Now researchers reporting in the October issue of Cell Metabolism, a Cell Press publication, appear to have an answer as to why. It seems a deficiency of the neuropeptide hormone orexin, an ingredient that encourages hunger and wakefulness, may leave them with a lack of energy-burning brown fat.

The findings may lead to orexin-based weight loss therapies for those with narcolepsy and for the rest of us, too, according to the researchers.

Orexins are rather unique in that they allow one to eat more and lose more at the same time, explained Devanjan Sikder of the Sanford-Burnham Research Institute. “It is a couch potato’s dream.”

Fat comes in one of two types: white or brown. White fat stores calories while brown fat burns them, generating heat in the process. There had been hints that orexins might influence body temperature, but it wasn’t clear exactly how.

The new evidence in mice shows that orexins are critical for the formation of mature brown fat from its precursors. With too little orexin, animals’ brown fat activity drops along with their energy expenditure. Likewise, mice injected with orexin show a substantial loss of fat.

The findings bolster the emerging concept that those with less active brown fat may be destined from birth, or even before, to be fatter. “They are somehow predisposed,” Sikder said.

There are already ways of stimulating brown fat’s production, but it isn’t easy to do. For instance, more brown fat is produced when you spend a lot of time in the cold. The new findings suggest that orexin therapies might be useful for increasing brown fat and literally melting extra calories away.

“One caveat is that orexin might increase arousal,” the researchers wrote, “although this is expected only under sleep deprived conditions.”

Sikder says it will now also be worthwhile to examine orexin-deficient people with narcolepsy to find out whether their brown fat activity is indeed compromised.

Source: Sleep Review Mag

They can be extremely dangerous for both the person suffering from the disorder as well as others around them when the attacks occur. Narcolepsy is a nerve disorder that tends to run in families, which means there is no way to prevent it. There is also no treatment for this disorder but prescription drugs and lifestyle adjustments can be used to manage the sleep attacks and symptoms.

This sleep disorder is a growing issue in our society today. It is important for us to learn about it because not only does it effect people with the disorder, it also effects those who come in contact with them in everyday life. Normal people go through the REM cycle after ninety minutes of sleep whereas narcoleptics go through the REM cycle within ten minutes of sleep. This is why they fall asleep for fifteen minutes and wake up feeling refreshed.

Narcoleptics feel extremely tired every three to fours hours and usually they end up falling asleep for a short time. I once had class with a boy who suffered from narcolepsy. He would randomly fall asleep in the middle of class and stay asleep for close to fifteen minutes. Everyone was very confused because we were unaware that he had this condition. That is why it is so important for people to learn the basic information about narcolepsy. You never know who you will meet with the condition. It could be anyone.

Source: UThink Blogs

“The cause of this rare form of inherited narcolepsy has been very difficult to study and is not well understood,” explains the senior study author, Dr Rosa Peraita-Adrados from the Gregorio Marañón University Hospital in Madrid, Spain. “To identify a causative mutation in familial narcolepsy, we performed a genetic analysis in the largest-ever reported family with 12 affected members and then performed an even more sensitive analysis of three affected members with narcolepsy and cataplexy.”

Dr Peraita-Adrados, co-author Dr Mehdi Tafti from the University of Lausanne in Switzerland, and their colleagues found that the myelin oligodendrocyte gene (MOG) in the affected family members harbored a mutation that was not present in unaffected family members or in hundreds of unrelated controls. Myelin is a protein produced by oligodendrocytes, support cells in the central nervous system. It is essential for proper functioning of the nervous system. When the researchers put the abnormal form of MOG in mouse oligodendrocytes, they observed that the MOG protein was not properly distributed within the cells. This suggests that the mutant MOG must not function properly.

Although further studies are needed to identify the links between myelin, oligodendrocytes, and narcolepsy, the finding is particularly intriguing because MOG has recently been linked to various neuropsychiatric disorders.

“Gene-expression studies in major depression, bipolar disorder, schizophrenia, and multiple sclerosis indicate that genes expressed in oligodendrocytes are downregulated, supporting the hypothesis that problems with oligodendrocytes might cause neurodevelopmental disorders,” concludes Tafti. “The identification of a mutation in MOG, so far unique to our family, not only provides insight into the pathogenesis of narcolepsy but also highlights the role of myelin and oligodendrocytes in disease susceptibility in other complex neuropsychiatric disorders.”

