Indication. Ingredients. Sentra AM Product Information

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1 Sentra AM Product Information Indication Sentra AM is intended for use in the management of chronic and generalized fatigue, fibromyalgia, post-traumatic stress syndrome (PTSD), neurotoxicity-induced fatigue syndrome, and impaired neurocognitive functions involving mental arousal, alertness, and memory. These conditions share an increased need for dietary choline, acetyl-l-carnitine, and glutamate to support neuromuscular, neuroendocrine, and neurocognitive functions dependent on acetylcholine. Sentra AM is a medical food that must be used under the active or ongoing supervision of a physician. Medical foods are intended to address the different or altered physiologic requirements that may exist for individuals who have distinctive nutritional needs arising from metabolic disorders, chronic diseases, injuries, premature birth associated with inflammation and other medical conditions, as well as from pharmaceutical therapies. 1 Acetylcholine is the primary neurotransmitter in the autonomic nervous system. It also plays a key role in the regulation of circadian rhythms, muscle function, arousal and alertness, memory, and the neuroendocrine response to stress. Cholinergic activity is influenced by glutamate and supported by acetyl-l-carnitine. Patients with disorders involving imbalances in acetylcholine activity benefit from increased availability of choline, glutamate, and acetyl-l-carnitine to restore homeostasis. Sentra AM is designed to provide a balance of neurotransmitters and other ingredients that support the metabolism and activity of acetylcholine. Ingredients Sentra AM is a proprietary blend of neurotransmitters and neurotransmitter precursors (choline bitartrate, L-glutamate); activators of precursor utilization (acetyl-l-carnitine, L-glutamate, cocoa powder); polyphenolic antioxidants (cocoa powder, grape-seed extract, hawthorn berry); an adenosine antagonist (cocoa powder); and an inhibitor of the attenuation of neurotransmitter production associated with precursor administration (grape-seed extract). The neurotransmitters and neurotransmitter precursors have been specifically selected based on scientific support for their roles in modulating cellular processes that support neuromuscular, neuroendocrine, and cognitive functions. These roles are summarized in this monograph in the section Scientific Support for Use of Sentra AM in Management of Disorders Involving Acetylcholine Imbalances. The other ingredients in the formulation are involved in neurotransmitter metabolism or are functional components of the Targeted Cellular Technology system. All of the ingredients included in Sentra AM are classified as generally recognized as safe (GRAS) by the United States Food and Drug Administration (FDA). To qualify for GRAS status, a substance that is added to a food, including a medical food, has to be supported by data demonstrating that it is safe when consumed in the amounts obtained from these foods as they are typically ingested or prescribed. 1 As defined in the guidelines issued by the Center for Food Safety and Nutrition, United States Food and Drug Administration (FDA). 1 P age

2 Targeted Cellular Technology Sentra AM has been formulated using Targeted Cellular Technology, an integrated molecular system that facilitates the uptake and utilization of neurotransmitter precursors by target cells within the nervous system. This 5-component patented system consists of (1) specific neurotransmitter precursors; (2) a stimulus for the neuronal uptake of these precursors by specific neurons; (3) an adenosine antagonist that blocks the inhibitory effect of adenosine on neuronal activity (adenosine brake); (4) a stimulus to trigger the release of the required neurotransmitters from targeted neurons; and (5) a mechanism to prevent attenuation of the precursor response, a well-known phenomenon associated with precursor administration. Use of Targeted Cellular Technology improves the metabolic efficiency of neurotransmitter synthesis, thereby reducing the amounts of precursors needed to correct neurotransmitter imbalances. Use of Targeted Cellular Technology also ensures that the appropriate amounts of neurotransmitter precursors are delivered to the target neurons with the appropriate timing. As such, Targeted Cellular Technology synchronizes the availability of the precursor supply with the fluctuating demand for the corresponding neurotransmitters, which is especially important for processes which are modulated by circadian rhythms and are therefore sensitive to the timing of synthesis and release of neurotransmitters such as acetylcholine, serotonin, nitric oxide, and histamine (1-4). Previous attempts to provide an exogenous source of precursor amino acids and other biogenic amines in the quantities required to support neurotransmitter synthesis for individuals with specific needs necessitated that large amounts of amino acids be added to the formulations. For patients whose precursor requirements were considerably higher than normal, the amounts of exogenous amino acids that were needed were not practical to consume on a daily basis. Moreover, ingestion of large quantities of amino acids increases the potential for adverse effects. Metabolic efficiency is also decreased when large amounts of amino acids are delivered to the cells at one time because intestinal membrane transport receptors would be rapidly saturated resulting in a reduction in fractional amino acid absorption and thus attenuation of the tissue response to the supplemental amounts provided. Improving metabolic efficiency in uptake and utilization of neurotransmitter precursors by target neurons with Targeted Cellular Technology allows ingestion of smaller amounts of amino acids to elicit the same response as larger amounts, making daily dosing more feasible and reducing the potential for tolerance. Unlike pharmaceutical products which are not innate components of the processes that regulate acetylcholinedependent neurological activity and thus may lose their effectiveness in a relatively short period of time, the effectiveness of Sentra AM is not attenuated. Metabolism Sentra AM is a source of amino acids, biogenic amines, and other nutrients formulated for patients with disorders involving imbalances in cholinergic activity which contribute to abnormalities in neuromuscular, neurocognitive, and neuroendocrine functions. Patients with these conditions require additional amounts of choline, glutamate, and acetyl-l-carnitine to restore homeostasis. Under normal physiological conditions, these nutrients are considered nonessential because endogenous synthesis is 2 P age

3 sufficient to satisfy metabolic demand. When needs are altered by conditions that increase metabolic demand, the usual rate of synthesis is no longer sufficient and these nutrients become conditionally essential, requiring that supplemental amounts be consumed. Glutamate. As a nonessential amino acid, glutamate is not normally dependent on exogenous sources, thus metabolic competition for this amino acid develops only under conditions of increased demand. For individuals with conditions that involve imbalances in cholinergic activity, the requirement for glutamate is increased to as maintain activity of glutamatergic neurons well as to provide a precursor for production of GABA. Under normal conditions, glutamate can be supplied by several sources including deamination of glutamine; however, glutamate synthesis competes for glutamine with other pathways that utilize it as a precursor of a number of cellular compounds such as the antioxidant glutathione (γglutamylcysteinylglycine), purines, pyrimidines, and urea (Figure 1). These competitive demands for glutamine limit the amount of glutamate and thus the amount of GABA available to function as neurotransmitters. As a source of glutamate, Sentra AM improves metabolic efficiency by ensuring that there are adequate amounts of both neurotransmitters available while conserving the supply of glutamine for its other uses. Figure 1. Competing Pathways of Glutamate Metabolism Sentra AM Choline. Both choline and carnitine are considered nonessential nutrients under normal physiological conditions. When the demand for choline is increased to supply additional precursor for synthesis of acetylcholine, supplemental amounts of choline are needed. Acetylcholine is produced from choline in an 3 P age

