Cross Reference to Related Application

This application is a continuation-in-part of Application Serial No. 08/744,550, filed November 6, 1996, which is a continuation in part of Application Serial No. 08/703,301, filed August 26, 1996.

Technical Field The present invention relates generally to multivitamin products.

It is becoming more and more accepted that the autonomic nervous system is very important in the health of individuals. Individuals are members of one of three groups - sympathetic, parasympathetic or balanced. Members of each group react differently to certain foods and agents than do members of the other groups. This is an important factor to be considered when prescribing vitamins to be taken by an individual.

People also fall into three other categories depending on the type of diet under which they best survive. These categories are moderate vegetarian, efficient balanced and moderate carnivore.

The sympathetic and parasympathetic autonomic nervous system types fall into these three diet types with the sympathetic type being more vegetarian and the parasympathetic more carnivore. Because of lack of the proper diet, exercise and exogenous factors people do not maintain autonomic balance

The present inventors have found that by using certain vitamins at certain levels in a unit dose provides for better autonomic balance and enhanced performance. This is different from the prior art since balancing the autonomic nervous system is targeted for the first time. That a purpose of the present invention is to provide unit doses of vitamins

That a further purpose is to provide unit doses containing levels of vitamins which vary depending on the individual characteristics as discussed above.

That a further objective of the present invention is to provide methods of combating diseases by using such unit doses. These and other objectives will become evident from the detailed description given below.

AH percentages and ratios used herein are by weight unless otherwise specified. Also all measurements referred to herein are made at 25°C.

Summary Of The Invention The present invention relates to multivitamin compositions in unit dose form.

Detailed Description Of The Invention The unit dose compositions comprise a multiple of vitamins. The history of the vitamins and their properties are described in greater detail below. Vitamins The vitamins used in the present compositions include the following:

Vitamin A Night blindness was a well-recognized disease in ancient Egypt. The cure, as expressed in the Papyrus Ebers and the London Medical Papyrus, was to apply topically to the eyes juice squeezed from cooked liver. The ancient Greeks, who were familiar with Egyptian medical practice, recommended the ingestion of cooked liver as well as its topical application. Interestingly, this tradition of applying cooked liver oil or juice topically to the eye has persisted in many societies to this day. The active principle of liver oil or juice, of course, is vitamin A.

In the early part of this century, Frederick Gowland Hopkins in England found that a growth-stimulating principle in milk was present in the alcoholic extract rather than in the ash, and soon thereafter Stepp in Germany identified one of these so-called "minimal qualitative factors" as a lipid. In 1913, E.V. McCollum and Marguerite Davis in Wisconsin showed that butter or egg yolk, but not lard, contained an essential growth factor for rats. They termed this factor "fat-soluble A."

Concomitantly, Osborn and Mendel in New Haven found a similar fat-soluble growth factor in cod liver oil and butter. Thus, 1913 marks the beginning of the modern nutritional history of Vitamin A.

The fact that active fractions from plant tissues were often colored, whereas those from liver and animal tissues were not, puzzled many investigators during the following decade, This problem finally was resolved when Moore in England showed that β-carotene was converted biologically to a colorless form of vitamin A, which was then stored in liver tissue. In 1930, Karrer and his colleagues in Switzerland determined the structures of both vitamin A and β-carotene. Five years later, Wald identified the chromophore of visual pigments as retinene, now termed retinal, thereby defining one of the primary functions of die vitamin. During the 1920s, the marked effects of vitamin A deficiency on appetite, growth, and tissue differentiation were also well noted. These early studies on vitamin A are well reviewed in Moore's elegant treatise. Thus, the need for vitamin

A is well recognized.

The level of vitamin A used in the compositions of the present invention is about 800 IU in the product for balanced vegetarian and about 1500 IU in the products for balanced carnivore.

Vitamin Bl (Thiamin) Although Neiching, the Chinese medical book, mentioned beriberi in 2697 B.C., it was not known for centuries that this illness was due to thiamin deficiency. In 1884, Takaki, a surgeon general of the Japanese navy, concluded that beriberi was caused by a lack of nitrogenous food components in association with excessive intake on non-nitrogenous food. In 191 1, Funk, a chemist working at the Lister Institute in London, was convinced that he had isolated the antiberiberi principle possessing an amine function from rice bran extracts, he named it "vitamine." His crystalline substance was shown later to have little antineuritic activity. In 1926,