Source: Sleep Review

The findings, which will be published online Aug. 22 in Annals of Neurology, a journal of the American Neurological Association and Child Neurology Society, show that a peak in narcolepsy cases occurred five to seven months after a peak in flu/cold or H1N1 infections in the country.

“Together with recent findings, these results strongly suggest that winter airway infections such as influenza A (including H1N1), and/or Streptococcus pyogenes are triggers for narcolepsy,” Mignot, a professor of psychiatry and behavioral sciences, and his colleagues wrote in the paper.

The study follows recent reports that a particular H1N1 vaccine, not one used in the United States or China, seemed to lead to narcolepsy. This new paper, however, found no correlation between vaccination and narcolepsy among the patients studied in China. “The new finding of an association with infection, and not vaccination, is important as it suggests that limiting vaccination because of a fear of narcolepsy could actually increase overall risk,” the authors wrote.

Approximately 3 million people worldwide suffer from narcolepsy, a neurological disease that is characterized by daytime drowsiness, irregular sleep at night and cataplexy — a sudden loss of muscle tone and strength. In 2009 Mignot and colleagues confirmed scientists’ long-held suspicion that narcolepsy is an autoimmune disease, caused when patients’ immune systems kill the neurons that produce the protein hypocretin.

Experts believe that a person has a genetic predisposition to the disease, and some environmental factor kicks his or her immune system into action leading to narcolepsy. As noted in the paper, past studies have shown that Streptococcus pyogenes infections, such as strep throat, have preceded the onset of narcolepsy in Caucasians, suggesting a role for upper airway infections in triggering the disease, Mignot said.

Last year, several European countries reported new cases of narcolepsy in children who had been vaccinated for the H1N1 strain of influenza; children who received the Pandemrix H1N1 vaccine in Finland, for example, faced a ninefold increased risk of narcolepsy. The World Health Organization led an investigation and determined that something about this particular vaccine acted in a “joint effort” with “some other, still unknown factor” to increase risk in those already genetically predisposed. (Pandemrix contains two adjuvants to invoke a stronger immune response; these additives are not included in the H1N1 vaccines used in the United States and China.)

For the new study, the researchers looked at the data of 906 patients who were diagnosed with narcolepsy in Beijing between September 1998 and February 2011, and determined the patients’ month of onset of cataplexy and sleepiness. They conducted brief phone interviews with 154 patients whose narcolepsy appeared after October 2009, the date of the first H1N1 vaccination administered in China. The researchers also queried the patients about their history of seasonal flu, H1N1 vaccinations and other diseases.

Mignot’s group found that the occurrence of narcolepsy onset was seasonal and significantly influenced by month. Onset was least frequent in November and most frequent in April; there was a five- to seven-month delay between the seasonal peak in flu/cold or H1N1 infections and the peak in narcolepsy onset occurrences.

The paper doesn’t show cause and effect, but it does show a strong correlation between narcolepsy onset and this seasonal pattern.

The team also found a threefold increase in disease onset following the 2009-10 H1N1 winter flu pandemic compared with other years.

Only a small amount — 5.6 percent — of the patients interviewed recalled receiving an H1N1 vaccine. The onset, the researchers concluded, is unlikely to be explained by vaccinations. Instead, as they wrote in the paper, these winter infections appear to “initiate or reactivate an immune response that leads to hypocretin cell loss and narcolepsy in genetically susceptible individuals.”

Mignot said the work is exciting because it provides insight on how the disease is triggered. “We’re much closer to understanding what’s happening in the autoimmune destruction of hypocretin cells,” he explained.

From a public-health standpoint, Mignot said the work suggests that getting vaccinated and avoiding influenza may provide a protective benefit to patients. He said, “It’s very possible that being vaccinated with a mild vaccine, one without the adjuvants in question, blocks you from getting a big infection that could increase your risk of narcolepsy.”

As for the differences between the findings of the study and what has been observed in Europe, Mignot said it’s possible that the strong immune response prompted by the Pandemrix vaccine increases the risk of narcolepsy. He emphasized, however, that more study is needed and that people shouldn’t avoid getting vaccinated.

“Even with Pandemrix, it’s still a very small risk — and there’s a bigger risk from dying of an infection if you don’t get vaccinated,” he said.

