Although there are a number of causes linked to obesity, the one  common thread among obese individuals is a disruption in the chemical balance which regulates appetite and satiety, otherwise known as the feeling of being full or satisfied.  The primary chemicals involved in the regulation of food intake and control of appetite are the neurotransmitters dopamine, norepinephrine, epinephrine, serotonin, acetylcholine, glutamate, D‑serine, and histamine.

Traditional approaches to appetite control have for the most part been unsuccessful in changing eating behavior. Many of the proposed treatments, particularly pharmaceutical agents, have significant side effects including death and serious heart valve disease. Most recently the FDA has reconsidered issuing approval for the weight loss drug Qnexa, which is a combination of the appetite suppressant phentermine and the anti-seizure drug topiramate. The side effects associated with this drug are extreme, and include memory loss, elevated heart rates, a higher rate of oral clefts in infants of women taking the drug during pregnancy, and possible cardiovascular problems.

Nervous System and Appetite Control

Food consumption is controlled by the nervous systems through complex feedback systems that respond to signals generated by physical and metabolic stimuli. These feedback systems evolved as a mechanism to ensure that energy stores were readily available during times where they would be needed most by the human body. Maintenance of a stable body weight is highly dependent on a persons “energy economy”, and the ability of a person to keep a balance of energy intake to energy expenditure.

The loss of appetite control in many obese patients reflects a disruption in the neuroendocrine networks that facilitate communication between the brain, adipocytes, and the gastrointestinal tract regarding the state of current energy reserves. Within the hypothalamus, information is communicated through chemical messengers called neurotransmitters regarding the size of energy reserves (body fat) available and is synchronized with information from the gastrointestinal tract about the volume and composition of food ingested. Gut to brain communication determines the amount of energy available and thus the adjustment in the amount needed to maintain sufficient energy reserves. Energy intake is then adjusted through the generation of appetite or satiety cues sent out through the nervous system via neurotransmitters. The hypothalamus establishes a threshold at which food intake must be initiated or terminated to maintain energy balance. This threshold level or “set point” ensures that the amount of food consumed will be sufficient to meet both current and future energy needs.

Amino Acid Deficiency and Obesity

It has been well established in numerous studies that obese patients experience deficiencies in specific amino acids. These key nutrients are the building blocks of life and are responsible for converting into the neurotransmitters needed for the effecient and reliable nervous system communication that regulates food intake. Regulation of appetite and satiety depends on a carefully orchestrated balance between the neurotransmitter-mediated feedback mechanisms that control the desire to eat, thus inappropriate eating behavior can arise from specific nutritional deficiencies that cannot be met by altering diet alone. For many obese individuals, the ability to regulate food intake has been compromised by impaired metabolic processes that increase amino acid turnover rates and deplete stores of neurotransmitters needed to help the brain and stomach distinguish the desire to eat from the need to eat.

Qnexa, Xenical, Alli and most of the appetite control aids available were developed using the current understanding of the way in which chemical processes function to regulate eating behavior. The synthetic nature of these drugs often create more problems than they solve and can often only be tolerated for short periods of time.  The safest and most effective approaches to controlling appetite and satiety, would be those that utilize nutrients which support the synthesis and activities of the specific chemicals involved in these processes rather than those which choose to manipulate chemicals that are either in short supply or nonexistent in an obese patient. The medication class of  medical foods have been developed to address neurotransmitter deficiencies in a number of disease states. For obese patients, these products can restore the balance of neurotransmitters and other ingredients essential to maintaining the central and peripheral feedback mechanisms that regulate appetite and satiety.

As precursors of serotonin and acetylcholine, tryptophan and choline are especially important to these patients as is glutamate which functions not only as a neurotransmitter but also as a precursor of GABA.  The concept that nutrient requirements are modified by disease has been recognized for more than 30 years, and is supported by studies which have shown changes in plasma, urinary, and tissue levels of nutrients associated with abnormalities in physiological endpoints reflective of specific pathologies (Lipincott Williams & Wilkin, 2006). These requirements can be estimated by determining the level of intake at which a physiological response is improved indicating that the balance between intake and metabolic demand has been favorably modified. The nature of the pathological characteristics of a disease will determine the relative amounts of nutrients needed to restore balance between intake and demand (Anderson GH, Johnston JL. Can J Physiol Pharmacol 1983). The degree of coordination between the activities of different neurotransmitters is an important consideration in assessing the amounts of dietary precursor needed (Anderson IM, Mortimore C ,Adv Exp Med Biol 1999).