Jansen and Donath, Dutch chemists working in Java, succeeded in isolating and crystallizing antibeπben factor from rice bran extracts By 1934 Williams, a U S chemist, had isolated a sufficient quantity of thiamin so that its structure could be determined It synthesis was accomplished in 1936 In 1937, Lohman and Schuster discovered that the active coenzyme form of thiamin was thiamin pyrophosphate (TPP, also known as cocarboxylase)

The level of vitamin Bl used in the compositions of the present invention is about 10 mg m the product for balanced vegetarian and about 6 mg in the products for balanced carnivore

Vitamin B2 (Riboflavin) The "water-soluble B" fraction, reported by McCollum and

Kennedy in 1916 to contain an antiberiberi substance was subsequently shown by Emmett and Luros (1920) and Smith and Hendπck (1926) to contain at least a second more heat-stable antipellagra factor, which was termed B2 It soon became apparent that this B2 fraction was a complex containing a yellow growth factor called riboflavin in England and vitamin G in the United States, as well as the subsequently identified pellagra-preventive factor (niacui) and the rat antidermatitis factor (vitamin B6) Although a water-soluble, yellow fluorescent compound was known in the latter part of the nineteenth century (Blyth, 1879) to occur in such natural materials as whey, association of the pigment with vitaminic properties was not secured until its isolation in 1933 by several groups Terms applied to riboflavin indicated the origin (e.g., lactoflavin (milk), ovoflavin (egg), hepato flavin (liver), and uroflavin (urine)) Warburg and Christian in Germany had meanwhile isolated by 1932 a yellow respiratory ferment (now called "Old Yellow Enzyme") from yeast This flavone protein was soon dissociated to a protem apoenzyme and a yellow prosthetic coenzyme that was clearly similar to riboflavin Stern and Holiday (1934) found that the coenzyme was an alloxazine deπvative, and Theorell (1934) demonstrated that it was a phosphate ester

By 1935, the groups of Kuhn at Heidelburg and Karrer in Zurich had achieved synthesis of the vitamin Theorell, in 1937, secured me structure of the simpler coenzyme as πboflavin 5'- phosphate (flavin mononucleotide, or FMN). By 1938, Warburg and Christian had isolated and characterized the more abundant but complex prosthetic group, flavin-adenine dinucleotide (FAD), and showed its participation as the coenzyme of D-amtno oxidase. In more recent years, it has become known that there are diverse natural flavins that have alterations in the side chain or πng system of the basic flavm structures. No less than four 8α-modιfied forms of FAD occur covalently attached to important flavoprotems in the mammal ^* the N(3)-hιstιdyl-lιnked cases of succmate and sarcosine dehydrogenases of the inner mitochondnal membrane, S-cysteinyl-linked onoamine oxidase of the outer mitochondnal membrane, and the N(l)-hιstιdy 1-1 inked L-gluconolactone oxidase of the liver fraction

The level of vitamin B2 used in the compositions of the present invention is about 10 mg in the product for balanced vegetarian and about 60 mg in the products for balanced carnivore

Niacin The search for the cause of pellagra, the classic disease now associated with niacin deficiency, is one of die most fascinating episodes in medical science First recognized

in 1735 by the Spanish physician, Casals, pellagra was rampant among many maize-eating populations throughout the world for the next two centuries. In the early 1900s the disease became an epidemic in the southeastern United States, and it was there that Goldberger established that pellagra was not an infectious disease but was caused by an unknown dietary deficiency. In 1937 Elvehjem et al. found that nicotinic acid was effective in treating pellagrous lesions in dogs and, within the year, nicotinic acid was reported to cure pellagra in humans.

In 1945 the amino acid tryptophan (Tφ) was shown to replace niacin in improving the growth of rats fed a high-corn diet. Tφ was firmly established as a niacin precursor by a series of studies demonstrating the Tφ supplements increased the excretion of niacin metabolites and that labeled niacin could be isolated from an incubation mixture of liver tissue and labeled Tφ. Tφ also proved to be a niacin precursor in humans and could at least partially replace the requirement for preformed niacin in the diet. The recognition that Tφ was a precursor of niacin explained the connection between corn-containing diets and pellagra because corn has a low content of both niacin and Tφ. Questions still remain about the cause of the pellagra epidemics, however, and deficiencies of other vitamins such as riboflavin may have been contributing factors. The underlying biochemical defects that lead to the symptoms of pellagra are also not understood.

The level of Niacin used in the compositions of the present invention is about 10 mg in the product for balanced vegetarian and about 10 mg in the products for balanced carnivore.

