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FMS (fibromyalgia syndrome, FMS) is a widespread musculoskeletal pain, fatigue cognitive dysfunction, sleep alteration disorder for which the causes are uncertain, but is increasingly understood as a brain disorder. More women than men are afflicted with FMS, and it affects people of all ages. Fibromyalgia Syndrome and chronic fatigue syndrome (CFS) are closely related. Gulf War Syndrome is a variant of FMS/CFS. The symptoms of FMS include:
POSSIBLE CAUSES FMS is characterized by autonomic nervous system dysfunction with organic alteration of the brain. The exact initiating cause of FMS remains elusive, but there are many triggering events thought to precipitate its onset. Examples include industrial trauma, automobile accident, exposure to environmental neurotoxins, or overwhelming stress. These triggering events initiate the brain alteration and the resulting loss of brain neurons. The destruction of brain neurons can be documented by new imaging methods including functional and spectral MRI. COMMON TREATMENTS Traditional treatments aim to improve sleep quality and reduce pain. Deep (stage 4) sleep is crucial for many body functions (such as tissue repair, antibody production, and the regulation of various neurotransmitters, hormones and immune system chemicals). The sleep disorder in FMS should be treated because it is a strong contributing factor to the symptoms of this condition. Medications that boost the body's level of serotonin and norepinephrine (neurotransmitters that modulate sleep, pain, and immune system function) are used. Observations in clinical practice have estimated that conventional treatments have resulted in a positive response rate of less than 5%. Clinicians have reported a 75% positive response rate using treatment with neurotransmitter precursors. Using functional MRI scans to record brain activity, calibrated pressure stimuli sufficient to produce slightly intense pain were applied to the left thumb of 30 fibromyalgia patients. Researchers were unable to find significant association between the level of depressive symptomatology and the intensity of activity in areas of the brain previously shown to be involved in pain processing. Researchers did find a link between the severity of depressive symptoms and brain activity in two areas of the brain not believed to be involved in pain intensity coding. Researchers compared brain activity patterns in seven fibromyalgia patients with concurrent major depression to a subgroup of seven fibromyalgia patients without depression and to seven control patients. The study did not reveal any difference in the degree of pressure pain sensitivity and patterns of pain-elicited brain activity between fibromyalgia patients with depression and fibromyalgia patients without depression. FMS and depression are independent syndromes requiring specifically directed therapy. Neurotoxicity Syndrome The clinical syndrome of central neurotoxicity consists of headaches, dizziness, sleep disorders, chronic fatigue, dysesthesias, temperature dysregulation, diarrhea, cognitive disorders and personality changes (1-28). The personality changes can include depression, anxiety, emotional lability, and anger. These symptoms have been considered non-specific and in some cases have been designated as neuropsychiatric rather than organic in origin. These signs and symptoms are the hallmark of a chronic autonomic nervous system disorder(29-38) . Several clinical syndromes are associated with these symptoms including Fibromyalgia(39-46) and Gulf War Syndrome(47;48). Neurotoxicity has been associated with the exposure to a number of environmental chemicals(49-55). These chemicals include heavy metals(56-79), nitrogen dioxide, methyl chloride, carbon tetrachloride, ethylene chloride, sarin gas(80-82), VX gas, phosgene, mustard gas, organopesticides, and airborne particulates (83). Exposure to these agents is associated with the symptoms of a neurotoxicity syndrome and anatomic evidence of neuropathy(83-85). In addition, severe afferent inputs to the autonomic centers of the brain can lead to cell destruction and neurotoxicity syndromes. The organic nature of these syndromes has been demonstrated objectively with heart rate variability, PET scanning, functional MRI and spectral MRI(86-107;107-186). Fibromyalgia Syndrome is characterized by widespread pain, alteration of sleep, chronic fatigue, stiffness, headache, irritable bowel syndrome and mood disorders(39;41;44;86;187-210). Fibromyalgia is associated with suppression of autonomic nervous system function measured by heart rate variability, PET scanning, and spectral MRI. The heart rate variability abnormality characteristic of fibromyalgia includes suppression of autonomic nervous system function as measured by reduced total power, suppression of parasympathetic function as measured by a reduced HF band and failure to activate parasympathetic activity during sleep. Depression is a co-morbid condition that occurs with fibromyalgia, but is associated with normal heart rate variability(211-216). Thus heart rate variability analysis combined with clinical criteria provides a definition of fibromyalgia(217-233). The case definition is specific because heart rate variability analysis is reproducible when measured day to day and is unaffected by placebo. An example of altered circadian activation in a patient with Fibromyalgia Syndrome:
The squares of the lower line are the patient with symptomatic Fibromyalgia Syndrome compared to the lower 2 SD limit of normal controls. The patient fails to activate parasympathetic function between midnight and 5 AM. Gulf War Syndrome is characterized by an irritable bowel syndrome, fatigue, sleep disorder, cognitive disorders, joint pain and headache(234-247). Gulf War Syndrome is associated with autonomic nervous system suppression, alteration of circadian autonomic nervous system function, abnormal PET scans, abnormal SPECT scans and abnormal spectral MRI(47). In 2004, the Veterans Administration recognized that the Gulf War Syndrome is related to a central neurotoxicity abnormality rather then a psychiatric illness(234). An example of failure to activate parasympathetic activity during sleeping hours, abnormalities of heart rate and abnormal QTc interval in the Haley, Shell, Charuvastra study of Gulf War Veterans with a Fibromyalgia Syndrome is depicted:
