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��#ࡱ#�################>###�� ############# ###�###########�#######����####�###�###�###�###�###�###�###�###�###�###�###�###� �������������������������������������������������������������������������������� �������������������������������������������������������������������������������� �������������������������������������������������������������������������������� �������������������������������������������������������������������������������� ���������������������������������������������������������������������#q`####�#�# ##############��####bjbjqPqP################## ###.�###:###:##��##############################��##########��##########��####### ###########�#####f#######f###f#######f#######f#######f#######f###############r ##�!###�#######�#######�#######�##�##### ƒ �###6.######h! ##�###ʄ##�4##f�######f�######f�######f�######A�##�###'�##�###��##D###� ######� ######� ######� ######� ######� ######� ##$####"##h###�$##R###! ######################f########�######################A�######A�#######�#######� ######!##############f#######f#######f�##############f�##�###"! ######�#######�#######�########�######f#######f�######f#######f�######� ##############�########################################################�######� ##############�###############�#######f#######f################################# ##############################�#######f�######��## ### #���##########�#######�##� ##�###############�###�###8!##0###h! ######�#######�$##########�###�$######�######################################### ##############################�###�###�$##############f#######�#######��##�###u� ##�###�#######��######��######################################��######��######�� ######!######!######################################�### ###################################��######��######��######h! #######�#######�#######�#######�##############6.######6.######6.##$H##Zv##� ##6.######6.######6.######Zv######z###�###^ ######n ######f#######f#######f#######f#######f#######f#######����###### ################################################################################ ################################################################################ ################################################################################ ################################################################################ ################################################################################ ################################################################################ ################################################################################ ###################Section XIII. The VitaminsOverviewThe diet is the source of some 40 nutrients for human beings. These classically are divided into energyyielding dietary components (carbohydrates, fats, and proteins), sources of essential and nonessential amino acids (proteins), essential unsaturated fatty acids (fats), minerals (including trace minerals), and vitamins (water-soluble and fat-soluble organic compounds) (see # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519735%22);" #Shils et al., 1999#). Vitamins, despite their diverse chemical composition, can be defined as organic substances that must be provided in small quantities from the environment because either they cannot be synthesized de novo in human beings or their rate of synthesis is inadequate for the maintenance of health [e.g., the production of nicotinic acid (# HYPERLINK "javascript:showDrugInfo(1473);" #niacin#) from tryptophan]. In most cases, the environmental source is the diet, but an obvious exception to this general rule is the endogenous synthesis of vitamin D under the influence of ultraviolet light. This definition differentiates vitamins from essential trace minerals, which are inorganic nutrients needed in small quantities. It also excludes the essential amino acids, which are organic substances needed preformed in the diet in much larger quantities. The term vitamin is restricted here to include only organic substances required for the nutrition of mammals; substances required only by microorganisms and cells in culture should be defined as growth factors, to prevent scientifically unsound claims for their therapeutic benefit as vitamins for human beings. When the vitamin occurs in more than one chemical form (e.g., # HYPERLINK "javascript:showDrugInfo(531);" #pyridoxine#, pyridoxal, pyridoxamine) or as a precursor (e.g., carotene for # HYPERLINK "javascript:showDrugInfo(648);" #vitamin A#), these analogs sometimes are referred to as vitamers.Although the individual vitamins differ widely in structure and function, some general statements do apply. Water-soluble vitamins are stored to only a limited extent, and frequent consumption is necessary to maintain saturation of tissues. Fatsoluble vitamins can be stored to massive degrees, and this property confers upon them a potential for serious toxicity that greatly exceeds that of the water-soluble group. As consumed, many vitamins are not biologically active and require processing in vivo. In the case of several water-soluble vitamins, activation includes phosphorylation (# HYPERLINK "javascript:showDrugInfo(601);" #thiamine#, # HYPERLINK "javascript:showDrugInfo(543);" #riboflavin#, nicotinic acid, # HYPERLINK "javascript:showDrugInfo(531);" #pyridoxine#) and also may require coupling to purine or pyridine nucleotides (riboflavin, nicotinic acid). In their major known actions, water-soluble vitamins participate as cofactors for specific enzymes, whereas at least two fat-soluble vitamins, A and D, behave more like hormones and interact with specific intracellular receptors in their target tissues.##Vitamin RequirementsDietary Reference IntakesIn many countries throughout the world, scientific committees periodically assess the evidence about the requirements of the population for individual nutrients. In the United States, the Food and Nutrition Board of the Institute of Medicine, National Academy of Sciences, with active involvement of Health Canada are taking a new approach to the Recommended Dietary Allowances (RDAs) that have been published since 1941. The development of Dietary Reference Intakes (DRIs) expands and replaces the RDA. DRIs are a family of reference values that are quantitative estimates of nutrient intakes designed to be used for planning and assessing diets for healthy people. They include RDAs as goals for intake of individuals, but also present three new types of reference values. These include Adequate Intake (AI), the Tolerable Upper Intake Level (UL), and the Estimated Average Requirement (EAR) (# HYPERLINK "Javascript:reloadParent(%22content.aspx? aID=519728%22);" #Yates et al., 1998#).The Food and Nutrition Board has embarked on a multiyear project to expand the framework for quantitative recommendations regarding nutrient intake, which includes evaluating both nutrients and other food components for impact on health. The review goes beyond criteria needed to prevent classical deficiencies and includes review of data related to risk of chronic diseases.Current recommendations for males and females of different ages are summarized in # HYPERLINK "javascript:windowReference('Reference', %20'popup.aspx?aID=519702');" #Tables XIII�1#, # HYPERLINK "javascript:windowReference('Reference',%20'popup.aspx?aID=519703');" #XIII�2#, and # HYPERLINK "javascript:windowReference('Reference',%20'popup.aspx? aID=519704');" #XIII�3#. # HYPERLINK "javascript:windowReference('Reference', %20'popup.aspx?aID=519702');" #Table XIII�1# contains RDAs for those nutrients yet to be reviewed by the DRI committee. # HYPERLINK "javascript:windowReference('Reference',%20'popup.aspx?aID=519703');" #Table XIII�2# contains the newly revised recommended intakes. Age groupings have been changed from the earlier RDA publications. Finally, # HYPERLINK "javascript:windowReference('Reference',%20'popup.aspx?aID=519704');" #Table XIII�3# contains the ULs for the newly revised intakes. The RDA for a given nutrient, which is an individual intake goal, represents the intake at which the risk of inadequacy is very small, about 2% to 3% of the population. Those with intakes below the recommended allowance will not necessarily develop a deficiency; however, their long-term risk of deficiency rises in proportion to the degree to which the recommended allowance is not met.Intakes at the level of RDAs or AIs would not necessarily be expected to replete an undernourished individual, nor would it be adequate for disease states which lead to increased requirements. Because the DRIs are based on data from the U.S. and Canada, they may not apply globally where food and indigenous practices may result in different bioavailability of nutrients.The tolerable upper intake level (ULs) is the highest level of daily intake that is likely to pose no risk of adverse health effects to most individuals. ULs are useful because of increased interest in and availability of fortified foods and continued use of dietary supplements. As the standing committee on the scientific evaluation of DRIs of the Food and Nutrition Board completes the review of each set of nutrients, reports are issued. For up-to-date information about these reports visit the Food and Nutrition Board home page at # HYPERLINK "http://www.nas.edu/iom/fnb" \t "_blank" #http://www.nas.edu/iom/fnb#.