Niacin amide This is another form of nicotinic acid, which is niacin. The level of Niacin used in the compositions of the present invention is from about 25 mg in the product for balanced vegetarian and about 30 mg in the products for balanced carnivore.

Vitamin B5 Vitamin B5 is also known as pantothenic acid.

A member of the vitamin B complex; it is a component of coenzyme A and may be considered a β-alanine derivative with a peptide linkage. It is involved in the release of energy from carbohydrate utilization and is necessary for synthesis and degradation of fatty acids, sterols, and steroid hormones; it also functions in the formation of poφhyrins. It occurs in all living cells and tissues. The natural product is dextrorotatory [rf(+)] and is the only form having vitamin activity.

The level of vitamin B5 used in the compositions of the present invention is about 60 mg in the product for balanced vegetarian and about 45 mg in the products for balanced carnivore. , Vitamin B6 Since the discovery and identification of the structure of vitamin B6 some

50 years ago, there have been significant advances in our knowledge of the functions of vitamin B6 and the quantitative need for this vitamin. Gyorgy and Lepkovsky were among the first to isolate vitamin B6 in crystalline form. In the subsequent decade Snell and co-workers were instrumental in elucidating die various forms of vitamin B6 and developing microbiologic analytic techniques for measuring diese forms in biologic systems.

The level of vitamin B6 used in the compositions of the present invention is about 12 mg in the product for balanced vegetarian and about 6.0 mg in the products for balanced carnivore.

Vitamin B12 The unraveling of the relation of vitamin B12 and folic acid to anemia traces back almost two centuries. In 1822, the physician Combe reported in Edinburgh on the "history of a case of anemia" that he surmised was due to "some disorder of the digestive and assimilative organs." Thus was launched the study of pernicious anemia in particular and megaloblastic anemia in general, after restimulation by physician Thomas Addison's description, 1849 and 1855, of what his contemporaries evidently recognized as pernicious anemia. The nutritional basis of pernicious anemia was suspected by the American physician Austin Flint in 1860, when he stated that "in these cases there exists degenerative disease of the glandular tubuli of the stomach." Another two-thirds of a century had passed when the classic work of physician William

Castle and his associates demonstrated that normal human gastric juice contains an "intrinsic factor" (i.e., within the body) that combines with an "extrinsic factor" (i.e., outside the body - in food) contained in animal protein to result in absoφtion of the "antipemicious anemia principle." Vitamin B12 was finally reported as isolated in 1948 in the United States, and three weeks later, entirely independently, in England. Berk and his associates showed that this vitamin was "extrinsic factor" and "antipemicious anemia principle."

Early reports of disease now recognizable as probable folate deficiency include those of Channing, Barclay, and Osier. A decade later Wills and her associates described in Hindu women in Bombay a macrocytic anemia, usually associated with pregnancy, that responded to therapy with a commercial preparation of autolyzed yeast called Marmite; these workers produced in monkeys a similar macrocytic anemia that responded to a "Wills factor" present in crude but not in purified liver extracts.

The more purified liver extract was found to be a fairly pure solution of vitamin B12, whereas the "Wills factor" from the crude liver extract was found to be folic acid. This was clarified by advances in knowledge of folic acid (e.g., the purification of pteroylglutamic acid in 1943, its crystallization in the same year, and its synthesis and structural identification in 1946) and by the isolation of vitamin B12 in crystalline form in 1948. The rapid isolation of d e vitamin was greatly aided by a microbiologic assay based on Shorb's discovery that the growth factor required by Lactobacillus lactis Domer was the "animal protein factor" necessary for animals fed an all-vegetable diet. The amounts of B12 present in liver extracts closely paralleled their potency in the treatment of pernicious anemia.

Folic acid has proved to be the same as the Wills factor; "vitamin M" contained in dried brewer's yeast that corrected the deficiency anemia, leukopenia, diarrhea, and gingivitis of monkeys; "vitamin Be" contained in yeast that corrected the deficiency syndrome in chicks characterized by anemia and growth failure; and the Norite eluate factor of liver, essential to the growth of Lactobacillus casei (and therefore also called the "L. casei factor"). Sulfanilamide was shown to act

by competitive inhibition of a bacterial metabolite, /κ ^* τα-aminobenzoic acid. This metabolite was later found to be an essential component of L. casei factor.