4 acetylation reaction catalyzed by choline acetyltransferase with acetyl coenzyme A (CoA) as the acetyl group donor (Figure 3). Figure 2. Biosynthesis of Acetylcholine The primary source of choline normally utilized in the synthesis of acetylcholine is phosphatidylcholine (lecithin), a membrane phospholipid which serves as a reservoir to supply choline for short-term needs (Figure 3). When the demand for acetylcholine exceeds the amount of choline that can be supplied by the hydrolysis of phosphatidylcholine from the membrane pool, dietary choline becomes an increasingly more important source. Sentra AM provides additional amounts of choline to meet the increased needs for acetylcholine when demand is elevated for an extended time period. By supplying an exogenous source of choline, Sentra AM prevents the depletion of membrane phosphatidylcholine and thus preserves the structural integrity of the cell. Figure 3. Sources of Acetylcholine Carnitine. The efficiency of the metabolic response to an increased demand for acetylcholine is enhanced by acetyl-l-carnitine (Figure 4). Acetyl-L-carnitine promotes the synthesis of acetylcholine and 4 P age

5 influences neurotransmitter activity by effects on neurotrophic factors and neurohormones, synaptic morphology, and synaptic transmission of multiple neurotransmitters (5-6). Sufficient amounts of acetyl- L-carnitine can normally be produced from acetylation of carnitine, an amino acid derived from lysine and methionine; however, as essential amino acids, lysine and methionine are utilized by multiple competing pathways and cannot sufficiently accommodate a sustained increase in demand for carnitine. Sentra AM provides acetyl-l-carnitine to ensure that an adequate supply of acetylcholine is available to support increased cholinergic activity without compromising amounts needed for its other roles in neurotransmission. Figure 4. Biosynthesis of Acetylcarnitine The need for carnitine is increased for synthesis of acetylcarnitine to meet the demand for additional acetyl groups to support the increased production of acetylcholine when cholinergic activity is high (Figure 5). Acetyl-L-carnitine is synthesized from carnitine in a reaction similar to acetylcholine synthesis from choline which involves the transfer of an acetyl group from acetyl CoA in an acetylation reaction catalyzed by carnitine acetyltransferase. Sufficient amounts of acetyl-l-carnitine can normally be produced from carnitine, but when the rate of cholinergic activity is elevated over extended periods, the demand for acetyl-l-carnitine cannot be met by endogenous synthesis alone. Sentra AM provides additional acetyl-l-carnitine to sustain an increased rate of acetylcholine synthesis and enhance its activity when the rates of cholinergic-mediated activities are increased. Figure 5. Role of Acetylcarnitine in the Biosynthesis of Acetylcholine 5 P age

6 In addition to its role as an acetyl group donor in the synthesis of acetylcholine, acetyl-l-carnitine also facilitates uptake of acetyl groups by cholinergic neurons. This role involves a membrane transport mechanism similar to that utilized for acetyl group transport in the pathway of fatty acid oxidation. In this pathway, acetylcarnitine serves as a membrane transport carrier of acetyl CoA groups which are released in the cytoplasm as endproducts of β-oxidation to undergo further oxidation by the tricarboxylic acid cycle in the mitochondria. Dosage The recommended dose of Sentra AM is 2 capsules taken in the morning. An additional dose may also be taken during the day if fatigue continues or returns. As with any medical food, the best dosing protocol should be determined by assessment of individual needs. Sentra AM can be taken with other prescription medications. There are no known interactions between Sentra AM and any medication. The amounts of each ingredient consumed at the recommended doses of Sentra AM are presented in Table 1. Table 1. Sentra AM Composition Ingredient mg/kg body weight 1 Choline bitartrate L-glutamate Acetyl-L-carnitine Grape seed extract Cocoa powder Hawthorn berry Dosing range of 2 to 4 capsules daily Side Effects and Contraindications As with any amino acid therapy, headache, nausea, or dry mouth may be experienced by some people after beginning treatment with Sentra AM. These symptoms are mild and temporary, and readily managed by increasing fluid intake. The development of side effects from Sentra AM can be minimized by careful titration of the dosage. All of the ingredients in Sentra AM are regularly consumed in amounts normally found in foods or dietary supplements; therefore development of an adverse reaction to Sentra AM is not expected to occur. 6 P age

7 Abbreviations and Definition of Terms The definitions for the abbreviations and terms referenced in this monograph are summarized in Table 2. Table 2. Abbreviations and Definitions of Terms Term/Abbreviation Antioxidants Autonomic Nervous System Biogenic Amine Cholinergic Circadian Rhythm Excitatory Neurotransmitters Glutamatergic HPA Axis Inhibitory Neurotransmitters Neurotransmitter NMDA Receptor Parasympathetic Nervous System Sarcolemma Suprachiasmatic Nucleus (SCN) Definition Molecules or enzyme systems that inhibit injury to cells from reactive oxygen or nitrogen species Part of the efferent division of the peripheral nervous system but includes visceral afferent neurons; motor component comprises two-neuron system of preganglionic (myelinated) and postganglionic (unmyelinated) neurons; divided structurally and functionally into parasympathetic and sympathetic nervous systems Biologically active substance that contains an amine group but does not have the characteristic structure of an amino acid, i.e., alpha carbon binding both an amino and carboxyl group Neurons that synthesize, package, and release choline A 24-hour cycle of physiological, biochemical, and behavioral processes controlled by the suprachiasmatic nucleus in the hypothalamus Molecules released from presynaptic cells at terminal nerve endings which transmit action potentials to adjacent neurons by depolarization of postsynaptic cell membranes resulting in a decreased stimulus threshold for firing which increases the frequency and rate of transmission of action potentials Neurons that synthesize, package, and release glutamate Hypothalamus-pituitary-adrenal axis; activation stimulates production and release of glucocorticoids; mediates physiological and metabolic responses to stress Molecules released from presynaptic cells at terminal nerve endings which transmit action potentials to adjacent neurons by hyperpolarization of postsynaptic cell membranes resulting in a increased stimulus threshold for firing which decreases the frequency and rate of transmission of action potentials Amino acids, biogenic amines, and other molecules that facilitate communication between the peripheral nervous system, spinal cord, and brain by generating a series of action potentials which are transmitted between neurons N-methyl-D-aspartate receptor; subfamily of glutamatergic receptors which require a coagonist for activation; mediates events that are critical components of pathological and/or prolonged pain states Component of the autonomic nervous system which functions to conserve and restore energy reserves; synaptic transmission mediated by cholinergic receptors; opposes the activity of the sympathetic nervous system; increases during sleep and subsides with waking A two-part membrane surrounding the muscle fiber which forms the synaptic cleft at the neuromuscular junction Bilaterally-paired nuclei in the hypothalamus situated above the point where the optic nerves cross; integrates and synchronizes information from peripheral oscillators which respond to temporal changes in environmental and internal cues such exposure to light, hormone levels, hunger and body temperature, then signals circadian time to the rest of the body 7 P age

