Vitamin K

Common Names: Vitamin K1, Phylloquinone

Clinical Name: Phylloquinone

Summary

Vitamin K

forms: Phylloquinone or phytonadione (K1), menaquinone (K2), menadione (K3).

overview of interactions:
• adverse drug effects: Aminoglycosides

• nutrient affected by drug: Amoxicillin

• nutrient affected by drug: Antibiotics

• nutrient affected by drug: Cephalosporins

• nutrient affected by drug: Cholestyramine

• nutrient affected by drug: Colestipol

• nutrient affected by drug: Corticosteroids including Prednisone

• nutrient affected by drug: Griseofulvin

• nutrient affected by drug: Mineral Oil

• nutrient affected by drug: Neomycin

• nutrient affected by drug: Phenobarbital

• nutrient affected by drug: Phenytoin (Dilantin®)

• nutrient affected by drug: Tetracyclines

chemistry:
• The naturally occurring forms of vitamin K are all fat soluble. They are stored in the liver, though not to any great extent. Stable to heat and reducing agents, they are destroyed by light, acid, alkali, oxidizing agents, and alcohol.
• Most supplemental forms of chlorophyll, as a vitamin K source, are water soluble.
• K1: phytonadione or phylloquinone (Aquamephyton): is a natural derivative from fish or plants.
• K2: menaquinone: fat-soluble form made by intestinal bacteria.
• K3: menadione: the synthetic water-soluble form tends to have a greater degree of toxicity.

metabolism:
• Vitamin K1 is absorbed in the upper GI tract and requires bile salts for absorption.

function:
• Vitamin K acts as a cofactor in the final synthesis of proteins with a modified amino acid residue.
This modified glutamic acid residue is found in bone proteins and can bind onto calcium ions to cause calcification.It is also found in the blood and along vessel walls, and along with platelet-derived phospholipid, binds calcium, and is an integral part of the clotting process.
• Vitamin K facilitates the action of calcium in building bone and clotting blood.
• Vitamin K is involved in the synthesis of a protein, osteocalcin, which is found in high amounts in bone. It allows calcium ions to bind, thus resulting in the calcification of bone.
• Vitamin K is involved in the synthesis of a kidney protein that functions in the inhibition of calcium oxalate stone formation via its ability to bind onto calcium in the kidneys.
• Vitamin K is involved in the synthesis of proteins C and S. These two proteins, formed in the liver, promote fibrinolysis and anti-coagulation. Thus, they are involved with reducing inflammation.

dietary sources:
• Lettuce, spinach, kale, cauliflower, cabbage, egg yolk, soybean oil, liver, kelp, alfalfa and other green plants, cow's milk, liver. Leafy green vegetables are the single best dietary source of vitamin K because of their high chlorophyll content.
• Probiotic flora in intestines with a healthy ecology normally manufacture vitamin K.

deficiency:
• A clinically significant vitamin K deficiency, as manifest by uncontrolled bleeding, is rare. Those cases which do develop are usually associated with malabsorption diseases.
• Infancy: Hemorrhagic disease of the newborn has been related to Vitamin K deficiency. This is due to poor transport across the placenta: especially with premature infants. Also, because of the relatively sterile infant gut, the ability to make vitamin K is impaired. The practice of supplementing pregnant women with vitamin K and providing vitamin K to newborn infants has significantly reduced the risk of deficiencies among infants, especially those who are breast-fed.
• Easy bleeding in children: especially spontaneous nose bleeds.
• Osteoporosis: A deficiency of vitamin K leads to impaired bone mineralization due to inadequate osteocalcin levels.
(Hart JP, et al. J Clin Endocrinol Metab. 1985 Jun;60(6):1268-1269; Hodges SJ, et al. Clin Sci (Colch). 1990 Jan;78(1):63-66; Hodges SJ, et al. Bone. 1991;12(6):387-389.)
• Vitamin E may interfere with the absorption and utilization of vitamin K.
• Many drugs, particularly antibiotics, cephalosporins and anticonvulsants such as phenytoin (Dilantin) directly interfere with vitamin K synthesis and metabolism.

proven or potential therapeutic uses: Blood clotting disorders (especially involving infants), (associated with deficiency), celiac disease (associated with deficiency), floaters (in eyes), fractures, inflammatory conditions, nausea and vomiting of pregnancy, rheumatoid arthritis, osteoporosis, prevention of calcium oxalate kidney stones, pruritus.

maintenance dose: 150 - 500 mcg per day.
• RDA: none established at this time.
It is estimated that adults need 70-140 mcg per day while infants require 20-100 mcg per day.
• Vitamin K (phytonodione) accumulates in the chlorophyll-forming parts of plant leaves and, thus, dark green leafy vegetables are an excellent source.
Vitamin K2 (menaquinone) is synthesized by probiotic bacterial flora in the large intestine.
• Optimal daily intake: 500 mcg.

therapeutic dose: 5 mg per day.
Phylloquinone (K1) is the preferred form for supplementation.

side effects: There are no known adverse side effects associated with vitamin K administration.

toxicity:
• No toxicities have been reported or suspected as being associated with natural vitamin K.
• Large doses of Menadione, the synthetic derivative, may produce hemolytic anemia and jaundice in the infant. Most toxicity is associated with IV use and may be related to allergies to various preservatives or incipients.
• Synthetic vitamin K toxicity: flushing, sweating, chest constriction, hemolytic anemia, kernicterus in infants.

contraindications: Patients taking anticoagulant drugs, especially Warfarin (Coumadin).



Interactions

nutrient affected by drug: Antibiotics including Amoxicillin

• mechanism: When antibiotics destroy all or most of the beneficial bacterial flora in the gut they eliminate the organisms that synthesize a high proportion of the body's vitamin K. Therefore, many antibiotics can indirectly cause a depletion of vitamin K.

• nutritional support: Anyone taking antibiotics for more than a few weeks would most likely benefit from supplemental vitamin K. Nevertheless, it is rare that such a depletion of vitamin K would produce noticeable symptoms. Restoration of the healthy bacterial flora that normally produce the Vitamin K is generally advisable after the use of any antibiotics. Vitamin K1 supplementation may be necessary and is available in some multivitamin formulas.

nutrient affected by drug: Cephalosporins

• mechanism: Cephalosporins both undermine with Vitamin K synthesis and interfere with its metabolism. Like any antibiotic, cephalosporins destroy the friendly bacterial flora of the intestines in the process of attacking pathogenic bacteria. One of the key functions of these probiotic bacteria in the digestive ecology is the synthesis of vitamin K synthesis. As a result of cephalosporin use, Vitamin K synthesis is reduced until the bacteria are reinforced through the use of supplemental flora. Cephalosporins also interfere directly with vitamin K metabolism, and as a result can lead to abnormal bleeding.
(Anonymous. Nutr Rev 1984;42(4):161-163.)

• nutritional support: Conservative nutritional practice indicates the value of supplementing with Vitamin K whenever cephalosporin is used. Generally, a multivitamin containing vitamin K may be adequate. However, if hemorrhage results from a cephalosporin antibiotic, a physician should be consulted for diagnosis and treatment. In such cases, vitamin K should initially be administered by IM injection.

nutrient affected by drug: Cholestyramine

• mechanism: Bile acid sequestrants, such as cholestyramine, decrease lipid digestion and absorption, as well as absorption of the fat-soluble vitamins and other nutrients.
(Roe DA. 1985: 158-159; Watkins DW, et al. Dig Dis Sci 1985 May;30(5):477-482; Hathcock JN. Fed Proc. 1985 Jan;44(1 Pt 1):124-129; West RJ, Lloyd JK. Gut. 1975 Feb;16(2):93-98.)