The term folic acid was coined in 1941 by Mitchell and co-workers because they found this material in a leafy vegetable (spinach). At that time, it was not recognized that vitamin B12, and not folic acid, was the active ingredient in the oral liver therapy that Minot and Muφhy reported in 1926 as successful in treating pernicious anemia (for which work they received the Nobel Prize in Medicine in 1934). Considerable progress has since been made in our understanding of the metabolic role of folic acid in health and disease, and of the use of folate antimetabolites in the treatment of some infectious diseases and cancers. The level of vitamin B12 used in the compositions of the present invention is about 90 meg in the product for balanced vegetarian and about 90 meg in the products for balanced carnivore.

Biotin Biotin is a water-soluble vitamin. Kogl and Tonnis isolated crystalline biotin in 1936. Du Vigneaud determined its chemical structure in 1942. The chemical synthesis of biotin was achieved by Harris in 1943. Further significant advances involved the identification of biotin as the prosthetic group of the biotin-containing carboxylases, understanding the molecular mechanism of the action of biotin in biotin enzymes and clarifying the regulatory features of biotin enzymes. The recognition of biotin-responsive multiple carboxyiase deficiency syndromes and die hypothesis of nonprosthetic group function for biotin are among recent development.

The level of Biotin used in the compositions of the present invention is about 21 meg in the product for balanced vegetarian and about 20 meg in the products for balanced carnivore.

Para Amino benzoic Acid Required by many organisms as a vitamin for growth, active in neutralizing the antibacteriostatic effect of some sulfonamide drugs.

The level of Para Amino benzoic Acid used in die compositions of the present invention is about 25 mg in die product for balanced vegetarian and about 35 mg in the products for balanced carnivore.

Vitamin C Among specific nutritional deficiency diseases, scurvy has ranked with d e highest in its toll of human suffering and death. The symptoms are rather characteristic and appear to be described as far back as the ancient civilizations of the Egyptians, Greeks, and Romans. The disease was rampant in the sea explorers of the sixteenth to eighteenth centuries, A.D., in whom typical .physical symptoms of bleeding and rotting gums, swollen and inflamed joints, dark blotches on the skin, and muscle weakness occurred widiin months of departure. Throughout this period, the British expeditions suffered greatly because of scurvy. Of Admiral Anson's six ships circling the globe in 1740 to 1744, only the flagship returned, and 1051 men died. The carnage prompted the British Admiralty to seek the cure for scurvy, and in 1747, the Scottish surgeon James Lind performed an early clinical nutrition experiment on board ship, whereby six different diet supplements given to six pairs of scorbutic sailors demonstrated the efficacy of oranges and lemons (and to a lesser extent apple cider) in curing scurvy. Yet Lind is credited erroneously with the

discovery Uiat citrus fruits can cure scurvy, which had been noted in many earlier accounts. In his famous 1753 Treatise of The Scurvy, Lind reasoned that scurvy resulted from blocked perspiration resulting from damp salty sea air, resulting in "putrid humors" mat had poisonous and noxious qualities when retained in d e body. Captain James Cook in voyages from 1 68 to 1775 first proved that long sea voyages, did not necessarily result in scurvy. Throughout diese voyages, he required diat the crew eat local greens and grasses at every opportunity, maintain cleanliness, and practice fastidious personal hygiene. The British Admiralty were beset by inconsistent and conflicting accounts of scurvy cures, and it was not until 48 years after Lind's experiment that lemon or lime juice was made a part of routine British naval provisions. The lessons of the Renaissance explorers were poorly learned by succeeding generations, however. Scurvy beseiged nineteenth century populations on land, including much of Europe during die Great Potato Famine, armies of the Crimean and United States Civil War, arctic explorers, and California gold rush communities. In 1907, scurvy was produced experimentally in the guinea pig, and from 1928 to 1930, Albert Szent-Gydrgy and Glen King independently published their isolation of vitamin C or "hexuronic acid." This pure substance alone was shown to prevent and cure scurvy in guinea pigs. It was later names ascorbic acid for its antiscorbutic properties. The molecular structure was determined and an effective laboratory synthesis was developed in 1933. The history of scurvy and vitamin C has been summarized in a well-annotated volume.

The level of vitamin C used in the compositions of the present invention is about 75 mg in the product for balanced vegetarian and about 50 mg in the products for balanced carnivore.