##Federal Regulations on Vitamins and MineralsThe United States Food and Drug Administration (FDA), under the authority of the Federal Food, Drug, and Cosmetic Act, regulates the labeling of vitamin and mineral products sold as foods or drugs. The Nutrition Labeling and Education Act of 1990 (NLEA), with the final rules published in the Federal Register in early 1993, has led to nutrition labeling on virtually all packaged food, new nomenclature for declaring nutrient contents using the term Daily Values (DVs), and a series of disease-specific health claims. The FDA has only limited authority to control the nutrient content of supplements, except those intended for use by children under 12 years of age and by pregnant or lactating women. However, because of uniform labeling procedures, the purchaser can determine what proportion of the recommended daily allowance for each nutrient is provided by a given amount of the food.The use of vitamins and other nutrients to treat disease comes under FDA review, either as foods for special dietary use, including food supplements, or as "over-the-counter" or prescription drugs, depending on the purposes for which the product is intended and the claims made for it. Nutrient products designed specifically for special application in medical treatment, such as parenteral solutions for hyperalimentation and so-called medical foods (e.g., defined formula diets), are evaluated for safety and efficacy, as are "over-the-counter" drugs containing vitamins and minerals.Dietary supplements are used by more than 50% of the U.S. population (# HYPERLINK "Javascript:reloadParent(%22content.aspx? aID=519734%22);" #Report of the Commission on Dietary Supplement Labels, 1997#). The most commonly used supplements are vitamins and minerals. Forty-seven percent of the U.S. population takes a vitamin and/or mineral supplement (# HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519727%22);" #USDA's 1994�1996 Continuing Survey of Food Intakes by Individuals, 1999#). The intense interest in supplements by consumers and those who market them has put pressure on Congress to keep this area free of regulation. The history of supplement regulation shows efforts by the FDA to regulate the potency and combinations of marketed nutrients and Congress taking action to prevent regulation.The Dietary Supplement Health and Education Act (DSHEA) resulted in substantial deregulation of supplement marketing and the assertions that can be made about their benefits (# HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519729%22);" #Bass and Young, 1996#). DSHEA broadens the definition of dietary supplements, which includes vitamins and minerals, and maintains their regulation as foods. Thus, a supplement must be safe under the conditions recommended on the label or under ordinary conditions of use. The responsibility for safety is placed on the manufacturer. This changes the FDA regulating procedure for supplements from one of preclearance to policing (see # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=410451%22);" #Chapter 3: Principles of Therapeutics#).##Range of Intakes of Vitamins and MineralsMany millions of individuals living in the United States regularly ingest quantities of vitamins vastly in excess of the RDA. One reason some people take vitamin supplements is the erroneous belief that such preparations provide extra energy and make one "feel better." This evidence of widespread nutritional self-medication should be kept in mind when taking a medication history from a patient.The use of vitamin supplements is medically advisable in a variety of circumstances where vitamin deficiencies are likely to occur. Such situations may arise from inadequate intake, malabsorption, increased tissue needs, or inborn errors of metabolism (see # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519724%22);" #Position of the American Dietetic Association, 1996#). In practice, these causes may overlap, as in the case of the alcoholic, who may have both inadequate food intake and impaired absorption. The patient who requires longterm total parenteral nutrition is absolutely dependent on supplemental vitamins added to the infusates. Unfortunately, a serious undersupply of parenteral multivitamin preparations in the United States has made it difficult to meet clinical demand.While gross vitamin deficiencies due to inadequate intakes are encountered in underdeveloped areas of the world, few florid cases are seen in the United States. Ongoing surveillance of dietary intake is conducted periodically by the United States government. Mean intakes consistently exceed RDA for several major vitamins (# HYPERLINK "javascript:showDrugInfo(648);" #vitamin A#, # HYPERLINK "javascript:showDrugInfo(601);" #thiamine#, # HYPERLINK "javascript:showDrugInfo(543);" #riboflavin#, # HYPERLINK "javascript:showDrugInfo(1473);" #niacin#, and # HYPERLINK "javascript:showDrugInfo(42);" #ascorbic acid#). Individuals living below the poverty level, particularly the elderly and ethnic minorities, may have a substantially greater risk of inadequate intake of some vitamins, especially vitamins A and C.Certain individuals are exposed to deficient intakes of vitamins as a result of eccentric diets, such as food faddism, and the avoidance of food because of anorexia. Intakes of vitamins less than those recommended also can occur in subjects on reducing diets and among elderly people who eat little food for economic or social reasons. The consumption of excessive amounts of alcohol also can lead to inadequate intakes of vitamins and other nutrients. Malabsorption of vitamins also is seen in various conditions. Examples include hepatobiliary and pancreatic diseases, prolonged diarrheal illness, hyperthyroidism, pernicious anemia, sprue, and intestinal bypass operations. Moreover, since a substantial proportion of vitamin K and # HYPERLINK "javascript:showDrugInfo(3230);" #biotin# is synthesized by the bacteria of the gastrointestinal tract, treatment with antimicrobial agents that alter the intestinal bacterial flora inevitably leads to decreased availability of these vitamins.Increased tissue requirements for vitamins may cause a nutritional deficiency to develop despite the ingestion of a diet that previously had been adequate. For example, requirements for some vitamins may be altered by the use of certain antivitamin drugs, such as the interference with the utilization of # HYPERLINK "javascript:showDrugInfo(266);" #folic acid# by # HYPERLINK "javascript:showDrugInfo(631);" #trimethoprim# (see # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519725%22);" #Roe, 1981#). Diseases associated with an increased metabolic rate, such as hyperthyroidism and conditions accompanied by fever or tissue wasting, also increase the body's requirements for vitamins.Finally, an increasing number of cases are recorded in which genetic abnormalities lead to an increased need for a vitamin. This often is due to an abnormality in the structure of an enzyme for which the vitamin provides a cofactor, leading to a decreased affinity of the abnormal enzyme protein for the cofactor (# HYPERLINK "Javascript:reloadParent(%22content.aspx? aID=519726%22);" #Scriver, 1973#).The impact of disease on requirements for nutrients may vary according to its phase and intensity. The need for therapy with vitamins may change throughout the course of the illness; eventually, cure should be associated with cessation of this therapy.##Chapter 63. Water-Soluble Vitamins: The Vitamin B Complex and Ascorbic AcidOverviewThis chapter provides a summary of physiological and therapeutic roles of members of the vitamin B complex and of # HYPERLINK "javascript:showDrugInfo(42);" #vitamin C#. The vitamin B complex comprises a large number of compounds that differ extensively in chemical structure and biological action. They were grouped in a single class because they originally were isolated from the same sources, notably liver and yeast. There are traditionally eleven members of the vitamin B complex�namely, # HYPERLINK "javascript:showDrugInfo(601);" #thiamine#, # HYPERLINK "javascript:showDrugInfo(543);" #riboflavin#, nicotinic acid, # HYPERLINK "javascript:showDrugInfo(531);" #pyridoxine#, # HYPERLINK "javascript:showDrugInfo(465);" #pantothenic acid#, # HYPERLINK "javascript:showDrugInfo(3230);" #biotin#, # HYPERLINK "javascript:showDrugInfo(266);" #folic acid#, # HYPERLINK "javascript:showDrugInfo(154);" #cyanocobalamin#, # HYPERLINK "javascript:showDrugInfo(3065);" #choline#, inositol, and paraaminobenzoic acid. Paraaminobenzoic acid is not considered in this chapter, as it is not a true vitamin for any mammalian species but is a growth factor for certain bacteria, where it is a precursor for folic acid synthesis. Although not a traditional member of the group, carnitine also is considered in this chapter because of its biosynthetic relationship to choline and the recent recognition of deficiency states. Folic acid and cyanocobalamin are considered in # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=516112%22);" #Chapter 54: Hematopoietic Agents: Growth Factors, Minerals, and Vitamins# because of their special function in hematopoiesis. Vitamin C is especially concentrated in citrus fruits and thus is obtained mostly from sources differing from those of members of the vitamin B complex.