks, those on supplement had significantly reduced hair-pulling. By the end of the 12 week study, 56 percent reported feeling much or very much improved, while only 16 percent on the placebo reported less pulling.
The study is published in the July, 2009 issue of the Archives of General Psychiatry.
“Trichotillomania is compulsive in the sense that people can’t control it. People feel unable to stop the behavior even though they know it is causing negative consequences,” said Jon Grant, M.D., J.D., a University of Minnesota associate professor of psychiatry and principal investigator of the study. “Some people don’t even know they are doing it.”
Those who have trichotillomania compulsively or habitually pull their hair to the point of noticeable loss. It is most commonly associated with women, but men can also be affected, and pulling can occur anywhere on the body. Grant believes 2 to 4 percent of the general population is impacted by trichotillomania on some level.
“These are people who have tried all kinds of things that have never worked,” Grant said. “The reality is that if you pull hair and it is on a noticeable part of the body, people are really disabled by this. It’s not easy to go out in public if people are noticing your bald spots. Self esteem is a huge problem. This supplement may offer hope.”
The study is significant on another level because it’s one of the first studies of compulsive behaviors to look at lowering levels of glutamate – a chemical that triggers excitement – in the brain to curb harmful behavior rather than serotonin, a naturally occurring chemical most commonly linked to compulsive behavior. This supplement affects levels of glutamate in a specific area of the brain, making it easier for patients to put the breaks on their harmful behavior.
For that reason, Grant believes glutamate modulators such as N-Acetylcysteine may be applicable to other disorders, addictions, and compulsive behaviors.
The study is funded by The University of Minnesota Medical School.
Questions remain on NACs true utility for this condition
A new retrospective study on the effects of N-acetylcysteine (NAC) on children with acute liver failure not caused by acetaminophen poisoning has found that the treatment was associated with a shorter hospital stay, higher incidence of liver recovery, and better survival after transplantation. The study is in the January issue of Liver Transplantation, a journal by John Wiley & Sons. The article is also available online via Wiley Interscience (http://www.interscience.wiley.com/journal/livertransplantation).
Acute liver failure in children is rare but can be fatal. Acetaminophen poisoning is a common cause, and is treated with NAC, which acts as an antidote, an anti-inflammatory agent and an antioxidant. One small, uncontrolled study suggested that NAC could also help children with non-acetaminophen induced acute liver failure, leading some medical centers to adopt the treatment. Recently, researchers led by Christine Kortsalioudaki of King’s College Hospital in London sought to retrospectively evaluate whether NAC is beneficial for those children.
They examined the medical records of 170 children who came to King’s College Hospital with non-acetaminophen induced acute liver failure between 1989 and 2004. Those treated before 1994 were not treated with NAC, while those who came after 1995 did receive NAC. All the children also received standard care to maintain normal tissue oxygenation and prevent and address complications of acute liver failure.
The children who received NAC spent fewer days in intensive care, and in the hospital overall. 43 percent survived with their native liver, compared to 22 percent of children who did not receive NAC. And death rates while awaiting transplant, after transplant, and after ten years were notably lower in children who had received NAC. Adverse effects were mentioned in just 11 percent of cases and NAC was discontinued in one.
“Our data demonstrates that NAC has minor, self-limited adverse effects and can be safely administered to children with non-acetaminophen induced acute liver failure,” the authors report. “Additionally this study suggests NAC may have a positive effect on the outcome of non-acetaminophen induced acute liver failure, improving the survival with native liver as well as post liver transplant survival.”
An accompanying editorial by Mike Leonis and William Balistreri of the Cincinnati Children’s Hospital Medical Center points out that the two groups compared in Kortsalioudaki’s study were markedly dissimilar in their clinical presentation which could account for some of the differences in outcomes. Also, further stratification of the NAC-treated group into middle and later years showed better outcomes in the latter group which would argue that the improvement was due to non-NAC related effects.
“This study does support the idea that intravenous NAC is a well-tolerated and safe medication for pediatric patients with acute liver failure,” Leonis and Balistreri write. However, it raises further question as to whether intravenous NAC is beneficial in pediatric patients with non-acetaminophen induced acute liver failure.
They point out that two current randomized-controlled prospective clinical trials are addressing this question. “Hopefully with the completion of both of these studies, convincing information will be available to guide clinicians on the true utility of NAC in non-APAP-induced ALF,” they conclude.
Article: “Safety and efficacy of N-Acetylcysteine in children with non-acetaminophen induced acute liver failure.” Kortsalioudaki, Christine; Taylor, Rachel; Cheeseman, Paul; Bansal, Sanjay; Mieli-Vergani, Giorgina; Dhawan, Anil. Liver Transplantation; January 2008.
Editorial: “Is there a ‘NAC’ to treating acute liver failure in children.” Leonis, Mike; Balistreri, William. Liver Transplantation; January 2008.