8 Term/Abbreviation Sympathetic Nervous System Targeted Cellular Technology Definition Component of the autonomic nervous system which functions to mobilize energy reserves; synaptic transmission mediated by cholinergic and adrenergic receptors; opposes the activity of the parasympathetic nervous system; responsive to stress; activity decreases during sleep and increases with waking A patented process which facilitates endogenous production, uptake, and utilization of neurotransmitter precursors Mechanism of Action Sentra AM has been formulated to provide a balance of neurotransmitters with well-defined roles in the metabolism of acetylcholine. Acetylcholine is the primary neurotransmitter of the sensory and motor circuits in the autonomic nervous system and the neuromuscular junction (7-10). Mechanism of neurotransmitter activity. Neurotransmitters are amino acids, biogenic amines, or amino acid derivatives which function as mediators of physiological responses to physical, chemical, or electrical stimuli. Neurotransmitters are released from storage vesicles in presynaptic neurons in response to action potentials at the distal nerve endings where they bind to receptors on postsynaptic neurons (Figure 6). Neurotransmitter binding alters the resting membrane potential of postsynaptic neurons generating an action potential which is transmitted to the terminal ending of the neuron where the sequence of electrochemical events is repeated until the signal reaches specific processing centers in the brain. The same mechanism of neurotransmitter-mediated electrochemical events is involved in transmission of output from the brain to target effector tissues or organs, and in transmission of signals originating within different regions of brain over the internal circuits between these regions. Figure 6. Neurotransmitter Activity in Presynaptic and Postsynaptic Neurons The rate of signal transmission between presynaptic and postsynaptic neurons in the central and peripheral nervous systems is dependent on the chemical nature of the neurotransmitter involved (7). Excitatory neurotransmitters released from presynaptic nerve terminals depolarize postsynaptic cell membranes which lowers the stimulus threshold for firing and increases the frequency and rate of 8 P age

9 transmission. Inhibitory neurotransmitters have the opposite effect of hyperpolarizing postsynaptic membranes which raises the stimulus threshold and decreases the frequency and rate of transmission. Although neurotransmitters can be classified as excitatory or inhibitory based on the primary effects they have on resting membrane potentials, these classifications do not always predict the response of the effector tissue or organ. Excitatory neurotransmitters can suppress a response by activation of inhibitory mechanisms and inhibitory neurotransmitters can activate a response by suppression of these mechanisms. Imbalances caused by deficiencies in one or more of the excitatory and inhibitory neurotransmitters, or changes in their binding affinities to postsynaptic receptors, will determine the intensity and duration of the signals transmitted (11-15). General roles of neurotransmitters. Acetylcholine has both excitatory and inhibitory effects in the sympathetic nervous system and excitatory effects in all parasympathetically-innervated tissues except cardiac smooth muscle where it acts as an inhibitory neurotransmitter eliciting a decrease in heart rate. Acetylcholine functions as an excitatory neurotransmitter in the hippocampus where memory is regulated and in the prefrontal cortex where arousal and alertness are regulated (16-17). The role of acetylcholine in modulation of arousal and memory as well as pain, stress, sleep, and vigilance also involves interactions with glutamate (8, 18-23). Glutamate is the major excitatory neurotransmitter in the central nervous system with widely distributed receptors in the brain which are concentrated in areas of high cholinergic activity. Under conditions where glutamatergic activity is inhibited, acetylcholine-mediated transmission is stimulated and cholinergic receptors in the hypothalamus are upregulated (8). Acetylcholine. Disorders characterized by muscle pain, fatigue, sleep disturbances, loss of memory, and poor concentration have a common underlying pathology involving deficits in cholinergic activity (24-29). Role in muscle function. Acetylcholine supports muscle function by propagation of autonomic motor impulses over efferent pathways from the brain to the muscle and transmission of sensory information on the length, tension, tone, and velocity of muscle fibers over afferent pathways from the muscle to the brain (9, 30-31). Muscle contraction is initiated by action potentials at distal motor nerve endings which open voltage-gated calcium channels which increases intracellular calcium concentration by allowing a rapid influx of calcium. The resulting increase in intracellular calcium concentration triggers a series of intracellular signaling events that release acetylcholine into the neuromuscular junction where it binds to cholinergic receptors on the motor endplate. Acetylcholine binding opens membrane sodium channels allowing increased sodium influx which depolarizes the postsynaptic membrane. The impulse is then propagated down the muscle fiber by continuation of this sequence of electrochemical events ending in muscle contraction. Role in cognitive function. Acetylcholine is also active in the processes of memory, alertness, and arousal which are regulated in the hypothalamus, hippocampus, and basal forebrain in areas where cholinergic neurons are concentrated proximal to regions of high glutamatergic activity (18, 24, 26, 32). The hypothalamus-pituitary-adrenal axis (HPA) is activated in the paraventricular nucleus of the hypothalamus in these areas of concentrated cholinergic activity by psychological, physiological and environmental stressors which trigger the release of acetylcholine to promote the secretion of 9 P age

10 corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) (8, 24, 26, 33). These neuropeptides bind to receptors on the corticotroph cells of the anterior pituitary triggering the release of ACTH into the systemic circulation for transport to the adrenal cortex where it binds to receptors that stimulate the secretion of glucocorticoids. The subsequent increase in circulating glucocorticoid levels activates metabolic processes that release glucose into the blood which is critical to the control of the flight-or-fight response, immune system activities, and regulation of neurotransmitter systems. The HPA axis and glucocorticoid release. The activation of the HPA axis is terminated by negative feedback circuits involving glucocorticoid binding to receptors in the hypothalamus which suppress CRH release and to receptors in the pituitary which suppress CRH-mediated release of ACTH (24). The effectiveness of these feedback loops may be compromised in chronic stress disorders by long-standing glucocorticoid suppression of CRH release which ultimately results in a blunted adrenal response to ACTH. As a consequence, stressed subjects show higher trough levels of cortisol than normal subjects under the same set of experimental conditions. Patients with chronic fatigue syndrome show a reduction in adrenal glucocorticoid activity which is consistent with a central nervous system defect in activation of the HPA axis that involves suppression of CRH activity in the hypothalamus. When the release of CRH is chronically suppressed, AVP becomes the primary secretagogue regulating ACTH levels. AVP normally acts synergistically with CRH to amplify ACTH release by the pituitary, but it also has a residual effect which stimulates the release of ACTH when CRH secretion is suppressed as long as there is sufficient cholinergic activity to mediate this effect. Modulation of circadian rhythms. Under non-stressed conditions, both glucocorticoid secretion and autonomic activity exhibit diurnal patterns that are coordinated with the sleep/wake cycle suggesting that circadian rhythms are involved in the regulation of these processes (26-27, 34-35). Acetylcholine plays a key role in modulation of circadian rhythm through transmission of signals initiated by changes in light to the suprachiasmatic nucleus (SCN). The SCN consists of bilaterally-paired nuclei comprising more than 20,000 neurons which are situated in the hypothalamus above the point where the optic nerves cross (11-15, 35-37). The SCN is the master clock which integrates and synchronizes input from peripheral oscillators responding to temporal changes in environmental and internal cues such light exposure, hormone levels, hunger, and body temperature, then signals circadian time to the autonomic nervous system and the rest of the body (10-11, 38-39). The SCN also organizes opposing signals from anatomically-separate sympathetic and parasympathetic neurons in the brainstem and paraventricular nucleus of the hypothalamus to determine autonomic output from the brain (10, 38). The pineal gland responds to SCN output by either ramping up or shutting down melatonin production with the corresponding increase or decrease in drowsiness (37, 40). The importance of acetylcholine in the transmission of circadian information in response to changes in light exposure supports a link between deficits in cholinergic activity and dysregulation of autonomic activity and glucocorticoid levels during the sleep/wake cycle (14, 35). Changes in cholinergic activity are closely coordinated with fluctuations in cortisol levels and in sympathetic/parasympathetic balance during periods of sleep and waking. The effects of acetylcholine on the release of CRH in the hypothalamus explains the higher levels of cortisol observed on awakening and the lower levels observed during the night (26). Cortisol concentrations are at the lowest levels at sleep onset when sympathetic activity is 10 P age