Source: Michelle Brandt, Stanford University Medical Center, via EurekAlert

Although narcolepsy may affect somebody’s life significantly there are many ways to deal with it. One way for someone suffering from narcolepsy to live comfortably is by using stimulants to counter the effects of the daytime fatigue and sleepiness that narcolepsy brings on. This includes the use of caffeine, energy drinks, drugs, or any other stimulants. Although this may help a little day to day with normal activities, prolonged use of stimulants to counter the effects of narcolepsy can make it worse. This can cause suffers to physically depend on the stimulants and while it is helping the individual combat the symptoms, it is not actually treating the disorder itself but obstructing it. This can change and damage the normal sleep cycle.

Another way for someone to combat narcolepsy is through prescribed medication. Gamma-hydroxybutyrate is a generic term for the only medication that is approved for treatment of narcolepsy. This way of treatment is effective as it can counter the daytime fatigue experienced, and improve overall sleep quality, which will in turn reduce the sleepiness experienced throughout the day. However, this drug has a high potential for abuse and it is expensive to obtain.

While pills and oral treatments are a way to help narcolepsy, a simple change in one’s lifestyle can help a sufferer. Someone suffering from narcolepsy could change their lifestyles so that they sleep during the day and be most productive during the night. Also, poor sleeping patterns at night can lead to the extreme fatigue during the daytime, where a change in nighttime sleeping patterns can help symptoms of narcolepsy. One way that can be used to help alleviate symptoms is through therapy. This can include hypnosis, or frequent short naps during the day. With hypnosis, the victim can have a deeper sleep and state of mind, causing less tiredness during the day.

Source: WebMD

Potentially clinically significant adverse reactions to a supratherapeutic dose could include cardiovascular, neurologic, psychiatric and gastrointestinal reactions such as: palpitations, tachycardia, hypertension, headache, tremor, tic, dyskinesia, dizziness, blurred vision, sweating, insomnia, agitation, euphoria, mania, anxiety, restlessness, nausea, diarrhea, constipation, dry mouth, and decreased appetite.

This product can be uniquely identified as an oval peach colored tablet, debossed with b/973 on one side and 2/0 on the other side. Barr distributed the affected lot between 06/11/09 and 06/16/09. Only lot 311756 is affected by this recall.

Customers who have this lot in their possession are instructed to cease using the product and return it to their pharmacy/distributor. Wholesalers and retailers should cease distribution and examine their inventory immediately.

Consumers with questions may contact 888-742-5578 from 8:00am – 8:00pm EDT Monday-Friday.

Barr Laboratories has not received any adverse events for this product lot.

The FDA has been apprised of this action.

Any adverse reactions experienced with the use of this product should also be reported to the FDA’s MedWatch Program by phone at 1-800-FDA-1088; by fax at 1-800-FDA-0178; by mail at MedWatch, HF-410, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787, or on the MedWatch website at http://www.fda.gov/Safety/MedWatch/default.htm.

The agreement to license ADX-N05 gives Addrenex the worldwide rights (excluding East Asia) to develop, manufacture and commercialize the compound from SK Life Science Business Division, the drug-discovery and development division of SK Holdings Co. Ltd., one of the largest multinational companies based in South Korea.

“The partnership with SK Holdings embodies our commitment to seeking global alliances that further our goal of developing drugs for adrenergic regulation,” said Steve Butts, Vice President of Commercial Operations for Addrenex Pharmaceuticals.

“We are pleased and excited to partner with an innovative, dynamic company such as SK Holdings, and we expect this to be the first of many global development partnerships for Addrenex,” he added.

The licensing deal with SK Holdings provides Addrenex with its fourth drug candidate to enter clinical trials in three years. Each of Addrenex’s drugs in development focuses on the treatment of medical conditions arising from an overactive or improperly regulated adrenergic system, a group of hormones and brain chemical messengers known as neurotransmitters. These hormones and neurotransmitters regulate diverse physiologic functions such as stress, pain, sleep and blood pressure.

Addrenex’s lead products are Clonicel(R) for the treatment of attention-deficit hyperactivity disorder (ADHD) and Sympres(R) for the treatment of hypertension. The company also plans to develop drugs to treat menopausal flushing and potentially pain, insomnia and migraines, all of which are impacted by the adrenergic system.