• nutritional support: Regular use of a high-potency multiple vitamin/mineral will replace the nutrients impeded by the drug.

nutrient affected by drug: Colestipol; along with Vitamin A, Vitamin D, Vitamin E and Folate

• mechanism: Colestipol, by design, reduces fat absorption and hence interferes with absorption of fat-soluble nutrients.
(Tonstad S, et al. Arch Dis Child 1996 Feb;74(2):157-160.)

• clinical concerns: This interaction raises serious questions given the accumulating experimental, epidemiological, and clinical evidence of an association between anti-oxidant vitamin intake and reduced risk of coronary heart disease.

• nutritional support: Vitamin K supplementation, as part of a multivitamin/-mineral formulation, would probably be of benefit for individuals taking colestipol.

nutrient affected by drug: Corticosteroids including Prednisone

• mechanism: Steroidal anti-inflammatory drugs cause increased loss of vitamin K through the urine. Though widely observed, the clinical implications of this pattern remain unclear.
(Buist RA. Intl Clin Nutr Rev 1984;4(3):114; Pronsky Z. 1991, 60.)

• nutritional support: Individuals using corticosteroids for periods longer than two weeks should consult with their prescribing physician and/or a nutritionally trained healthcare professional about the potential need to supplement with vitamin K to counter the depleting effects of the drug(s). A typical dose in such situations would be in the range of 65-80 mg of vitamin K per day, a level easily obtained by eating leafy green vegetables.

nutrient affected by drug: Griseofulvin

• mechanism: Griseofulvin, like other antibiotics, can destroy all or most of the beneficial bacterial flora that synthesize a high proportion of the body's vitamin K in the gut. This can indirectly cause a depletion of vitamin K.

• nutritional support: Vitamin K1 is available in some multivitamin formulas. Anyone taking antibiotic drugs for more than a few weeks would most likely benefit from supplemental vitamin K, even though it is rare that such a depletion of vitamin K would produce noticeable symptoms.

nutrient affected by drug: Mineral Oil

• mechanism: Mineral oil, as a lipid solvent, may absorb many substances and/or interfere with normal absorption of vitamin K and other nutrients.

• research: While there is some disagreement, most research has found that mineral oil interferes with the absorption of many nutrients, including beta-carotene, calcium, phosphorus, potassium, and vitamins A, D, K, and E. Chronic use of mineral oil can cause a deficiency of vitamins A, D, E, and K, being fat soluble, as a result of their being absorbed by the oil. This is especially problematic during pregnancy as the regular ingestion of mineral oil may reduce the assimilation of critical nutrients. The malabsorption of vitamin K can result in an increased anticoagulant activity by coumarin anticoagulants, as a result of this adverse effect of mineral oil.
(Clark JH, et al. Am J Dis Child 1987 Nov;141(11):1210-1212; Holt GA.1998, 176.)

• nutritional concerns: If using mineral oil for any extended period of time, regular use of a multivitamin supplement, containing more than 100 mcg of vitamin K per daily dose, would be beneficial. Malabsorption of fat-soluble vitamins due to ingestion of mineral oil can be minimized by administering mineral oil on an empty stomach or consuming vitamin or mineral supplements at least two hours before or after the mineral oil. In general it is advisable to limit the internal use of mineral oil to periods of less than one week.

nutrient affected by drug: Neomycin

• research: Neomycin, taken orally, impairs vitamin K absorption and has been shown to decrease vitamin K levels. Extended use of neomycin internally would also exert a detrimental effect upon the probiotic intestinal flora responsible for vitamin K synthesis.
(Robinson C, Weigly E. 1984, 46-54; Olson JA. Am J Clin Nutr. 1987 Apr;45(4):687-692; Salet J, et al. Arch Fr Pediatr. 1968 Oct;25(8):961.)

• nutritional support: Individuals taking neomycin internally for more than 2-3 days may benefit from taking supplemental vitamin K at doses of 65-80 mg per day. Such supplementation would be especially important for nursing infants; consult the prescribing physician in such situations for a recommended dose. Individuals using neomycin topically will not experience problems related to impaired absorption of vitamin K.

nutrient affected by drug: Phenobarbital

• research: Phenobarbital interferes with vitamin K metabolism as indicated by a raised serum osteocalcin level. This finding may be of importance in the pathogenesis of side effects of these medications. In regard to pregnancy, the use of phenobarbital has been associated with vitamin K deficiencies in newborns.
(Keith DA, et al. Clin Pharmacol Ther 1983 Oct;34(4):529-532; Cornelissen M, et al. Am J Obstet Gynecol 1993 Mar;168(3 Pt 1):923-928.)

• nutritional support: At this point research has produced no consensus as to appropriate therapeutic dose of vitamin K to counter the adverse effects of phenytoin. Increasing the amount of green leafy vegetables in the diet could provide multiple benefits, in addition to enhancing vitamin K levels. Further supplementation with 1 mg vitamin K1 daily would also be prudent for most individuals taking phenytoin. Among pregnant women taking anticonvulsants, research indicates that a higher dose of vitamin K1, 10 mg per day, can prevent vitamin K deficiency in their infants.
(Cornelissen M, et al. Am J Obstet Gynecol 1993 Mar;168(3 Pt 1):923-928.)

nutrient affected by drug: Phenytoin (Dilantin®)

• research: Phenytoin interferes with vitamin K metabolism as indicated by a raised serum osteocalcin level. In regard to pregnancy, the use of phenytoin has been associated with vitamin K deficiencies in newborns. Children born of mothers using phenytoin have been known to suffer from calcification problems and one study with rats has indicated a role in birth defects involving excessive calcification, such as represented by Binder's Syndrome.
(Keith DA, et al. Clin Pharmacol Ther 1983 Oct;34(4):529-532; Keith DA, et al. Med Hypotheses 1979 Dec;5(12):1347-1351; Cornelissen M, et al. Am J Obstet Gynecol 1993 Mar;168(3 Pt 1):923-928; Howe AM, et al. Aust Dent J 1992 Dec;37(6):453-460.)

• nutritional support: At this point research has produced no consensus as to appropriate therapeutic dose of vitamin K to counter the adverse effects of phenytoin. Increasing the amount of green leafy vegetables in the diet could provide multiple benefits, in addition to enhancing vitamin K levels. Further supplementation with 1 mg vitamin K1 daily would also be prudent for most individuals taking phenytoin. Among pregnant women taking anticonvulsants, research indicates that a higher dose of vitamin K1, 10 mg per day, can prevent vitamin K deficiency in their infants.

nutrient affected by drug: Tetracyclines

• mechanism: When antibiotics destroy all or most of the beneficial bacterial flora in the gut they eliminate the organisms that synthesize a high proportion of the body's vitamin K. Therefore, many antibiotics can indirectly cause a depletion of vitamin K.

• nutritional support: Anyone taking antibiotics for more than a few weeks would most likely benefit from supplemental vitamin K, even though it is rare that such a depletion of vitamin K would produce noticeable symptoms. Restoration of the healthy bacterial flora that normally produce the vitamin K is generally advisable after the use of any antibiotics. Vitamin K1 supplementation, in the range of 65-80 mg per day, may be necessary and is available in some multivitamin formulas. Leafy green vegetables are the best dietary sources of vitamin K.

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Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.


References

Anonymous. New examples of vitamin K-drug interaction. Nutr Rev 1984;42(4):161-163. (Review)

Bell RG, Caldwell PT, Holm EE. Coumarins and the vitamin K-K epoxide cycle. Lack of resistance to coumatetralyl in warfarin-resistant rats. Biochem Pharmacol. 1976 May 1;25(9):1067-1070.