Diseases with pathologies that involve imbalances in neurotransmitters will increase the requirements for certain amino acids and other dietary precursors to restore homeostasis (Bazzichi L, Palego L, Giannaccini G et al; Clin Biochem 2009). For most of these amino acids and dietary precursors, uptake by target neurons is a concentration-driven process; therefore, intakes must be sufficient to increase the extracellular to intracellular concentrations to levels high enough to drive a rapid rate of uptake (Fernstrom JD; J Am Diet Assoc 1994;94). The rate of precursor uptake by target neurons is important to neurotransmitter synthesis because the enzymes involved are found only in these neurons and thus the amount of substrate available is the limiting factor in neurotransmitter production (Wurtman RJ, Hefti F, Melamed E; Pharmacol Rev 1980). As blood levels of dietary precursors rise in response to increased intakes, the concentration-driven rate of precursor uptake by target neurons is increased, making more substrate available for neurotransmitter production and subsequent release . Changes in intakes of dietary precursors of these neurotransmitters will therefore influence physiological responses by affecting neurotransmitter availability (Fernstrom JD, Fernstrom MH;Nutr Rev 2001)

A large body of peer-reviewed published data supports the basis for increased requirements of tryptophan, glutamate, and choline in conditions  which depend on neurotransmitter balance. Patients who show decreased blood levels of certain amino acids despite maintaining their usual protein intake may find that Rx only medical foods can help address the deficiency of  amino acids that are selectively increased as a result of specific physiological requirements associated with their disease (Hasselmo ME, Fehlau BP;J Neurophysiol 2001). Rx only medical foods can help patients suffering from sleep disorders address the competitive demands for certain amino acids. Increasing the availability of precursor molecules can imporve the supply of neurotransmitters available that regulate and maintain the various sleep cycles.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used by physicians to treat patients with a variety of inflammatory and non-inflammatory conditions. They are the most commonly prescribed drug class, with more than 100 million prescriptions written each year(1). Billions of dollars are spent each year on prescription NSAIDs despite their dangerous side effect profiles, and these only account for about 10% of all NSAID use, the remainder being over the counter.

NSAIDs are associated with significant drug related morbidity and mortality.  In the late 1990’s it was estimated 16,500 died and over 100,000 were hospitalized from NSAID induced GI bleeds(2).  This complication accounted for 1/3 of the total cost of arthritis care(3,4).  Patients over the age of 65, with concomitant medications and disease states are the most likely to suffer the adverse side effects associated with NSAID use(5). Alternative medications to NSAIDs to treat pain have problems as well.  Narcotic analgesics, although effective, have high addictive potential, are sedating, cause constipation, and urinary retention.  Tricyclic antidepressants, dual reuptake inhibitors, anti epileptics, and others commonly used to treat neuropathic pain and chronic musculoskeletal pain have a long list of harmful side effects, all of which often far outweigh their perceived benefit.

NSAIDs block prostaglandin synthesis, and should be classified more as an anti-prostaglandin agent rather than an anti-inflammatory agent. NSAIDs have actually been shown to increase inflammation within the body (6). The inhibitory effects of an NSAID are due to their ability to block prostaglandin production, thus blocking the production of long acting pain signaling chemicals. Inhibiting prostaglandin production has a very dire unintended consequence for many patients, and that is the rapid demise of the gastric mucosal defense system.

Prostaglandins modulate virtually every aspect of mucosal defense. It is widely understood that mucosal prostaglandin deficiency increases susceptibility to ulcer formation and that exogenous administration of supplemental prostaglandins reduces ulcer risk. Continued NSAID use endangers the lining of the stomach, and prevents the body from naturally repairing itself. Physicians and patients interested in pain management must be aware of these facts, so that they can make an informed decision as to what medications are appropriate for them to use and for what duration.  It is vital that patients understand the mechanisms by which the drugs they take affect their body in order to achieve effective and safe healthcare.