11 decreased and parasympathetic activity is increased. Prior to awakening, sympathetic activity increases while parasympathetic activity decreases and cortisol concentration is increased reaching peak levels shortly after awakening (26-27). Elevated cortisol levels promote wakefulness, mental arousal, and alertness and sensitize the HPA axis to negative feedback control (24, 33, 41-44). Glutamate and GABA. Circadian rhythms are also modulated by glutamate and γ-aminobutyric acid (GABA), giving both of these neurotransmitters a role in regulation of the autonomic nervous system, glucocorticoid secretion, and mental alertness and arousal (14, 35, 45). The diurnal balance in the activities of autonomic-innervated organs is therefore regulated by the cooperative effects of acetylcholine, glutamate, and GABA on the circadian input sent to the SCN (13, 35). Imbalances in acetylcholine and glutamate can thus interfere with normal fluctuations in cortisol levels and autonomic nervous system activity over a 24-hour period (14, 35-37). The disruption of normal diurnal patterns of cortisol secretion by impaired cholinergic ganglionic synaptic transmission is an important cause of autonomic failure (46). Scientific Support for Use of Sentra AM in Management of Disorders Involving Acetylcholine Imbalances The use of Sentra AM in the management of chronic and generalized fatigue, fibromyalgia, PTSD, neurotoxicity-induced fatigue syndrome, and impaired neurocognitive processes involving mental arousal, alertness, and memory is supported by experimental and clinical data which have identified specific roles for each ingredient in the metabolism and function of acetylcholine. The observations that clinical syndromes characterized by fatigue often involve musculoskeletal pain and are aggravated by physical or emotional stressors, and that patients with fibromyalgia and chronic fatigue syndrome frequently report sleep disturbances, impaired memory, poor concentration, and an abnormal hormonal response to stress suggest that imbalances in cholinergic activity is a common thread linking these conditions (8, 24-25, 30, 33, 42, 47-49). Acetylcholine and carnitine. Muscle fatigue and weakness reflect a failure of muscle fibers to generate and sustain force reflecting cholinergic deficits in the motor neurons of the brainstem and neuromuscular junction (18). Skeletal muscle dysfunction increases the responsiveness of nocioceptors (pain receptors) to various stimuli contributing to the heightened sensitivity to pain observed in chronic fatigue syndrome and fibromyalgia, and disrupts the balance in neuroendocrine control of the stress response caused by abnormalities in CRH release (42, 49). Administration of exogenous corticosteroids enhances choline uptake by central cholinergic neurons indicating that acetylcholine is involved in the feedback regulation of corticosteroid levels and suggests that this feedback mechanism is less responsive to elevated cortisol levels in chronic disorders characterized by muscle pain and fatigue associated with choline insufficiency. (33, 50). Acetyl-L-carnitine enhances acetylcholine-modulated regulation of cortisol levels under nonstressed conditions by facilitating glucocorticoid binding to receptors in the hippocampus resulting in suppression of CRH release and consequently, the moderation of corticosteroid levels (5). Impaired muscle and neurological functions. Peripheral nerve damage can also compromise muscle function by decreasing the sensitivity of motor neurons to acetylcholine (8). Clinical signs of acute 11 P age

12 cholinergic toxicity are related primarily to central nervous system injury with the resultant neurological and neurobehavioral abnormalities of fatigue, inability to concentrate, memory deficits, confusion, and generalized weakness (33, 51). Neuronal degeneration of hippocampal cells has been observed with organophosphate-induced alterations in behavior and with cognitive deficits such as impaired learning and memory. Acetyl-L-carnitine protects against neurogeneration in the hippocampus by facilitating the neuronal binding of nerve growth factor and by providing a substrate pool of acetyl CoA to generate the increased energy needed for tissue repair (5, 52). The pattern of muscle pain exhibited by patients with fibromyalgia (i.e., tender points) has also been observed in patients with PTSD and increased rates of PTSD are often present in patients with fibromyalgia suggesting a relationship between abnormalities in muscle function and neuroendocrine response to stress characteristic of both conditions (25, 42, 44). Patients with fibromyalgia will typically exhibit more than half of the symptoms associated with PTSD. Moreover, fibromyalgia as well as chronic fatigue syndrome are often associated with psychiatric comorbid conditions including PTSD which may contribute to the development or persistence of symptoms. The relevance of this finding to the pathophysiology of fibromyalgia and chronic fatigue syndrome is that the onset and course of these illnesses are exacerbated by physical and emotional stressors (24). Interactions with glucocorticoids. The muscle pain common to both fibromyalgia and chronic fatigue syndrome has been associated with inappropriate levels of cortisol in response to stress which has been attributed to blunted secretion of cortisol (24, 42, 48). Patients with chronic fatigue syndrome show a general tendency for reduced adrenocortical responsiveness appearing to be a result of prolonged suppression of CRH release in the hypothalamus consistent with a central nervous system defect in activation of the HPA axis rather than a primary adrenal defect or a defect in the negative feedback mechanism of elevated glucocorticoids on ACTH (24, 42). Dysregulation of the HPA axis also contributes to changes in sleep patterns which have been related to psychological stress and frequently reported in patients with fibromyalgia and chronic fatigue syndrome (33, 48-49). The close association between diurnal changes in acetylcholine levels normally observed in non-stressed conditions are closely coordinated with glucocorticoid secretion, mental arousal, and mental alertness (14, 35, 41, 43). Patients with chronic fatigue syndrome and fibromyalgia do not exhibit these normal diurnal fluctuations in plasma cortisol levels but maintain elevated levels throughout the day (24). The disturbances in the sleep cycle in these illnesses in the absence of stress are associated with abnormal fluctuations in plasma cortisol levels suggesting that these pathologies reflect dysregulation of autonomic activity involving the effects of cholinergic deficits on circadian rhythms. After exposure to experimentally-induced psychological stress, sleep patterns were least disturbed in subjects with the highest density of cholinergic neurons in the hypothalamus at the location of the SCN where circadian rhythms are regulated (48).Subtle alterations in HPA axis activity associated with reduced ACTH levels over a full circadian cycle and during the usual morning physiological peak of ACTH secretion have been reported in patients with chronic fatigue syndrome which supports the connection between sleep disturbances and impaired stress responses that are frequently observed in conjunction with muscle pain and fatigue (27-28, 44). 12 P age