Bell RG, Ren P. Inhibition by warfarin enantiomers of prothrombin synthesis, protein carboxylation, and the regeneration of vitamin K from vitamin K epoxide. Biochem Pharmacol. 1981 Jul 15;30(14):1953-1958.

Bell RG. Metabolism of vitamin K and prothrombin synthesis: anticoagulants and the vitamin K--epoxide cycle. Fed Proc. 1978 Oct;37(12):2599-2604. (Review)
Abstract: Vitamin K is primarily located in hepatic microsomes, where the vitamin K-dependent carboxylation in prothrombin synthesis occurs. Recent evidence supports the idea that the carboxylation is linked to the metabolism of the vitamin--specifically the cyclic interconversion of vitamin K and vitamin K epoxide. The primary site of action of coumarin and indandione anticoagulants appears to be an inhibition of the epoxide-to-vitamin K conversion in this cycle. There is a correlation between the inhibition of prothrombin synthesis and the regeneration of vitamin K from the epoxide by anticoagulants. In hamsters and warfarin-resistant rats prothrombin synthesis and the epoxide-K conversion are less sensitive to warfarin than in the normal rat. The epoxide-K conversion is impaired in resistant rats, which may explain their high vitamin K requirement. There is also a correlation between vitamin K epoxidation and vitamin K-dependent carboxylation, but the apparent link may be because vitamin K hydroquinone is an intermediate in the formation of the epoxide and also the active form in carboxylation. The vitamin K-epoxide cycle is found in extrahepatic tissues such as kidney, spleen, and lung and is inhibited by warfarin.

Bengmark S. Ecological control of the gastrointestinal tract. The role of probiotic flora. Gut 1998 Jan;42(1):2-7. (Review)

Buist RA. Drug-nutrient interactions - an overview. Intl Clin Nutr Rev 1984;4(3):114. (Review)

Clark JH, Russell GJ, Fitzgerald JF, Nagamori KE. Serum beta-carotene, retinol, and alpha-tocopherol levels during mineral oil therapy for constipation. Am J Dis Child 1987 Nov;141(11):1210-1212 .
Abstract: Twenty-five children with chronic constipation underwent serial monitoring of serum beta-carotene, retinol (vitamin A1), and alpha-tocopherol (vitamin E) levels during mineral oil therapy. Mineral oil was administered between meals. Patients were monitored for up to four months of therapy. Mean serum beta-carotene levels fell from 1.0 +/- 0.5 mumol/L (55.7 +/- 26.0 micrograms/dL) to 0.7 +/- 0.4 mumol/L (35.9 +/- 22.1 micrograms/dL) after the first month of mineral oil therapy and remained depressed throughout the remainder of the study. Serum alpha-tocopherol levels remained unchanged throughout the observation period. There was a modest increase in serum retinol levels during the study, especially after three months (from 1.48 +/- 0.84 mumol/L [42.3 +/- 24.1 micrograms/dL] to 2.22 +/- 0.77 mumol/L [63.5 +/- 22.1 micrograms/dL]). We conclude that while a short course of mineral oil can induce a reduction in the serum level of beta-carotene, the treatment has no adverse effect on serum levels of retinol and alpha-tocopherol.

Combs AB, Porter TH, Folkers K. Anticoagulant activity of a naphthoquinone analog of vitamin K and an inhibitor of coenzyme Q10-enzyme systems. Res Commun Chem Pathol Pharmacol. 1976 Jan;13(1):109-114.
Abstract: Synthetic 2-hydroxy-3-h-dodecylmercapto-1,4-naphthoquinone is an analog of both vitamin K1 and coenzyme Q10. This naphthoquinone analog is an effective inhibitor of coenzyme Q10-enzymes of mammalian mitochondria, which are components of electron transfer mechanisms of respiration and coupled oxidative phosphorylation. This analog increased the prothrombin time in rats when it was administered orally or parenterally. Vitamin K1 reversed the prothrombin time increase, but that form of coenzyme Q, hexahydrocoenzyme Q4, which has the same phytyl side chain as vitamin K1, did not reverse the increase, constituting the biological differentiation between vitamin K and coenzyem Q. Two benzoquinone analogs of coenzyme Q10, 5-n-octadecylmercapto-2,3-dimethoxy-1,4-benzoquinone and 5-beta-naphthylmercapto-2,3-dimethoxy-1,4-benzoquinone, the latter being a strong inhibitor of coenzyme Q10-enzymes, did not increase the prothrombin time under comparable conditions.

Cornelissen M, Steegers-Theunissen R, Kollee L, Eskes T, Vogels-Mentink G, Motohara K, De Abreu R, Monnens L. Increased incidence of neonatal vitamin K deficiency resulting from maternal anticonvulsant therapy. Am J Obstet Gynecol 1993 Mar;168(3 Pt 1):923-928.
Abstract: OBJECTIVE: The null hypothesis of our study is that the incidence of vitamin K deficiency in mother-infant pairs exposed to anticonvulsant drugs is not higher than in controls. STUDY DESIGN: In this multicenter observational case-control study, 25 pregnant women receiving anticonvulsant therapy and 25 pregnant controls were studied for PIVKA-II (protein induced by vitamin K absence of factor II) and vitamin K1 concentrations at 32 weeks' gestation and at delivery. RESULTS: PIVKA-II was detectable in 54% of cord samples of the anticonvulsant group and in 20% of controls (chi 2, p = 0.01). In both groups vitamin K1 cord blood levels were predominantly below the detection limit. Maternal vitamin K1 concentrations were lower in women with epilepsy than in controls (Wilcoxon's rank sum test, p < 0.05), but PIVKA-II was rarely present. CONCLUSIONS: The incidence of vitamin K deficiency is increased in neonates exposed to anticonvulsant drugs prenatally. Their mothers, however, are rarely vitamin K deficient.

Cornelissen M, Steegers-Theunissen R, Kollee L, Eskes T, Motohara K, Monnens L. Supplementation of vitamin K in pregnant women receiving anticonvulsant therapy prevents neonatal vitamin K deficiency. Am J Obstet Gynecol 1993 Mar;168(3 Pt 1):884-888.
Abstract: OBJECTIVE: The null hypothesis of this study is that extra vitamin K administered to pregnant women on a regimen of enzyme-inducing anticonvulsant therapy will not decrease the frequency of symptoms of vitamin K deficiency in their neonates. STUDY DESIGN: A multicenter case-control study was performed on 16 pregnant women on anticonvulsant therapy who received 10 mg of vitamin K1 daily from 36 weeks of pregnancy onward. Concentrations of PIVKA-II (protein induced by vitamin K absence for factor II) and of vitamin K1 were determined in cord blood and compared with those in 20 controls. RESULTS: In none of 17 cord samples was PIVKA-II detectable, compared with 13 of 20 in controls (chi 2, p < 0.001). Median cord vitamin K1 level was 530 pg/ml compared with below detection limit in most controls. CONCLUSIONS: Antenatal vitamin K1 treatment decreases the frequency of vitamin K deficiency in neonates of mothers on anticonvulsant therapy.