1. http://www.medscape.com/viewarticle/538039
2. Wolff M, Lichtenstein D, Singh G.  Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs.  N Engl J Med. 1999; 340(24):1888-99.
3. Johnson R, Hornbrook M, Hooker R, et al.  Analysis of the costs of NSAID-associated gastropathy.  Experience in a US health maintenance organization.  Pharmacoeconomics.  1997; 12(1):76-88.
4. Sheen C, MacDonald T.  Gastrointestinal side effects of NSAIDs-pharmacoeconomic implications.  Expert Opin Pharmacotherapy.  2002; 3(3):265-9.
5. Burmester G, Lanas A, Biasucci L, et al.  The appropriate use of non-steroidal anti-inflammatory drugs in rheumatic disease:  opinions of a multidisciplinary European expert panel.  Ann Rheum Dis.  2011; 70(5):818-22.
6. http://journals.lww.com/americantherapeutics/Abstract/publishahead/A_Double_Blind_Controlled_Trial_of_a_Single_Dose.99686.aspx

]]> http://medicalfoods.com/articles/archives/86/feed 0 http://medicalfoods.com/articles/archives/77 http://medicalfoods.com/articles/archives/77#comments Fri, 11 Nov 2011 23:32:32 +0000 Staff http://medicalfoods.com/articles/?p=77 Read more →]]> Gulf War illness is a multi symptom chronic illness, featuring a multitude of  symptoms that include but are not limited to fatigue, recurring neuropathic pain, memory dysfunction, cognitive disorders, balance disturbances, and depression. Gulf War illness afflicts an estimated 175,000 military personnel who were deployed to the 1991 Persian Gulf War (1). There have been a number of studies associating Gulf War illness with exposure to specific neurotoxic chemicals ( 2–4 ), including organophosphate pesticides, pyridostigmine bromide, and low-level sarin nerve gas, all of which are cholinergic stimulants that inhibit cholinesterase, the enzyme responsible for synthesizing acetylcholine, and can cause persistent brain changes ( 1,4 ). Recently Gulf War illness has been categorized into three primary variants: syndrome 1 (impaired cognition), syndrome 2 (confusion- ataxia), and syndrome 3 (central neuropathic pain) (2,3).

The neurotransmitter of most interest in Gulf War illness is acetylcholine (Ach). In the autonomic nervous system Ach plays a pivotal role in skeletal muscle movement, as well as in the regulation of smooth muscle and cardiac muscle. Ach is the most prevalent neurotransmitter in the human body and is instrumental in maintaining normal circadian sleep/wake cycles as well as modulating the sympathetic response to stress. In the central nervous system acetylcholine plays a pivotal role in learning, memory, and mood. Ach is synthesized from choline, an amino acid found in many foods and certain medical food products. Toxic chemicals that affect the structure of the CNS and functioning of the ANS will impair the synthesis of Ach in the human body hindering many of the restorative processes associated with the autonomic nervous system.

The structural changes of vital components of the central nervous system (CNS) as a result of exposure to these chemicals can lead to sustained physiologic problems and continued autonomic nervous system (ANS) dysfunction yielding more complicated and costly health issues many years after exposure. For example, in 2010 the U.S. Department of Veterans Affairs (VA) officially recognized the direct correlation of increased rate of early onset Parkinsons Disease (PD) among Vietnam veterans and exposure to Agent Orange during the Vietnam War (5). The general mismanagement of exposure to toxic chemicals among the Veteran population has dramatically increased the cost of healthcare to the VA.

Active military personnel are not the only people at risk for exposure to brain altering toxic chemicals. Victims of the 1995 Tokyo subway sarin attack showed reduced hippocampal volume and reduced volumes of insular cortex and surrounding white matter (6) similar to those veterans of the 1991 gulf war (7). The heroic first responders to the 9/11 bombings of the World Trade Center were exposed to clouds of toxic dust that ultimately affected ANS function yielding numerous health issues years later. According to the Mount Sinai study, 48 percent of rescue workers with asthma, 38 percent with sinusitis, and 43 percent with GERD were also diagnosed with at least one mental health condition (8). The early recognition of autonomic dysfunction associated with toxic exposure can help veterans and civilians manage future health problems and avoid the emotional and financial costs of managing chronic disease.

1. August 2, 2010. Binns JH , Barlow C , Bloom FE , et al (Research Advisory Committee on Gulf War Veterans’ Illnesses). Gulf War Illness and the Health of Gulf War Veterans. Washington, DC: Department of Veterans Affairs. http://www1.va.gov/rac-gwvi/ . Published 2008 .

2.  Haley RW , Kurt TL , Hom J . Is there a Gulf War Syndrome? searching for syndromes by factor analysis of symptoms . JAMA 1997 ; 277 ( 3 ): 215 – 222 .

3. Haley RW , Luk GD , Petty F . Use of structural equation modeling to test the construct validity of a case defi nition of Gulf War syndrome: invariance over developmental and validation samples, service branches and publicity . Psychiatry Res 2001 ; 102 ( 2 ): 175 – 200 .