In panel A the hourly parasympathetic activity of the HF Band shows failure to activate parasympathetic function from midnight to 5 AM (solid circles lower band). In panel B the mean heart rate is depicted in symptomatic See-Bees compared to non-symptomatic control See-Bees indicating a higher mean heart rate at night in the patients with the Fibromyalgia Syndrome. In panel C, the mean QTc interval is depicted. The symptomatic subjects have increased QTc intervals almost every hour of the day reflecting sympathetic imbalance. The heart rate variability patterns of Gulf War Syndrome and Fibromyalgia Syndrome are identical. Both syndromes are related to altered autonomic nervous system function. Fibromyalgia and Gulf War Syndromes show many symptomatic and objective similarities. Patients with Gulf War Syndrome are frequently diagnosed with fibromyalgia. The syndromes may be indistinguishable and may reflect a common pathway of brain injury. There is increasing evidence that both are the result of injury to the central nervous system, particularly the autonomic nervous system. Treatment for either syndrome has had limited success in the past. Nutritional Deficiencies Associated with Fibromyalgia Syndrome Patients with sleep disorders demonstrate a nutritional deficiency of tryptophan, choline, and GABA. They have reduced blood levels of serotonin and 5-hydroxytryptophan. Obese patients use more tryptophan than lean patients and obese patients have an increased frequency of sleep disorders. Reduced calorie diets result in a further fall in blood tryptophan, and exacerbate sleep disorders. An increase in calories sufficient to achieve adequate tryptophan levels may increase weight gain, rendering correction of the tryptophan deficiency unlikely with normal diet. Choline deficiency is associated with sleep disorders particularly those associated with sleep apnea syndromes. Choline deficiency is also associated with liver disease and cognitive disorders. The Institute of Medicine recommends at least 500 mg of choline per day for adults. Although choline deficiency is associated with cognitive and memory abnormalities in humans, the amounts of choline required to maintain cognitive function must be individualized. A physician must assess the role of choline deficiency in cognitive disorders in individual patients. Pain disorders are frequently associated with a deficiency of nitric oxide, GABA, serotonin, and acetylcholine precursors. Pain is also associated with insensitivity to circulating GABA. Fibromyalgia Syndrome is associated with a reduced concentration of circulating tryptophan and 5-hyroxytryptophan. Intracellular concentrations of serotonin are directly related to blood concentrations of tryptophan and 5-hydroxytryptophan. There is a reduced spinal fluid concentration of serotonin reflecting the reduced circulating tryptophan and 5–hydroxytryptophan. Fibromyalgia Syndrome is associated with decreased blood levels of growth hormone and a four-fold increase in spinal fluid levels of Substance P, the pain mediating brain hormone. Both growth hormone and Substance P are related to the intracellular levels of serotonin. When brain serotonin is decreased, growth hormone levels fall. As serotonin levels fall, substance P increases rendering patients more sensitive to pain stimuli. Restoration of serotonin production in patients with Fibromyalgia Syndrome is essential to initiate restorative sleep and restore autonomic function. Serotonin production can only be repaired with nutritional management of tryptophan and 5-hydroxytryptophan since the body cannot synthesize these precursor amino acids. Management of Fibromyalgia Syndrome Sentra PM ™ is begun as one capsule at night and increased to two at bedtime as necessary. Sentra AM is given as two capsules each morning. Theramine™ is given every four to six hours as needed. The Sentra PM ™, Sentra AM, and Theramine regimen can be used with or without conventional pharmaceutical therapy. The doses of pharmaceuticals should be reduced and titrated to need. Non-pharmaceutical therapies can be used concurrently (Mayo ref) to manage the Fibromyalgia Syndrome.
Medical Food Classification Sentra PM ™ is a Medical Food formulated by practicing physicians to meet the nutritional requirements for inducing sleep, promoting restorative sleep, and reducing snoring. Sentra PM ™ provides the amino acids that are precursors to the neurotransmitters that have been depleted in humans, neurotransmitters that induce sleep, promote restorative sleep, and reduce snoring. Under the regulations of the Food and Drug Administration, Medical Foods may only be used when a patient is under the ongoing care of a physician or other licensed healthcare practitioner. Medical Foods are used for the dietary management of disease states with known nutritional deficiencies. Medical Foods must contain ingredients from the human diet. Medical Foods cannot be sold directly to patients or used without medical supervision. Distinctive Nutritional Requirements Indications for Use
Neurotransmitter Production from Nutrients in the Human Body
Targeted Cellular Technology This unique five-component process allows milligram quantities of neurotransmitter precursors to enter the cells and produce the required neurotransmitters. This process includes a neurotransmitter precursor, an uptake stimulator, a neuron activator, an adenosine brake inhibitor, and attenuation releaser. Previous attempts to use neurotransmitter precursors have required much larger quantities of the precursors to elicit a therapeutic effect making it functionally impossible for a patient to ingest gram quantities of a precursor agent on a daily basis. The use of the Targeted Cellular Technology™ process also prevents the development of tolerance. Unlike pharmaceutical agents that lose their effectiveness in a relatively short period, Sentra PM ™ maintains its effectiveness and does not attenuate. Sentra PM™ Ingredients: Targeted Cellular Technology and Sentra PM™ Sentra PM ™ is designed to produce the neurotransmitters serotonin and acetylcholine Serotonin is the neurotransmitter that initiates sleep. Acetylcholine is the neurotransmitter that maintains Delta IV-V deep sleep and facilitates REM sleep. Sentra PM ™ is designed to provide serotonin and acetylcholine precursors to enhance the production of the serotonin and acetylcholine neurotransmitters. Background: Sentra PM ™ contains a formula blend of selected GRAS (generally regarded as safe) ingredients that come from the normal human food chain. The primary ingredients are key amino acids, the building blocks of proteins. The Sentra PM ™ formula is designed to induce increased neurotransmitter function in patients with sleep disorders. The Sentra PM ™ formula is designed to increase the function of the neurotransmitters serotonin and acetylcholine. The Sentra PM ™ formula is based on a five-component patent pending process. The patent pending process provides for a five-component system to allow for the conversion of a neurotransmitter precursor into a neurotransmitter. The five component system includes: (1) each neurotransmitter is synthesized from an amino acid precursor, (2) stimulation of the uptake of the