Corrigan JJ Jr. The effect of vitamin E on warfarin-induced vitamin K deficiency. Ann N Y Acad Sci 1982;393:361-368.
Abstract: Vitamin K-deficient animals and humans developed a more severe coagulopathy when treated with vitamin E, which was due to further reduction in the vitamin K-dependent coagulation factors (II, VII, IX, and X). This phenomenon was not seen in normal vitamin K-sufficient animals or human subjects. The mechanism by which vitamin E causes this effect is not known. These coagulation factors are produced by the liver in precursor forms and are converted to functional proteins by a vitamin K-dependent reaction. Analysis of one of these coagulation factors, prothrombin (factor II), in plasma of vitamin K-deficient animals and humans treated with vitamin E was done in this study. The precursor of factor II is antigenically similar to biologically active factor II and can be activated to form thrombin by Echis carinatus venom. The data showed that functional factor II coagulant activity was reduced below base in warfarin-treated humans and animals given vitamin E. Factor II antigen as determined by electroimmunoassay in humans and factor II coagulant activity as measured using Echis venom in animals were unchanged and no different from untreated controls. The data suggest that vitamin E acts at the vitamin K-carboxylase step of carboxylation of precursor prothrombin and not in the synthesis of the precursor protein.

Craciun AM, Wolf J, Knapen MH, Brouns F, Vermeer C. Improved bone metabolism in female elite athletes after vitamin K supplementation. Int J Sports Med 1998 Oct;19(7):479-484.
Abstract: In female elite athletes strenuous exercise may result in hypoestrogenism and amenorrhoea. As a consequence a low peak bone mass and rapid bone loss are often seen in relatively young athletes. In postmenopausal women, increased intake of vitamin K may result in an increase of serum markers for bone formation, a decrease of urinary markers for bone resorption, and a decrease in urinary calcium loss. In the present paper we report an intervention study among eight female athletes, four of whom had been amenorrhoeic for more than one year, whereas the others had been using oral contraceptives. All participants received vitamin K supplementation (10 mg/day) during one month, and various bone markers were measured before and after treatment. At baseline the athletes not using oral contraceptives were biochemically vitamin K-deficient as deduced from the calcium binding capacity of the circulating bone protein osteocalcin. In all subjects increased vitamin K was associated with an increased calcium-binding capacity of osteocalcin. In the low-estrogen group vitamin K supplementation induced a 15-20% increase of bone formation markers and a parallel 20-25% decrease of bone resorption markers. This shift is suggestive for an improved balance between bone formation and resorption.

Fukushima Y, Kawata Y, Hara H, Terada A, Mitsuoka T. Effect of a probiotic formula on intestinal immunoglobulin A production in healthy children. Int J Food Microbiol 1998 Jun 30;42(1-2):39-44.
Abstract: The anti-infectious effect of probiotics has recently been reported and one mechanism may be the non-specific stimulation of immunity. This study was performed to elucidate the influence of a probiotic formula on intestinal microflora and local immunity in healthy children. A follow-up formula containing viable bifidobacteria was given to seven healthy Japanese children (15 to 31 months old) for 21 days. During intake of the formula, the administered strain was detected in feces from five subjects (71%) and total fecal bifidobacteria slightly increased. Fecal levels of total IgA and anti-poliovirus IgA during intake of the formula were significantly higher than those before intake (P < 0.05). The increase in local IgA levels resulting from ingestion of the probiotic formula may contribute to enhancement of the mucosal resistance against gastrointestinal infections.

Fuller R, Gibson GR. Modification of the intestinal microflora using probiotics and prebiotics. Scand J Gastroenterol Suppl 1997;222:28-31.
Abstract: Probiotics and prebiotics modulate the composition of the human gut microbiota. The beneficial effects may result from suppression of harmful microorganisms or stimulation of organisms which contribute in a positive way to the nutrition and health of the host. Both types of supplement represent an attempt to reconstitute the gut flora to its normal composition which has been adversely affected by dietary and environmental stresses.

Fuller, R. Probiotics in human medicine. Gut 1991 Apr;32(4):439-442. (Review).

Gismondo, MR, Lo Bue, AM, Chisari, G, et al. Competitive activity of a bacterial preparation on colonization and pathogenicity of C. pylori. A clinical study. Clin Ter 1990;134:41-46. [Article in Italian]

Harris JE. Interaction of dietary factors with oral anticoagulants: Review and application. J Am Diet Assoc 1995 May;95(5):580-584. (Review)

Hart JP, Shearer MJ, Klenerman L, Catterall A, Reeve J, Sambrook PN, Dodds RA, Bitensky L, Chayen J. Electrochemical detection of depressed circulating levels of vitamin K in osteoporosis. J Clin Endocrinol Metab. 1985 Jun;60(6):1268-1269.
Abstract: If gamma-carboxylation, by the vitamin K1 - cycle, of glutamate residues of bone-matrix peptides is essential for the formation of bone, the circulating levels of this vitamin might indicate the potential efficiency of this process. Methods involving HPLC with electrochemical detection have very recently been developed for assaying the low levels of vitamin K1 that occur in normal plasma. Using such methods, we found that the circulating levels of vitamin K1 in osteoporotic patients (who had sustained either spinal crush-fractures or fractures of the neck of the femur) were significantly lower than those of age-matched control subjects.

Hodges SJ, Pilkington MJ, Shearer MJ, Bitensky L, Chayen J. Age-related changes in the circulating levels of congeners of vitamin K2, menaquinone-7 and menaquinone-8. Clin Sci (Colch). 1990 Jan;78(1):63-66.
Abstract: 1. Through the vitamin K1 cycle, phylloquinone is now known to play an active role, not only in relation to prothrombin, but also in the synthesis of bone peptides. 2. The recent development of a sensitive method allowed the demonstration of a deficit of vitamin K1 in the circulation of osteoporotic subjects. 3. Vitamin K2, namely the menaquinones of various chain-lengths, has been shown by others to be more effective than vitamin K1 in the curative rat bioassay. 4. Earlier reports had shown that the concentration of menaquinones in human liver may exceed that of vitamin K1. But previous methods were too insensitive for testing the normal circulating levels of menaquinones in the human. 5. The new sensitive method has now been applied to measuring the circulating levels of vitamin K1 and of two of the menaquinones, namely menaquinone-7 and menaquinone-8. 6. In normal individuals, the circulating levels of vitamin K1 were the same, irrespective of age. 7. In young normal subjects, the combined levels of menaquinone-7 and menaquinone-8 were at least the same as the level of vitamin K1. In elderly normal subjects, there was a marked deficit of menaquinone-8.

Hodges SJ, Pilkington MJ, Stamp TC, Catterall A, Shearer MJ, Bitensky L, Chayen J. Depressed levels of circulating menaquinones in patients with osteoporotic fractures of the spine and femoral neck. Bone. 1991;12(6):387-389.
Abstract: Vitamin K1 functions in the conversion of glutamate residues, present in certain bone peptides, into the putatively active gamma-carboxyglutamate form. We have shown previously that the circulating levels of vitamin K1 are depressed in osteoporotic patients. However, it is known that menaquinones (vitamin K2:MK) may be more effective than vitamin K1 in this conversion of the inactive to active form of glutamate residues. A procedure for measuring such menaquinones has now demonstrated a marked deficiency of MK-7 and MK-8 in patients with osteoporotic fractures. It is suggested that estimates of circulating levels of K1, MK-7, and MK-8 might provide a biochemical risk marker of osteoporotic fractures.

