Lona to from the parenteral administration of 10 mg of phylloguinone daily. Paradoxically, the administra: tion of large doses of vitamin K or its analogs in aan attempt to correct the hypoprothrombinemia as sociated with severe hepatitis or cirrhosis may actually result ina further depression of ‘the Prothrombin concentration, ‘The mechanism for this is unknown. The vitamin does not, apparently, further depress hepatic function, (See Shifter and Steigmann, 1954; Douvtes, 1965.) “The response of hypoprothrombinemia to pa rentetal vitamin K administration has been. used 4s a test to distinguish between jaundice duet obstruction and that due to hepatocellular disease (Unger and Shapiro, 1948; Deutsch, 1966), Drug-Induced Hypoprothrombinemia. Antico agulant drugs such as bishydroxycoumerin. and its congeners act_as competitive antagonists of vitamin K- and interfere with the hepatic. bie- synthesis of prothrombin and factors Vil, IX, and X (see Chapter 65). These proteins then disap- pear from the blood at rates dependent on their Individual turnover rates: factor. VII declines first, followed, in order, by factor X, prothrombin, and factor TX, Excessive hypoprothrombinemia or bleeding produced by the administration of coumarin of indanedione anticoagulants can be corrected ina riod of a few hours by the administration of tamin K. Phylloquinone is much more effective than menadione or its derivatives (see Grimm finger, 1965), and should be used to counteract the effects of overdosage or overresponse 10 these anticoagulants. Mild overdosage may be. treated simply by drug withdrawal or dose reduction, or by the administration of single dose of 1 to 5 mg ot phylloquinone. Larger’ doses of phyllo- quinone may interfere “with subsequent anti coagulant therapy. I bleeding is severe, the immediate adminsication of 20 t0 40 mg of phyllo- quinone is indicated. Additional doses. st 4-hour intervals may be necessary to return prothrombin levels to normal. Transfusion of fresh whole blood may also be appropriate ‘After large doses of phylloquinone have been administered, it is difficlt to produce hypopro- thrombinemia with bishydroxycoumarin for” sev- eral days, If severe hypoprothrombinemia should occur as 4 result of the administration of large amounts of Salicylates, the treatment would be the: same as that outlined for bishydroxycoumarin induced hhypoprothrombinemia, after withdrawal Of the salicylates. Vitamin K may be of help in combating the bleeding and hypoprothrombinemnia following the bite of the tropical American pit viper or ether species whose venom destroys OF inactivates. pro- thrombin Finally, hypoprothcombinemia is also associated with excessive intake of vitamin A. Two mecha: nisms appear to be involved: (1) an inhibition of intestinal Bacterial biosynthesis of mensguinone 20h aporitbca 194 acm bem ravsame vans orca 2 PRL TH: theo ‘and (2) a direct antagonism of the hepatic actions of vitamin K (eee Green, 1966), VITAMIN E Introduction. Few vitamins have been more ex- tensively investigated in recent years than has vta- min E. In animals, the signs of deficiency include structural. and functional. abnormalities of many ‘organs and organ systems. Attending these ‘mor- phological alterations are biochemical defects that appear to involve fatty acid metabolism and ‘Rumerous other enzyme systems / Notable is the fact that many signs and symptoms 8 vitamin E deficiency in animals superficially resemble disease Sates in humans; however, there iste un: equivocal evidence that vitamin E is of nutritional significance in man or is of any value in therapy. History. The existence of vitamin E was frst demonstrated in 1922 by Evans and Bishop, who found that female rats required @ then-unteco nized dietary principle in order to sustain a norm pregnancy. Deficient animals were found to ovt- Inte and conceive normally, but at some time dur ing the period of gestation death and