neurotransmitter precursor is required to initiate the conversion of a precursor to a neurotransmitter, (3) since most neurons are inhibited from firing, an adenosine antagonist such as and cocoa powder is added to disinhibit the neuron, (4) stimulation of neurons to release a specific neurotransmitter is required, and (5) a system must be used to prevent attenuation of the precursor response, a well known precursor phenomena. Sentra PM ™ has been formulated to encompass this five-component system. The Sentra PM ™ formula targets the neurotransmitters acetylcholine and serotonin. Sentra PM™and Clinical Testing Physiologic testing of autonomic nervous system function has been performed on individuals taking Sentra PM ™ Patients without sleep disorders display normal parasympathetic activation during sleep as measured by Heart Rate Variability. Normal parasympathetic action results in restorative sleep. Patients with sleep disorders display reduced parasympathetic activity. There have been two open label trials of Sentra PM ™ to induce and maintain sleep, there has been one open label trial of Sentra PM ™ to reduce the frequency of snoring, and there have been eight open label trials of Sentra PM™ Dosage One or two capsules of Sentra PM ™ should be taken daily at bedtime. An additional dose of Sentra PM ™ can be used if the patient awakens during the night and cannot fall back to sleep. As with all Medical Food products, the best dosing protocol is established by the healthcare practitioner in coordination with the requirements of each individual. Sentra PM™ and Prescription Drugs In patients taking pharmaceutical agents to induce and maintain sleep, it is suggested that the medication dosage should be reduced gradually. Sentra PM ™ may be taken with the pharmaceutical sleep agent at bedtime. If restorative sleep is obtained with the combination, the drug may be slowly tapered off under medical supervision. Side Effects The side effect profile of Sentra PM ™ is comparable to the rate of food intolerance in the community. The ingredients of Sentra PM ™ are derived from nutrient based compounds found in the normal food chain. Food intolerance is an adverse reaction to food that does not involve the body's immune system. When starting any amino acid therapy, some people complain of mild headaches, stomach upset, or mouth dryness. These symptoms are mild and temporary and can be managed by consuming fluids and carefully the dose. A rare individual may feel jittery or over-stimulated and this effect is relieved by lowering the dose. Sentra PM ™ is designed to produce acetylcholine and serotonin, two of the neurotransmitters that are involved in sleep disorders(248-309) (298;310-351) (352-364). If the timing and secretion of these three neurotransmitters are altered, normal sleep cycles and restorative sleep do not occur. For example the benzodiazepine drugs, including Ambien, reduce sleep latency, but abolish phase IV- V sleep and REM sleep. Sentra PM ™ is designed to produce neurotransmitters related to physiologic functions including initiation of sleep, maintenance of sleep, and re-induction of sleep upon awakening during the night. In the Sentra PM ™ formulation, choline is used as a precursor to acetylcholine and 5-hydroxyl tryptophan is used to induce the physiologic production of serotonin(365);. Thus, the Sentra PM ™ formula contains the neurotransmitter precursor In the Sentra PM ™ formula, ginkgo biloba is used as an uptake stimulator(366-371). Glutamic acid is used to produce glutamate, a neuronal stimulator(372-403). Cocoa is used to disinhibit the adenosine break(404-414) (415-418). Grape seed extract, containing polyphenols(419-422), is used to avoid the attenuation usually associated with neurotransmitter precursor administration. Release of serotonin initiates sleep and reduces latency (257;260;267;274;285;293;322;325;329;423-458) (298;302;341;459-477). The timing of serotonin release is critical to initiation of sleep. The amount of serotonin released is critical to initiation of sleep. At the initiation of sleep, a small amount of serotonin is released. The amount of serotonin peaks within several hours after sleep initiation. The failure to produce serotonin, the production of insufficient serotonin, or the production of excessive amounts of serotonin will result in the failure to initiate sleep. Serotonin is intimately involved in sleep apnea, snoring, REM sleep, and depression associated with sleep disorders(267;331;433;478-524) (480;480;521;521;525-533;533;534;534;535;535-538;538-542;542-547;547-566) (567-586). An alteration of the tryptophan/serotonin axis will result in altered sleep patterns. Appropriate and timely of serotonin will ameliorate sleep disorders. Production of acetylcholine after initiation of sleep results in production of restorative Delta IV-V sleep(298;325;335;341;350;587-629). Following the burst of serotonin that initiates sleep, acetylcholine release increases the duration of phase IV and V restorative sleep. In addition, the release of acetylcholine increases the frequency of REM episodes and the duration of these episodes. The commonly used hypnotics including Ambien abolish phase IV and V sleep and inhibit REM sleep.
Accordingly, the Sentra PM ™ formula contains precise proprietary amounts of The Sentra PM ™ formula is designed to provide precursors for known neurotransmitters that sleep. The amino acid precursors are 5-hydroxytryptophan and choline. In addition, Sentra PM ™ depends on activation of amino acid utilization by glutamate, and the theobromine in cocoa. Several open label trials have been performed using the combination of 5-hydroxytryptophan, choline, and cocoa. These trials have shown induction of sleep, maintenance of sleep, reduced snoring and restorative sleep. Nutritional Deficiency Associated with Sleep Disorders Patients with sleep disorders experience a nutritional deficiency of tryptophan, choline, and sometimes GABA. Patients with sleep disorders have reduced blood levels of serotonin(305;630-659) and 5-hydroxytryptophan. Moreover, obese patients use more tryptophan than normal patients. Finally, reduced calorie diets that are frequently reduced protein diets, result in a further fall in blood tryptophan, and exacerbate sleep disorders. Thus, patients with sleep disorders experience a deficiency of tryptophan. (660-686). There is an alteration of tryptophan metabolism in patients with sleep disorders(687;688;688-694;694-703;703-705;705;706;706-710;710-725;725;726;726-732;732-775) (776;777;777-783;783-788;788-795;795-803;803-807;807-835). Choline deficiency is associated with sleep disorders(335;338;341;448;464;592;836-853) (854-857), particularly those associated with sleep apnea syndromes(278;278;858;858-863;863-875;875-878;878-890;890-893;893;894;894-896;896-931).