13 Disordered autonomic function. The absence of diurnal variations in cortisol levels are accompanied by abnormal circadian patterns in autonomic nervous system activity in fibromyalgia, chronic fatigue syndrome, and PTSD providing additional evidence for the involvement of imbalances in acetylcholine in these disorders (24, 32). Fibromyalgia, chronic fatigue syndrome, and PTSD are increasingly recognized as diseases of disordered autonomic nervous system function in which both sympathetic and parasympathetic activity are suppressed, with a relatively greater suppression of parasympathetic function and thus more pronounced symptoms of sympathetic deficits (42, 47, 49). Exposure to different stressors activates efferent sympathetic pathways concurrently with somatomotor efferent pathways within several regions of the brain including the paraventricular nuclei of the hypothalamus where cholinergic activity is concentrated (30). Disorganization of this somatomotor-sympathetic circuitry may be involved in the maladaptive physiological and emotional responses to stress associated with muscle pain and fatigue. Glutamate and acetylcholine interactions. Interactions between glutamate and acetylcholine have been identified in mechanisms of pain, arousal, vigilance, and memory (8, 18-23). Glutamatergic neurons are widely distributed in the brain and concentrated in areas of high cholinergic activity. Under conditions where glutamatergic receptor activity is inhibited, cholinergic transmission is stimulated and its receptors are upregulated in the hypothalamus (8). Acetylcholine is also a coagonist required for activation of the N-methyl-D-aspartate (NMDA) receptor, a special type of glutamate receptor which modulates a number of processes including pain and memory formation and processing (8, 18). The acetylcholine receptor and the NMDA receptor are co-expressed and anatomically adjacent on cell membranes. Both acetylcholine and glutamate initiate and maintain arousal in the perifomical lateral hypothalamus and both promote vigilance in the basal forebrain through modulation of hypocretin-secreting or orexin-secreting neuron activity which mediate neuroendocrine control of arousal (20-23, 53). Orexins, which are also involved in the stress response, are decreased in hypothalamic disorders (18). Acetylcholine and glutamate stimulate wakefulness through synaptic transmission of light-induced signals to the SCN (8, 34-35). Desynchronization of the wake-promoting effects of glutamate and acetylcholine with the sleep-promoting effects of other neurotransmitters disrupts the normal circadian rhythms which modulate the sleep-wake cycle as well as the activation of the HPA axis and the balanced activity of the autonomic nervous system during periods of sleep and wakefulness (14-15, 34-36, 54). Patients with fibromyalgia who experience sleep disturbances have significantly higher blood glutamine levels than controls indicating that glutamate metabolism may be altered in this disorder (8, 55). Many of the activities integral to the stress response are mediated by glutamate neurotransmission in the prefrontal cortex where components of cognitive function such as working memory and vigilance are regulated suggesting that glutamatergic activity may have a role in mechanisms by which stress affects cognition (26). Disturbances in cholinergic and glutamatergic activity have been implicated in memory defects ( 26, 56-58). Severe damage to the hippocampus in areas where cholinergic and glutamatergic neurons are located creates profound difficulties in forming new memories (anterograde amnesia) and often affects memories formed prior to the damage (retrograde amnesia) (16, 59-60). Memory is also impaired by diminished activity in the cholinergic centers in the hypothalamus and basal forebrain where wakefulness and the ability to concentrate and stay alert are regulated (8, 56, 61-63). Glutamate has an important role in 13 P age

14 modulating the processes that establish long term potentiation (LTP), a form of neural plasticity widely believed to be one of the main neural mechanisms by which memory is stored in the hippocampus (18, 64-65). The hippocampus is one of the first areas of the brain to show damage in Alzheimer s disease, and memory problems and disorientation are among the first symptoms of the disease (18). Disorders of acetylcholine metabolism have also been associated with Alzheimer s Disease and other dementias, and degeneration of cholinergic innervation in the hippocampus and cerebral cortex is a frequent observation (17, 66-70) (59, 71-74). Cholinesterase inhibitors which maintain acetylcholine concentrations in cholinergic synapses to prevent cholinergic deficits are often used in the pharmacological treatment of Alzheimer s disease (70, 75). Carnitine and cholinergic activity. Acetyl-L-carnitine enhances cholinergic activity by promoting the synthesis of acetylcholine and by its own cholinomimetic effects (5). By increasing the availability of acetylcholine, acetyl-l-carnitine acts similarly to cholinesterase inhibitors except that it promotes acetylcholine synthesis instead of inhibiting its hydrolysis. Although the exact mechanism by which acetyl-l-carnitine enhances acetylcholine synthesis by cholinergic neurons has not been identified, it may be similar to the mechanism that stimulates uptake of acetyl CoA by the mitochondria. Cholinergic activity may be further enhanced by acetyl-l-carnitine through effects that block the postsynaptic inhibitor potential of cholinergic receptors. Acetyl-L-carnitine also directly influences synaptic transmission by a mechanism which is independent of acetylcholine involving neurotrophic factors, neurohormones, synaptic morphology, and the coordination of the activities of multiple neurotransmitters (6). A summary of the roles of each of the ingredients in Sentra AM is presented in Table 3. Table 3. Roles of the Sentra AM Ingredients in Acetylcholine-Dependent Activities Ingredient Effector Molecules Effects Roles Choline Acetylcholine Inhibitory neurotransmitter (midbrain reticular formation) Glutamate Glutamate GABA Excitatory neurotransmitter (basal forebrain) Excitatory neurotransmitter Acetyl-L-carnitine Acetyl-L-carnitine Precursor uptake stimulator; cholinomimetic agent Primary neurotransmitter of the autonomic nervous system; initiates muscle contraction; modulates circadian rhythms based on changes in light exposure, activates the HPA axis, and mediates autonomic nervous system activity, memory, alertness, and arousal; promotes vigilance in the basal forebrain; interacts with glutamate and is a coagonist of the NMDA glutamate receptor involved in pain and memory formation and processing Interacts with acetylcholine; modulates circadian rhythms and circadian-driven processes, arousal, alertness, and memory; depolarizes hypocretin (orexin) neurons to stimulate arousal; activates the NMDA receptor Enhances production of acetylcholine; blocks the postsynaptic inhibitor potential of cholinergic receptors; directly stimulates cholinergic synaptic effects; influences neurotrophic factors, neurohormones and synaptic morphology; coordinates the activities of multiple neurotransmitters 14 P age