resorption of the fetuses occurred. Lesions in. the textes were also described, and for & while vitamin E was te- ferred to as the “antiserlity vitamin.” Further studies, however, revealed. the more. widespread effets of deficiency of the vitamin (see below). Some experiments seem to indicate that vitamin E is not an essential dietary constituent in animals; at present, the significance of these reports must Mill be evaluated, but they add further com- plexities 10 an already complex. and sometimes ‘confusing picture (see Wagner and Folkers, 1963), Chemistry. The vitamin was isolated by Evans and coworkers (1936) from wheat germ oil. Fight urally occurring tocopherols with vitamin E ac- tivity" are now known. Alphe-tocopherol” (5.7,8- tuimethyl tocol) is considered to be the most im- portant tocopherol since it comprises about 90% fof the tocopherols in animal dssues and displays the greatest biological activity in most bioassay sy3- tems. It was identified chemically by Fernholtz (1938) and symhesized by Karrer and associates (1938). Optical isomerism affects activity; d forms ‘are more active than 1 forms on hac. GO com cay pt TC pewhrenor sevens cH ‘Alpho ecapherot Alpha-tocopherol bears a striking structural simi larity to the 6-chromanol form of coenzyme Qu with which it shares biological activity in several systems (see Smith ef al, 1963) One’of the important ‘chemical features of theViranow E tocopherols ie that they are antioxidants. Further more, the compounds form reversible oxidation: reduction systems (see Dam, 1957). The toco. pherols deteriorate slowly on exposure 10 air or Ultraviolet Hight. Pharmacological Actions and Physiological Func fion. Aside ffom relieving symptoms of its de- ficiency in animals, vitamin E displays no. phar macological effects end no toxicity. Nonetheless, ‘numerous contradictory findings and claims for the actions and mechanisms of action characterize the literature on vitamin E. A major part_of the nutritive of therapeutic value of vitamin E in ani- nals appears to be related to ils properties as an antioxidant (see Dam, 1987; Horwitt, 1965). In acting as an antioxidant, vitamin E presumably prevents oxidation of essential cellular constituents, ‘Of prevents the formation of toxie oxidation prod: lus such as the peroxidatiba products formed from unsaturated fatty acids that have been de- {ected in ifs absence, In those cases where vitamin E is acting as an antioxidant, other antioxidants, ‘unrelated in structure to the vitamin, can substitute {or it in preventing oF alleviating the deficiency syndrome. ‘Some symptoms of vitamin E deficiency in ani mals are not relieved by other antioxidanis, and it is presumed in these cases that the vitamin is act- ing in a more specific manner (see Schwarz, 1965; Diplock eral, 1968). Wagner and Folkers (1963) cite experiments that question the essential mature of vitamin E. By dietary manipulations, animals have been raised that are capable of producing normal off- spring in the absence of vitamin E or other anti- oxidants in their diet, Tissues of these animals appear to be devoid of the vitamin, Wagner and Folkers, on the basis of these and other observa tions, further question whether vitamin E may not merely be mimicking the actions of a member of the coenzyme Q group, which is almost identical jn structure to alpha-tocopherol, possesses similar biological activities, and is present normally inti sues, (Als0 see Symposium, 1965.) Symptoms of Deficiency. Although manifesta- tions of vitamin E. deficiency in experimental animals are protean in nature, effects On the repro- ductive, muscular, cardiovascular, and hemato- poietic systems are most important because they bear the closest resemblance to the clinical syn- ddromes alleged to be benefited by vitamin E ther- apy. ‘Reproductive System. With the exception of the the work cited by Wagner and Folkers (1963), evi ence indicates that. vitamin