Hodis HN, Mack WJ, LaBree L, Cashin-Hemphill L, Sevanian A, Johnson R, Azen SP. Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. JAMA 1995 Jun 21;273(23):1849-1854.
Abstract: OBJECTIVE--To explore the association of supplementary and dietary vitamin E and C intake with the progression of coronary artery disease. DESIGN--A subgroup analysis of the on-trial antioxidant vitamin intake database acquired in the Cholesterol Lowering Atherosclerosis Study, a randomized, placebo-controlled, serial angiographic clinical trial evaluating the risk and benefit of colestipol-niacin on coronary artery disease progression. SETTING--Community- and university-based cardiac catheterization laboratories. SUBJECTS--A total of 156 men aged 40 to 59 years with previous coronary artery bypass graft surgery. INTERVENTION--Supplementary and dietary vitamin E and C intake (nonrandomized) in association with cholesterol-lowering diet and either colestipol-niacin or placebo (randomized). OUTCOME--Change per subject in the percentage of vessel diameter obstructed because of stenosis (%S) determined by quantitative coronary angiography after 2 years of randomized therapy on all lesions, mild/moderate lesions (< 50%S), and severe lesions (> or = 50%S). RESULTS--Overall, subjects with supplementary vitamin E intake of 100 IU per day or greater demonstrated less coronary artery lesion progression than did subjects with supplementary vitamin E intake less than 100 IU per day for all lesions (P = .04) and for mild/moderate lesions (P = .01). Within the drug group, benefit of supplementary vitamin E intake was found for all lesions (P = .02) and mild/moderate lesions (P = .01). Within the placebo group, benefit of supplementary vitamin E intake was not found. No benefit was found for use of supplementary vitamin C exclusively or in conjunction with supplementary vitamin E, use of multivitamins, or increased dietary intake of vitamin E or vitamin C. CONCLUSIONS--These results indicate an association between supplementary vitamin E intake and angiographically demonstrated reduction in coronary artery lesion progression. Verification from carefully designed, randomized, serial arterial imaging end point trials is needed.

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998.

Holzapfel WH, Haberer P, Snel J, Schillinger U, Huis in't Veld JH. Overview of gut flora and probiotics. Int J Food Microbiol 1998 May 26;41(2):85-101. (Review)
Abstract: Scientific developments in recent years have opened new frontiers and enable a better understanding of the gastrointestinal tract (GIT) as a complex and delicately balanced ecosystem. This paper focuses on more recent information related to the microbial population of the GIT and its functional role in human physiology and health. Special attention is also given to modern approaches for improving or stabilising the intestinal system and its functioning by the deliberate application of viable microbial cultures, so-called 'probiotics', selected for special functional properties.

Howe AM, Webster WS, Lipson AH, Halliday JL, Sheffield LJ. Binder's syndrome due to prenatal vitamin K deficiency: a theory of pathogenesis. Aust Dent J 1992 Dec;37(6):453-460.
Abstract: There is evidence that vitamin K-deficiency during human pregnancy can be caused by the therapeutic use of warfarin or phenytoin. The pregnancy histories of three cases of Binder's syndrome are reported. One was associated with warfarin exposure, one with phenytoin exposure and one with alcohol abuse. It is proposed that Binder's syndrome can be caused by prenatal exposure to agents that cause vitamin K-deficiency. Sprague-Dawley rats were treated from postnatal day 1 to 12 weeks with daily doses of warfarin (100 mg/kg) and concurrent vitamin K1 (10 mg/kg). This regimen creates a net extra-hepatic vitamin K-deficiency. The treated rats developed with a distinct facial appearance characterized by a markedly reduced snout. Histological examination showed that the normally non-calcified septal cartilage was extensively calcified. It is proposed that normal growth of the septal cartilage is necessary for the development of the profile of the nose and midface and that normal growth will only take place while the septal cartilage is uncalcified.

Jie KS, Gijsbers BL, Knapen MH, Hamulyak K, Frank HL, Vermeer C. Effects of vitamin K and oral anticoagulants on urinary calcium excretion. Br J Haematol. 1993 Jan;83(1):100-104.
Abstract: In a subgroup of postmenopausal women vitamin K induced a decrease of the urinary calcium loss. This effect was significant (P < 0.0001) in the so-called fast losers of calcium (calcium/creatinine ratio > 0.5). To find out whether vitamin K antagonists would have an opposite effect, a study was started among 141 persons on long-term oral anticoagulant therapy. In this population the number of fast losers was recorded, and compared to that in a group of age- and sex-matched non-treated controls. Notably in young men the fraction of fast losers was significantly higher in the anticoagulant-treated group than in the control group (25 v 0%, P < 0.02). Differences between treated and nontreated groups may also be found in other markers for calcium and bone metabolism, notably in serum osteocalcin concentration and in urinary hydroxyproline excretion. The conclusion of our study is that oral anticoagulant treatment must be regarded as a potential risk factor for a high loss of urinary calcium.

Kasper H. Protection against gastrointestinal diseases--present facts and future developments. Int J Food Microbiol 1998 May 26;41(2):127-131.
Abstract: The importance of the intestinal microflora and, more specifically its composition, in physiological and pathophysiological processes in the human GIT is becoming more evident. Examples of such processes are translocation, the production and resorption of endotoxins, immune-modulation, and colonic motility. This leads to new possibilities for prevention and therapy of diseases, mainly of the gastrointestinal organs. New discoveries are specifically related to the beneficial effects of lactobacilli which have been discussed for decades. It is possible to increase the proportion of lactobacilli in the gastrointestinal microflora by consumption of fermented dairy products or by oral administration of specific non-digestible substrates such as oligofructose. Results from clinical trials and scientific studies have confirmed the preventive and therapeutic effects of selected strains of lactobacilli in viral- and bacterial-induced intestinal infections, in positively influencing immunological parameters, in normalizing the intestinal motility, and in inhibiting metabolic events in the gut lumen which promote colonic carcinogenesis. Nevertheless, there are still unresolved issues which can only be answered by well designed and well controlled clinical trials.

Keith DA, Gundberg CM, Japour A, Aronoff J, Alvarez N, Gallop PM. Vitamin K-dependent proteins and anticonvulsant medication. Clin Pharmacol Ther 1983 Oct;34(4):529-532.
Abstract: Certain anticonvulsant drugs, especially phenytoin and phenobarbital, interfere with vitamin K metabolism as indicated by a raised serum osteocalcin level. This finding may be of importance in the pathogenesis of side effects of these medications.

Keith DA, Gallop PM. Phenytoin, hemorrhage, skeletal defects and vitamin K in the newborn. Med Hypotheses 1979 Dec;5(12):1347-1351.
Abstract: The vitamin K-dependent hemostatic factors are present in reduced quantities at birth and may decrease further in the first few days of life. Administration of vitamin K1 on day 1 prevents hemorrhagic disease of the newborn. Maternal ingestion of anticonvulsants puts the newborn at greater risk from hemorrhage, possibly as a result of induction of fetal microsomal enzymes with a resultant increased oxidative degradation of vitamin K which gives rise to a vitamin K deficiency and other concomitant clinical results, for example skeletal defects. Evidence for this sequence of events is presented and the widespread effect of vitamin K deficiency on the fetus is discussed.