“ADX-N05 represents a significant advance toward expanding our product portfolio into a more diverse set of disorders for which there is a considerable unmet need for treatment,” said Moise Khayrallah, Ph.D., CEO of Addrenex Pharmaceuticals. “As an orphan disease, narcolepsy has few treatment options on the market that are safe, convenient and address all the symptoms of the disorder.”

In preclinical studies, ADX-N05 (also known as SKL-N05) has demonstrated several potential benefits over currently marketed drugs for narcolepsy, according to Khayrallah. ADX-N05 has shown the potential to treat excessive daytime sleepiness as well the associated symptom of cataplexy, an abrupt and temporary episode of weakness that can result in collapse. ADX-N05 also exhibited the potential to decrease DREM, the direct transition from wakefulness to an REM sleep state. In extensive clinical and toxicology studies, ADX-N05 was demonstrated to be safe and well tolerated.

“We are delighted to enter into a partnership with an experienced company such as Addrenex, and we are confident that Addrenex will successfully develop and commercialize ADX-N05 for the treatment of narcolepsy and other potential indications in the CNS area,” said Byong-Sung Kwak, Ph.D., Senior Executive Vice President of SK Holdings.

Addrenex plans to begin phase 2 testing of ADX-N05 as a treatment for narcolepsy later this year. The company may also investigate ADX-N05 as adjunct therapy for depression. According to Khayrallah, the compound has numerous potential applications because it is thought to engage multiple neurotransmitters, including dopamine and noradrenalin, that play a role in a variety of disorders.

Under the terms of the contract, Addrenex will pay licensing fees and royalties to SK Holdings Co. Ltd., as well as milestone payments for achieving specific clinical endpoints and sales performance goals.

About Addrenex

Addrenex specializes in the development of drugs, diagnostic tools and intervention methods aimed at normalizing adrenergic function and, thereby, helping patients regain control of symptoms related to adrenergic dysregulation. Adrenergic dysregulation is the root cause or major contributing factor for multiple medical conditions. Currently, Addrenex has three products in clinical trials and a library of over 400 compounds available for future development.

About SK Holdings (Released by SK Holdings)

SK Life Science Business, a division of SK Holdings, is actively engaged in the innovative discovery and testing of novel therapeutic compounds in the field of neuroscience to treat epilepsy, depression, anxiety, schizophrenia, neuropathic pain and neurodegenerative disorders. The company has eight new drug candidates in clinical or preclinical development, including their lead compound, Carisbamate, being developed by Johnson & Johnson Pharmaceutical Research & Development, and ADX-N05, which is ready to enter phase 2 trials. In addition to drug development, SK Life Science Business focuses on the custom manufacturing of pharmaceutical intermediates and API with unique and cost-effective technologies, including continuous reactions and low-temperature reactions.

Source: Addrenex Pharmaceuticals, Inc

The work, which will be published online May 3 in Nature Genetics, could lead to better treatments for the sleep disorder and help immunologists understand other, more common autoimmune diseases, such as multiple sclerosis and juvenile diabetes.

“We’re now getting the main pieces of what’s happening in narcolepsy,” said Mignot, a Howard Hughes Medical Institute investigator who has been studying the disease for more than two decades. “What’s most satisfying to me is that we’re bringing this story to a close and that we can use narcolepsy as a model for other diseases.”

Narcolepsy affects about one in 2,000 people and is characterized by daytime drowsiness, irregular sleep at night and cataplexy-a sudden loss of muscle tone and strength. Mignot and others showed in the late 1990s that the disease stems from a lack of hypocretin, a hormone that promotes wakefulness; they later showed that narcoleptics are missing brain cells that produce this hormone.

Mignot and others believe that the body’s immune system plays a role in killing hypocretin-making cells, primarily because of scientific literature showing a link between narcolepsy and a variant for the human leukocyte antigen, or HLA, gene. The immune system uses HLAs to differentiate between “self” cells and foreign cells (and attacks those presented as foreign), and most autoimmune diseases are associated with variants of HLA. In recent studies, more than 90 percent of narcolepsy patients were shown to carry one such variant.

“For a long time, people have suspected narcolepsy had something to do with the immune system-that it was killing cells that produce hypocretin,” said Mignot, a professor of psychiatry and behavioral sciences and director of Stanford’s Center for Narcolepsy. “But there hasn’t been direct proof.”