Eis essential! for ‘normal reproduction in several mammalian species below the primate level. The most complete ob- servations have been mage on rats. In the male fat, prolonged deficiency produces. irceversible Sterility due to. degeneration of the germinal epithelium. Inthe vitamin E-deficent female, prea- nancy terminates in about 10 days with fetal death 1695 and resorption of the uterine contents. The funda- imental mechanism by which vitamin E deficiency interferes with reproduction is obscure. Fat me~ tabolism andthe antioxidant properties of the titamin appear to be involved and probably are interrelated, at leest_in the rat. [Not only. the fount of vitamin Ein the diet But also the mount Of unsaturated fatty acids in the diet af- fects reproduction (Dam et al, 1949). Moreover, antioxidants incorporated into the dict can com: pletely obviate the need for vitamin E for normal growth and reproduction in the rat (Crider eal 1961). Thus, the essential nature of vitamin Ein pregnancy is unclear. (On the basis of such animal studies, vitamin E has been used in man for the treatment of habitus] abortion and sterility in the male and female. Tt hnas also been used in toxemia of pregnancy, dis orders of menstruation, vaginitis, and menopausal Symptoms. In spite of early enthusiastic usage of sltumin E, there is no conclusive evidence that the Vitamin is of any beneficial eect in any of these conditions ‘Muscular System. Ia many species, notably monkey, rabbit, and guinea pig, a vitamin E-de- felent diet leads to the development of muscular dary in addon to weltdefined anntomical lesions, Metabolic abnormalities, including creat furia, increased oxygen uptake of affected muscles, fnd changes in the activity of numerous enzyme systems, are also seen (see Mason, 1960), The fnatomical and biochemical changes ean be pre ented, reversed, or ameliorated with —alph tocopherol or other lipid-soluble antioxidants, in lading coenzyme Q.” The pathogenesis of the ‘dystrophy, aside from a possible relationship be tween vitamin E and enzyme systems involved in ‘muscle metabolism, is unknown. Tappel and as- fociates (1963) attribute tissue damage tO. the Telease of cathepsin, ribonuclease, p-alactosidase, fand.sulfatase from Iysosomes damaged by. the ion of fatty and acid. peroxidation products Concurrently, tissue breakdown products such as amino acids, creatine, and allantoin appear in the Grin, Even though ‘muscular dystrophy accom- panies vitamin E deficiency in the monkey (Din- hing and Day, 1957), there is no evidence of @ vitamin E deficiency nor a therapeutic response to the administration of the vitamin in muscular ystrophy in man (see Pappenheimer, 1943; Ber- neske ef al, 1960). Similarly, patients with cystic fibrosis of "the pancreas or chronic. steatorzhea Gee Nitowsky er ol, 1962; Binder and Spiro, 1967) frequently have abby and atrophic muscles ‘with focal lesions similar 10 those seen in experi- mental animals with muscular dystrophy induced by vitamin E depletion, but teatment of these patients with vitamin E likewise has failed t0 pro- vce a significant improvement in muscle strength (Levin etal, 1961) Cardiovascular Systems, The lesions produced in skeletal muscle by a defciency of viamin E apparently are also found in cardiac muscle of Several species The cardiac lesions are sometimes1696 Far-Souuate Vitamins associated with ECG changes and even with beat fare ett ofthe hang vain Es been usd in many types of cardia Snorer and in peripheral vascular Gueas, Caeflly controled Slinal studies have fated to. demonstrate any beret fom he vitamin that could ot be mathe bythe use of # placebo (ice Bact et ale 1948: Boneaanset of, 1549, Ravin ad Rite, 1939: Bort of the Council, 1950)-— Hematopoietic System. Ta several anima specin delency of itamin Eig asonate With am anemia that ha features ofboth abnormal hema topolesis and decremed eythrocyte ifetine Erythrocytes from such