Vitamin D Vitamin D has existed on Earth for at least 500 million years. It was first produced in ocean dwelling phytoplankton while they were exposed to sunlight for photosynthesis. Although the physiologic function of vitamin D in these lower life forms is unknown, vitamin D and its precursors may have acted either as a natural sunscreen to absorb high energy ultraviolet radiation, dius protecting ultraviolet sensitive organelles and macromoiecules, or as a photochemical signal. For reasons that are not understood, terrestrial vertebrates during evolution became dependent on vitamin D for the development and maintenance of their ossified skeletons. The principal physiologic function of vitamin D is all vertebrates including humans is to maintain serum calcium and phosphorus concentrations in a range that supports cellular processes, neuromuscular function, and bone ossification. Vitamin D accomplishes mis goal by enhancing the efficiency of the small intestine to absorb dietary calcium and phosphorus, and by mobilizing calcium and phosphorus stores from bone.

Vitamin D is inherently biologically inactive and requires successive hyroxylations in the liver and kidney to form 1,25-dihydroxyvitamin D (1,25 (OH D), the biologically active form of vitamin D. 1,25 (OH^D interacts with a specific nuclear receptor in its target tissues that results in a biologic response. Recent evidence suggests that 1,25 OH^D may also have rapid actions on

intracellular calcium, phosphatidy linos itol metabolism, and cyclic guanosine triphosphate (GTP) metabolism.

The identification of vitamin D metabolites led to me development of assays for them. These assays have become valuable diagnostic tools for evaluating patients witii hypocalcemic, hypercalcemic, and metabolic bone disorders.

The major target tissues for l,25(OH>2D are the intestine and bone; however, nuclear receptors for l,25(OH)2D have been identified in several other tissues and in cultured tumor cells. l,25(OH)2 inhibits die proliferation and induces terminal differentiation of many tumor and normal cultured cells that possess its receptor. These observations have been die impetus for a re-evaluation of die physiologic and pharmacologic actions of 1 ,25(OH>2D.

The level of vitamin D used in the compositions of die present invention is about 50 IU in the product for balanced vegetarian and about 25 IU in die products for balanced carnivore.

Vitamin E During the past decade diere have been many developments relating to nutritional and clinical aspects of vitamin E. Methods for assessment of nutritional status have been reexamined critically and improved, particularly with the advent of high performance liquid chromatography (HPLC) to separate the major vitamin E isomers of die tocopherol family. Populations of vitamin E deficient patients have been identified and studied with respect to pathologic alterations that might be attributed to die deficiency state. The occurrence of hemolysis in vivo due to tocopherol deficiency has been confirmed and shown to be clinically significant in both infants and older patients with intestinal malabsoφtion. In addition, it has been demonstrated convincingly in recent years that neurologic dysfunction with degenerative lesions in the spinal cord can develop in chronic vitamin E deficiency, yet, die vitamin remains as enigma and a continued challenge to both nutritional and clinical scientists. The subcellular role of vitamin E has been particularly difficult to establish, although it clearly functions as a biologic antioxidant. Partly as a result of this gap in knowledge, confusion also persists among medical scientists as to the indications for vitamin E therapy. Although medical benefits of tocopherol pharmacodierapy have been claimed when large doses of dietary supplements were taken by individuals not deficient in vitamin E, the evidence for favorable responses in generally unconvincing. The tragic E-Ferol experience using high-dose parenteral vitamin E merapy in newborn premature infants reinforces the risks associated with ip trial-and-error approach to clinical problems.

Nevertheless, the essentiality of this vitamin for humans has been well established during die past two decades, and many challenging new concepts have emerged from relevant basic research. The search for clinical disturbances in the human deficiency state has been aided by extensive investigation of the pathobiology of vitamin E deficiency in lower animals. Provocative experimental results in free radical biology have stimulated every increasing interest during recent years in die antioxidant capability of vitamin E. Thus, review of vitamin E requires comprehensive

discussion of current multidisciplinary research, including information on free radical biology and lipid peroxidation.

The level of vitamin E used in the compositions of the present invention is about 50 IU in the product for balanced vegetarian and about 50 IU in the products for balanced carnivore. Vitamin K Long periods of time may elapse between the discovery of a given vitamin deficiency disease, the isolation and determination of die structure of the vitamin, and die final elucidation of its metabolic structure. This is true of vitamin K: its deficiency disease, fatal hemorrhage, was discovered in 1929, its isolation and structure determination was accomplished in 1939, and its metabolic function was suspected only after a new amino acid, y-carboxyglutamic acid (Gla), was discovered in bovine protiirombin in 1974. It is now established tiiat vitamin K is part of a membrane-bound carboxylase system that participates in the posttranslational carboxylation of a number of vitamin K-dependent proteins.

