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Medical Foods Classification Theramine™ is a Medical Food formulated to be used by practicing physicians for the nutritional management of pain syndromes. Theramine™ helps to modulate neurotransmitters involved in acute and chronic pain including nitric oxide, GABA, serotonin and brain histamine. 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. Medical Foods are used for the dietary management of disease states with known nutritional deficiencies. Medical Foods must contain ingredients from the human diet that are designated as “generally regarded as safe (GRAS). Medical Foods cannot be sold directly to patients without physician supervision. Distinctive Nutritional Requirements A critical component of the definition of Medical Foods is the requirement that they are formulated to address a distinctive nutritional deficiency. FDA scientists have proposed a physiologic definition of a distinctive nutritional deficiency as follows1: “the dietary management of patients with specific diseases requires, in some instances, the ability to meet nutritional requirements that differ substantially from the needs of healthy persons. For example, in establishing the recommended dietary allowances for general, healthy population, the Food and Nutrition Board of the Institute of Medicine, National Academy of Sciences, recognized that different or distinctive physiologic requirements may exist for certain persons with "special nutritional needs arising from metabolic disorders, chronic diseases, injuries, premature birth, other medical conditions and drug therapies”. Thus, the distinctive nutritional needs associated with a disease reflect the total amount needed by a healthy person to support life or maintain homeostasis, adjusted for the distinctive changes in the nutritional needs of the patient as a result of the effects of the disease process on absorption, metabolism and excretion.” It was also proposed that in patients with certain disease states who respond to nutritional therapies, a physiologic deficiency for the nutrient is assumed to exist. For example, if a patient with chronic pain responds to an arginine formulation by decreasing perceived pain, a deficiency of arginine is assumed to exist. The measurement of the pain response is performed by the use of either a visual analog scale or a Likert scale. Patients with acute and chronic pain are known to have nutritional deficiencies of Choline is required to fully potentiate nitric oxide and serotonin synthesis and function. A deficiency of choline leads to reduced function of NMDA receptors, GABA function, and serotonin response. Low fat diets are usually choline deficient. Flavonoids alter inflammation by multiple mechanisms and pathways. Low fat diets and diets deficient in flavonoid rich foods result in inadequate flavonoid concentrations, impeding anti-inflammatory responses. Provision of arginine, choline and flavonoid with antioxidants, in the correct proportions can restore the production of beneficial neurotransmitter response involved in pain modulation. Indications for Use
Distinctive Nutritional Requirements Pain disorders are associated with a deficiency of nitric oxide, GABA, serotonin, and acetylcholine. 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 relative short period of time, Theramine™ maintains its effectiveness and does not attenuate. Targeted Cellular Technology™ andTheramine™ Theramine™ has been formulated to influence the neurotransmitters that inhibit neuronal firing and reduce inflammation. Serotonin, GABA, acetylcholine and nitric oxide inhibit neuronal firing. Serine inhibits certain -proteins of the opioid receptor resulting in activation of the opioid receptor. Nitric oxide in the spinal cord and brain 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™ induces low dose nitric oxideandprovides -arginine at low dose along with choline and -glutamine to inhibit the NMDA receptor and activate the opioid receptor. 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. In addition, 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 thromboxanes. 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. In addition, L-histidine inhibits the NMDA receptor to further suppress pain producing neurons. 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, as well as activation and release of substance P that produces the perception of 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 their 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 has demonstrated activation of parasympathetic function. Theramine™ has been tested in patients with Fibromyalgia, trigeminal neuralgia, back pain, headache, osteoarthritis, tendonitis, and post herpetic neuropathic pain. Clinical crossover trials have been performed to assess the ability of Theramine™ to reduce pain. Independent published clinical trials show that low dose arginine, choline and GABA given alone reduce the perception of pain. Theramine™ Dosage Theramine™ is intended to be given in a two-capsule dose, taken one to four times daily as directed by the physician. 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 physician 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 drug dosage 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. 