annals. have.inetened sscepiiliy "hemolysis by oxidising apens such as ile hydrogen perotde, Indeed in ran this evo lsboratory tet i the only consistent finding. associated with low plasma, tocopherol levels (ace Leonard and Losowsky, 1967). Presume ably, tocopherol protets the lipids inthe erythro. cyte membrane from peroxidation, which fess in'membrave destruction and hemolysis Four ciical situations have now teen reported to include alpha-tocopherolresponsive anemia (see Darby, 1968; Symposium, 1968). (1). A. ‘macrocytie, megaloblastic anemia observed in chil dren with severe proteincalorie malnutrition, while Unresponsive to treatment with iron, cyanocc- balamin, folic acid, or ascorbic acid, was success. fully reversed with large doses of alpha-tocopherol acetate (Majaje? al. 1963; Whitaker et al, 1967), ‘This anemia resembles that produced by vitamin E depletion in the monkey (see Fitch, 1968), and, like it, also responds to coenzyme Q_ (Dinning ef aly 1962, 1963). (2) Premature infants may @evelop a hemolytic anemia that is sometimes associated with increased erythrocyte suscepti ty to peroxide hemolysis and low plasma tovoph erol levels. This anemia, while not responsive to iron, eyanocobatamin, of folic acid, does respond to 200 to 800 mg of alpha-tocopherol acetate (Oski and Barness, 1967). In-addition 10 the hemato- logical response, alpha-tocopherol was also reported to eltve the edema and skin lesions accompany- ing vitamin E deficiency and’a diet high in poly. unsaturated fatty acids (Hassan er al, 1966)” (3) Erythrocytes that hemolyze spontaneously in vliro constitute one characteristic of the acanthocytosis syndrome, Patients with this rare genetic disease lack plasma pelipoprotein and, therefore, have ile or no circulating alpha-tocopherol. Further, they have impaiced intestinal absorption of the vitamin. Parenteral administration of 100 mg of alpha-tocopherol acetate raised the plasma alpha- tocopherol levels and apparently corrected the autohemolytic feature of the disease for several weeks (Kayden eral, 1965). (4) In malabsorption syndromes. characterized by steatorrhea (et. sprue, cystic fibrosis, chronic pancreatitis), alpha tocopherol is not absorbed. Here, 100, decreased erythrocyte lifetime and. incteaied erythrocyte Sensitivity to hydrogen peroxide are coincident with low plasma alpha-tocopherol levels. These patients after longterm deprivation may develop other abnormalities associated with vitamin E deficiency [Chap. 77} in animals, such as muscle weakness and necrosis, reatinutia, and deposition of ceroid pigment in intestinal smooth musele. Only the creatiauria and hematological abnormalities are responsive to alpha-tocopherol administration, Adult. man, in. tentionally deprived of vitamin E over an extended period of time, has similar hematologicat lesions {and responds to alpha-tocopherol administration (Horwit et at, 1963). While the evidence outlined above seems to implicate vitamin E in normal hematopotesis, other factors must also be considered, Patients with each ‘of the above syndromes have multiple deficiencies, for example, Furthermore, the ability of the co: enzymes Q, selenium, and’ the sulfur-aming acids to relieve “tocopherol deficient” syndromes 10 vary- ing degrees provides further complications for a definitive interpretation. (See Symposium, 1965, 1968; Whitaker et al, 1967.) Human Requirements. Ina long-term con trolled study of vitamin E depletion in man, Hor- and coworkers (see Horwitt, 1962) found that plasma vitamin E concentration declined sig- nificantly only after months on a deficient diet. ‘There were no clinical manifestations of the deple- tion. From these studies, Horwitt estimates that @ daily intake of 10 to 30 mg of vitamin E is sof- ficient to maintain vitamin E blood levels within the normal range{Diets containing large amounts fof unsaturated fatlyvacids inerease the daly te urement (Harris and Embree, 