Despite intensive effort in several laboratories over the past 15 years, the vitamin K- dependent γ-glutamylcarboxylase has not yet been isolated and its reaction mechanism is not yet clear, although progress is being made. Furthermore, in this age of molecular biology, die gene that codes for this enzyme has not yet been cloned. What has become clear, however, is that vitamin K is not only associated with coagulation, but also with additional functions in bone, kidney, and possibly other tissues.

The level of vitamin K used in the compositions of die present invention is about 0.50 mg in the product for balanced vegetarian and about 0.50 mg in die products for balanced carnivore.

Folic Acid The unraveling of die relation of vitamin B12 and folic acid to anemia traces back almost two centuries. In 1822, d e physician Combe reported in Edinburgh on d e "history of a case of anemia" mat he surmised was due to "some disorder of the digestive and assimilative organs." Thus was launched die study of pernicious anemia in particular and megaloblastic anemia in general, after restimulation by physician Thomas Addison's description, 1849 and 1855, of what his contemporaries evidently recognized as pernicious anemia. The nutritional basis of pernicious anemia was suspected by the American physician Austin Flint in 1860, when he stated diat "in diese cases there exists degenerative disease of die glandular tubuli of the stomach." . Another two-thirds of a century had passed when the classic work of physician William

Castle and his associates demonstrated mat normal human gastric juice contains an "intrinsic factor" (i.e., within die body) diat combines wiui an "extrinsic factor" (i.e., outside die body - in food) contained in animal protein to result in absoφtion of the "antipemicious anemia principle." Vitamin B12 was finally reported as isolated in 1948 in die United States, and three weeks later, entirely independently, in England. Berk and his associates showed that this vitamin was "extrinsic factor" and "antipemicious anemia principle."

Early reports of disease now recognizable as probable folate deficiency include those of Channing, Barclay, and Osier. A decade later Wills and her associates described in Hindu women in Bombay a macrocytic anemia, usually associated with pregnancy, that responded to therapy widi a commercial preparation of autolyzed yeast called Marmite; these workers produced in monkeys a similar macrocytic anemia mat responded to a "Wills factor" present in crude but not in purified liver extracts.

The more purified liver extract was found to be a fairly pure solution of vitamin B12, whereas die "Wills factor" from the crude liver extract was found to be folic acid. This was clarified by advances in knowledge of folic acid (e.g., the purification of pteroylglutamic acid in 1943, its crystallization in the same year, and its synthesis and structural identification in 1946) and by die isolation of vitamin B12 in crystalline form in 1948. The rapid isolation of the vitamin was greatly aided by a microbiologic assay based on Shorb's discovery mat the growth factor required by Lactobacillus lactis Domer was die "animal protein factor" necessary for animals fed an all-vegetable diet. The amounts of B12 present in liver extracts closely paralleled their potency in die treatment of pernicious anemia.

Folic acid has provide to be the same as the Wills factor; "vitamin M" contained in dried brewer's yeast diat corrected die deficiency anemia, leukopenia, diarrhea, and gingivitis of monkeys; "vitamin Be" contained in yeast that corrected the deficiency syndrome in chicks characterized by anemia and growth failure; and die Norite eluate factor of liver, essential to the growth of Lactobacillus casei (and therefore also called die "L. casei factor"). Sulfanilamide was shown to act by competitive inhibition of a bacterial metabolite, αrα-aminobenzoic acid. This metabolite was later found to be an essential component of L. casei factor.

The term folic acid was coined in 1941 by Mitchell and co-workers because diey found d is material in a leafy vegetable (spinach). At that time, it was not recognized that vitamin B12, and not folic acid, was the active ingredient in me oral liver therapy that Minot and Muφhy reported in 1926 as successful in treating pernicious anemia (for which work they received die Nobel Prize in Medicine in 1934). Considerable progress has since been made in our understanding of ie metabolic role of folic acid in health and disease, and of die use of folate antimetabolites in die treatment of some infectious diseases and cancers. The level of Folic acid used in the compositions of die present invention is about 65 meg in the product for balanced vegetarian and from about 125 meg in the products for balanced carnivore.