15 Ingredient Effector Molecules Effects Roles Cocoa Powder caffeine Adenosine antagonist Binds to adenosine receptors to disinhibit the adenosine brake which promotes the inhibitory effect of adenosine on neuronal activity (76-77) Grape seed extract Polyphenols Antioxidant Preserves receptor membrane integrity and prevents attenuation of responses to neurotransmitter precursors (78-80) Hawthorn Berry Flavonoids, oligomeric proanthocyanidins, triterpene acids Antioxidant Preserves receptor membrane integrity (81) Nutritional Requirements in Disorders Involving Acetylcholine Imbalances The nutritional requirements of most interest to patients with chronic disorders associated with muscle pain, fatigue, sleep disturbances, loss of memory, and poor concentration are nutrients and dietary factors that support the effects of acetylcholine on neuromuscular, neurocognitive, and neuroendocrine functions. Sentra AM is formulated with balanced amounts of choline, glutamate, and carnitine, which contribute to or enhance the synthesis and activity of acetylcholine, using Targeted Cellular Technology to control the timing of the release of these ingredients. Balance in the production and release of neurotransmitters is important to neurotransmission because it is the highly integrated functions and complexity of the multiple feedback loops between them that determine the net input received by the brain. These interactions explain why an imbalance in the intake of a nutrient or dietary factor which supports the synthesis or activity of any one neurotransmitter can influence the activities of the others, potentially inducing absolute and relative deficiencies (34, 81-84). Nutrient requirements in disease. 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 (85). 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 (86-94). The degree of coordination between the activities of different neurotransmitters is an important consideration in assessing the amounts of dietary precursors needed (87-88, 90, 94-99). Nutrient effects on neurotransmitter balance and activity. Diseases with pathologies that involve imbalances in neurotransmitters will increase the requirements for certain amino acids and other dietary precursors to restore homeostasis (2, 55, 85-91, ). 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 (88, 95-96, ). 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 15 P age

16 amount of substrate available is the limiting factor in neurotransmitter production (89, ). 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 (96, ). Changes in intakes of the dietary precursors of these neurotransmitters will therefore influence physiological responses by affecting neurotransmitter availability (34, 82, 89, 91-96, 102, 104, ). A large body of peer-reviewed published data supports the basis for increased requirements of glutamate (6, 16, 24, 26, 32, 74, 107, 113) and choline (17, 21, 50, 70-72, 86-88, 90-91, 93, 99, , , ) in conditions which depend on neurotransmitter balance (83, 86-89, 93-99, , ). Patients with fibromyalgia show decreased blood levels of certain amino acids despite maintaining their usual protein intake indicating that the needs for these amino acids are selectively increased in these patients (55). This observation may be explained by the competitive demands for these amino acids by different metabolic pathways which results in a decreased supply of precursors available for neurotransmitter synthesis (See Section on Metabolism in this monograph). Certain physiologic and biochemical mechanisms must exist in order for nutrient consumption to affect neurotransmitter synthesis (136).These conditions are listed below. The extent to which neurotransmitter synthesis in any particular neuron is affected by changes in precursor availability will vary directly with the firing frequency of the neuron. Consequently, precursor administration can produce selective physiologic effects by enhancing neurotransmitter release from some but not all of the neurons potentially capable of utilizing the precursor for the particular effect. It is also useful in predicting when administering the precursor might be useful for amplifying a physiologic process or for treating a pathologic state. Conditions that Support Effects of Dietary Precursors on NeurotransmitterSynthesis 1. Absence of significant feedback control of plasma precursor levels 2. Ability of plasma precursor levels to control influx into or efflux from the central nervous system 3. Presence of a low-affinity (unsaturated) transport system mediating the flux of precursor between blood and brain 4. Low-affinity kinetics of enzyme that initiates conversion of precursor to neurotransmitter 5. Lack of in vivo end-product enzyme inhibition by the neurotransmitter Requirement for choline. Acetylcholine is produced in the terminal endings of cholinergic neurons and in regions of the brain where choline acetyltransferase is concentrated. Under steady state conditions, the brain enzyme is not completely saturated, thus the rate of acetylcholine production is driven by the availability of choline and acetyl CoA (55, 109, 117). Dietary choline is the primary contributor to plasma 16 P age

17 choline levels accounting for a greater proportion of the plasma concentration than de novo synthesis (117, 119, 127, ). The rate of choline transport across the blood brain barrier is increased by an amount proportional to the increase in serum concentration and is followed by an increase in the release of acetylcholine from cholinergic neurons (109). In the brain, most of the free choline is phosphorylated to phosphatidylcholine (lecithin) in order to moderate the rate of acetylcholine synthesis in the presence of increased availability of precursor; however, the appearance of choline in cerebrospinal fluid confirms that there is a pool of free choline in the brain (50, 55, 125). Membrane reserves. Incorporation of choline into membrane phosphatidylcholine provides a ready reserve of precursor for acetylcholine synthesis over periods of short duration (50). Under steady state conditions, most of the choline utilized for acetylcholine synthesis is obtained from hydrolysis of membrane phosphatidylcholine (50, 114, , 137). Dietary choline becomes an increasingly more important source of precursor over prolonged periods as membrane phosphatidylcholine is depleted. If a supplemental source is not provided at this time, cell membrane function will be compromised causing apoptosis (50, 114, 118, , 141). Blood and urine levels. Since changes in choline levels in the blood and urine correspond to changes in dietary choline intake, measurements of choline levels in these body fluids have been used to evaluate choline status following dietary deficiency or augmentation. Low blood levels of choline indicate that the requirements for the dietary precursors are not being met at current levels of intake (50, 109, 119, 126). Serum choline levels are more responsive to supplementation with dietary choline than to a choline deficiency with increases of as much as 52% observed with supplementation (89) compared with decreases of 20% observed with a choline-deficient diet (50). Central nervous system concentrations. Although serum choline levels are decreased by a choline-free diet, brain choline levels remain relatively stable indicating that the brain is given metabolic priority at the expense of other tissues when the amount of free choline available is limited (125). Brain phosphatidylcholine levels decrease in parallel with the decrease in serum choline which further suggests that brain choline concentration is maintained within narrow limits at the expense of larger tissue pools of phosphatidylcholine and other phospholipid precursors (serine and ethanolamine) (50, 119). Data from an experimental study in rats showed that brain choline concentration increased within 5 hours following oral administration of choline chloride (124). The consumption of a choline-free diet for 7 days lowered serum choline and brain phosphatidylcholine concentration suggesting that choline kinase, the controlling enzyme in phospholipid synthesis, is unsaturated with substrate in vivo and thus may serve as a modulator of the response of brain choline concentrations to alterations in the supply of circulating choline. Other studies have confirmed that dietary choline can be utilized by central cholinergic neurons as a precursor of acetylcholine (125). An increase in plasma choline in response to choline supplementation promotes the expression of high affinity choline transporters on cholinergic neurons which regulate the synaptic availability of choline and facilitate the release of acetylcholine from these neurons (50, 141). Synaptic acetylcholine levels are regulated by a negative feedback mechanism in which accumulation of the neurotransmitter inhibits transporter activity on cholinergic neurons to prevent further uptake of 17 P age