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 and to increase the function of the neurotransmitters serotonin, GABA, nitric oxide, and acetylcholine. In addition, flavonoids2-25 and L-histidine26-29 reduce inflammation. The Theramine™ 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 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 to target the neurotransmitters serotonin, GABA, 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 pain30-47. 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 is detected by two different types of peripheral nociceptor neurons, -fiber nociceptors contain slowly conducting unmyelinated axons, and - nociceptors contain thinly myelinated axons48-60. During inflammation and pain, nociceptors become sensitized, discharge spontaneously, and produce ongoing pain. Prolonged and frequent firing of -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 stimulants61-110. 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 plasticity111-135. This plasticity136-185 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 pain186-192. 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 brain193-221. These messenger molecules include simple molecules, amino acids, neurotransmitters and neuropeptides. The important neurotransmitters that modulate pain include serotonin222-244, nitric oxide245-260, acetylcholine238, 261-277 and GABA278-287. The neuromodulators include the g-protein of the opioids receptor288-307 and the NMDA receptor. The neuropeptides include substance P. Inflammation is controlled by the glucocorticoids, the prostaglandin cascade and activation of cytokines. 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 P34, 86, 308-345. 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 tachykinins346-360. 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 co- localized 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 hyper excitability 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 P361-388. The presynaptic NMDA receptors, located on the terminals of small-diameter pain fibres, facilitate and prolong the transmission of nociceptive messages, through the release of substance P and glutamate389-405. 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 systems406-419. Therapies directed at the presynaptic NMDA receptor and substance P can therefore ameliorate persistent pain states. Importantly, a series of molecules can inhibit the NMDA-receptors and substance P release. These molecules include serotonin392, 397, 420-467,397, 397, 468, 468-478, nitric oxide254, 392, 468, 479-525, capsaicin526-534, GABA535-554 and adenosine555-594. The inhibition of the NMDA-receptors and substance P results in antinociception and reduced pain perception. The activation of the NMDA-receptors and release of substance P results in nociception and increased pain perception. Serotonin The serotonergic neurons are present in the spinal cord595-601 and brain40, 602-604 pain centers. The production of serotonin by these neurons contributes importantly the modulation of pain209, 216, 605-629. An increase in serotonin in the spinal cord and brain regulate the pain threshold605, 630-672. Serotonin is co localized with substance P in the pain neurons209, 323, 673-688. 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 neurons689-691. 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 pain392, 692-694. In response to the production of Substance P, the brain 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, and natural opioids. Thus, the brain’s chemicals try to suppress the release of substance P, and “down regulate” the perception of pain. Serotonin40, 323, 392, 673, 677, 695-739 40, 672, 717, 740-759 and GABA760 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 perception761-810. Acetylcholine is a natural antinociceptive agent that acts through the serotonin system. Release of acetylcholine into the pain centers reduces sensitization811, 812, reduces pain threshold, and decreases the firing of the pain inducing neurons. Stimulation of the presynaptic acetylcholine neurons results in the production of serotonin that 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 brain813-822. GABA neurons in the dorsal horn synapse are stimulated by incoming presynaptic glutamate end terminals823-834. Glutamate is a stimulatory neurotransmitter while GABA is an inhibitory neurotransmitter835-847. 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-P848-861. GABA is an important inhibitory neurotransmitter that inhibits the perception of pain. GABA also 397, 862-879inhibits 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 -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 -glutamate released by activation of the NMDA-receptors into the vicinity of these pain neurones and can be reduced in function by the application of the inhibitory neurotransmitter GABA397, 880-897. 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 pain247, 730, 898-929. 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 1984930-936. To provide an antinociceptive effect the adenosine brake must be disinhibited. Disinhibition of the adenosine brake results in reduced pain perception. Cocoa and caffeine are frequently included in analgesic preparations because of its ability to disinhibit the adenosine brake629, 937-941. Histidine Histidine is converted to histamine in the brain942-946. Brain histamine induces the release of cortisol by stimulation of brain ACTH27, 947-954. 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 formulated to produce serotonin, GABA, 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 formulated 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 as precursors to neurotransmitters that activate the GABA-receptor. 