##The Vitamin B ComplexThiamineHistory# HYPERLINK "javascript:showDrugInfo(601);" #Thiamine#, or # HYPERLINK "javascript:showDrugInfo(601);" #vitamin B1#, was the first member of the vitamin B complex to be identified. Lack of thiamine produces a form of polyneuritis known as beriberi; this disease became widespread in East Asia in the nineteenth century due to the introduction of steam-powered rice mills, which produced polished rice lacking the vitamin-rich husk. A dietary cause for the disease was first indicated in 1880, when Admiral Takaki greatly reduced the incidence of beriberi in the Japanese Navy by adding fish, meat, barley, and vegetables to the sailors' diet of polished rice. In 1897, Eijkman, a Dutch physician working in Java where beriberi also was common, showed that fowl fed polished rice develop a polyneuritis similar to beriberi and that it could be cured by adding the rice polishings (husks) or an aqueous extract of the polishings back into the diet. He also demonstrated that rice polishings could cure beriberi in human beings.In 1911, Funk isolated a highly concentrated form of the active factor and recognized that it belonged to a new class of food factors, which he called vitamines, later shortened to vitamins. The active factor subsequently was named # HYPERLINK "javascript:showDrugInfo(601);" #vitamin B1#; in 1926 it was isolated in crystalline form by Jansen and Donath, and in 1936 its structure was determined by Williams. The Council on Pharmacy and Chemistry adopted the name # HYPERLINK "javascript:showDrugInfo(601);" #thiamine# to designate crystalline vitamin B1.Chemistry# HYPERLINK "javascript:showDrugInfo(601);" #Thiamine# contains a pyrimidine and a thiazole nucleus linked by a methylene bridge. Thiamine functions in the body in the form of the coenzyme thiamine pyrophosphate (TPP). The structures of thiamine and thiamine pyrophosphate are as follows:# INCLUDEPICTURE "http://www.accessmedicine.com/loadBinary.aspx?filename=good_c063if001.gif" \* MERGEFORMATINET ###The conversion of # HYPERLINK "javascript:showDrugInfo(601);" #thiamine# to its coenzyme form is carried out by the enzyme thiamine diphosphokinase, with # HYPERLINK "javascript:showDrugInfo(9);" #adenosine# triphosphate (ATP) as the pyrophosphate (PP) donor. Antimetabolites to thiamine that inhibit this enzyme have been synthesized. The most important of these are neopyrithiamine(pyrithiamine) and oxythiamine.Pharmacological Actions# HYPERLINK "javascript:showDrugInfo(601);" #Thiamine# is practically devoid of pharmacodynamic actions when given in usual therapeutic doses; even large doses produce no discernible effects. Isolated clinical reports of toxic reactions to the long-term parenteral administration of thiamine probably represent rare instances of hypersensitivity.Physiological FunctionsThe vitamins of the B complex function in intermediary metabolism in many essential reactions; some of these functions are summarized in # HYPERLINK "javascript:windowReference('Reference',%20'popup.aspx?aID=519624');" #Figure 63�1#. # HYPERLINK "javascript:showDrugInfo(601);" #Thiamine# pyrophosphate, the physiologically active form of thiamine, functions in carbohydrate metabolism as a coenzyme in the decarboxylation of # INCLUDEPICTURE "http://www.accessmedicine.com/images/special/alphalower.gif" \* MERGEFORMATINET ###-keto acids such as pyruvate and # INCLUDEPICTURE "http://www.accessmedicine.com/images/special/alphalower.gif" \* MERGEFORMATINET ###-ketoglutarate and in the utilization of pentose in the hexose monophosphate shunt; the latter function involves the thiamine pyrophosphate�dependent enzyme transketolase. Several metabolic changes of clinical importance can be related directly to the biochemical action of thiamine. In thiamine deficiency, the oxidation of # INCLUDEPICTURE "http://www.accessmedicine.com/images/special/alphalower.gif" \* MERGEFORMATINET ###-keto acids is impaired, and an increase in the concentration of pyruvate in the blood has been used as one of the diagnostic signs of the deficiency state. A more specific diagnostic test for thiamine deficiency is based upon measurement of transketolase activity in erythrocytes (# HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519637%22);" #Brin, 1968#). The requirement for thiamine is related to metabolic rate and is greatest when carbohydrate is the source of energy. This fact is of practical significance for patients who are maintained by parenteral nutrition and who thereby receive a substantial portion of their calories in the form of dextrose. Such patients should be given a generous allowance of the vitamin.# HYPERLINK "javascript:windowReference('Reference',%20'popup.aspx?aID=519624');" ## INCLUDEPICTURE "http://www.accessmedicine.com/loadBinary.aspx? name=good&filename=good_c063f001t.gif" \* MERGEFORMATINET ####�# HYPERLINK "javascript:windowReference('Reference',%20'popup.aspx?aID=519624');" #Figure 63�1. Some Major Metabolic Pathways Involving Coenzymes Formed from WaterSoluble VItamins.#�(Abbreviations are defined in the text throughout this chapter.)#Symptoms of DeficiencySevere # HYPERLINK "javascript:showDrugInfo(601);" #thiamine# deficiency leads to the condition known as beriberi. In Asia, this is due to consumption of diets of polished rice, which are deficient in the vitamin. In Europe and North America, thiamine deficiency is seen most commonly in alcoholics, although patients with chronic renal failure on dialysis and patients receiving total parenteral nutrition also may be at risk. A severe form of acute thiamine deficiency also can occur in infants.The major symptoms of # HYPERLINK "javascript:showDrugInfo(601);" #thiamine# deficiency are related to the nervous system (dry beriberi) and to the cardiovascular system (wet beriberi). Many of the neurological signs and symptoms are characteristic of peripheral neuritis, with sensory disturbances in the extremities, including localized areas of hyperesthesia or anesthesia. Muscle strength is lost gradually and may result in wrist-drop or complete paralysis of a limb. Personality disturbances, depression, lack of initiative, and poor memory also may result from lack of the vitamin, as may syndromes as extreme as Wernicke's encephalopathy and Korsakoff's psychosis (see below). Cardiovascular symptoms can be prominent and include dyspnea on exertion, palpitation, tachycardia, and other cardiac abnormalities characterized by an abnormal electrocardiogram (ECG) (chiefly low R-wave voltage, T-wave inversion, and prolongation of the Q-T interval) and cardiac failure of the high-output type. Such failure has been termed wet beriberi; there is extensive edema, largely as a result of hypoproteinemia from an inadequate intake of protein or concomitant liver disease together with failing ventricular function.Absorption, Fate, and ExcretionAbsorption of the usual dietary amounts of # HYPERLINK "javascript:showDrugInfo(601);" #thiamine# from the gastrointestinal tract occurs by carrier-mediated active transport (# HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519662%22);" #Said et al., 1999#); at higher concentrations, passive diffusion also is significant (# HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519661%22);" #Rindi and Ventura, 1972#). Absorption usually is limited to a maximal daily amount of 8 to 15 mg, but this amount can be exceeded by oral administration in divided doses with food. Cellular thiamine uptake is mediated by a specific plasma membrane transporter, which recently has been cloned (# HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519640%22);" #Diaz et al., 1999#; # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519641%22);" #Dutta et al., 1999#).In adults, approximately 1 mg of # HYPERLINK "javascript:showDrugInfo(601);" #thiamine# per day is completely degraded by the tissues, and this is roughly the minimal daily requirement. When intake is at this low level, little or no thiamine is excreted in the urine. When intake exceeds the minimal requirement, tissue stores are first saturated. Thereafter, the excess appears quantitatively in the urine as intact thiamine or as pyrimidine, which arises from degradation of the thiamine molecule. As the intake of thiamine is increased further, more of the excess is excreted unchanged.Therapeutic UsesThe only established therapeutic use of # HYPERLINK "javascript:showDrugInfo(601);" #thiamine# is in the treatment or the prophylaxis of thiamine deficiency. To correct the disorder as rapidly as possible, intravenous doses as large as 100 mg per liter of parenteral fluid commonly are used. Once thiamine deficiency has been corrected, there is no need for parenteral injection or the administration of amounts in excess of daily requirements except in instances when gastrointestinal disturbances preclude the ingestion or absorption of adequate amounts of vitamin.The syndromes of # HYPERLINK "javascript:showDrugInfo(601);" #thiamine# deficiency seen clinically can range from beriberi through Wernicke's encephalopathy and Korsakoff's syndrome to alcoholic polyneuropathy. Because normal metabolism of carbohydrate results in consumption of thiamine, it has been observed repeatedly that administration of # HYPERLINK "javascript:showDrugInfo(2458);" #glucose# may precipitate acute symptoms of thiamine deficiency in marginally nourished subjects. This also has been noted during the correction of endogenous hyperglycemia. Thus, in any individual whose thiamine status may be suspect, the vitamin should be given before or along with dextrose-containing