18 choline. Anticholinergic drugs such as chlorpromazine, atropine, and cholinesterase inhibitors decrease acetylcholine release by inhibition of these transporters (69, 114, 142). Dietary choline deficiency. Clinical evidence of a human choline deficiency was first reported in adults receiving total parenteral nutrition (TPN) (121, 143). These patients exhibited hepatic morphologic and aminotransferase abnormalities which were reversed by choline-supplemented TPN. The effects of inadequate choline intakes on physiological endpoints are rapidly observed. Clinical signs of deficiency were documented in men with otherwise normal nutritional status after consuming a choline-deficient diet for a period of < 2 weeks (133). Changes in blood and urine markers of organ dysfunction (muscle and liver enzymes) were also been reported in these men. Decreases in plasma levels of choline and phosphatidylcholine accompanied by elevated alanine aminotransferase, a biochemical marker of liver damage, and elevated creatine kinase, a biological marker of muscle damage, have also been observed with a dietary choline deficiency (116, 122, 130, 133, 144). Muscle and liver damage are the most frequently observed signs of an inadequate intake of dietary choline. Fatty liver results from depletion of the phosphatidylcholine pool which limits membrane fatty acid transport leading to fat accumulation. The fragility of phospholipid-depleted membranes and apoptosis are the primary contributors to muscle damage in a choline deficiency (123). Catabolism of phosphatidylcholine drives cellular uptake of choline indicating that increased hydrolysis of the membrane phospholipid signals an increased demand for choline (50). In addition to effects on liver and muscle function, dietary choline deficiency has also been associated with sleep apnea syndromes, disorders of restorative sleep, and memory disorders (86, 105, 109, 130, 132, 145). Age-related memory loss was exacerbated by choline deficiency in rats and mice. In a double blind study conducted in normal college students, explicit memory measured by the number of trials in a serial-learning word test was improved after a single dose of 10 g of choline taken with 25 g phosphatidylcholine (124). Memoryenhancing effects were also observed in a randomized, double-blind, placebo-controlled trial conducted in adults with memory deficits but excluded dementia after supplementation with 1000 mg cytidine diphosphocholine (CDP-choline), a precursor of phosphatidylcholine, The amounts of choline required to maintain cognitive function in humans is unknown and therefore must be individualized for each patient. There is currently no recommended dietary allowance (RDA) for choline; however, based on a review of the available data, the Food and Nutrition Board of the Institute of Medicine has established 550 mg as an adequate intake level for adults, with an upper tolerable limit of 3000 to 3500 mg (146). Since the richest dietary sources of choline are eggs and high fat meats, many adults, particularly women and those who are on fat-restricted diets, are not consuming the recommended amounts (129). A high degree of individual variation in choline requirements may exist. In one study, 10% of subjects required 850 mg/d of choline to prevent clinical signs of muscle and liver damage. Requirement for carnitine. Evidence of acetyl-l-carnitine deficiency has also been documented in patients with fibromyalgia, chronic fatigue syndrome, mild depression (dysthymia), and multiple sclerosis by several clinical studies which reported statistically significant improvements in musculoskeletal pain, fatigue, and memory in these patients after consuming g/d of acetyl-l-carnitine over periods from 8-24 weeks indicating that needs for carnitine were increased by these diseases (134, 145, ). 18 P age

19 The effects of supplemental acetyl-l-carnitine on cognitive function were examined in a study of 23 patients with mild Alzheimer s disease who had been previously nonresponsive to cholinesterase inhibitors. After 3 months of treatment with 2 g/d of acetyl-l-carnitine with a cholinesterase inhibitor, the rate of response to treatment increased from 38% to 50% in this group of patients (52). Improvements in functional status following consumption of supplemental amounts of acetyl-l-carnitine have also been reported in elderly adults (>70 years) with debilitating physical and mental fatigue (148). In a double-blind placebo-controlled trial of 102 patients clinically diagnosed with fibromyalgia, those who received supplemental acetyl-l-carnitine for a 10-week period had statistically significantly fewer numbers of tender points compared with controls and also had significantly lower self-assessed total myalgic scores, a composite measure of fatigue, tiredness upon awakening, and sleep experience (134). Consumption of supplemental dietary carnitine as acetyl-l-choline by 30 patients with chronic fatigue syndrome for 24 weeks in an open-label study found statistically significant improvements in mental fatigue (p=0.014) and general fatigue (p=0.004) in 59% of patients (149). Two weeks after supplementation with acetyl-l-carnitine was stopped, 52% of patients in this study reported a worsening of fatigue. A summary of support for increased needs of specific nutrients in patients with sleep disorders is found in Table 4. Table 4. Observations Supporting Increased Nutrient Requirements in Disorders Involving Imbalances in Acetylcholine Nutrient Blood/Tissue/Urinary Levels Clinical Observations and Associated Biochemical Findings Choline Low blood levels Muscle pain, sleep disturbances, and impaired memory; sleep apnea syndromes and disorders of restorative sleep; decreased parasympathetic autonomic nervous system activity; increased creatine phosphokinase and alanine transaminase; myocyte and lymphocyte apoptosis Glutamate Low blood levels Insomnia, fragmented sleep; anterograde and retrograde amnesia; loss of synaptic inhibition; seizures; GABA deficiency characterized by a basic depressive state, sleep disorders, and other clinical symptoms; loss of synaptic inhibition Carnitine Low plasma levels Muscle pain, morning grogginess, fatigue associated with mild depression (dysthymia), chronic fatigue syndrome, fibromyalgia, Alzheimer's Disease, and multiple sclerosis; cholinergic deficits Clinical Validation of Sentra AM The relationship between intakes of dietary precursors and production of the corresponding neurotransmitters has been validated by observations of improvements in neurotransmitter-mediated clinical outcomes with supplemental intakes of these dietary factors (6 29, 45, 59-60, 83, 87, 89-90, P age