1963); diets con. taining selenium, sulfur-amino ‘acids, chromenols, or antioxidants decrease the requirement, ‘The 1968 recommendations of the Food and [Nutrition Board of the Natioaat Research Council included, for the first time, 30 LU. of vitamin E per day for adult men and 25 LU. per day for ‘adult women Human milk (in contrast 10 cows! milk) has suffetnt alphe-tocopherol to meet nor- ral infant requirements. Tocopherols are present in adequate amounts in the normal adult diet, and Excretion. Vitamin E is absorbed from the gastrointestinal tract by a mech anism probably similar to that for the other fat soluble vitamins, Vitamin E enters the blood stream by way of the lymph. Tt appeats first in chylomi- trons and then primarily associated with plasma Bulipoproteins (MeCormick er af, 1960).. Vitamin Eis distributed to all tissues, Tissue stores can pro- vide a source of the vitamin for long periods of time, as evidenced by the long time animals must bbe Kept on a vilomin E-deficient diet before signs of deficiency appear. Seventy 10 80%. of an intravenously admine istered dose of radioactive vitamin Eis excreted by the liver over a petiod of a week; the balance appears as metabolites in the urine. The urinary Imetabolites are glucuronides of tocopheroniec acid and its “rlactone (Simon e7 @f., 1956). In some Assay systems these metabolites display significant vitamin E-tike activity” and. ate considered by some to be the active form of the vitamin (Green et al, 1961; Schwarz, 1961), Tocopheronie acid Absorption, FatVirani Kano thas not, however, been isolated from tissues. Sev- eral other metabolites with quinone structures have bbeen found in tissues; one Of these is very similar in structure to ubiquinone and may be related 10 ain active form of the vitamin (see Green and Me- Hale, 1965). Plasma levels vary widely among normal indi- viduals. There have been many stdies in which atiempis have been made (0 correlate the level of plasma tocopherol with disease states. In general, focopherol levels of the plasma appear to be re” Tated more closely to dietary intake and defects in intestinal absorption of fat than {0 the presence oF absence of disease (see Darby et al, 1949; Dju er al, 1958). Low tocopherol levels are generally associated, however, with an increased susceptibility Of erythrocytes to hemolysis by oxidizing. agents (Leonard and Losowsky, 1967). Bioassay and Unitage. The vitamin E activity of foods maybe determined chemically, or bio assayed for the protection afforded "pregnant female rats against death of the fetus. One inter: ational unit is equivalent to the activity of Img of dlhalpha-tocopheryl acetate, d-Alpha-tocophers] acetate has a. potency of 1.86 LU,/mg; «alpha tocopherol, 149 1.U,/mg, Preparations. dl-Alphactocopheryl acetate. d- alphacocopheryt acetate, and dl-alpha-tocopheral ate official in the US.P. Decavitamin, the US. Standard multivitamin. preparation, nov includes the equivalent of 11 mg of daipha-tocopheryl acetate. Available capsules and tablets contain 30, 50, 100, or 200 mg of tocopherol oF tocopheryl acetate; there ae also injectable forms containing 30, 100, or 200 mg/ml, Several multivitamin tabe iets, capsules, and drops contain small amounts of vitsmin E, Therapeutic Uses It has been exceedingly dit ficult to enabish a iect ‘correlation Cetween Mitsmin’E deficiency and clinically well-defined deficiency syndrome, The inc of eflcacy of i tmin E ia the trestment of those seas man that bear some resemblance 10 wtamin E defieney in animaly, names, halal abortion, progressive muscular dystrophy and. eardiovasclar desi, fas been dtuswd, These are by no means the only Gordes in which vitamin E therapy ha been Studied. The lat extends Tom minor skin alerts fo schizophrenia. With the possibie exception of Jt potential vale fn treating the anemiae rot ded with exteme proteslarie malputtion ie Inatoriy, or sesnibecgtous Gee above), res {Tih aiphatocopherl have in general been so ds ppointing tht the conclosion seems used that, \[atipretent, there is'no unesuivocal evidence tha [Bitmin Eat ty there we Aballi, A. and deLamerens §. Coagulation changes "in the aeonata} period snd in esl infancy. Pediat Cluny Nec, 1962, 9, 385-815 Almauist, Hed and Stebstad, CL. R. Hemorthaie Vira E 1697 chick diseate of dietary oritin, J, biol. Chem 11, w0s-103. Babior, BM.” Role of vitamin Kin clotting factor ‘symthesi. 