Inositol Nutritional scientists have been interested in inositol (myo-inositol) as a nutrient since die early 1940s, when its essentiality in certain rodent models was first suggested. Inositol depletion resulted in alopecia in mice, and in die accumulation of fat in the liver of rats fed certain diets. Since then, however, it has become apparent that aldiough inositol is a physiologically essential growth factor at the cellular level, it is only required as a dietary nutrient in certain species and under certain dietary conditions. Presently, interest in inositol nutrition is focused on its

potential importance in clinical situations. It is now recognized that dietary inositol may have therapeutic potential in complementing the treatment of several disorders in which altered inositol metabolism occurs. Inositol and its derivatives are widely distributed in nature and occur in animals, higher plants, fungi, and bacteria where they perform essential metabolic functions. Inositol metabolism in mammalian cells has been the subject of many studies and has been reviewed in detail. Present research interest in inositol biosynthesis and degradation if focused particularly on its role in inositol-containing phospholipids and their functions as cellular mediators of signal transduction, metabolic regulation, and growth. The pioneering contributions of Hokin and Hokin and of Michell are noteworthy in this regard. Interest in this rapidly expanding field is evidenced by the appearance of more than 50 new papers per month in the English scientific literature dealing widi various facets of inositol phospholipid metabolism. Several in-depth reviews on this topic are available.

The level of Inositol used in the compositions of die present invention is about 10 mg in die product for balanced vegetarian and about 10 mg in the products for balanced carnivore. Choline Choline is a quaternary amine that is ubiquitously distributed in foods. It is required to make the phospholipids phosphatidylcholine, lysophosphatidylcholine, choline plasmalogen, and sphingomyelin - essential components of all membranes. It is a precursor for the biosynthesis of die neurotransmitter acetylcholine and also is an important source of labile methyl groups. Choline, first discovered by Strecker in 1862, was chemically synthesized in 1866. It was known to be a component of phospholipids, but he pauiway for its biosynthesis was first described in 1941 by du Vigneaud. The route for its incoφoration into phosphatidylcholine (lecidiin) was not elucidated until 1956. The importance of choline as a nutrient was first appreciated during die pioneering work on insulin. Depancreatized dogs, maintained on insulin therapy, developed fatty infiltration of the liver and died. Administration of raw pancreas prevented hepatic damage; the active component was the choline moiety of pancreatic phosphatidylcholine. In 1935, the association between a low-choline diet and fatty infiltration of the liver in rats was recognized. The term lipotropic was coined to describe choline and other substances iat prevented deposition of fat in the liver. Subsequently, researchers suggested diat the liver disease associated with alcoholism might respond to choline therapy. However, little data supported this hypothesis. The assays for choline available at the time were not particularly sensitive or specific, and the dierapy did not prove to be effective.

In 1975, Wurtman and colleagues and Haubrich and associates reported diat administration of choline accelerated die synthesis and release of the acetylcholine by neurons. At die same time, technical breakthroughs in the assay of choline made it possible to accurately detect picomoles of the substance. A revival of interest in choline ensued, resulting in a plethora of publications characterizing die metabolism, physiologic effects, and pharmacology of choline. Much attention has been given to the effects of supplemental choline on brain function. Still unresolved, however, is

die question of whe ier choline is normally required as part of the human diet. Choline has been considered a dispensable nutrient for humans because of an endogenous pathway for the de novo biosyndiesis of choline moiety via the sequential methylation of phosphatidyiethanolamine, and because a choline deficiency syndrome has been difficult to identify in health humans as most common foods contain choline.

Several lines of evidence suggest that choline is indeed an essential nutrient for humans: (1) human cells grown in culture have an absolute requirement for choline; (2) health humans fed diets deficient in choline have decreased plasma choline concentrations: (3) malnourished humans have diminished plasma or serum choline concentrations; (4) humans fed intravenously with solutions containing little or now choline develop liver dysfunction diat is similar to mat seen in cholien- deficient animals; and (5) in other mammals, including die monkey, choline deficiency results in severe liver dysfunction. These arguments clearly do not prove or disprove that humans require dietary choline. Diminished tissue levels of a nutrient associated with dietary deficiency are suggestive of a nutrient requirement, but deficiency should also be associated with deterioration of organ function if a nutrient is essential. The presence of a pathway for endogenous synthesis does not make a nutrient dispensable. This review includes a discussion of the expected biochemical and physiologic uses for choline, die expected effects of choline deficiency, and evidence of a requirement for choline in the human's diet.

The level of Choline used in the compositions of the present invention is about 30 mg in e product for balanced vegetarian and about 35 mg in the products for balanced carnivore.

Beta carotene Beta carotene is provitamin A. It is transformed to vitamin A in the liver.