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 a precursor to GABA stimulants, and choline as a precursor to acetylcholine. In the Theramine™ formula, glutamine is used as an uptake stimulator955-960. Glutamic acid is used to produce GABA, a neuronal inhibitor961-992. Histidine is used as a precursor to histamine, thereby increasing cortisol. Cocoa is used to disinhibit the adenosine brake993-1003 1004-1007. Grape seed extract, containing polyphenols1008-1011, is used to avoid the attenuation usually associated with neurotransmitter precursor administration. Accordingly, the Theramine™ formula contains precise proprietary amounts of 5-hydroxytryptophan, glutamine, histidine, arginine, choline, cocoa powder, and grape seed extract. 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, adenosine, and acetylcholine. Several open label trials have been performed using these combinations to inhibit pain and inflammation. Nutritional Deficiencies Associated with Pain Syndromes Patients with pain disorders frequently exhibit nutritional deficiencies of tryptophan, choline, arginine, and GABA. Patients with pain disorders frequently have reduced blood levels of serotonin1012-1042 and 5-hydroxytryptophan. Thus, patients with pain disorders are frequently deficient in tryptophan. 1043-1069. There is an alteration of tryptophan metabolism in patients with pain disorders1070, 1071, 1071-1077, 1077-1086, 1086-1088, 1088, 1089, 1089-1093, 1093-1108, 1108, 1109, 1109-1115, 1115-1158 1159, 1160, 1160-1166, 1166-1171, 1171-1178, 1178-1186, 1186-1190, 1190-1218. Choline deficiency is associated with Pain Disorders1219-1242 1243-1246. In acute and chronic pain disorders, the pain threshold is decreased and 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-hydroxy tryptophan, arginine, GABA and choline in chronic pain disorders. Arginine Deficiency and Pain Disorders254, 1247-1253 -arginine is a conditional essential amino acid in humans and is the substrate for the spinal cord nitric oxide (NO) synthase (cNOS), that metabolizes this amino acid to L-citrulline and NO, a powerful inhibitor of spinal cord pain syndromes.The impaired availability of NO in the spinal cord and brain can be managed by providing the correct nutrients that are deficient and in the correct proportions. Disease states frequently contribute to nutrient deficiencies and the nutrient deficiencies exacerbate the perception of pain.1254-1264. In humans, maintenance of plasma L-arginine is mainly dependent on the dietary intake of L-arginine1265-1289, 1289-1325. Studies indicate that L-arginine therapy is associated with an increase in surrogate markers of NO production, such as plasma nitrates and exhaled NO1326-1347. Since circadian patterns1320, 1348-1352 have been described for several phenomena related to arginine function1353-1362 physiological variations of plasma L-arginine concentrations influence pain syndromes. Therefore, timing and amount of arginine ingestion is important in regulation of plasma arginine and NO production that cannot be achieved by diet alone. GABA Deficiency and Pain Disorders386, 1363-1383 GABA is intimately related to both the NMDA and opioids receptors in the periphery, spinal cord and brain. GABA blood levels are directly related to dietary ingestion of GABA. GABA deficiency diets do not produce adequate GABA to control pain syndromes. Pain syndromes increase utilization and degradation of GABA. Administration of GABA and gabaergic agents reduce perceived pain. Histidine Deficiency and Pain Syndromes1384-1417 Histidine is intimately related to both the substance P and opioid receptors in the periphery, spinal cord and brain. Histidine blood levels are directly related to dietary ingestion of histidine. Histidine deficiency diets do not produce adequate histidine to control pain syndromes. Pain syndromes increase utilization and degradation of histidine. Administration of histidine reduces perceived pain. In addition, histidine alters inflammation by influencing the prostaglandin cascade and causing release of glucocorticoids1418. Flavonoid Deficiency and Pain Syndromes8, 10, 13, 18, 19, 1419-1452 Flavonoids contained in a variety of plant sources including cocoa and grape seed influence amino acid utilization and impact on pain and inflammation10, 1453-1484. Flavonoids are a group of polyphenolic compounds that occur widely in fruit, vegetables, tea, grape, red wine, and chocolate1485-1494. Cocoa and chocolate products have the highest concentration of flavonoids among commonly consumed food items1495-1497. Over 10% of the weight of cocoa powder consists of flavonoids, catechin and epicatechin. Flavonoids influence prostaglandin cascades and alter pain pathways directly. Diets, particularly those deficient in fruits and vegetables do not produce adequate quantities of dietary flavonoids. In addition, increased utilization of flavonoids occurs in pain syndromes. Serine Deficiency and Pain 1498-1523 Serine influences the g-proteins of both the NMDA and opioids receptor systems. A serine deficiency will lead to insensitivity to both natural and synthetic inhibitors of the pain response. The synthetic inhibitors include opioids, opioid like agents and other analgesics. Serine deficiency is common when protein restriction occurs. Summary of Nutritional Deficiency in Pain