1 Evidence forthe participation of vitamin Kin the conversion of a polypeptide. precursor 10 factor VII. Biochim. Diop, Aeta, 1966, 125, 606 io, Baer, Si Heine, W, 1: and Gelfond, D. B. Use of ‘itamin Ein heart disease. sim J. med, Se, 1948, pigysa2-sa?. Berneike, G. M. Butson, A. RCs Gauld, E, Ni and ‘eey, Dinka! wl of igh dosage vitamin E ‘Roman muscular dpsttophy. Cam med. ase. Jy 1960, #2, 8-821, Bindee, HJ. and Spire, H.M. Tocopherol deficiency in man, Ain ein, Nairy 1967, 20, 394-603. Butt, H. Rs Snel A. Ms and Osterberg. AE. The tke of vitamin K an bile i treatment of hemor bie diathesis in cases of jaundice. Proc. Sia Meet Mayo Clin. 1938, 13, 74-00 Commitee on Nutrition, American Academy of Pedi ‘es. ‘Vitamin K compounds and the water solve fnalogues: sein therapy and prophylaxis. Pediatrie, Sprineheld, 1961, 28. 801-507 Crider Qe Alaupovic, P and Johoson, B.C. Func: thom and metabalain of sitamin ill. Vitamin E nd aationdants inthe netraion of the rat. Nutr, 1961, 75, 6-70, Dam, Ht. ‘Cholestrinstofwechsel in, Huhnereieen und Huhnchen. Biochem. Z, 1929,.215, 415-492. Dam, Hs Granados, Hs and Prange, L._Taflcnce of 1 ilerent Tats on reproduction capacity of viamin Ecdefiiem rts. Acta physiol. scan, 1949, 18, 161 to, Dam, H., and Schonheyder, F. The antihaemorrhagie vitamin of the chick. Nature, Lond. 1998, 135, 652 a Dam, H.; Schonheyder, Fs and Tage-Hamsen, E Stud ies om the mode of ction of amin K. Biochem. J 1936, 30, 1073-1079. Darby, W. J: Ferguson, Mary Ellen; Furman, R. H.: Lemley, Janet My Bail, CT and Meneel, G. R- Plasma tocopherols in Benth and dscase Ann N.Y. ead. Sey 1943, 92, 328-333, Dinning, J. §. and Day, PL. Vitamin E deficiency Inthe monkey. . exp Med, 1981, 103, 398-402 Dianing. 7.8: Fitch, Da Shunk, C.F! and Folkers, IK The respomse ofthe aneme and dystrophic mon key to treatment with coemsyme Qe Aim, chem Soe, 1965, 84, 2007-2008 Dinning, 3-8; Mola}, A. Si Azzam, 8. Az Darby, ‘Wad: Shunk, C. Hi and Folkers, K.” Response of ‘macrocytic aperia in children tothe coenzyme: Qe Shromanol, Aint. ett, Nur, 3963, 13, 169-192 Diplock, A Ti Cauthorne, MAS Murrell EAs Grech, J: aad. Bunyan, J.” Mescurement of ip Peronidtion and. actocopherol extrution ons nd In sive and ther sigifeanee in connection with {he bllogial function of sitmin EB J. Nutr, 196d, 22, 465-472, Dj, M. ¥.j Mason. K. Es and Fier, LJ. Vitamin E {locephere) in hursan vetoes from birth to old age Ain clin Nuts 1988, 6, 30-0, Donegan, C. Ky Messet, A. Ls Orgaia, B.S. and ufin, JM. Nepative cess of tocopherol therapy in cardiovascular dheases Ans Le med. Set, 1908, 27, 390399, Douvies, PA. Etec of hish parenteral doses of vitae ‘min K analogs and serum albumin on the prttom- bin level "and ier function in alcoholic. cirrhosis ‘Ard ig. Dis. 1965, 10, 306-313 [Esans, HL ML, and Bishop. K.'. On the elatonship ‘berseen fey “and "sutven, Il, "The. ovation 1935,1698 Far-Souuot rhythm inthe ra on inadequate nutritional regimes J. metab, Res, 923, 1, 319-386. fans, HM; Emerson, O. Hi; and Emerson, Gladys ‘A. “The isolation from wheat gezm oil of an sco. hl, qtocopherol having propertis of vkamin 4B bik, Cher, 1936, 113. 319332, Feraholt,F."'On the constitution’ of tocopherol. T.Ari chem. Soc, 1938, 60, T0705, Fick, P. Ge Biedier, Gi and Brozli, HL Dose re ‘sponse and minimal daly requirement for vitamin K In man J. appl Physic! 1967, 23. 387-289, Green, J: Edwin, E, Bs Diplock A. T3 and Bunyan, J ‘The eilect of 2 wstersoluble metabolite of eetaco. herol on whiquinane in the rit, Biochim. Diophys Acta, B61, 49. 