Medical Food Classification Sentra AM™ is a Medical Food formulated by practicing physicians to meet the nutritional requirements of patients who need to improve cognitive function and memory, achieve mental arousal, and maintain mental alertness. Sentra AM™ provides the nutrients to support acetylcholine production by neurons. Acetylcholine is the important neurotransmitter supporting cognitive function, mental arousal, and memory. Under the regulations of the Food and Drug Administration, Medical Foods can only be used when a patient is under the ongoing care of a physician or other healthcare provider. Medical Foods are used for the management of disease states with known nutritional deficiencies. Medical Foods must contain ingredients found in the human diet and cannot be sold directly to patients without the supervision of a healthcare professional. Distinctive Nutritional Deficiencies Associated with Cognitive Disorders Choline deficiency is associated with liver disease and cognitive disorders. The Institute of Medicine recommends at least 500 mg of choline per day for adults. Although choline deficiency is associated with cognitive and memory abnormalities in humans, the amounts of choline required to maintain cognitive function in humans must be individualized. An individual physician must assess the role of choline deficiency in cognitive disorders in individual patients.
Neurotransmitter Production in the Human Body by Sentra AM™
This unique five-component process allows milligram quantities of neurotransmitter precursors to enter the cells and produce the required neurotransmitters. This process includes a neurotransmitter precursor, an uptake stimulator, a neuron activator, an adenosine brake inhibitor, and attenuation releaser. Previous attempts to use neurotransmitter precursors have required much larger quantities of the precursors to elicit a therapeutic effect making it functionally impossible for a patient to ingest large gram quantities of a precursor agent on a daily basis. The use of the Targeted Cellular Technology™ process also prevents the development of tolerance. Unlike pharmaceutical agents that lose their effectiveness in a relatively short period, Sentra AM™ maintains its effectiveness and does not attenuate. Sentra AM™ Ingredients: Targeted Cellular Technology and Sentra AM ™ Sentra AM™ is designed to produce the neurotransmitter acetylcholine. Acetylcholine is the body's most important neurotransmitter and functions in all aspects of the autonomic nervous system. Acetylcholine is the neurotransmitter for the post-synaptic ganglion of the autonomic nervous system and is the neurotransmitter for the presynaptic ganglion of both the sympathetic and parasympathetic nervous systems. The terminal nerve roots of the neurons that control muscle contraction depend on acetylcholine; a deficiency of acetylcholine leads to muscle fatigue. Moreover, memory depends on acetylcholine production in the hippocampus. Arousal and alertness depends on acetylcholine function in the prefrontal cortex. Sentra AM™ is designed to increase and maintain the production of acetylcholine by peripheral neurons and brain cells. Sentra AM™ contains choline and acetylcarnitine as precursors to acetylcholine production. Choline is an essential amino acid and choline deficiency leads to a number of disease states. The FDA allows a health claim for choline in the prevention of certain forms of liver disease. It is well recognized that defects of acetylcholine function are part of a number of disease states including Alzheimer’s disease, vascular dementia, chronic fatigue, memory disorders, neurotoxicity related to pesticides and heavy metals and other environmental toxins. Sentra AM™ is designed to support the production of acetylcholine. Sentra AM™ and Clinical Testing Significant physiologic testing has been performed on patients both before and after taking Sentra AM™ to measure parasympathetic function and circadian variations in sleep and wake patterns. Patients with symptoms of chronic fatigue and fibromyalgia show reduced parasympathetic function and reduced concentrations of choline in the brain. There have been open label trials of Sentra AM™ in normalizing parasympathetic nervous system function. These studies used analysis of heart rate variability, PET scans, and spectral MRI data to demonstrate reduced choline function prior to treatment. Sentra AM™ Dosage Sentra AM™ is intended to be given daily in the morning. The usual dose of Sentra AM™ is two capsules. An additional dose can be used during the day if fatigue continues or returns. As with all Medical Food products, the best dosing protocol is established by the healthcare provider in coordination with the requirements of each individual. Sentra AM™ and Prescription Drugs There are no known interaction associated with Sentra AM™ and prescription drugs. Side Effects The side effect profile of Sentra AM™ is comparable to the rate of food intolerance in the community. The ingredients of Sentra AM™ are derived from nutrient based compounds found in the normal food chain. Food intolerance is an adverse reaction to food that does not involve the body's immune system. When first starting any amino acid therapy, some people complain of mild headaches, stomach upset, or mouth dryness. These symptoms are mild and temporary and can be managed by drinking plenty of fluids and carefully titrating the dose. Rarely, some individuals feel jittery or over-stimulated. These side effects are relieved by lowering the dose. Background Sentra AM™ contains a blend of selected GRAS (generally regarded as safe) ingredients that are found in the normal human food chain. The primary ingredients are key amino acids, the building blocks of proteins. Sentra AM™ is designed to induce increased neurotransmitter function associated with mental arousal, mental alertness, improved cognition, and memory. Sentra AM™ increases the function of the neurotransmitters acetylcholine and glutamate. The Sentra AM™ formula is based on a five-component patent pending process that allows for the conversion of a precursor into a neurotransmitter. The five component system includes the following: (1) amino acid precursors, (2) stimulation of the uptake of the precursor to initiate conversion to a neurotransmitter, (3) an adenosine antagonist such as caffeine or cocoa powder is added to disinhibit the neuron, (4) stimulation of neurons to release a specific neurotransmitter, and (5) a system to prevent attenuation of the precursor response. Sentra AM™ has been formulated to encompass this five-component system. The Sentra AM™ formula targets the neurotransmitters acetylcholine and glutamate. Sentra AM™ is designed to produce two neurotransmitters acetylcholine, and glutamate. The two neurotransmitters are involved in mental arousal(603;932-980), mental alertness(981-1029), memory(464;1030-1082), cognition and concentration(166;1043;1044;1083-1108). A disorder of acetylcholine metabolism is associated with Alzheimer’s Disease(1076;1109-1141) and other dementias(150;169;1118;1142-1173). Pharmaceutical approaches to treatment of Alzheimer’s disease have focused on inhibiting the breakdown of acetylcholine. The Institute of Medicine(1174), that sets dietary recommendations for nutrients, has recommended that choline be defined as an essential nutrient with a minimum ingestion of 500 mg per day and health claims for choline administration be defined. The FDA has recently agreed to this recommendation and approved an initial health claim for choline in liver disease http://www.fda.gov/ohrms/dockets/dockets/dockets.htm, The Institute of