fluids; all alcoholic patients seen in an emergency room should routinely receive 50 to 100 mg of thiamine. The clinical findings depend on the amount of deprivation. Encephalopathy and Korsakoff's syndrome result from severe deprivation, whereas beriberi heart disease occurs in less-deficient subjects; polyneuritis is observed in milder deprivation. The following discussion describes briefly the varieties of thiamine deficiency and their treatment.Alcoholic Neuritis Alcoholism is the most common cause of # HYPERLINK "javascript:showDrugInfo(601);" #thiamine# deficiency in the United States. Alcoholic neuritis is caused by an inadequate intake of thiamine. Two factors contribute to such inadequate intake in the chronic alcoholic: (1) Appetite usually is poor, so food consumption drops; and (2) a large portion of the caloric intake is in the form of alcohol. The symptoms of neurological involvement in alcoholics are those of a polyneuritis with motor and sensory defects. Wernicke's syndrome is an additional serious consequence of alcoholism and thiamine deficiency. Certain characteristic signs of this disease, notably ophthalmoplegia, nystagmus, and ataxia, respond rapidly to the administration of thiamine but to no other vitamin. Wernicke's syndrome may be accompanied by an acute global confusional state that also may respond to thiamine. Left untreated, Wernicke's encephalopathy frequently leads to a chronic disorder in which learning and memory are impaired out of proportion to other cognitive functions in the otherwise alert and responsive patient. This disorder (Korsakoff's psychosis) is characterized by confabulation, and it is less likely to be reversible once established (# HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519687%22);" #Victor et al., 1971#). Although the thiamine stores of some patients with Wernicke's encephalopathy are similar to those in patients without neurological findings, it has been found that patients with Wernicke's encephalopathy have an abnormality in the thiamine-dependent enzyme transketolase (see # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519675%22);" #Haas, 1988#). In such instances, marginal concentrations of thiamine might produce serious neurological damage. The prevalence of Wernicke's encephalopathy in Australia decreased following the introduction of thiamine-enriched flour (# HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519652%22);" #Harper et al., 1998#).Chronic alcoholics with polyneuritis and motor or sensory defects should receive up to 40 mg of oral # HYPERLINK "javascript:showDrugInfo(601);" #thiamine# daily. The Wernicke-Korsakoff syndrome represents an acute emergency that should be treated with daily doses of at least 100 mg of the vitamin, intravenously.Infantile Beriberi# HYPERLINK "javascript:showDrugInfo(601);" #Thiamine# deficiency also occurs as an acute disease in infancy and may run a rapid and fulminating course. Although rare in modern societies, infantile beriberi has been a common cause of infant death throughout this century in regions where rice consumption is high. It still is of significance in Third World countries and is related to the low content of thiamine in breast milk of thiamine-deficient women. The onset consists of loss of appetite, vomiting, and greenish stools, followed by paroxysmal attacks of muscular rigidity. Aphonia due to loss of laryngeal nerve function is a diagnostic feature. Signs of cardiac involvement are prominent, and death may occur within 12 to 24 hours unless vigorous treatment is instituted. Infants with mild forms of this condition respond to oral therapy with 10 mg of thiamine daily. If acute collapse occurs, doses of 25 mg intravenously can be given cautiously, but the prognosis remains poor.Subacute Necrotizing EncephalomyelopathyThis is a fatal inherited disease of children. Neuropathological features resemble those of the Wernicke-Korsakoff syndrome, and clinical features include difficulties with feeding and swallowing, vomiting, hypotonia, external ophthalmoplegia, peripheral neuropathy, and seizures. Although the syndrome may have multiple causes, the distribution of lesions and the elevated plasma concentrations of pyruvate and lactate suggest a pathogenetic relationship to # HYPERLINK "javascript:showDrugInfo(601);" #thiamine#; however, this remains unproven (see # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519675%22);" #Haas, 1988#). Some cases appear to be caused by a circulating inhibitor of the enzyme that synthesizes thiamine triphosphate from thiamine pyrophosphate in the nervous system. Metabolic abnormalities also have been found in tissue samples from affected infants, including defects in pyruvate dehydrogenase and cytochrome c-oxidase (# HYPERLINK "Javascript:reloadParent(%22content.aspx? aID=519656%22);" #Medina et al., 1990#). Other inborn errors of metabolism that are sensitive to the administration of thiamine also have been described (see # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519683%22);" #Scriver, 1973#).Cardiovascular DiseaseCardiovascular disease of nutritional origin is observed in chronic alcoholics, pregnant women, persons with gastrointestinal disorders, and those whose diet is deficient for other reasons. When the diagnosis of cardiovascular disease due to # HYPERLINK "javascript:showDrugInfo(601);" #thiamine# deficiency has been made correctly, the response to the administration of thiamine is striking. One of the pathognomonic features of the syndrome is an increased blood flow due to arteriolar dilation. Within a few hours after the administration of thiamine, the cardiac output is reduced and the utilization of oxygen begins to return to normal. If edema is present and due to myocardial insufficiency, diuresis results after proper therapy. However, individuals suffering from a chronic deficiency may require protracted treatment. The usual dose of thiamine is 10 to 30 mg three times daily, given parenterally. The dosage can be reduced and the patient maintained on oral medication or by dietary management after signs of the deficiency state have been reversed. It is emphasized that administration of # HYPERLINK "javascript:showDrugInfo(2458);" #glucose# may precipitate heart failure in individuals with marginal thiamine status. All patients potentially in this category should receive thiamine prophylactically; 100 mg is commonly given intramuscularly or added to the first few liters of intravenous fluid. Gastrointestinal DisordersIn experimental and clinical beriberi, certain symptoms are referable to the gastrointestinal tract. On this basis, # HYPERLINK "javascript:showDrugInfo(601);" #thiamine# has been used uncritically as a therapeutic agent for such unrelated conditions as ulcerative colitis, gastrointestinal hypotonia, and chronic diarrhea. Unless the disease being treated is the direct result of a deficiency of thiamine, the vitamin is not efficacious.Neuritis of PregnancyPregnancy increases the # HYPERLINK "javascript:showDrugInfo(601);" #thiamine# requirement slightly. The neuritis of pregnancy takes the form of multiple peripheral nerve involvement, and the signs and symptoms in well-developed cases resemble those described in patients with beriberi. The problem may occur because of poor intake of thiamine or in patients with hyperemesis gravidarum. Proof that the neuritis is due to thiamine deficiency is gained in those cases in which dramatic clinical improvement follows thiamine therapy. The dose employed is from 5 to 10 mg daily, given parenterally if vomiting is severe.Megaloblastic Anemia# HYPERLINK "javascript:showDrugInfo(601);" #Thiamine#-responsive megaloblastic anemia (TRMA) with diabetes mellitus and deafness is an autosomal recessive disease that responds to large doses of thiamine. This disorder was shown to be caused by mutations in the plasma membrane�associated thiamine transporter (# HYPERLINK "javascript:windowReference('Reference',%20'popup.aspx? aid=519326&id=ch63bib8');" #Diaz et al., 1999#; # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519644%22);" #Fleming et al., 1999#). Defective thiamine transport in cultured fibroblasts from TRMA patients is associated with decreased cell survival, apparently by enhanced apoptosis (# HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519667%22);" #Stagg et al., 1999#).RiboflavinHistoryAt various times from 1879 onward, series of yellow-pigmented compounds have been isolated from a variety of sources and designated as flavins, prefixed to indicate the source (e.g., lacto-, ovo-, and hepato-). Subsequently it has been demonstrated that these various flavins are identical in chemical composition.In the meantime, water-soluble vitamin B had been separated into a heat-labile antiberiberi factor (B1) and a heat-stable growth-promoting factor (B2), and it was eventually appreciated that concentrates of so-called # HYPERLINK "javascript:showDrugInfo(543);" #vitamin B2# had a yellow color. In 1932, Warburg and Christian described a yellow respiratory enzyme in yeast, and in 1933 the yellow pigment portion of the enzyme was identified as vitamin B2. All doubt as to the identity of vitamin B2 and the naturally occurring flavins was removed when lactoflavin was synthesized and the synthetic product was shown to possess full biological activity. The vitamin was designated as # HYPERLINK "javascript:showDrugInfo(543);" #riboflavin# because of the presence of ribose in its structure.