During this study, the researchers ran whole-genome scans-which allow for the analysis of hundreds of thousands of genetic variations-of 1,800 people carrying the same HLA gene variant. Of the group, 800 had narcolepsy, and the goal was to find what differentiated these people from control subjects. The team found that a specific variation of a gene belonging to T cells-specialized immune cells that play a role in all immune responses-was present in narcolepsy.

Because T cells are involved, Mignot believes the mechanism behind narcolepsy stems from the immune system. “Our discovery clearly shows narcolepsy is an autoimmune disease,” he said.

“This is a very important finding,” said Merrill Mitler, PhD, a sleep disorders expert and program director at the National Institute of Neurological Disorders and Stroke, who was not involved in the study. “It puts in place another piece of the puzzle and shows a way to link [this gene variant] to hypocretin-containing neurons via an autoimmune attack.”

Mignot said it’s likely that HLA and this T cell variant interact in a way that kills hypocretin cells. How exactly this interaction is triggered is not yet known, and he said future studies will focus on solving this mystery. Once more details emerge, he said, scientists may be able to identify people who are predisposed to narcolepsy and block specific gene variants in that person to stop the development of the disease.

In the meantime, Mignot expects the findings to aid researchers studying other autoimmune diseases. No other autoimmune disease has shown an association with this specific T cell gene, he noted.

“I’m sure immunologists are going to be very excited,” said Mignot of the findings. “If we can work out what happens specifically in patients with narcolepsy, we’ll be able to better understand the role of T cells in other autoimmune diseases that are more complicated and difficult to detect.”

The work was primarily funded by NINDS. The co-first authors are Juliette Faraco, PhD, and Joachim Hallmayer, MD; other Stanford co-authors are Ling Lin, MD, PhD; Minae Kawashima, PhD, and Mali Einen.

The Stanford University School of Medicine consistently ranks among the nation’s top 10 medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children’s Hospital. For information about all three, please visit here.

Source: Stanford University School of Medicine

Modafinil, a wake-promoting drug used in the treatment of sleep disorders, may enhance cognition and is used off-label for the treatment of cognitive dysfunction in some psychiatric disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder [ADHD]). The Physicians’ Desk Reference cautions that it can produce psychoactive and euphoric effects typical of central nervous system stimulant drugs, and there is debate surrounding its potential for abuse, according to background information in the article.

The mechanisms of action of modafinil are not well understood but are believed to differ from those of stimulant medications (such as methylphenidate and amphetamine), which increase dopamine (a neurotransmitter in the brain essential for the normal functioning of the central nervous system) in the brain by targeting the dopamine transporters, a mechanism that underlies the abuse potential of these drugs. However, there is growing evidence that dopamine may also play a role in the mode of action of modafinil.

Nora D. Volkow, M.D., of the National Institute on Alcohol Abuse and Alcoholism, Bethesda, Md., and colleagues at Brookhaven National Laboratory conducted a study to test whether modafinil, at therapeutic doses, would elevate extracellular (located or occurring outside of cells) dopamine in the brain by blocking the dopamine transporter. The study included 10 healthy men, between the ages of 23-46 years, who received either placebo or modafinil: 200 mg, the dose recommended for narcolepsy; or 400 mg, a dose shown to be beneficial for the treatment of ADHD. The effects of modafinil on extracellular dopamine and on dopamine transporters were measured by positron emission tomography (a radiographic technique used to examine biochemical activity in tissue).

The researchers found: “In this pilot study, modafinil acutely increased dopamine levels and blocked dopamine transporters in the human brain. Because drugs that increase dopamine have the potential for abuse, and considering the increasing use of modafinil for multiple purposes, these results suggest that risk for addiction in vulnerable persons merits heightened awareness.”

Modafinil also increased dopamine in the nucleus accumbens, a brain region critical for the rewarding effects of drugs of abuse.

“Modafinil was developed with an expectation that a medication could have a non-dopaminergic target for its wake-promoting effects. However, the current findings in humans, along with preclinical studies, documenting the indispensable role of dopamine in the wake-promoting effects of modafinil, support modafinil’s dopamine-enhancing effects as a mechanism for its therapeutic actions.”

Source: JAMA and Archives Journals.