417A. Gaiminger, P. “Biologia! activity of the various vite ‘in K forms. Vitame Horm, 1966, 24, 08-618, Hareh, P-L, and Embree, N.. Quanthatve consi ‘ration of the elect of polyunsaturated fatty ect Content of the diet upon the fegultement Tor vi min E. Amd. clin Nutr, 1963, 13, 385-392. Hassan, Ha" Hashim, S.A‘; Van lhe, 1. Bz and ‘Sebréll W. H._ Syidrome in premature infants asso- ‘lated with low plasma vitamin levels and ish Polyunsaturated fatty acd. diet Aim. J. elim Nutr, 166, 79, 147-157 Hawkins, W, B, and Briskhous, K. M._ Prothrombin deficiency the cause of bleeding in bile fstula dogs Te exp. Med, 1936, 63 795-01. Hill, Roberta Bs Gaetan $; Paolucci, Anna Mara; ‘RomaRao, P. bs Alden, Rosemarie: Ranhotra, G. Shah, D. Vis Shaby V. Ks and Tohnson, B.C.” Vit rnin K and biosynthesis of protein and prothrombin, B biol. Chem, 1968, 245, 3930-293. Horwitt, M. K. "Iotertelations between vitainin E and ‘polyunsaturated fatty acids in adult men. Vitams Horm, 1962, 20, 341-338. Role ‘of vitamin E, selenium, and potyunsat ‘rated fatty acids in linal. and experimental mus le disease, Fedn Proc. Fedn Arm, Socs exp. Bio, 96s, 2468-72 Horwit, MK; Century, Bs and Zeman, A A. eythrocyte survival time and reticulocyte level after tocopherol depletion in. man. Am. J lin. Nut. 1963, 12, 99-106. Kareer) P) Feizsche, H Ringler, B. Hz and Salo- mon, H,, q-Tocoplieral. Hel. chim. Acia, 1938, 27, 520-525. Kayden, H, 35 Silber, Rand Kessman, C. E. The fole of vitamin E deficiency in the sbporm auto: Femoljss of acanthocytosi. Trans. dss. Am. Payens, 1965, 78, 334-382 Leonard, BJ and Losowsky, M.S. Relationship be ween plasma wismin E level and peronde herol- Je tes im homan subjects, dim. clin. Nur, 1967, So. 795-798 Levi, $1 Gordon, M. H.; Nuowshy, HM; Goldman, “Caripens di Sant Agnese, P and. Cordon, HH Studie of tocopherol deficiency in infants and chile Sten Vi, Evalgation of muscle siengih and effect OF tocopherol soninistation in chien With os tie bros Pediatrie, Springheld, 1961, 27, STH Ses McCormick, E, C; Cornwell, B, Gi and Brown, 5. B. Stodies on the dstution of tecopherol ke human serum, 2, Lipa Rex, 1960, 1, 221-228 Mai A. $3 Dinning, 1 Ss Azzam, 8. A and Darby, Wd.” Vitamin E responsive megalblastic anemia In infants with protemmesione malnutrition. Am. J lime Nutr, 1963, 12, 374-37 Nitowily, TH M2" Hsu, KS and Gordon, HH. ‘Vitamin, E requirements of human iolans: Vilas Hore, 1962, 20, 359-371 ViTanuns (Chap. 771 Ost, F A, and Barnes I, A. Vitamin E defceney: ‘a previously unrecognized cause of hemolyi anew in'the premature ila. J. Pediat, 1967, 70, 211-330, Pot, FJ. and Stewart, J. K.. Observations onthe ‘plasma prothrombin and the effects of vienin Kin fates with ner” or blary ast dene. tn, Quick. &, Ty Staney-Browa, Mz and Bancroft, F. W. "A sudy of the coaaulation defect n hemophilia snd fn jaundice, ain, Js med. Sor, 1935, 190, 901-51 avin I'S, aod Kate, KH.” Vitamin Fin the teat ‘ment of ansina pectoris, New Enel J. Meds 1989, 2a0, 331-333. Report of the Council on Foods and Nutrition. De- J poiences of the fat-soluble vitamins J. Am: med, D™ Ass, 1950, 144, 34-48, Schwarz, K." A possible site of action of vitamin E in inermediany metabolism. Am J. clin, Nutr, 19st, 9, Part 2, 11-15, Role of vitamin E, selenium, and related fac. {ors in experimental nutttional Iver disease. Fedn Proc. Fedn Am. Socs exp. Biol, 1968, 24, 5-61. Shiiter, Hy and Stciemann, Fo "The. effect of large ‘doses of ‘synthetic Wtamia K and Ky on the pro ‘hrombin time of patents wih Hier disease. J. Lab, flim, Med, 1954, 44, 930-991, Sion, EJ. Gross, Charlotte Si and Milhorat, Ade. ‘The metabolism of vitamin EJ. biol. Chem, 1956, 27, 191-817. Sinith, H. Pz Warner, E. Dz and Brinkhous, KM. ‘roiheombin deficiency and the bleeding tendency in liver injury (chloroform tloniation). J. rap. Med 1937,"66, 801-811 Smith, 