# INCLUDEPICTURE "http://www.accessmedicine.com/loadBinary.aspx?filename=good_c063if002.gif" \* MERGEFORMATINET ###Chemistry# HYPERLINK "javascript:showDrugInfo(543);" #Riboflavin# carries out its functions in the body in the form of one or the other of two coenzymes, riboflavin phosphate, commonly called flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD). Their structures are shown above.# HYPERLINK "javascript:showDrugInfo(543);" #Riboflavin# is converted to FMN and FAD by two enzyme-catalyzed reactions, shown as # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519372%22);" #Reactions (63�1)# and # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519373%22);" #(63�2)#:# HYPERLINK "javascript:showDrugInfo(543);" #Riboflavin# + ATP # INCLUDEPICTURE "http://www.accessmedicine.com/images/special/rightarrow.gif" \* MERGEFORMATINET ###FMN + ADP���(63�1)FMN + ATP # INCLUDEPICTURE "http://www.accessmedicine.com/images/special/rightarrow.gif" \* MERGEFORMATINET ###FAD + PP���(63�2)Pharmacological ActionsNo overt pharmacological effects follow the oral or parenteral administration of # HYPERLINK "javascript:showDrugInfo(543);" #riboflavin#.Physiological FunctionsFMN and FAD, the physiologically active forms of # HYPERLINK "javascript:showDrugInfo(543);" #riboflavin#, serve a vital role in metabolism as coenzymes for a wide variety of respiratory flavoproteins, some of which contain metals (e.g., xanthine oxidase).Symptoms of DeficiencyThe features of spontaneous or experimentally produced # HYPERLINK "javascript:showDrugInfo(543);" #riboflavin# deficiency have been reviewed by # HYPERLINK "Javascript:reloadParent(%22content.aspx? aID=519679%22);" #McCormick (1989)#. Sore throat and angular stomatitis generally appear first. Later, glossitis, cheilosis (red, denuded lips), seborrheic dermatitis of the face, and dermatitis over the trunk and extremities occur, followed by anemia and neuropathy. In some subjects, corneal vascularization and cataract formation are prominent.The anemia that develops in # HYPERLINK "javascript:showDrugInfo(543);" #riboflavin# deficiency is normochromic and normocytic and is associated with reticulocytopenia; leukocytes and platelets are generally normal. Administration of riboflavin to deficient patients causes reticulocytosis, and the concentration of hemoglobin returns to normal. Anemia in patients with riboflavin deficiency may be related, at least in part, to disturbances in # HYPERLINK "javascript:showDrugInfo(266);" #folic acid# metabolism.The problem in the clinical recognition of # HYPERLINK "javascript:showDrugInfo(543);" #riboflavin# deficiency is that certain features, such as glossitis and dermatitis, are common manifestations of other diseases, including deficiencies of other vitamins. Recognition of riboflavin deficiency also is difficult because it rarely occurs in isolation. In nutritional surveys of children in an urban area and of randomly selected hospitalized patients, deficiency of riboflavin was observed frequently, but almost invariably in conjunction with other vitamin deficiencies. Riboflavin deficiency has been observed likewise in association with deficiencies of other vitamins in a large proportion of urban alcoholics of low economic status. Biochemical evidence of riboflavin deficiency has been observed in newborn infants treated with ultraviolet light for hyperbilirubinemia. Breast-fed infants are most susceptible to this problem because of the relatively low riboflavin content in breast milk. Assessment of riboflavin status is made by correlating dietary history with clinical and laboratory findings. Biochemical tests include evaluation of urinary excretion of the vitamin (excretion of less than 50 # INCLUDEPICTURE "http://www.accessmedicine.com/images/special/mulower.gif" \* MERGEFORMATINET ###g of riboflavin daily is indicative of deficiency). Although concentrations of flavins in blood are not of diagnostic value, an enzyme activation assay that utilizes glutathione reductase from erythrocytes correlates well with riboflavin status (# HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519660%22);" #Prentice and Bates, 1981#).Human RequirementsThe Recommended Dietary Allowance (RDA) of # HYPERLINK "javascript:showDrugInfo(543);" #riboflavin# is 1.3 mg/day for men and 1.1 mg/day for women (see # HYPERLINK "javascript:windowReference('Reference',%20'popup.aspx?aID=519703');" #Table XIII�2#). Turnover of riboflavin appears to be related to energy expenditure, and periods of increased physical activity are associated with a modest increase in requirement.Food Sources# HYPERLINK "javascript:showDrugInfo(543);" #Riboflavin# is abundant in milk, cheese, organ meats, eggs, green leafy vegetables, and whole-grain and enriched cereals and breads.Absorption, Fate, and Excretion# HYPERLINK "javascript:showDrugInfo(543);" #Riboflavin# is absorbed readily from the upper gastrointestinal tract by a specific transport mechanism involving phosphorylation of the vitamin to FMN [# HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519371%22);" #Reaction (63�1)#; # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519686%22);" #Jusko and Levy, 1975#]. Here and in other tissues, riboflavin is converted to FMN by flavokinase, a reaction that is sensitive to thyroid-hormone status and inhibited by # HYPERLINK "javascript:showDrugInfo(120);" #chlorpromazine# and by tricyclic antidepressants; the antimalarial # HYPERLINK "javascript:showDrugInfo(533);" #quinacrine# also interferes with the utilization of riboflavin. Riboflavin is distributed to all tissues, but concentrations are uniformly low, and little is stored. When riboflavin is ingested in amounts that approximate the minimal daily requirement, only about 9% appears in the urine. As the intake of riboflavin is increased above the minimal requirement, a larger proportion is excreted unchanged. # HYPERLINK "javascript:showDrugInfo(1218);" #Boric acid#, a common household chemical, forms a complex with riboflavin and promotes its urinary excretion. Boric acid poisoning, therefore, may induce riboflavin deficiency.# HYPERLINK "javascript:showDrugInfo(543);" #Riboflavin# is present in the feces. This probably represents vitamin synthesized by intestinal microorganisms, since, on low intakes of riboflavin, the amount excreted in the feces exceeds that ingested. There is no evidence that riboflavin synthesized by the bacteria in the colon can be absorbed.Therapeutic UsesThe only established therapeutic application of # HYPERLINK "javascript:showDrugInfo(543);" #riboflavin# is to treat or prevent disease caused by deficiency. Ariboflavinosis seldom occurs in the United States as a discrete deficiency but may accompany other nutritional disorders. Specific therapy with riboflavin, 5 to 10 mg daily, should thus be given in the context of treating multiple nutritional deficiencies. A recent randomized, controlled trial of high-dose riboflavin (400 mg/day) in patients suffering migraine headaches showed significant reductions in attack frequency and illness days (# HYPERLINK "Javascript:reloadParent(%22content.aspx? aID=519664%22);" #Schoenen et al., 1998#).Nicotinic AcidHistoryPellagra (from the Italian pelleagra, "rough skin") has been known for centuries in countries where maize is eaten in quantity, notably Italy and in North America. In 1914, Funk postulated that the disease was due to dietary deficiency. Over the next few years, Goldberger and his colleagues demonstrated conclusively that pellagra could be prevented by increasing the dietary intake of fresh meat, eggs, and milk. Goldberger subsequently produced an excellent animal model of human pellagra, "black tongue," by feeding deficient diets to dogs. Although initially thought to be a deficiency of essential amino acids, pellagra soon was found to be prevented by a distinct heat-resistant factor in "water-soluble B" vitamin preparations.In 1935, Warburg and associates obtained nicotinic acid amide (nicotinamide) from a coenzyme isolated from the red blood cells of the horse; this stimulated interest in the nutritional value of nicotinic acid. Since liver extracts were known to be highly effective in curing human pellagra and canine black tongue, Elvehjem and associates prepared highly active concentrates of liver; in 1937, they identified nicotinamide as the substance that was effective in the treatment of black tongue. Proof was established by the demonstration that synthetic nicotinic acid derivatives also were effective in alleviating the symptoms of black tongue and in curing human pellagra. Goldberger and Tanner previously had shown that # HYPERLINK "javascript:showDrugInfo(2362);" #tryptophan# could cure human pellagra; this effect later was determined to be due to the conversion of tryptophan to nicotinic acid. # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519649%22);" #Goldsmith (1958)# produced pellagra experimentally in human beings by feeding a diet deficient in nicotinic acid and tryptophan.Nicotinic acid also is known as # HYPERLINK "javascript:showDrugInfo(1473);" #niacin#, a term introduced to avoid confusion between the vitamin and the alkaloid # HYPERLINK "javascript:showDrugInfo(435);" #nicotine#. Pellagra now is quite uncommon in the United States, probably as a direct result of supplementation of flour with nicotinic acid since 1939. ChemistryNicotinic acid functions in the body after conversion to either nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP). It is to be noted that nicotinic acid occurs in these two nucleotides in the form of its amide, nicotinamide. The structures of nicotinic acid, nicotinamide, NAD, and NADP are shown below, where R= H in NAD and R= PO3H2 in NADP. Synthetic analogs with antivitamin activity include pyridine-3sulfonic acid and 3-acetyl pyridine.