The level of Beta carotene used in the compositions of the present invention is about 880 mg in die product for balanced vegetarian and about 825 mg in the products for balanced carnivore.

Bioflavonoid A group of naturally occurring substances thought to maintain normal conditions in the walls of the small blood vessels. The bioflavonoids are widely distributed among plants, especially citrus fruits, black currants, and rose hips (hespiridin, rutin, quercitin). They have little or no medicinal value.

The level of Bioflavonoid used in the compositions of die present invention is about 75 mg in the product for balanced vegetarian and about 75 mg in the products for balanced carnivore. . The levels given above can be varied by ± 20% of the level stated, preferably ± 10% of the level given. Other Components

In addition to die vitamins, odier components may be added to the unit dose mixture, but care needs to be taken to ensure diat the components do not interfere with the ability of the vitamins to perform their functions. Suitable additional components include carboxymethyl cellulose.

Methods of Manufacture

The vitamins can simply be mixed togedier in a dry state and put into a suitable unit dose delivery device such as a capsule, sachet or other unit dose which does not involve significant compaction. The unit doses can also be mixed with an appropriate solvent such as water to form a solution or suspension before use and can be used by patients who prefer liquids or are unable to take materials by mouth through use of intravenous or peroneal infusion.

Composition Use

The unit dose compositions of the present invention are ingested in the same manner as o ier unit doses are. Oftentimes, die unit dose is ingested with die aid of water or odier liquid.

The following examples further describe and demonstrate preferred compositions of die present invention. The examples are given solely for illustration and are not to be considered as limitations of this invention as many variations thereof are possible without departing from die spirit and scope of die invention.

Example I Balanced Carnivore Multivitamin Specifications

Form Amt in Multivitamin

Vitamin A 1500 IU Vitamin Bl 6 mg Vitamin B2 6 mg Niacin 10 mg Niacinamide 30 mg Vitamin B5 45 mg Vitamin B6 6 mg Vitamin Bl 2 90 meg Biotin 21 meg

Parabenzoic Acid 35 mg Vitamin C 50 mg Vitamin D 25 IU Vitamin E dl-alpha 50 IU Vitamin K 0.5 mg Folic acid 125 meg Inositol 10 mg Choline 35 mg Beta carotene 825 IU Biσflavoroids 75 mg

Example 2 Balanced Vegetarian Multivitamin Specifications

Form Amt in Multivitamin

Vitamin A 800 IU

Vitamin Bl 10 mg

Vitamin B2 10 mg

Niacin 10 mg

Niacinamide 25 mg

Vitamin B5 60 mg

Vitamin B6 12 mg

Vitamin B12 90 meg

Biotin 20 meg

Parabenzoic Acid 25 mg

Vitamin C 75 mg

Vitamin D 50 IU

Vitamin E dl-alpha 50 IU

Vitamin K 0.5 mg

Folic acid 65 meg

Inositol 10 mg

Choline 30 mg

Beta carotene 880 IU

Bioflavoroids 75 mg

Example 3

New Moderate Carnivore Multivitamin Specifications

Form Amt in Multivitamin

Vitamin A 750 IU

Vitamin Bl 0.5 mg

Vitamin B2 1 mg

Niacin • 0 mg

Niacinamide 37.5 mg

Vitamin B5 16 mg

Vitamin B6 1 mg

Vitamin B 12 55 meg

Biotin 1.5 meg

Parabenzoic Acid 1.5 mg

Vitamin C 30 mg

Vitamin D 25 IU Vitamin E dl-alpha 50 IU Vitamin K 1 mg Folic acid 32.5 meg Inositol 21 mg Choline 36 mg Beta carotene 5000 IU Bioflavoroids 25 mg

Example 4

New Moderate Vegetarian Multivitamin Specifications

Form Amt in Multivitamin

Vitamin A 333 IU

Vitamin Bl 33 mg Vitamin B2 25 mg

Niacin 3 mg

Niacinamide 7 mg

Vitamin B5 0 mg

Vitamin B6 25 mg Vitamin B 12 6 meg

Biotin 33 meg

Parabenzoic Acid 33 mg

Vitamin C 35 mg

Vitamin D 70 IU Vitamin E dl-acetate 10 IU

Vitamin K 1 mg

Folic acid 150 meg

Inositol 5 mg

Choline 6 mg Beta carotene 833 IU

Bioflavoroids 80 mg

It is to be appreciated, of course, that die composition described in the Examples can be dosed in one single dose or in multiple doses, such as two or three or more, so long as the total dosage amount is met.