Kempin SJ. Warfarin resistance caused by broccoli. N Engl J Med 1983 May 19;308(20):1229-1230. (Letter)

Kendall MJ, Chan K. Drug-induced malabsorption. Xenobiotica 1973 Nov;3(11):727-744. (Review)

Knapen MH, Hamulyak K, Vermeer C. The effect of vitamin K supplementation on circulating osteocalcin (bone Gla protein) and urinary calcium excretion. Ann Intern Med. 1989 Dec 15;111(12):1001-1005.
Abstract: STUDY OBJECTIVE: To determine whether vitamin K administration affects urinary calcium excretion in postmenopausal women. DESIGN: Before- and after-trials with a 2-week treatment period. SUBJECTS: Healthy postmenopausal women (55 to 75 years old) were recruited from the convents in and around Maastricht. Controls (25 to 40 years old) were healthy premenopausal volunteers. INTERVENTION: Daily administration of 1 mg of vitamin K for 2 weeks. MEASUREMENTS: Serum immunoreactive osteocalcin: hydroxylapatite binding (HAB) capacity of serum immunoreactive osteocalcin; excretion of calcium, hydroxyproline, and creatinine in the urine during the last 2 h of a 16-h fasting period. RESULTS: In premenopausal women, no effect of vitamin K administration was seen. In the postmenopausal group, vitamin K induced increased serum immunoreactive osteocalcin concentration; normalization of the HAB capacity of serum immunoreactive osteocalcin (this marker was less than 50% that of the controls in the pretreatment samples); a decrease in urinary calcium excretion, notably in the "fast losers" of calcium; and a parallel decrease in urinary hydroxyproline excretion in the fast losers of calcium. CONCLUSIONS: The serum immunoreactive osteocalcin level may vary with vitamin K status. This variance should be taken into consideration if osteocalcin is used as a marker for osteoblast activity. Vitamin K is one factor that may play a role in the loss of bone mass in postmenopausal osteoporosis.

Lankaputhra WE, Shah NP. Antimutagenic properties of probiotic bacteria and of organic acids. Mutat Res 1998 Feb 2;397(2):169-182.
Abstract: Antimutagenic activities of live and killed cells of 6 strains of Lactobacillus acidophilus and 9 strains of bifidobacteria and of organic acids usually produced by these probiotic bacteria were determined using 8 potent chemical mutagens and promutagens. The mutagens and promutagens used were N-methyl, N'-nitro, N-nitrosoguanidine; 2-nitroflourene; 4-nitro-O-phenylenediamine; 4-nitroquinoline-N-oxide; Aflatoxin-B; 2-amino-3-methyl-3H-imidazoquinoline; 2-amino-1-methyl-6-phenyl-imidazo (4,5-b) pyridine, and 2-amino-3-methyl-9H-pyrido (3,3-6) indole. The mutagenicity of these mutagens and antimutagenic activity of probiotic bacteria against the mutagens were determined according to the Ames TA-100 assay using a mutant of Salmonella typhimurium. Efficiency of bacterial cells in binding or inhibiting these mutagens was also investigated. Live cells of probiotic bacteria showed higher antimutagenic activity and their efficiency in inhibiting the mutagens was better than killed bacterial cells. Live bacterial cells bound or inhibited the mutagens permanently, whereas killed bacteria released mutagens upon extraction with dimethyl sulfoxide. Among the organic acids, butyric acid showed highest inhibition of mutagens followed by acetic acid. Lactic and pyruvic acids did not show appreciable levels of inhibition.

Levy J. Immunonutrition: the pediatric experience. Nutrition 1998 Jul;14(7-8):641-647.
Abstract: The health benefits of specific nutrients in the diet are reviewed as they pertain to the pediatric population and its unique needs. Secretory immunoglobulins, lysozyme, interferon, and growth factors, among others, are known to confer immunological advantages to breast milk. Inhibition of bacterial pathogens, as well as permissive growth of a protective colonic ecoflora occur as a result of various cellular and biochemical mechanisms at play. The immunomodulatory properties of minerals such as iron, zinc, and selenium, are presented and the newly recognized protective role of vitamin A and its importance in developing countries and in conditions of compromised nutrition are discussed. The review also covers the role of arginine, glutamine, and nucleotides in adaptive responses of the developing gut and in pathologic states such as necrotizing enterocolitis, short bowel syndrome, and inflammatory bowel disease. Probiotics (specific microbial feeds with potential benefits to the host), and prebiotics (dietary components such as complex carbohydrates able to change the colonic microenvironment fostering colonization with non-enteropathogens) are areas of current interest because they offer alternatives for the management of the growing problem of multiple antibiotic resistance and overwhelming infections in the hospitalized patient.

Lim JM, McKay M. Food-drug interactions. Drug Information Bulletin. Los Angeles: UCLA Dept. of Pharmaceutical Services, 15(2), 1995.

Lim KS, Huh CS, Baek YJ. Antimicrobial susceptibility of bifidobacteria. J Dairy Sci. 1993 Aug;76(8):2168-2174.
Abstract: The antimicrobial susceptibility of 37 strains of bifidobacteria to 18 antimicrobial agents was determined by a macrodilution broth method. Most of the strains used were isolated from commercial yogurts and starters. Tested organisms were usually sensitive to Gram-positive spectrum antibiotics (bacitracin, erythromycin, lincomycin, and vancomycin), and most of the organisms were inhibited by a concentration < 1.56 micrograms/ml. Erythromycin was the most active agent; all strains were inhibited by < .19 microgram/ml. beta-Lactam antibiotics (penicillin G, ampicillin, methicillin, and cephalothin), showing a wide range of minimum inhibitory concentration, were less effective than Gram-positive spectrum antibiotics. Most strains were somewhat resistant to cephalothin, exhibiting inhibition at concentrations of 6.25 to 25.0 micrograms/ml. Test organisms were most resistant to kanamycin, neomycin, paromomycin sulfate, nalidixic acid, and polymyxin B sulfate; inhibition occurred only at > or = 50 micrograms/ml, and strains were somewhat less resistant to gentamicin and streptomycin. Susceptibility to nitrofurantoin and tetracycline was variable; minimum inhibitory concentrations ranged from 1.56 to 50.0 and .39 to 50.0 micrograms/ml, respectively, but chloramphenicol had a narrow range from 1.56 to 6.25 micrograms/ml.

Linzenmeier G, Haralambie E, Dermoumi H. [Short-term oral chemoprophylaxis before intestine surgery. Quantitative determination of bacteria and fungi in stool specimens]. Zentralbl Bakteriol [Orig A] 1979 Apr;243(2-3):326-335. [Article in German]
Abstract: The methods of quantitative analysis of aerobe and anaerobe microbes and fungi stool specimens are described. The results of the studies in health people are compared to the results in patients undergoing surgical treatment of intestinal tract. A group of these patients received Neomycin and Bacitracin orally as short-time chemoprophylaxis to diminish possible woundinfection and/or sepsis. After oral medication germs as Bifidobacterium, Bacteroides and Clostridium (not Cl. perfringens) are reduced or lost, Veillonella, Eubacterium, Fusiformis, Peptostreptococcus and Lactobacillus were suppressed. Resistant strains of E. coli and Enterococci increased to high concentration/g faeces. After treatment the rate of gram-negative bacteria resistant to Neomycin increased. This might be of epidemiologically importance for the distribution of microbes resistant to Neomycin and other aminoglycosides as Klebsiella, Candida spec. and Torulopsis.

Marz R. Medical Nutrition From Marz. Second Edition. Portland, OR. 1997.

Matteuzzi D, Crociani F, Brigidi P. Antimicrobial susceptibility of Bifidobacterium. Ann Microbiol (Paris). 1983 May-Jun;134A(3):339-349.
Abstract: The susceptibility pattern of 459 strains of bifidobacteria, representing 15 species, to 16 antimicrobial agents was determined by the broth dilution method. The majority of the strains derived from human faeces. Penicillin G, erythromycin, clindamycin, vancomycin and bacitracin were the most active compounds; they inhibited 90% of the strains at less than 1.6 micrograms/ml. All strains were susceptible to chloramphenicol (MIC90 = 2.0-5.8 micrograms/ml) and also to lincomycin (MIC50 = 0.64-1.5 micrograms/ml). Neomycin, streptomycin and tetracycline presented a great variability in their activity. Most strains were resistant to polymyxin B, nalidixic acid, kanamycin, gentamicin and metronidazole. The only variation in susceptibility which was observed among the different species concerned Bifidobacterium suis, which generally appeared to be more resistant than other species.