# INCLUDEPICTURE "http://www.accessmedicine.com/loadBinary.aspx?filename=good_c063if003.gif" \* MERGEFORMATINET ###Pharmacological ActionsNicotinic acid and nicotinamide are identical in their function as vitamins. However, they differ markedly as pharmacological agents, reflecting the fact that nicotinic acid is not directly converted to nicotinamide, which arises only from metabolism of NAD. The pharmacological effects and toxicity of nicotinic acid in man include flushing, pruritus, gastrointestinal distress, hepatotoxicity, and activation of peptic ulcer disease. Large doses of nicotinic acid (2 to 6 g per day) are sometimes used in the treatment of hyperlipoproteinemia (see # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=508376%22);" #Chapter 36: Drug Therapy for Hypercholesterolemia and Dyslipidemia#). The important toxic effects of nicotinic acid are generally seen only with these doses.Physiological FunctionsNAD and NADP, the physiologically active forms of nicotinic acid, serve a vital role in metabolism as coenzymes for a wide variety of proteins that catalyze oxidation-reduction reactions essential for tissue respiration. The coenzymes, bound to appropriate dehydrogenases, function as oxidants by accepting electrons and hydrogen from substrates and thus becoming reduced. The reduced pyridine nucleotides, in turn, are reoxidized by flavoproteins. NAD also participates as a substrate in the transfer of ADP-ribosyl moieties to proteins. The metabolic pathway for conversion of nicotinic acid to NAD has been elucidated for a variety of tissues, including human erythrocytes. [See # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519404%22);" #Reactions (63�3)#, # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519405%22);" #(63�4)#, and # HYPERLINK "Javascript:reloadParent(%22content.aspx? aID=519406%22);" #(63�5)# below, where PRPP is 5-phosphoribosyl-1-pyrophosphate. NADP is synthesized from NAD according to # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519407%22);" #Reaction (63�6)#.] The biosynthesis of NAD from # HYPERLINK "javascript:showDrugInfo(2362);" #tryptophan# is more complicated. Tryptophan is converted to quinolinic acid by a series of enzymatic reactions; quinolinic acid is converted to nicotinic acid ribonucleotide, which enters the pathway at # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519405%22);" #Reaction (63�4)#. Nicotinic acid + PRPP # INCLUDEPICTURE "http://www.accessmedicine.com/images/special/rightarrow.gif" \* MERGEFORMATINET ###Nicotinic Acid Ribonucleotide + PP��(63�3)Nicotinic Acid ribonucleotide + ATP # INCLUDEPICTURE "http://www.accessmedicine.com/images/special/rightarrow.gif" \ * MERGEFORMATINET ###Desamido-NAD + PP��(63�4)Desamido-NAD + Glutamine + ATP # INCLUDEPICTURE "http://www.accessmedicine.com/images/special/rightarrow.gif" \* MERGEFORMATINET ###NAD + Glutamate + ADP + P��(63�5)NAD + ATP # INCLUDEPICTURE "http://www.accessmedicine.com/images/special/rightarrow.gif" \* MERGEFORMATINET ###NADP + ADP��(63�6)Symptoms of DeficiencyA deficiency of nicotinic acid leads to the clinical condition known as pellagra. Pellagra is characterized by signs and symptoms referable especially to the skin, gastrointestinal tract, and central nervous system, a triad frequently referred to as dermatitis, diarrhea, and dementia, or the "three D's." Pellagra now occurs most often in the setting of chronic alcoholism, protein-calorie malnutrition, and deficiencies of multiple vitamins. An erythematous eruption resembling sunburn first appears on the back of the hands. Other areas exposed to light (forehead, neck, and feet) are later involved, and eventually the lesions may be more widespread. The cutaneous manifestations are characteristically symmetrical and may darken, desquamate, and scar.The chief symptoms referable to the digestive tract are stomatitis, enteritis, and diarrhea. The tongue becomes very red and swollen and may ulcerate. Salivary secretion is excessive, and the salivary glands may be enlarged. Nausea and vomiting are common. Steatorrhea may be present, even in the absence of diarrhea. When present, diarrhea is recurrent and stools may be watery and occasionally bloody.Symptoms referable to the central nervous system are headache, dizziness, insomnia, depression, and impairment of memory. In severe cases, delusions, hallucinations, and dementia may appear. Motor and sensory disturbances of the peripheral nerves also occur. Common laboratory findings include macrocytic anemia, hypoalbuminemia, and hyperuricemia.Biochemical assessment of deficiency is attempted by the measurement of urinary excretion of methylated metabolites of nicotinic acid (e.g., N-methylnicotinamide). These tests do not provide unequivocal evidence of deficiency. The measurement of nicotinamide in blood and urine has not been shown to be useful in evaluating # HYPERLINK "javascript:showDrugInfo(1473);" #niacin# status. In most cases, the diagnosis rests on a correlation of clinical findings with the response to supplemental nicotinamide.Human RequirementsAs indicated above, the dietary requirement for this vitamin can be satisfied not only by nicotinic acid but also by nicotinamide and the amino acid # HYPERLINK "javascript:showDrugInfo(2362);" #tryptophan#. Therefore, the nicotinic acid requirement is influenced by the quantity and the quality of dietary protein. Administration of tryptophan to normal human subjects, as well as to patients with pellagra, and analysis of urinary metabolites indicate that an average of 60 mg of dietary tryptophan is equivalent to 1 mg of nicotinic acid. This conversion rate is reduced in women taking oral contraceptives. The minimal requirement of nicotinic acid (including that formed from tryptophan) to prevent pellagra averages 4.4 mg/1000 kcal. The RDA of # HYPERLINK "javascript:showDrugInfo(1473);" #niacin# is 14 and 16 mg/day for women and men, respectively (see # HYPERLINK "javascript:windowReference('Reference', %20'popup.aspx?aID=519703');" #Table XIII�2#).The relationship between the nicotinic acid requirement and the intake of # HYPERLINK "javascript:showDrugInfo(2362);" #tryptophan# has helped to explain the historical association between the incidence of pellagra and the presence of large amounts of corn in the diet. Corn protein is low in tryptophan, and the nicotinic acid in corn and other cereals is largely unavailable. When cornmeal provides the major portion of dietary protein, pellagra will develop at levels of intake of nicotinic acid that would be adequate if the dietary protein contained more tryptophan. Intake of animal protein is high among Americans; tryptophan thus helps significantly to meet the daily requirement for # HYPERLINK "javascript:showDrugInfo(1473);" #niacin#.Food SourcesNicotinic acid is obtained from liver, meat, fish, poultry, whole-grain and enriched breads and cereals, nuts, and legumes. # HYPERLINK "javascript:showDrugInfo(2362);" #Tryptophan# as a precursor is provided by animal protein, in particular. Absorption, Fate, and ExcretionBoth nicotinic acid and nicotinamide are absorbed readily from all portions of the intestinal tract, and the vitamin is distributed to all tissues. When therapeutic doses of nicotinic acid or its amide are administered, only small amounts of the unchanged vitamin appear in the urine. When extremely high doses of these vitamins are given, the unchanged vitamin represents the major urinary component. The principal route of metabolism of nicotinic acid and nicotinamide is by the formation of Nmethylnicotinamide, which, in turn, is metabolized further.Therapeutic Uses Nicotinic acid, nicotinamide, and their derivatives are used for prophylaxis and treatment of pellagra. In the acute exacerbations of the disease, therapy must be intensive. The recommended oral dose is 50 mg, given up to ten times daily. If oral medication is impossible, intravenous injection of 25 mg is given two or more times daily. Pellagra may occur in the course of two metabolic disorders. In Hartnup's disease, intestinal and renal transport of # HYPERLINK "javascript:showDrugInfo(2362);" #tryptophan# is defective. In some patients with carcinoid tumors, large amounts of tryptophan are utilized by the tumor for the synthesis of # HYPERLINK "javascript:showDrugInfo(2362);" #5hydroxytryptophan# and 5-hydroxytryptamine (serotonin).The response to nicotinic acid or its derivatives is dramatic. Within 24 hours, the fiery redness and swelling of the tongue disappear and sialorrhea diminishes. Associated oral infections heal rapidly. Other infections of mucous membranes also disappear. Nausea, vomiting, and diarrhea may stop within 24 hours, and at the same time the patient is relieved of epigastric distress, abdominal pain, and distention. Appetite also improves. Mental symptoms are quickly relieved, sometimes overnight. Confused patients become mentally clear, and those who are delirious become calm, adjusted to their environment, and remember with insight the events of