Medicine recommends that adults, particularly during pregnancy, consume at least 500 mg per day of choline. Low fat/low protein diets do not provide 500 mgs of choline per day. Patients who do not consume eggs or a full glass of milk per day usually do not ingest 500 mgs per day of choline. In the Sentra AM™ formula, Ginkgo Biloba is used as an uptake stimulator(369;1175-1179). Glutamic acid is used to produce glutamate, a neuronal stimulator(375;382;384;388;398;1180-1206). Cocoa is used to disinhibit the adenosine break(410;1207-1216) (1217-1220). Grape seed extract, containing polyphenols(1221-1224), is used to avoid the attenuation usually associated with neurotransmitter precursor administration. In order to test the effects of Sentra AM™ on acetylcholine metabolism, heart rate variability testing from high resolution 24-hour ECG recordings was performed before and after treatment with Sentra AM™ .These studies were performed in patients who had a fibromyalgia like syndrome associated with exposure to an environmental toxin. The defect in parasympathetic function was established by using quantitative audio vestibular testing. The patients were then studied in a double-blind manner with high resolution PET scanning and quantitative spectral MRI that could measure brain choline and glutamate concentrations in the human brain. The control group included patients from the same community who were not exposed to the toxic agent. The brains of patients exposed to the toxin exhibited abnormal PET scans. These abnormalities were located at the origin of the vagus nerve, the hypothalamus, and cerebellar-midbrain connections. These same areas of the brain exhibited reduced concentrations of both choline and glutamate.
These patients exhibited reduced parasympathetic activity as measured by spectral analysis of heart rate variability. This measurement is directly related to parasympathetic activity. In open label trials, the patients' symptoms of fatigue, temperature dysregulation, memory dysfunction, cognitive function, and concentration improved. Parasympathetic function returned toward normal.
The improvement in acetylcholine dependent parasympathetic function has been maintained for more then two years. Nutritional Deficiency of Choline The FDA has approved the recommendations of the Institute of Medicine to establish criteria for choline deficiency. Chronic fatigue and dementias have been associated with relative choline deficiency and abnormal acetylcholine metabolism. Nutritional Deficiency Associated with Cognitive Disorders Choline deficiency is associated with liver disease and cognitive disorders (1034;1225-1274). The Institute of Medicine recommends an intake of at least 500 mg of choline per day for adults. Although choline deficiency is associated with cognitive and memory abnormalities in animals, the amounts of choline required to maintain cognitive function in humans is unknown and must be individualized for each patient.
Medical Food Classification Theramine ™ is a Medical Food formulated by practicing physicians to be used for the management and relief of pain and inflammation. Under the regulations of the Food and Drug Administration, Medical Foods can only be used when a patient is under the ongoing care of a physician or other healthcare provider. Medical Foods are used for the management of disease states with known nutritional deficiencies. Medical Foods must contain ingredients from the human diet. Medical Foods cannot be sold directly to patients without physician supervision. Indications for Use
Distinctive Nutritional Requirements Pain disorders are frequently associated with a deficiency of nitric oxide, GABA, serotonin, and acetylcholine precursors. Pain is also associated with insensitivity to circulating GABA. Neurotransmitter Production in the Human Body
Theramine™ Ingredients: Targeted Cellular Technology This unique five component process allows milligram quantities of neurotransmitter precursors to enter the cells and produce the required neurotransmitters. This process includes a neurotransmitter precursor, an uptake stimulator, a neuron activator, an adenosine brake inhibitor, and an attenuation releaser. Previous attempts to use neurotransmitter precursors have required much larger quantities of the precursors to elicit a therapeutic effect, making it functionally impossible for a patient to ingest gram quantities of a precursor on a daily basis. The use of the Targeted Cellular Technology process also prevents the development of tolerance. Unlike pharmaceutical agents that lose their effectiveness in a relatively short period of time, Theramine™ maintains its effectiveness and does not attenuate. Targeted Cellular Technology and Theramine™ Theramine ™ is designed to influence the neurotransmitters that inhibit neuronal firing and reduce inflammation. Serotonin, GABA, and acetylcholine and NO inhibit neuronal firing. Serine inhibits certain g-proteins of the opioid receptor resulting in activation of the opioid receptor. Nitric oxide has dual effects on pain; at low dose it inhibits pain by activation of nNOS while at high doses it exacerbates pain by activation of iNOS. Theramine ™ provides L-arginine at low dose along with choline and L-glutamine to inhibit the NMDA and opioid receptors. Acetylcholine is the neurotransmitter that activates and maintains the parasympathetic nervous system. Activation of the sympathetic nervous system promotes pro-inflammatory cytokines while activation of the parasympathetic nervous system suppresses the pro-inflammatory cytokines. Increased acetylcholine production inhibits production of substance P. L-histidine produces brain histamine that promotes production of naturally occurring glucocorticoids. Glucocorticoids inhibit inflammation by blocking the production of the prostaglandins, including both prostacyclines and thromoxanes. The action of the glucocorticoids is synergistic with nitric oxide pathways. Thus, Theramine ™ is designed to reduce inflammation and act synergistically with ASA and NSAIDs. Theramine ™ is designed to inhibit neuronal firing of pain neurons and reduce inflammation. Pain Production and Modulation Pain is a complex process involving local receptors, transmission to the spinal cord, transmission to the brain and multiple brain centers. Activation of the inflammatory process is related to prostaglandins and pro-inflammatory cytokines. In addition, activation and release of substance P produces pain. Anatomically, there are numerous ascending excitatory and descending inhibitory pathways in pain signal transmission. Centralization (cephalad relocation in the central nervous system) of the pain signal generators occur spontaneously or after these neural pathways are interrupted, leading to pain syndromes. Advanced reflex sympathetic dystrophy, deafferentation pain, and phantom pain phenomenon are just a few examples. Pain can be classified into five different types, i.e., visceral, somatic, referred, neuropathic, and psychogenic, according to the origins of pain signal generation. Pain syndromes result from different mixtures of these five types. In acute pain (predominantly nociceptive), visceral, somatic, and referred mechanisms play important roles in the pain perception. In chronic pain (frequently non-nociceptive), neuropathic and psychogenic mechanisms prevail, resulting in physical and mental suffering and disability. These concepts indicate that pain is a complex phenomenon involving firing neurons, inflammation, release of neurotransmitters, and activation of brain centers. To reduce pain, firing neurons must be inhibited and inflammation controlled.