and Inflammation Syndromes Patients with pain syndromes may have nutritional deficiencies of L-arginine, choline1524-1557, tryptophan, serine, GABA and certain antioxidants 1558-1590. The relationship of arginine to pain syndromes is particularly illustrative. Patients with pain syndromes have reduced plasma levels of L-arginine and have been shown to respond to oral administration of 1591-1604 L-arginine. Arginine reduced diets result in a fall of circulating L-arginine. Patients with defects of arginine utilization have activation of the arginase pathway that diverts arginine from production of nitric oxide to production of deleterious nitrogen molecules such as peroxynitrite thus leading to a reduced production of nitric oxide for a given arginine blood level1605-1627. Supplementation with antioxidants and arginine can restore the production of beneficial nitric oxide production1628-1665. The removal of L-arginine from the diet for one day in healthy individuals causes a significant decrease in plasma L-arginine concentrations during the awake period followed by a spontaneous return to normal morning basal concentrations overnight1289, 1320, 1666, 1667. In the same subjects, a normal amount of L--arginine in the diet (3.8 g/d) was associated with a rise in plasma L-arginine concentration after each meal. Plasma L-arginine changes reflect the balance between complex inter-organ processes leading to movement of the amino acid into and out of the circulation. Endogenous synthesis of L-arginine occurs primarily in the kidney and to a lesser extent in the liver via conversion of citrulline to L-arginine. However, the liver does not contribute significantly to the maintenance of the plasma concentrations of L-arginine, since the amino acid synthesized in this organ is routed towards its local utilization The mean dietary intake of L-arginine in industrialized countries is 3–6 g/day1289, 1668-1676; 60% of this exogenous source appears in the general circulation. Isotopic studies have shown that the net rate of de novo arginine synthesis in healthy humans is not affected by a 6–7 day arginine-free diet. 25, 26. Consequently, it has been proposed that whole-body arginine homeostasis in healthy adults may be achieved principally via a modulation in the level of dietary arginine intake and/or with regulation in the rate of its catabolism to ornithine and glutamate. An L-arginine-free diet is associated with a gradual decrease in plasma concentration– reaching 47% of the baseline value after 7 hours. Comparison with the normal diet also demonstrated a significant decrease in the 3- AUC intervals.0. L-arginine is the substrate for endothelial NO synthesis, a reaction that is catalyzed by the constitutive endothelial enzyme eNOS. NO plays a key role in the regulation of vascular tone and platelet aggregation and adhesion. Changes due to hypercholesterolemia, hypertension and aging, conditions associated with impairment of the L-arginine/NO pathway result in increased need for L-arginine compared to normal subjects. Physiological variations of plasma L-arginine concentrations are either induced by an increase in arginine utilization or reduced arginine in the diet. Altered plasma L-arginine concentrations influence NO production impairing prostaglandin regulation. As indicated in the summary above, a critical component of the definition of a Medical Food is the requirement for a distinctive nutritional deficiency. The FDA has proposed a physiologic definition of a distinctive nutritional deficiency1677: “However, the dietary management of patients with specific diseases requires, in some instances, the ability to meet nutritional requirements that differ substantially from the needs of healthy persons. For example, in establishing the recommended dietary allowances for general, healthy population, the Food and Nutrition Board of the Institute of Medicine, National Academy of Sciences recognized that different or distinctive physiologic requirements may exist for certain persons with "special nutritional needs arising from metabolic disorders, chronic diseases, injuries, premature birth, other medical conditions and drug therapies”. Thus, the distinctive nutritional needs associated with a disease reflect the total amount needed by a healthy person to support life or maintain homeostasis, adjusted for the distinctive changes in the nutritional needs of the patient as a result of the effects of the disease process on absorption, metabolism and excretion.” An extension of this definition is that if a person with the disease responds to the nutrient, a physiologic deficiency for the nutrient exists. For example, if a patient with a pain syndrome responds to arginine by decreasing the blood pressure, a deficiency of arginine exists. If providing nutrient based management of pain, the pain is reduced, a deficiency of the requisite amino acids exists. Theramine™ can be used alone and in conjunction with pharmaceuticals. Management of the nutritional deficiencies associated with the pain syndrome can help manage the dose and side effects of the pharmaceutical agent. In the clinical crossover study, Theramine™ was used alone and along with a single daily dose of naproxen. The reduced dose of naproxen was effective when used with nutritional management compared to a four time daily dose of naproxen.
© 2006 Physician Therapeutics LLC & Nationwide Medical Foods
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