20 94, 97, 99, 106, , 126, 135, 140, ). A change in the levels of a neurotransmitter in the blood and/or its metabolites in cerebrospinal fluid following ingestion of a dietary precursor from a medical food reflect the uptake and utilization of the nutrient or dietary factor for synthesis of the neurotransmitter by target cells, thus demonstrating the biological availability of dietary precursors and the clinical utility of the medical food as a source of these precursors (25, 81, 82, 85, 87, 89, 92-94, 96-98, 106, 108, , 125, , 131, , 145, , , ). The clinical benefits which may be obtained from medical foods can be validated by the observed changes in biological, physiological, and clinical endpoints following ingestion by individuals with specific conditions. If an individual with low blood arginine levels ingests a medical food containing supplemental arginine and subsequently shows an increase in blood levels (biological availability) accompanied by an increase in nitric oxide production (physiological response) followed by improvement in an associated functional parameter (forced expiratory volume in 1 second; FEV 1 ) (clinical response), the clinical benefit of this medical food as a source of precursors of nitric oxide has been validated. Similarly, if an individual with fibromyalgia or chronic fatigue syndrome shows an increase in choline in blood or urine after ingesting a medical food containing choline (biological availability) followed by increased concentrations of acetylcholine or increased cholinergic activity (physiological change) associated with increased muscle strength, normalized diurnal fluctuations in cortisol and autonomic activity (clinical response) or improved memory, the clinical benefit of this medical food as a source of acetylcholine has been validated. Sentra AM has been formulated with specific ratios of choline, glutamate, and acetyl-l-carnitine using Targeted Cellular Technology to control the timing of the release of each ingredient. If sufficient amounts of these nutrients are not available, or their availability is not well-synchronized with demand, deficits in cholinergic activity may develop contributing to muscle pain, fatigue, sleep disturbances, loss of memory, and poor concentration (36, 87). Biological Availability Studies conducted in human subjects have confirmed the bioavailability of choline and carnitine from dietary supplementation. In a study of 11 healthy young men, the concentration of choline-containing compounds in the brain measured by proton MR spectroscopy ( 1 H-MRS) were increased by approximately 6.2% following ingestion of a single dose of 50 mg/kg choline as choline bitartrate (117). This increase in blood levels was equated with a potentially biologically important 10-22% increase in phosphatidylcholine. Peak concentrations of free choline, acetylcholine, glycerophosphocholine, and phosphatidylcholine were achieved 2 hours after choline ingestion. The appearance of choline and acetyl-l-carnitine in cerebrospinal fluid following oral administration has also been reported indicating that dietary sources of these amines are taken up and utilized by the central nervous system (5, 50). 20 P age

21 Physiological Response Changes in parasympathetic nervous system activity relative to sympathetic activity are characteristic of transitions between periods of sleep and wakefulness. The relative activities of the parasympathetic and sympathetic nervous systems can be assessed under different conditions by autonomic nervous system function tests. Because autonomic activity cannot be consciously altered, it is considered an objective tool for identification of abnormalities in parasympathetic and sympathetic activities and the processes which are regulated by these systems. Without intervention, parasympathetic nervous system activity is stable with repeated measurements. Spectral analysis heart rate variability is an autonomic function test which directly measures parasympathetic activity (163). This method analyzes heart rate from rr-intervals for each heartbeat on high resolution 24-hour ECG recordings using a complex mathematical formula (fast Fourier transform. From the analysis, bands that define total heart rate variability or autonomic function (HF band) can be identified. Heart Rate Variability Analysis was used to assess parasympathetic activity in a crossover study of 5 subjects before and after taking Sentra PM for a 60-day period. Changes in parasympathetic activity between midnight and 5:00 AM were plotted against a normal pattern of change as depicted in Figure 10. These subjects showed a normal pattern of change in parasympathetic activity which was similar in magnitude before and after taking Sentra PM. The results of this study indicated that Sentra PM does not alter the normal increase in parasympathetic activity observed during sleep by a statistically significantly amount in subjects who do not show an abnormal pattern at baseline. This observation is consistent with the pattern of parasympathetic activity that would be expected from a normal sleep pattern reflecting balanced activity of neurotransmitters that modulate circadian rhythms and thus autonomic balance. Parasympathetic activity was also measured by heart rate variability analysis in an open-label study of patients with fibromyalgia who exhibited abnormal parasympathetic nervous system function at baseline. Treatment with Sentra AM normalized parasympathetic activity in these patients, which amounted to a 40% increase in parasympathetic activity from baseline compared with a 20% decrease in controls. (Figure 7). This difference was statistically significant (p<0.001). 21 P age

22 Figure 7. Effect of Sentra AM on Parasympathetic Function Percent change in HF Band Controls Sentra AM -40 p< Parasympahtetic Function Measured by HF Band on HIgh Resolution 24-hour ECG Monitoring-3 Month Treatment The effects of Sentra AM on acetylcholine metabolism were also tested by measurement of parasympathetic activity in patients who had a fibromyalgia-like syndrome associated with exposure to an environmental toxin. The results were compared to a control group of fibromyalgia patients from the same community who were not exposed to the toxic agent. Quantitative audio vestibular testing was used to confirm defects in parasympathetic function. Brain concentrations of choline and glutamate were measured in a double-blind manner using high resolution positron emission tomography (PET) scanning and quantitative spectral magnetic resonance imaging (MRI). The PET scans revealed abnormalities at the origin of the vagus nerve, the hypothalamus, and cerebella-midbrain connections in patients exposed to the toxin at sites where concentrations of both choline and glutamate were reduced (Figure 8 and Figure 9). 22 P age

23 Figure 8. Results of PET Scans of Patients with Fibromyalgia: Neurotoxicity vs. Controls 23 P age

24 Figure 9. Results of PET Scans of Patients with Fibromyalgia: Neurotoxicity vs. Controls Clinical Response Symptoms of chronic fatigue and fibromyalgia are associated with reduced parasympathetic function accompanied by reduced choline concentration in the brain. Parasympathetic nervous system abnormalities in patients with reduced acetylcholine function at baseline were normalized by treatment with Sentra AM as confirmed by the results of heart rate variability analysis, PET scans, and spectral MRI data. At the same time, symptoms of fatigue, temperature dysregulation, memory dysfunction, cognitive function, and concentration were also improved. Selected References 1. Borgonio A, Witte K, Stahrenberg R, Lemmer B. Influence of circadian time, ageing, and hypertension on the urinary excretion of nitric oxide metabolites in rats. Mech Ageing Dev 1999;111: Brown DW. Abnormal fluctuations of acetylcholine and serotonin. Med Hypotheses 1993;40: Brown RE, Stevens DR, Haas HL. The physiology of brain histamine. Prog Neurobiol 2001;63: Tangphao O, Chalon S, Coulston AM et al. L-arginine and nitric oxide-related compounds in plasma: comparison of normal and arginine-free diets in a 24-h crossover study. Vasc Med 1999;4: P age

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