The Inflammation Cascade
Theramine™ and Clinical Testing Testing of autonomic nervous system function has been performed on individuals taking Theramine ™ and analysis of heart rate variability has shown activation of parasympathetic function. Theramine ™ has been tested in patients with Fibromyalgia, trigeminal neuralgia, back pain, headache, osteoarthritis, tendonitis, and the post herpetic neuropathic pain. Independent published clinical trials show that low dose arginine reduces pain. Theramine™ Dosage Theramine ™ is intended to be given in a two-capsule dose, taken one to four times daily as directed by the healthcare provider. Theramine ™ can also be used with a low dose of aspirin or NSAID once daily. As with all Medical Food products, the best dosing protocol is established by the healthcare provider in coordination with the requirements of each individual. Theramine™ and Prescription Drugs In patients taking pharmaceutical agents to relieve pain, it is suggested that the medication dosage may be reduced gradually, as tolerated. If pain relief is obtained with the combination, the drug should be slowly tapered under medical supervision. Side Effects The side effect profile of Theramine ™ is comparable to the rate of food intolerance in the community. The ingredients of Theramine ™ are derived from nutrient based compounds found in the normal food chain. Food intolerance is an adverse reaction to food that does not involve the body's immune system. When first starting any amino acid therapy, some people complain of mild headaches, stomach upset, and nausea or mouth dryness. These symptoms are mild and temporary and can be managed by drinking plenty of fluids and carefully titrating the dose. Rarely, some individuals feel jittery or over-stimulated. These side effects are relieved by lowering the dose. Background Theramine ™ contains a formula blend of selected GRAS (generally regarded as safe) ingredients that are found in the human food chain. The primary ingredients are key amino acids, the building blocks of proteins. The Theramine ™ formula is designed to maximize neurotransmitter function in patients with pain disorders. The Theramine ™ formula is designed to increase the function of the neurotransmitters serotonin, GABA, norepinephrine, nitric oxide, and acetylcholine. The Theramine ™ formula is based on a five-component patent pending process (Targeted Cellular Technology™). The patent pending process provides for a five-component system to allow for the conversion of a neurotransmitter precursor into a neurotransmitter. The five component system includes: (1) each neurotransmitter is synthesized from an amino acid precursor, (2) stimulation of the uptake of the neurotransmitter precursor is required to initiate the conversion of a precursor to a neurotransmitter, (3) since most neurons are inhibited from firing, an adenosine antagonist such as and cocoa powder is added to disinhibit the neuron, (4) stimulation of neurons to release a specific neurotransmitter is required, and (5) a system must be used to prevent attenuation of the precursor response, a well known precursor phenomena. Theramine ™ has been formulated to encompass this five-component system. The Theramine ™ formula targets the neurotransmitters serotonin, GABA, norepinephrine, nitric oxide, and acetylcholine. Definitions The pathophysiology of pain involves a very complex interaction of many different peripheral and central structures. Nociception is the mechanism whereby noxious stimuli are transmitted and perceived by the brain as pain(1275-1292). An increase in nociception refers to increase in pain perception. Antinociception refers to the mechanism of decreased pain perception. Improved antinociception means decreased pain. Under physiologic conditions, nociceptive signals are generated by stimuli that activate specialized nerve fibers, the nociceptors. Thus, pain signals are generated and travel on specialized neurons to the spinal cord and brain which are interpreted as pain. Pain can be acute or it can become chronic. Pain is detected by two different types of peripheral nociceptor neurons, C-fiber nociceptors contain slowly conducting unmyelinated axons, and A-delta nociceptors contain thinly myelinated axons(1293-1305). During inflammation and pain, nociceptors become sensitized, discharge spontaneously, and produce ongoing pain. Prolonged and frequent firing of C-fiber nociceptors causes release of neurotransmitters which act on receptors in the spinal cord. Activation of these receptors causes the spinal cord neuron to become more responsive to all of its inputs, resulting in central sensitization. Pain-receptor activation not only increases the cell's response to pain stimuli, but also decreases neuronal sensitivity to antinociceptive receptor stimulants(1306-1355). Thus, reduction of pain requires desensitizing pain neurons and decreasing the rate of firing of these neurons. When acute pain becomes chronic there is a change in the neuron pathways that is termed plasticity(1356-1380). This plasticity(1381-1430) involves both sensitization to stimuli and increased transmission at the level of the spinal cord and the brain. Thus, in both acute and chronic pain syndromes, there is an increased in the firing of neurons to generate the perception of pain(1431-1437). The treatment of acute and chronic pain syndromes requires a decrease in the perception of pain signals and a reduction in the firing of pain neurons. Chemical Messengers There are a large number of messenger molecules that determine the sensitivity of the peripheral pain receptors, their transmission to the spinal cord, and transmission to the brain(1438-1466). These messenger molecules include simple molecules, amino acids, neurotransmitters and neuropeptides. Neuropeptides and Substance P There are a series of neuropeptides that are important in the perception and modulation of pain. The most important is substance P(1279;1331;1467-1504). Substance P has been extensively studied and is considered the prototypic neuropeptide of the more than 50 known neuroactive molecules. After seven decades of study, the physiologic role of substance P is known to be a modulator of nociception. Substance P is involved in signaling