4. Golomb BA . Acetylcholinesterase inhibitors and Gulf War illnesses . Proc Natl Acad Sci U S A 2008 ; 105 ( 11 ): 4295 – 4300 .

5. http://www.federalregister.gov/articles/2010/08/31/2010-21556/diseases-associated-with-exposure-to-certain-herbicide-agents-hairy-cell-leukemia-and-other-chronic

6. Yamasue H , Abe O , Kasai K , et al . Human brain structural change related to acute single exposure to sarin . Ann Neurol 2007 ; 61 ( 1 ): 37 – 46 .

7. Chao LL , Rothlind JC , Cardenas VA , Meyerhoff DJ , Weiner MW . Effects of lowlevel exposure to sarin and cyclosarin during the 1991 Gulf War on brain function and brain structure in U.S. veterans . Neurotoxicology 2010 ; 31 ( 5 ): 493 – 501 .

8. http://www.mssm.edu/departments-and-institutes/preventive-medicine/about-us/news/first-long-term-study-of-world-trade-center-rescue-and-recovery-workers-shows-widespread-health-problems-ten-years-after-9-11

The Introduction of the medical food Theramine into the therapeutic class of pain management provides physicians with a new tool for the short and long term management of pain without risk of adverse side effects. Unlike NSAIDs, COX-2 inhibitors, and addictive narcotics, Theramine addresses the neurotransmitter deficiencies associated with pain syndromes and provides the critical signaling chemicals necessary to improve pain perception and reduce inflammation. Theramine has been subject to two randomized double blind clinical trials, and has shown statistically relevant improvements in pain. (http://www.ptlcentral.com/Clinical-Trials.php)

In 2005 the FDA issued warnings against the long term use of NSAIDs. According to FDA, ”long-term controlled clinical trials have not been conducted with most NSAIDs.” “However,” the agency says, “the available data suggest that use of these drugs may increase CV risk.” According to the FDA Medication Guide, NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. These chances increase with longer use of NSAID medicines, in people who have heart disease. Additionally FDA declares that NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).” NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding can happen without warning symptoms and may cause death. The chance of a person getting an ulcer or bleeding increases when that person is prescribed an NSAID for a long period of time, is taking medicines called “corticosteroids” and “anticoagulants”, is a smoker, drinks alchohol, is over the age of 65, or in general poor health. According to FDA, NSAID medicines should only be used exactly as prescribed, at the lowest dose possible for your treatment, and for the shortest time needed.

 The injured worker is very much at the mercy of their employer’s plan and their doctor. Work related injuries often incorporate extensive pain management. Workers compensation patients are frequently prescribed pain medication for extended periods of time to manage their injury and assist with their recovery. Physicians are very much aware of the side effects associated with NSAIDs and Narcotics, but often have no other choice than to provide them to patients for long periods of time  as well as at doses well above the FDA recommendations.

Primum non nocere or “ first do no harm” is part of the Hippocratic oath taken by physicians, and is considered to be one of the guiding principles of medicine. The addition of Theramine to the compendium of care for workers compensation patients provides physicinas with a more flexible dosing schedule of more dangerous pain medicines or their outright replacement.  The recent proliferation of Theramine in workers compensation cases can be attributed to the efficacy and safety profile of the product, as well as a physicians desire to provide a safe and efficaceuos medicine that is in allignment with the Hippocratic oath.

At the start of the trial, there were no statistically significant differences in low back pain when assessed by these widely accepted scales nor were there any differences in the blood markers of inflammation. At the day 28 measurement, both the medical food group and combined therapy group (medical food with naproxen) had significant reduction in lower back pain as compared to the naproxen-alone group. The medical food and naproxen group also showed improvement of not only pain perception but functionality too when compared to the naproxen-alone group.

The naproxen-alone group showed significant elevations in CRP, alanine transaminase, and aspartate transaminase when compared with the other groups, which indicates that the NSAID actually increased overall inflammation in the body. The medical food alone or when administered with naproxen showed no significant change in liver function tests or CRP. This data implies that the medical food potentially mitigates the pro-inflammatory effects of naproxen alone. The medical food (Theramine) appeared to be effective in relieving back pain without causing any significant side effects and may provide a safe alternative to presently available therapies. This trial was published in the American Journal of Therapeutics, November 2010. This trial was also repeated a year later using the same methodology except the company used once daily 250 mg ibuprofen in the place of naproxen and the company also measured interleukin 6 as well. The results of this second trial have not been published yet, but yielded near identical results to the initial trial. To read the Theramine and Naproxen trial in detail visit www.ptlcentral.com.