1.1; Bhagavan, HN Hil R, B; Gaetan, Ss Raat, P. Bs. Crider, Q. E,; Johoson, B.C Shunk. CH Wagner, AF and Folkers, K. Biot logical activities of compounds in the viainin E, vitamin K and coenzyme Q eroups in chicks, rabbis tnd vals Arche Biochem, Biophys, 1963, 101, 388 385, Tappel, A. Le, Savant, P. Li and Shibko, S._Lyso- Tomes: cstbution in. animal hydrolytic capacty and other properties. In, Lysasomes (a Ciba Foun dation sympentam). (de Reuek, A. V.'S, and Cam. ‘ron, Margaret P, 0s) Lite, Brown & Co, Bor tons J. & A. Churehily Ltd, London, 1963. Uneer, P.N., and Shapto, S._ Prothrombin response to Parenteral administration of large. doves of simi Winttubjcts with normal liver function and i eases of lier disease” standardaed test for atimation of Repatic funetin. J. elm Invert, 1948, 27, 39-47. Washer, AE, and Folkery K’ Considerations of ‘erat od Quashbialogcal’ civies for coenayme O'and vitamins E and K- Perspecr. Biol Med, 1963, 8, 347-386 Warner, ED; Briakhous, K. M: and Smith, H. P. Bleeding tendency of cbsivutive jaundice: prouom. bin decioney and dietary factors. Proc. Soe. ex. Diol Medd. 1998, 97, 634-630. Wetting, K. WW. Hemorrhage in the newborn and vita ‘min K prophlant 7. Pediat, 1962, 61, 686-692, Whisker Jeane, Fort, Elganor’ G.i_ Vimokesaet, ‘Serine! and. Dinning, J. 8. Hematologic response to vitamin E in the anenia associated with retei= fsloriemalnutetion, am. J. clin, Nutr, 198%, 20, Sato, yan, RM. The obstetrical significance of factors aifecting the metabolam of bltubia, wih particular feference to the role of viamin K: Obstet! gymec. Surv, 1963, 78, 333-358, Zinkham, W. Ho, and Chids, B, Effect of vitamin K fant naphthalene metsbottes on glitthione metsbo~ Im of exythroeyes from normal newborns and PaVirani K AnD Virani E tients with naphthalene hemolytic anemia. A.M.A. J: Dig, Child, 1987, 94, 420-423, Monographs end Reviews Dam, H. Influence of antioxidants and redox sub- Staness on signe of titania E deficiency. Pharmac. Revs, 198%, 9, 16 Dam i, and Sondetgaad, E. Vitamin K. In, The ‘Eneymien Ind edy Vol. 3 (Boyer, P. Da Lardy, Hi find Marback, K} eds.) Academie Press, inc, New York, 1960. Darby, W. 3. Tocopherol-responsve anemias in man. Vitems Horm, 1968, 26, 685-599. Deutsch, EVitamin Kin medi practice: adults. Vitam Horm. 1966, 24, 65-60, Finkel MJ. Vitamia Gand vitamin K analogues. Clin, Pharmac. Ther, 1981, 2, 94-814 Fitch C. Dy "Experimental snemias i primates due 10 ‘itamin E deftency. Vitams Horm, 1968, 26, 501 sia Given, J. Antagonists of vitemin K, Vitems Horm, 1966, 34, 619-8 Greeny J, and Melile, D. Quinones related to vit ‘min E, In, Biochemistry of ‘Quinones, (Morton, RA, ed)’ Academic Pret, Ine, New York, 1968, pp. 261-285 Wer, O, and Wis, ©. Chemitey and biochemistry ‘of the K vitamins, Vitema Horm, 1999, 17, 5492. 1699 Lederer, Ey and Vilkas. M._ Phosphorylation of deriv- ‘ves of the sitamin K group. Fitams Horm. 1966, 34, 409-226, Marlss, C.. Chemtry and fonction of vitamin K. in Blood Cloning Eneymology. (Seevet, W. He.) (Aéadenie Press Tne, New York 1967, pp.” 557= as Miwon, KE, Effet of nutsiional deficiencies upon Vhuscle. In, Structure and. Function of Muscle (Bourne, G, Ha ed.) Academic Press, Inc, New ‘York, 1960. Ost F.'As and Naiman, 1. L Hematological Probe ems in ihe Newborn W. Hi, Saunders Co, Philae eipha, 1966, Pappenheier, A.M. Muscular disorders associated "Unis deficiency of viamin E- Physiol. Rev 1943, 23,37-50. Pennock, 3 F, Occurrence of vitamins K and related ‘ulnones, Vitgns Horm, 1966, 24, 307-329. symposium, (Various author.) Intereationships fimong viamia E, coenzyme Q, and selenium, Fed Proc. Fedn dm. Socr exp. Blo 1968, 24, 35-92. Symposium, (Various authors) Recent advances. in eseateh of vitamins K and elated quinones. (iar fins Ky ubiguinones or “coenzyine Q,_plastogue ones), Vitame Horm, 1966, 24, 293-689, sympostim, (Various auibor.)” Hematological aspects ‘of visa E. Am. Jem, Nutr, 1968, 21, 1-56.