the intensity of noxious or aversive stimuli. Genetic studies in mice and development of substance P antagonists provide more recent results that support the redefinition of the central role of substance P. Evidence suggests that this neuropeptide is an integral part of the spinal cord and central nervous system pathways involved in the pathogenesis of musculoskeletal pain Substance P is a member of the neurotransmitter-neuropeptide family called tachykinins(1505-1519). Substance P is an eleven-amino acid neuropeptide that appears in both the central and peripheral nervous systems. It is involved in the transmission of pain and modulates inflammatory and immune responses. Substance P is a neuromodulator that responds to pain stimuli, released like a neurotransmitter, but diffuses more widely and has longer lasting effects. Several lines of evidence have supported the concept that substance P. serves as a neurotransmitter for afferents that are activated by a noxious stimuli. Importantly, antinociceptive agents such as opioids suppress substance P. Behavioral and electrophysiological studies have indicated that substance P neurons are colocalized with the NMDA-receptors in the dorsal column of the spinal cord. These cells are responsible for transmission of painful stimuli from the periphery to the brain. The sensitization and firing of these neurons are under control of substance P and the NMDA-receptors are responsible for both acute and chronic pain perception. Activation of substance P results in a decrease of pain threshold, increased firing of pain neurons, and activation of other pain transmitters. Inhibition of substance P results in decreased pain perception, increasing the pain threshold and decreased firing of pain neurons. NMDA-Receptors Severe or prolonged tissue or nerve injury can induce hyperexcitability of dorsal horn neurons of the spinal cord, resulting in persistent pain, an exacerbated response to noxious stimuli (hyperalgesia), and a lowered pain threshold (allodynia). These changes are mediated by the NMDA (N-methyl-D-aspartate)-type glutamate receptors in the spinal cord with the release of substance P(1520-1547). The presynaptic NMDA receptors, located on the terminals of small-diameter pain fibers, facilitate and prolong the transmission of nociceptive messages, through the release of substance P and glutamate(1548-1564). When the NMDA-receptors are activated, glutamate is released which increases neuron firing and causes release of substance P. The effects of the NMDA-receptors operates through the G. protein signaling systems(1565-1578). Norepinephrine and alpha2-adrenoreceptor There are norepinephrine neurons throughout the pain centers of the spinal cord and brain(1285;1755-1780). The norepinephrine neurons contribute significantly to modulation of pain responses. The norepinephrine neurotransmitter modulates pain through the alpha2-adrenorecptors(1627;1781-1829). The receptors that are responsive to norepinephrine produce significant antinociception and relieve pain. Production of norepinephrine and activation of the alpha2-adrenoreceptor will potentiate the natural opiate receptors. Any activation of the norepinephrine and alpha2-adrenoreceptor systems will serve as natural opioid. The norepinephrine neurons are post-synaptic neurons. The presynaptic neurons for the norepinephrine system are acetylcholine dependent. Stimulation of the acetylcholine presynaptic neurons will stimulate norepinephrine production. The precursor to acetylcholine production is choline. Serotonin The serotonergic neurons are present in the spinal cord(1830-1836) and brain(1285;1837-1839) pain centers. The production of serotonin by these neurons contributes importantly to the modulation of pain(1454;1461;1840-1864). An increase in serotonin in the spinal cord and brain regulate the pain threshold(1840;1865-1907). Serotonin is colocalized with substance P in the pain neurons(1454;1482;1908-1923). Stimulation of serotonin production in these neurons will inhibit production of substance P. Also production of serotonin in the substance P neurons will increase adenosine production by the substance P neurons(1924-1926). The increase in adenosine production inhibits the substance P neurons and prevents their secretion of substance P. Serotonin production will inhibit the NMDA-receptors further preventing release of substance P and reducing pain(1551;1927-1929). The brain dispatches in response to production of Substance P dispatches its own batch of pain inhibiting neurochemicals, and directs them toward the area of the spinal cord where substance P had been released. These chemicals include serotonin, norepinephrine, and natural opioids. Thus, the brain’s chemicals try to suppress the release of substance P, and “down regulate” the perception of pain. Serotonin(1285;1482;1551;1828;1908;1912;1930-1973), norepinephrine(1285;1788;1828;1907;1974-1992) and GABA(1993) are the brain chemicals that are used to inhibit the production of substance P. Acetylcholine Numerous studies have implicated the role of the central cholinergic system in pain perception(1994-2043). Acetylcholine is a natural antinociceptive agent that acts through the serotonin and a norepinephrine systems. Release of acetylcholine into the pain centers reduces sensitization(2044;2045), reduces pain threshold, and decreases the firing of the pain inducing neurons. Stimulation of the presynaptic acetylcholine neurons results in the production of norepinephrine and serotonin which further reduces pain perception. Choline is the precursor for acetylcholine and can stimulate the production of presynaptic acetylcholine. GABA GABA is a neurotransmitter that dampens pain signals in the spinal cord and brain(2046-2055). GABA neurons in the Dorsal Horn synapse with incoming presynaptic glutamate end terminals(2056-2067). Glutamate is a stimulatory neurotransmitter while GABA is an inhibitory neurotransmitter(2068-2080). When GABA transmitters activate GABA receptors on the glutaminergic nerve terminals, Chloride channels are opened. There is an inhibition of the release of glutamate and substance-P(2081-2094). GABA is an important inhibitory neurotransmitter that inhibits the perception of pain. GABA also (1556;2095-2112)inhibits the NMDA-receptor, particularly in cells responsible for pain perception and cells that release substance P and other pain neuropeptides. A major facilitatory effect of the central nervous system responding to noxious stimuli involves the interaction between L-glutamate and substance P. GABA is a major inhibitory neurotransmitter in the mammalian CNS and GABA binding sites and GABA containing neurons have been characterized in almost all pain-related structures. Even slight alterations in the excitability of multireceptive dorsal horn neurons can dramatically influence the pain response. The excitatory receptive neurons are most commonly surrounded by inhibitory stimuli. The number of excitatory neurons can be increased by the application of L-glutamate released by activation of the NMDA-receptors into the vicinity of these pain neurons and can be reduced in function by the application of the inhibitory neurotransmitter GABA(1556;2113-2130). Nitric Oxide In several peripheral neurons, the spinal cord, and the central nervous system, nitric oxide acts as a neurotransmitter that is involved in the perception of pain(1964;2131-2163). Importantly, nitric oxide is involved in synaptic plasticity particularly in the nociception process. There is a biphasic response to nitric oxide. Nitric oxide particularly that induced by neuronal nitric oxide synthetase, produces an antinociceptive affect by activating natural opioids. The production of nitric oxide potentiates not only natural opioids but also interacts with beneficial prostaglandins. The combination of nitric oxide with stimulation of prostaglandins reduces both pain and inflammation. Production of small doses of nitric oxide from arginine will result in reduced pain perception and inflammation. Adenosine The ability of adenosine analogs to provide antinociception has been known since 1984(2164-2170). To provide an antinociceptive effect the adenosine brake must be disinhibited. Disinhibition of the adenosine brake results in reduced pain perception. Caffeine is frequently included in analgesic preparations because of its ability to disinhibit the adenosine brake(1864;2171-2175). Histidine Histidine is converted to histamine in the brain(2176-2180). Brain histamine induces the release of cortisol by stimulation of brain ACTH(2181-2189). The release of cortisol is a natural anti-inflammatory mediator. The use of histidine to control inflammation is part of the nutrient modulation of pain and inflammation. Theramine ™ is designed to stimulate production of serotonin, GABA, norepinephrine, nitric oxide and acetylcholine, the neurotransmitters that are involved in pain disorders. If the timing and secretion of these neurotransmitters are effectively modulated acute and chronic pain disorders are more effectively managed. Theramine ™ is designed to produce neurotransmitters related to physiologic pain nociception and antinociception functions. In the Theramine ™ formulation, choline is used as a precursor to acetylcholine, arginine is a precursor to nitric oxide and 5-hydroxytryptophan is used to induce the physiologic production of serotonin, GABA and glutamine are used are precursors to neurotransmitters that activate the GABA-receptor. Choline is used to stimulate the presynaptic ganglion associated with norepinephrine release. Thus, the Theramine ™ formula contains the neurotransmitter precursor 5-hydroxytryptophan as a precursor to serotonin, arginine as a precursor to nitric oxide, GABA and glutamine as precursors to GABA stimulants, and choline as a precursor to acetylcholine. In the Theramine ™ formula, glutamine is used as an uptake stimulator(369;2190-2194). Glutamic acid is used to produce GABA, a neuronal inhibitor(375;382;384;388;398;2195-2221). Histidine is used as a precursor to histamine, thereby increasing cortisol. Cocoa is used to disinhibit the adenosine brake(410;2222-2231) (2232-2235). Grape seed extract, containing polyphenols(2236-2239), is used to avoid the attenuation usually associated with neurotransmitter precursor administration. Accordingly, the Theramine ™ formula contains precise proprietary proportions of 5-hydroxytryptophan, cocoa powder, grape seed extract, glutamine, histidine, arginine and choline. The Theramine ™ formula is designed to provide precursors for known neurotransmitters that induce and maintain antinociception and reduce pain and inflammation. The amino acid precursors are 5-hydroxytryptophan, GABA, glutamine, histidine, arginine and choline. In addition, Theramine ™ depends on inhibition of pain neurons by GABA, glutamine, serotonin, norepinephrine, adenosine, and acetylcholine. Several open label trials have been performed using these combinations to inhibit pain and inflammation. Nutritional Deficiencies Patients with pain disorders frequently exhibit nutritional deficiencies of tryptophan, choline, and GABA. Patients with pain disorders often have reduced blood levels of serotonin (305;634;637;644;645;655;657;2240-2263) and 5-hydroxytryptophan. Moreover, obese patients use more tryptophan than lean patients. Reduced calorie diets that are frequently low in protein, result in a further fall in blood tryptophan, glutamine and can exacerbate pain disorders. Thus, patients with pain disorders are frequently deficient in tryptophan. (660;663;666;667;670-672;675;676;678-680;683;685;2264-2276). There is an alteration of tryptophan metabolism in patients with pain disorders (688;688;694;694;703;703;705;705;706;706;710;710;725;725; 726;726;732;732;2277-2356) (777;777;783;783;788;788;795;795;803;803;807;807;2357-2410). Choline deficiency is associated with pain disorders (335;338;341;448;464;592;841;842;853;2411-2425) (2426-2429). In acute and chronic pain disorders, the pain threshold is increased and the rate of neuron firing is increased. Thus, the peripheral nerves, spinal cord and brain produce insufficient neurotransmitters to prevent release of such neuropeptides as substance P. There are known nutritional deficiencies of 5-hydroxytryptophan, arginine, GABA, and choline in chronic pain disorders Reference List (Note: Large Reference File 480kb) © 2006 Physician Therapeutics LLC & Nationwide Medical Foods
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