Mayer J. Iatrogenic malnutrition. Postgrad Med. 1971 Mar;49(3):247-249.

Merkel R. The use of menadione bisulfite and ascorbate in the treatment of Nausea and Vomiting of pregnancy. Am J Ob and Gyn. 1952 Aug 416-418.
Abstract: 64 out of 70 consecutive cases were helped with complete relief of symptoms in 3 days. 3 cases had the vomiting halted but not the nausea.

Noto V, Taper HS, Jiang YH, Janssens J, Bonte J, De Loecker W. Effects of sodium ascorbate (vitamin C) and 2-methyl-1,4-naphthoquinone (vitamin K3) treatment on human tumor cell growth in vitro. I. Synergism of combined vitamin C and K3 action. Cancer. 1989 Mar 1;63(5):901-906.

Olson JA. Recommended dietary intakes (RDI) of vitamin K in humans. Am J Clin Nutr. 1987 Apr;45(4):687-692.

Pronsky Z. Powers and Moore's Food-Medications Interactions. Ninth Edition. Food-Medication Interactions. Pottstown, PA, 1991.

Race TF, Paes IC, Faloon WW. Intestinal malabsorption induced by oral colchicine. Comparison with neomycin and cathartic agents. Am J Med Sci. 1970 Jan;259(1):32-41.

Robinson C, Weigly E. Basic Nutrition and Diet Therapy. New York: MacMillan, 1984.

Roe DA. Diet and Drug Interactions. New York: Van Nostrand Reinhold, 1989.

Roe DA. Drug-induced Nutritional Deficiencies. 2nd ed. Westport, CT: Avi Publishing, 1985: 158-159.

Roe DA. Risk factors in drug-induced nutritional deficiencies. In: Roe DA, Campbell T, eds. Drugs and Nutrients: The Interactive Effects. New York: Marcel Decker, 1984: 505-523.

Salet J, Pean G, Hansel S, Baudon JJ. [Acute avitaminosis K in infants associated with diarrhea treated by antibiotics]. Arch Fr Pediatr. 1968 Oct;25(8):961. [Article in French]

Taper HS, de Gerlache J, Lans M, Roberfroid M. Non-toxic potentiation of cancer chemotherapy by combined C and K3 vitamin pre-treatment. Int J Cancer 1987 Oct 15;40(4):575-579.
Abstract: The influence on the survival of ascitic liver tumor (TLT)-bearing mice of combined vitamins C and K3 administered before or after a single i.p. dose of 6 different cytotoxic drugs, all commonly used in human cancer therapy, was investigated. Combined i.p. administration of these vitamins produced a distinct chemotherapy-potentiating effect for all drugs examined, especially when injected before chemotherapy. This potentiating treatment did not increase the general and organ toxicity that accompanies cancer chemotherapy. The possible generation of peroxides followed by membrane lipid alteration, DNase activation and DNA destruction by combined vitamin C and K3 in catalase-deficient cancer cells might be involved in the mechanisms of this selective potentiation.

Taper HS, Keyeux A, Roberfroid M. Potentiation of radiotherapy by nontoxic pretreatment with combined vitamins C and K3 in mice bearing solid transplantable tumor. Anticancer Res 1996 Jan;16(1):499-503.
Abstract: BACKGROUND: The effect of intraperitoneal and oral pretreatment with combined vitamins C and K3 on the single dose radiotherapy of a transplantable solid mouse tumor have been investigated. MATERIALS AND METHODS: Groups of mice bearing intramuscularly transplanted liver tumors, were orally and parenterally pretreated with combined vitamins C and K3 and locally irradiated with single doses of 20, 30, or 40 Gy of X-rays. After this treatment tumor dimensions were measured twice weekly and the approximate tumor volume in groups of pretreated vitamins and irradiated mice was compared to the groups of mice only irradiated and to the absolute control groups without any therapy. RESULTS: This nontoxic pretreatment produced statistically significant potentiation of radiotherapy induced by 20 to 40 Gy of X-rays doses in groups of 11 to 20 mice. Combined vitamins C with K3 most probably constitute a redox-cycling system producing hydrogen peroxide and other active oxygen species to which cancer cells are selectively sensitive due to their frequent deficiency in enzymatic defense system against free oxyradicals agression. CONCLUSIONS: A possible introduction of such nontoxic and selective potentiation procedure into classical protocols of human cancer therapy appears to be generally accessible and without any additional risk for patients.

Tomita A, Fujita T, Takatsuki K, Shiono M, Yamauchi N. [47 Ca kinetic study and vitamin K 2 in postmenopausal osteoporosis]. Horumon To Rinsho. 1971 Sep;19(9):731-736. [Article in Japanese] Also, Post menopausal osteoporosis CA study with vitamin K2. Clin Endocrinol 1971;19:731-736.
Abstract: It was found that in osteoporotic women treated with vitamin K2, urinary calcium loss was reduced by 18-50%.

Tonstad S, Sivertsen M, Aksnes L, Ose L. Low dose colestipol in adolescents with familial hypercholesterolaemia. Arch Dis Child 1996 Feb;74(2):157-160.
Abstract: The effects of orange flavoured colestipol granules, 10 g/day, in 37 boys and 29 girls aged 10-16 years with familial hypercholesterolaemia were examined first in an eight week double blind, placebo controlled protocol, then in open treatment for 44-52 weeks. All patients were on a low fat diet. Low density lipoprotein cholesterol levels were reduced by 19.5% by colestipol v 1.0% by placebo. Levels of serum folate, vitamin E, and carotenoids were reduced in the colestipol group, but not the vitamin E/cholesterol and carotenoid/cholesterol ratios or serum concentrations of vitamins A and D. After one year of colestipol, two thirds of the participants remained in the study, of whom half took > or = 80% of the prescribed dose. Those who took > or = 80% of the dose had a greater decrease in serum 25-hydroxyvitamin D levels than those who took < 80%. No adverse effects on weight gain or linear growth velocity were observed. Although low dose colestipol effectively reduces low density lipoprotein cholesterol levels, only a minority of adolescents adhered to the new formulation for one year. Folate and possibly vitamin D supplementation is recommended.

Trovato A, Nuhlicek DN, Midtling JE. Drug-nutrient interactions. Am Fam Physician 1991 Nov;44(5):1651-1658.(Review)

USDA: Composition of Foods. USDA Handbook #8 Washington DC, ARS, USDA, 1976-1986.

van Haarlem LJ, Knapen MH, Hamulyak K, Vermeer C. Circulating osteocalcin during oral anticoagulant therapy. Thromb Haemost 1988 Aug 30;60(1):79-82.
Abstract: In this paper we present the following observations: 1) In sheep vitamin K-antagonists like phenprocoumon induce a decrease of the serum levels of osteocalcin (bone Gla-protein) and of the affinity of the circulating osteocalcin for hydroxyapatite. 2) In sheep vitamin K counteracts the effect of phenprocoumon on the blood coagulation system, but not that on the osteocalcin production. 3) In human subjects vitamin K-antagonists also lead to decreased levels of serum osteocalcin and a low affinity of the protein for hydroxyapatite. 4) These two variables reached steady-state levels within 24 h after the start of oral anticoagulant treatment and--at continuation of the therapy--they remained low for at least several years.

Venugopal M, Jamison JM, Gilloteaux J, Koch JA, Summers M, Giammar D, Sowick C, Summers JL. Synergistic antitumor activity of vitamins C and K3 on human urologic tumor cell lines. Life Sci 1996;59(17):1389-1400.