Cortisol is one of the few hormones essential for life. It is responsible for a number of actions within the body and its’ release is predominantly influenced by circadian and ultradian rhythms. Dopamine is a key neurotransmitter responsible for mood, concentration, craving mechanisms, and many mental and physicial functions that is produced from tyrosine hydroxylase. A dysregulation of cortisol activity and noradreniline can ultimately lead to autonomic nervous systme dysfunction.

The actions of cortisol can be considered a mechanism to mobilize energy sources (amino acids, fatty acids, glycerol) from tissues to provide energy, specifically glucose, for the brain, heart and other vital organs. When the delicate balance of hormone production and dopamine synthesis is disrupted by the chronic stress of reccurrent stimuli the body will reroute vital neurotransmitters and consume amino acids at a greater pace to compensate for the perceived threat by mobilizing energy sources. Over time, this condition witll leave the autonomic and central nervous systems depleted of essential neurotransmitters required to sustain normal physiologic function and ultimately feed the further degradation of an unbalanced system.

The administration of specific amino acid based medical foods such as Sentra AM and Sentra PM can aid the body’s recovery by providing the precursor molecules that restore essential neurotransmitters such as actetycholine, serotonin, and dopamine. Restoring balance back to a dysfunctional autonomic nervous system by reestablishing normal parasymathetic activity is an essential component for solving the PTSD puzzle.

Sandy Bigelow, Ph.D., principal at Vanguard Global Associates, said, “Medical foods are supposed to be developed for the dietary management of a disease; they need to provide nutritional sustenance, necessary macro and micronutrients, and vitamins and minerals.”

Esra Ogru, Ph.D., chief operating officer, and Jeremy Cottrell, Ph.D., research scientist, Phosphagenics, said: “Medical foods differ from normal foods in that they have substantiated health-promoting or disease-preventing benefits beyond the basic delivery of nutrients. And, they differ from nutritional supplements in that they are not designed for use by healthy people, but rather as a therapy for a particular medical condition under the guidance of a medical practitioner.”

Marshall Fong, vice president of marketing at Ganeden Biotech, added, “These products [medical foods] must be specially formulated and processed instead of being a naturally occurring food.”

Original medical foods formulas were engineered for those with genetic diseases that could not handle certain nutrients. For example, patients with phenylketonuria (PKU) cannot metabolize the amino acid phenylalanine. “In the 1950s, formulas were developed for those who couldn’t metabolize more than 100 to 150 mg/d of phenylalanine,” Bigelow said. “PKU warnings on soda cans and other products are often necessary due to phenylalanine’s use in aspartame. Where history collides: one of the first formulas produced as a medical food was in the 1950s by Mead Johnson Nutrition so people with PKU could eat and sustain their lives. In the beginning, FDA regulated them as drugs because they were for diseases, but later switched them as regulated food products.” However, Bigelow noted FDA found it untenable to regulate these products as drugs because, as such, they would have to assure the active ingredients were produced in the product at a particular level, which is difficult to do for nutrition formulas; so, in turn, FDA created a new category (in the regulatory sense) and regulated them as foods. And, in 1988 Congress defined what a medical food was in the Orphan Drug Act.

Sheila M. Campbell, Ph.D., R.D., in her paper, “History of Tube Feeding”, (Nutrition in Clinical Practice 2006;21:411-15), said, “The first commercially available [enteral] formulas were elemental. They came on the market in the late 1960s. The formulas were tested by U.S. National Aeronautics and Space Administration (NASA) in an attempt to develop a residue-free formula for use by astronauts.” An elemental formula’s macronutrients are in simple forms, so little or no digestion is needed before absorption. NASA was looking for ways to eliminate the issue of disposing of human waste in outer space, but the formulas were not used due to their poor taste profile.

“As medical foods are used the treat a specific medical condition, they are administered with oversight from a health care professional,” Ogru and Cottrell said. “This could be intensively as part of hospitalized treatment, even via a nasogastric tube, but typically, medical foods will be consumed orally.”

Ensure was introduced in 1973 by a division of Abbott Nutrition, Ross Products. It was, “the first intact-nutrient, lactose-free, ready-to-use adult medical nutrition product in the United States. It was an ‘all-purpose’ product, designed for tube feeding and oral supplementation,” Campbell noted in her 2006 paper. Glucerna® was the first enteral formula to be patented and was developed in 1989 by Ross Products for patients with diabetes, and Pedialyte® was one of the first retail medical foods for children. read more (external site)  »