their psychotic state. So specific are nicotinic acid and its derivatives in this regard that they can be used as diagnostic agents in patients with frank psychoses but with questionable additional evidence of pellagra. Large doses of # HYPERLINK "javascript:showDrugInfo(1473);" #niacin# are recommended, especially when the psychosis is associated with encephalopathy. The dermal lesions blanch and heal, but this occurs more slowly. The vitamin has less effect on cutaneous lesions that are moist, ulcerated, or pigmented. The porphyrinuria associated with pellagra also disappears.Pellagra may be complicated by # HYPERLINK "javascript:showDrugInfo(601);" #thiamine# deficiency with associated peripheral neuritis. This complication does not respond to nicotinic acid or its congeners and must be treated with thiamine. Many pellagrins also benefit from additional therapy with # HYPERLINK "javascript:showDrugInfo(543);" #riboflavin# and # HYPERLINK "javascript:showDrugInfo(531);" #pyridoxine#.In gram doses, nicotinic acid lowers circulating concentrations of low-density-lipoprotein cholesterol and triglycerides, plasma fibrinogen, and lipoprotein(a). Nicotinic acid therefore is used in the management of hyperlipoproteinemias (see # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=508376%22);" #Chapter 36: Drug Therapy for Hypercholesterolemia and Dyslipidemia#).Nicotinamide has shown promise in the primary prevention of type I diabetes mellitus in high-risk individuals (# HYPERLINK "Javascript:reloadParent(%22content.aspx? aID=519642%22);" #Elliott et al., 1996#; # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519655%22);" #Lampeter et al., 1998#). Large population-based intervention trials currently are in progress. PyridoxineHistoryIn 1926, dermatitis was produced in rats by feeding a diet deficient in # HYPERLINK "javascript:showDrugInfo(543);" #vitamin B2#. However, in 1936 Gy�rgy distinguished from vitamin B2 the water-soluble factor whose deficiency was responsible for the dermatitis and named it # HYPERLINK "javascript:showDrugInfo(531);" #vitamin B6#. The structure of the vitamin was elucidated in 1939. Several related natural compounds (# HYPERLINK "javascript:showDrugInfo(531);" #pyridoxine#, pyridoxal, pyridoxamine) have been shown to possess the same biological properties, and therefore all should be called vitamin B6. However, the Council on Pharmacy and Chemistry has assigned the name pyridoxine to the vitamin.ChemistryThe structures of the three forms of vitamin B6�that is, # HYPERLINK "javascript:showDrugInfo(531);" #pyridoxine#, pyridoxal, and pyridoxamine�are shown below.# INCLUDEPICTURE "http://www.accessmedicine.com/loadBinary.aspx?filename=good_c063if004.gif" \* MERGEFORMATINET ###The compounds differ in the nature of the substituent on the carbon atom in position 4 of the pyridine nucleus: a primary alcohol (# HYPERLINK "javascript:showDrugInfo(531);" #pyridoxine#), the corresponding aldehyde (pyridoxal), an aminoethyl group (pyridoxamine). Each of these compounds can be utilized readily by mammals after conversion in the liver to pyridoxal 5'-phosphate, the active form of the vitamin.Antimetabolites to # HYPERLINK "javascript:showDrugInfo(531);" #pyridoxine# have been synthesized and are capable of blocking the action of the vitamin and producing signs and symptoms of deficiency. The most active is 4-deoxypyridoxine, for which the antivitamin activity has been attributed to the formation in vivo of 4deoxypyridoxine-5-phosphate, a competitive inhibitor of several pyridoxal phosphate�dependent enzymes.Isonicotinic acid hydrazide (# HYPERLINK "javascript:showDrugInfo(326);" #isoniazid#; see # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=512909%22);" #Chapter 48: Antimicrobial Agents: Drugs Used in the Chemotherapy of Tuberculosis, Mycobacterium avium Complex Disease, and Leprosy#), as well as other carbonyl compounds, combines with pyridoxal or pyridoxal phosphate to form hydrazones; as a result, it is a potent inhibitor of pyridoxal kinase. Enzymatic reactions in which pyridoxal phosphate participates as a coenzyme also are inhibited, but only by much greater concentrations than those required to inhibit the formation of pyridoxal phosphate. Isoniazid thus appears to exert its antivitamin B6 effect primarily by inhibiting the formation of the coenzyme form of the vitamin.Pharmacological Actions# HYPERLINK "javascript:showDrugInfo(531);" #Pyridoxine# has low acute toxicity and elicits no outstanding pharmacodynamic actions after either oral or intravenous administration. However, neurotoxicity may develop after prolonged ingestion of as little as 200 mg of pyridoxine per day (# HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519663%22);" #Schaumberg et al., 1983#; # HYPERLINK "Javascript:reloadParent(%22content.aspx? aID=519659%22);" #Parry and Bredesen, 1985#).Physiological FunctionsAs a coenzyme, pyridoxal phosphate is involved in several metabolic transformations of amino acids�including decarboxylation, transamination, and racemization�as well as in enzymatic steps in the metabolism of sulfur-containing and hydroxyamino acids. In the case of transamination, enzyme-bound pyridoxal phosphate is aminated to pyridoxamine phosphate by the donor amino acid, and the bound pyridoxamine phosphate is then deaminated to pyridoxal phosphate by the acceptor # INCLUDEPICTURE "http://www.accessmedicine.com/images/special/alphalower.gif" \ * MERGEFORMATINET ###-keto acid. # HYPERLINK "javascript:showDrugInfo(531);" #Vitamin B6# also is involved in the metabolism of # HYPERLINK "javascript:showDrugInfo(2362);" #tryptophan#. A notable reaction is the conversion of tryptophan to 5-hydroxytryptamine. In vitamin B6�deficient human beings and in animals, a number of metabolites of tryptophan are excreted in abnormally large quantities. The measurement of these urinary metabolites, particularly xanthurenic acid, following loading with tryptophan is used as a test of vitamin B6 status. The conversion of # HYPERLINK "javascript:showDrugInfo(1443);" #methionine# to cysteine also is dependent on the vitamin.Interactions with DrugsBiochemical interactions occur between pyridoxal phosphate and certain drugs and toxins. The relationship with # HYPERLINK "javascript:showDrugInfo(326);" #isoniazid# has been discussed above. Prolonged use of # HYPERLINK "javascript:showDrugInfo(469);" #penicillamine# can cause deficiency of # HYPERLINK "javascript:showDrugInfo(531);" #vitamin B6#. The drugs # HYPERLINK "javascript:showDrugInfo(157);" #cycloserine# and # HYPERLINK "javascript:showDrugInfo(295);" #hydralazine# are also antagonists of the vitamin, and administration of vitamin B6 reduces the neurological side effects associated with the use of these compounds. Vitamin B6 enhances the peripheral decarboxylation of # HYPERLINK "javascript:showDrugInfo(1402);" #levodopa# and reduces its effectiveness for the treatment of Parkinson's disease (see # HYPERLINK "Javascript:reloadParent(%22content.aspx? aID=503000%22);" #Chapter 22: Treatment of Central Nervous System Degenerative Disorders#).Symptoms of DeficiencySkinSeborrhealike skin lesions about the eyes, nose, and mouth accompanied by glossitis and stomatitis can be produced within a few weeks by feeding a diet poor in vitamin B complex plus daily doses of the vitamin antagonist 4-deoxypyridoxine. The lesions clear rapidly after the administration of # HYPERLINK "javascript:showDrugInfo(531);" #pyridoxine# but do not respond to other members of the B complex.Nervous SystemConvulsive seizures may occur when human beings are maintained on a diet deficient in # HYPERLINK "javascript:showDrugInfo(531);" #pyridoxine#, and these seizures can be prevented by the vitamin. The induction of convulsive seizures by pyridoxine deficiency may be the result of a lowered concentration of gamma-aminobutyric acid; glutamate decarboxylase, a pyridoxal phosphate�requiring enzyme, synthesizes this inhibitory central nervous system (CNS) neurotransmitter (see # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=413525%22);" #Chapter 12: Neurotransmission and the Central Nervous System#). In addition, pyridoxine deficiency leads to decreased concentrations of the neurotransmitters # HYPERLINK "javascript:showDrugInfo(443);" #norepinephrine# and 5hydroxytryptamine. A peripheral neuritis associated with carpal synovial swelling and tenderness (carpal tunnel syndrome) has been attributed in some cases to deficiency of pyridoxine, although earlier claims that high doses of pyridoxine reverse carpal tunnel syndrome have not been confirmed (# HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519666%22);" #Smith et al., 1984#). ErythropoiesisAlthough dietary deficiency of # HYPERLINK "javascript:showDrugInfo(531);" #pyridoxine# in human beings may cause anemia rarely, the usual pyridoxine-responsive anemia apparently is not due to inadequate supplies of this vitamin as judged by normal standards. This type of anemia is described in # HYPERLINK "Javascript:reloadParent(%22content.aspx? aID=516112%22);" #Chapter 54: Hematopoietic Agents: Growth Factors, Minerals, and Vitamins#.Human RequirementsThe requirement for # HYPERLINK "javascript:showDrugInfo(531);" #pyridoxine# increases with the amount of protein in the diet. The average adult minimal requirement for pyridoxine is about 1.6 mg per day in individuals ingesting 100 g of protein per day (# HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519651%22);" #Hansen et al., 1997#). The current RDA for pyridoxine has been set at 1.3 mg for young adult men and women, with modest increases for individuals above 50 years of age (see # HYPERLINK "javascript:windowReference('Reference',%20'popup.aspx? aID=519703');" #Table XIII�2#).Food Sources# HYPERLINK "javascript:showDrugInfo(531);" #Pyridoxine# is supplied by meat, liver, wholegrain breads and cereals, soybeans, and vegetables. Substantial losses occur during cooking, and pyridoxine is sensitive to both ultraviolet light and oxidation.Absorption, Fate, and Excretion# HYPERLINK "javascript:showDrugInfo(531);" #Pyridoxine#, pyridoxal, and pyridoxamine are readily absorbed from the gastrointestinal tract following hydrolysis of their phosphorylated derivatives. Pyridoxal phosphate accounts for at least 60% of circulating # HYPERLINK "javascript:showDrugInfo(531);" #vitamin B6#. Pyridoxal is thought to be the primary form that crosses cell membranes. The principal excretory product when any of the three forms of the vitamin is fed to human beings is 4-pyridoxic acid, formed by the action of hepatic aldehyde oxidase on free pyridoxal (see # HYPERLINK "Javascript:reloadParent(%22content.aspx? aID=519689%22);" #Leklem, 1988#).Therapeutic UsesAlthough there is no doubt that # HYPERLINK "javascript:showDrugInfo(531);" #pyridoxine# is essential in human nutrition, the clinical syndrome of simple pyridoxine deficiency is rare. Nevertheless, it may be presumed that an individual with a deficiency of other members of the B complex may also have a deficiency of pyridoxine. Therefore, pyridoxine should be a component of therapy for individuals suffering from a deficiency of other members of the B complex. On the basis that pyridoxine is essential in human nutrition, it is incorporated into many multivitamin preparations for prophylactic use.As indicated above, # HYPERLINK "javascript:showDrugInfo(531);" #vitamin B6# influences the metabolism of certain drugs and vice versa. With considerable justification, vitamin B6 is given prophylactically to patients receiving # HYPERLINK "javascript:showDrugInfo(326);" #isoniazid# to prevent the development of peripheral neuritis. In addition, # HYPERLINK "javascript:showDrugInfo(531);" #pyridoxine# is an antidote for the seizures and acidosis in patients who have ingested an overdose of isoniazid.The concentration of pyridoxal phosphate is reduced in the blood of women who are pregnant or who are taking oral contraceptives, although the recommended intakes of # HYPERLINK "javascript:showDrugInfo(531);" #vitamin B6# appear to be sufficient to meet the requirements of such individuals.# HYPERLINK "javascript:showDrugInfo(531);" #Pyridoxine#-responsive anemia is a well-documented but uncommon condition. The use of the vitamin in this disease is discussed in # HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=516112%22);" #Chapter 54: Hematopoietic Agents: Growth Factors, Minerals, and Vitamins#. A group of genetically determined clinical states of "pyridoxine dependency," manifested by a requirement for large amounts of the vitamin, include pyridoxine-responsive anemias in patients without apparent pyridoxine deficiency, a seizure disorder in infants that responds to the administration of pyridoxine, and those abnormalities characterized by xanthurenic aciduria, primary cystathioninuria, or homocystinuria (see # HYPERLINK "Javascript:reloadParent(%22content.aspx? aID=519672%22);" #Fowler, 1985#).Pantothenic AcidHistory# HYPERLINK "javascript:showDrugInfo(465);" #Pantothenic acid# was first identified by Williams and associates in 1933 as a substance essential for the growth of yeast. Its name, derived from Greek words signifying "from everywhere," is indicative of the wide distribution of the vitamin in nature. The role of pantothenic acid in animal nutrition was first defined in chicks, in which a deficiency disease characterized by skin lesions was known to be cured by fractions prepared from liver extract. Although first thought to be a form of "chick pellagra," it was not cured by nicotinic acid. In 1939, Woolley and coworkers and also Jukes demonstrated that the chick antidermatitis factor was pantothenic acid. Elucidation of the biochemical function for the vitamin began in 1947 when Lipmann and coworkers showed that the acetylation of # HYPERLINK "javascript:showDrugInfo(1574);" #sulfanilamide# required a cofactor that contained pantothenic acid.ChemistryPantothenate consists of pantoic acid complexed to # INCLUDEPICTURE "http://www.accessmedicine.com/images/special/betalower.gif" \* MERGEFORMATINET ###-alanine. This is transformed in the body to 4'-phosphopantetheine by phosphorylation and linkage to # HYPERLINK "javascript:showDrugInfo(160);" #cysteamine#; this derivative is incorporated into either coenzyme A or acyl carrier protein, the functional forms of the vitamin. The chemical structures of # HYPERLINK "javascript:showDrugInfo(465);" #pantothenic acid# and coenzyme A are as follows:# INCLUDEPICTURE "http://www.accessmedicine.com/loadBinary.aspx?filename=good_c063if005.gif" \* MERGEFORMATINET ###Many analogs of # HYPERLINK "javascript:showDrugInfo(465);" #pantothenic acid# have been studied in an attempt to find an antimetabolite. Although active antagonists have been synthesized (e.g., # INCLUDEPICTURE "http://www.accessmedicine.com/images/special/omegalower.gif" \* MERGEFORMATINET ###-methyl pantothenate) and are of value as research tools, they are not therapeutic agents.Pharmacological Actions# HYPERLINK "javascript:showDrugInfo(465);" #Pantothenic acid# has no outstanding pharmacological actions when it is administered to experimental animals or normal human beings, even in large doses.Physiological FunctionsCoenzyme A serves as a cofactor for a variety of enzyme-catalyzed reactions involving transfer of acetyl (two-carbon) groups; the precursor fragments of various lengths are bound to the sulfhydryl group of coenzyme A. Such reactions are important in the oxidative metabolism of carbohydrates, gluconeogenesis, degradation of fatty acids, and the synthesis of sterols, steroid hormones, and porphyrins. As a component of acyl carrier protein, pantothenate participates in fatty acid synthesis. Coenzyme A also participates in the posttranslational modification of proteins, including N-terminal acetylation, acetylation of internal amino acids, and fatty acid acylation. Such modifications can influence the intracellular localization, stability, and activity of the proteins.Symptoms of DeficiencyDeficiency of # HYPERLINK "javascript:showDrugInfo(465);" #pantothenic acid# is manifested by symptoms of neuromuscular degeneration and adrenocortical insufficiency. By administering a diet devoid of pantothenic acid, a syndrome is produced that is characterized by fatigue, headache, sleep disturbances, nausea, abdominal cramps, vomiting, and flatulence, with complaints of paresthesias in the extremities, muscle cramps, and impaired coordination (# HYPERLINK "Javascript:reloadParent(%22content.aspx? aID=519645%22);" #Fry et al., 1976#). Pantothenic acid deficiency has not been recognized in human beings consuming a normal diet, presumably because of the ubiquitous occurrence of the vitamin in ordinary foods.Human Requirements# HYPERLINK "javascript:showDrugInfo(465);" #Pantothenic acid# is a required nutrient, but the magnitude of need is not known precisely. There is no RDA for pantothenic acid. The adequate intake is set at 5 mg/day for adults. Intakes for other groups are proportional to caloric consumption. In view of the widespread distribution of pantothenic acid in foods, dietary deficiency is very unlikely. Food Sources# HYPERLINK "javascript:showDrugInfo(465);" #Pantothenic acid# is ubiquitous. It is particularly abundant in organ meats, beef, and egg yolk. However, pantothenic acid is easily destroyed by heat and alkali.Absorption, Fate, and Excretion# HYPERLINK "javascript:showDrugInfo(465);" #Pantothenic acid# is absorbed readily from the gastrointestinal tract. It is present in all tissues, in concentrations ranging from 2 to 45 # INCLUDEPICTURE "http://www.accessmedicine.com/images/special/mulower.gif" \* MERGEFORMATINET ###g/g. Pantothenic acid apparently is not degraded in the human body, since the intake and the excretion of the vitamin are approximately equal. About 70% of the absorbed pantothenic acid is excreted in the urine.Therapeutic UsesNo clearly defined uses for # HYPERLINK "javascript:showDrugInfo(465);" #pantothenic acid# exist, although it commonly is included in multivitamin preparations and in products for enteral and parenteral alimentation.Biotin HistoryIn 1916, Bateman observed that rats fed a diet containing raw egg white as the sole source of protein developed a syndrome characterized by neuromuscular disorders, severe dermatitis, and loss of hair. The syndrome could be prevented by cooking the protein or by administering yeast, liver, or extracts of these. In 1936, K�gl and T�nnis isolated from egg yolk a factor in crystalline form that was essential for growth of yeast, which they called # HYPERLINK "javascript:showDrugInfo(3230);" #biotin#. It was then demonstrated that biotin and the factor that protected against egg-white toxicity were the same (# HYPERLINK "Javascript:reloadParent(%22content.aspx?aID=519650%22);" #Gy�rgy, 1940#). In 1942, duVigneaud established the structural for