Watkins DW, Khalafi R, Cassidy MM, Vahouny GV. Alterations in calcium, magnesium, iron, and zinc metabolism by dietary cholestyramine. Dig Dis Sci 1985 May;30(5):477-482.
Abstract: Cholestyramine is an effective drug for the reduction of plasma cholesterol because of its ability to sequester intestinal bile acids. Since metabolic alterations, including diminished intestinal absorption of vitamin D and osteomalacia have been reported with long-term use of this resin, the influence of cholestyramine on dietary balance of four mineral elements has been investigated. Wistar-strain rats were fed either a 2% cholestyramine or control diet for one month. Dietary intakes and fecal and urinary excretions of calcium, magnesium, iron, and zinc were determined using atomic absorption spectrophotometry during three, 3-day balance periods. Cholestyramine-fed rats had a net negative balance for calcium and a lower net positive balance for magnesium, iron, and zinc than the controls. Other effects of cholestyramine were an increased urinary excretion of calcium and magnesium, a decreased urinary zinc, and an alkalinization of urine. Blood and tissue cation content was unchanged except for a reduction in serum magnesium with resin feeding. Alterations in calcium, magnesium, and zinc metabolism might be explained by inadequate vitamin D absorption from the intestine followed by an increased secretion of parathyroid hormone. A diminished iron absorption due to resin binding could account for the reported disturbance in iron balance.

Weibert RT, Le DT, Kayser SR, et al. Correction of excessive anticoagulation with low-dose oral vitamin K1. Ann Intern Med 1997 Jun 15;126(12):959-962.
Abstract: BACKGROUND: Despite earlier acceptance of oral vitamin K1 (phytonadione) for the treatment of excessive anticoagulation, some recent guidelines do not recommend its use. OBJECTIVE: To reevaluate the efficacy of oral vitamin K1 in correcting excessive anticoagulation. DESIGN: Case series. SETTING: Anticoagulation clinics at two university medical centers. PATIENTS: 81 outpatients who had an international normalized ratio (INR) greater than 5.0 but did not have significant bleeding. INTERVENTIONS: Withholding 1 or 2 doses of warfarin, administering 2.5 mg of oral vitamin K1, measuring the INR after 24 to 48 hours, and adjusting the warfarin dose. MEASUREMENTS: INRs were obtained from a portable capillary fingerstick monitor or from an automated photooptical coagulometer. RESULTS: In 68 of 71 patients (96%), oral vitamin K1 lowered the INR from between 5.0 and 10.0 to less than 5.0 without inducing resistance to further anticoagulation. CONCLUSIONS: Withholding 1 or 2 doses of warfarin and administering 2.5 mg of oral vitamin K1 is a reliable, safe, and inexpensive way to rapidly correct excessive anticoagulation (INR > 5.0) in patients who do not have serious bleeding episodes and have an INR of less than 10.0.

Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food. Ann Intern Med 1994 Nov 1;121(9):676-683. (Review)
Abstract: PURPOSE: To evaluate the quality of studies about drugs and food interactions with warfarin and their clinical relevance. DATA SOURCES: MEDLINE and TOXLINE databases from 1966 to October 1993 using the Medical Subject Headings warfarin, drug interactions, and English only. STUDY SELECTION: All articles reporting original data on drug and food interactions with warfarin. DATA EXTRACTION: Each report, rated independently by at least two investigators (using causality assessment), received a summary score indicating the level of assurance (level 1 = highly probable, level 2 = probable, level 3 = possible, and level 4 = doubtful) that a clinically important interaction had or had not occurred. Inter-rater agreement was assessed using a weighted kappa statistic. RESULTS: Of 793 retrieved citations, 120 contained original reports on 186 interactions. The weighted kappa statistic was 0.67, representing substantial agreement. Of 86 different drugs and foods appraised, 43 had level 1 evidence. Of these, 26 drugs and foods did interact with warfarin. Warfarin's anticoagulant effect was potentiated by 6 antibiotics (cotrimoxazole, erythromycin, fluconazole, isoniazid, metronidazole, and miconazole); 5 cardiac drugs (amiodarone, clofibrate, propafenone, propranolol, and sulfinpyrazone); phenylbutazone; piroxicam; alcohol (only with concomitant liver disease); cimetidine; and omeprazole. Three patients had a hemorrhage at the time of a potentiating interaction (caused by alcohol, isoniazid, and phenylbutazone). Warfarin's anticoagulant effect was inhibited by 3 antibiotics (griseofulvin, rifampin, and nafcillin); 3 drugs active on the central nervous system (barbiturates, carbamazepine, and chlordiazepoxide); cholestyramine; sucralfate; foods high in vitamin K; and large amounts of avocado. CONCLUSIONS: Many drugs and foods interact with warfarin, including antibiotics, drugs affecting the central nervous system, and cardiac medications. Many of these drug interactions increase warfarin's anticoagulant effect.

Werbach MR. Foundations of Nutritional Medicine. Tarzana, CA: Third Line Press, 1997, 221-222. (Review).

West RJ, Lloyd JK. The effect of cholestyramine on intestinal absorption. Gut. 1975 Feb;16(2):93-98.
Abstract: Cholestyramine in a mean dosage of 0-6 g/kg/day has been given to 18 children with familial hypercholesterolaemia for between one and two and a half years. With prolonged treatment folate deficiency occurred, as evidenced by a fall in the mean serum folate concentration from 7-7 ng/ml before treatment to 4-4 ng/ml for patients on treatment for over one year; a corresponding lowering of red cell folate was also seen. Oral folic acid 5 mg daily overcame this depletion, and should be given to all patients on long-term anion exchange resins. Prothrombin time has remained normal in all patients; there has been a significant decrease in the mean serum concentrations of vitamins A and E and of inorganic phosphorus over the first two years of treatment, although values remain within the normal range. The routine administration of fat-soluble vitamins appears unnecessary but it is prudent to measure prothrombin time and serum vitamins A and E at intervals. In children who were having a normal intake of dietary fat five out of seven tested had faecal fat of over 5 g/day while on cholestyramine. No child has developed diarrhoea, and growth has been normal. The concentrations of serum iron, vitamin B12, plasma calcium, and protein did not change significantly in any patient.

Yerby MS. Problems and management of the pregnant woman with epilepsy. Epilepsia 1987;28 Suppl 3:S29-36. (Review)
Abstract: Pregnancies occurring in women who are epileptic are considered to be high risk. These women are at increased risk of seizures during pregnancy, labor, and delivery and of pregnancy complications and adverse pregnancy outcomes. Pregnancy alters the pharmacokinetics of anticonvulsant drugs, the levels of which decline as pregnancy advances. Not all drugs are altered in a similar manner, however. The rate of congenital malformations in infants of epileptic mothers is 2.4 times higher than in the general population. Malformations occur with all of the commonly used anticonvulsant drugs. The possible mechanisms of teratogenicity include folic acid antagonism, fetal tissue binding, and toxic effects of metabolic intermediates. Therapy with more than one drug increases the risk of congenital malformations. A unique hemorrhagic phenomenon in the infants of epileptic mothers has been reported and appears to be the result of a deficiency of vitamin K-dependent clotting factors. When taken by a pregnant woman, all antiepileptic drugs except valproic acid manifest themselves in breast milk, but only if the infant exhibits evidence of sedation should breastfeeding be discontinued. The dilemma for the physician treating the pregnant epileptic woman is to protect the mother from seizures and the fetus from unnecessary exposure to anticonvulsant medications.