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To clarify the mechanism of absorption and metabolism of K vitamins (VK), we administered phylloquinone (K1) and menaquinone-4 (MK-4) orally to male Wistar rats whose portal and femoral veins were cannulated. Blood was collected 9 times up to 120 min later, and 50 microliters plasma was used for VK analysis by high performance liquid chromatography (HPLC) using a modification of our previous method. There were no significant differences between portal and femoral venous VK concentrations throughout all the experiments. When K1 and MK-4 were administered simultaneously, K1 appeared in plasma at 15 min, and MK-4 at 10 min. The concentration of MK-4 was significantly higher than that of K1 up to 60 min. In contrast to the single administration, the MK-4 concentration was reduced after 60 min. After K1 single administration, the MK-4 was not detected in either portal or femoral venous plasma up to 120 min. These results suggested that (1) the main absorption route of both VK may be the extra-portal pathway, (2) MK-4 is absorbed faster than K1 (3) some interactions may exist between K1 and MK-4 and (4) the intestinal cells might not be the major site to transform K1 into MK-4.

We report the deliberate ingestion of a superwarfarin product, brodifacoum, in a 39-y-old male. He presented with prothrombin and partial thromboplastin times of 150 and 113 sec, respectively. His coagulopathy was corrected by administration of blood products and phytonadione. To maintain normal clotting studies this patient required the highest maintenance dose of phytonadione, 200 mg/d, reported to date. The patient was able to tolerate this dose for 5 mo without adverse effects.

Vitamin K1 levels were measured by high performance liquid chromatography in cord blood (n = 33) and at the age of 97-120 h after administration of 2 mg of vitamin K1 orally (n = 88) or 1 mg of vitamin K1 by im injection (n = 88). Vitamin K1 levels were less than 0.05 micrograms/l in cord blood. The mean (range), SEM, mode and median values (micrograms/l) for the infants given oral vitamin K1 were 17.99 (1-56), 1.25, 8 and 15.5 and those for the infants given im vitamin K1 15.83 (2-57), 1.01, 11 and 14, respectively. The t-test showed no significant difference in the mean values (p = 0.09) in the infants given oral or im vitamin K.

To determine the best way to reverse the excessive effect of regular anticoagulation in patients with INR > 5 and no bleeding complications, 23 patients with INR > 5 were randomly subdivided into two groups: group A (n = 12) discontinued warfarin for one day and group B (n = 11) received 2 mg of vitamin K1 orally in addition to the usual warfarin dose. INR was determined after 24 h (day 1), after which both groups continued with their usual dose of warfarin. After 48 h (day 2), warfarin dosage was changed according to the INR value. On day 9, INR values were determined again. Five out of twelve patients in group A had INR values > 5 on day 1. One patient in group A had an INR value < 5 both on days 1 and 2. All eleven patients in group B had INR values < 5 on day 1, and all but one on day 2. On day 9, INR values were acceptable (INR 2.0-4.5) in ten group A patients and eight group B patients. These findings suggest that a low oral dose of vitamin K1 is a convenient treatment for excessive anticoagulation in patients with no bleeding complications.

Rats were made vitamin K-deficient by feeding them a 1:1 (w/w) mixture of a commercial vitamin K-depleted diet and boiled white rice. After one week of treatment the rats had developed severe vitamin K deficiency, resulting in Thrombotest values of 5-10% of the initial values. In this experimental system the efficacy of phylloquinone (K1) was compared with that of menaquinone-4 (MK-4) by measuring the extent to which the Thrombotest was normalized after the administration of varying doses of the respective vitamins. Oral administration of the vitamins showed that the efficacy of K1 was at least two-fold higher than that of MK-4. As comparable results were obtained after subcutaneous administration of the vitamins, we conclude that after oral administration the intestinal absorption had been quick and nearly complete. A less pronounced effect of K1 and MK-4 was found after colorectal administration. For both forms of vitamin K relatively high amounts (well above the physiological concentration) were required before significant effects on the Thrombotest could be observed. Therefore these data demonstrate the importance of sufficient dietary vitamin K consumption in rats. The efficacy of other menaquinones may be investigated in the same experimental animal model system.

The plasma disposition of a new mixed-micellar preparation (KONAKION MM, Roche) of phylloquinone (vitamin K1) has been studied in 25 healthy, fully breast-fed, newborn babies, randomized to receive a single dose of either 1.5 mg i.m. (11 babies) or 3 mg p.o. (14 babies). Venous blood samples were collected at 25 h, 4 days, and 24 days. After p.o. administration, the median plasma phylloquinone concentration increased to 89 ng/ml after 24 h, then decreased to 51 ng/ml after 4 days; the respective concentrations after i.m. injection were 146 ng/ml and 34 ng/ml. The higher plasma phylloquinone level in the i.m. group after 24 h was not statistically significant compared with that of the p.o. group, but the reversed higher concentration in the p.o. group after 4 days was significant (p < 0.01). After 24 days the median plasma phylloquinone had decreased to 0.44 ng/ml (range 0.19-1.44) and 1.05 ng/ml (range 0.37-1.87) in the p.o. and i.m. groups, respectively. There was a significant difference between these plasma concentrations (p < 0.01). They were within or above the reference adult fasting range (0.17-0.68 ng/ml). The narrow range of plasma concentrations at 24 h and 4 days suggests a greater consistency of absorption from this micellar preparation than from other emulsion-based preparations. Further studies are required to assess the long-term protection of a single oral dose against late hemorrhagic disease of the newborn. Until such time, breast-fed babies given this preparation orally should receive (an) additional dose(s).

Bioavailability of phytonadione was investigated after oral administration to beagle dogs. The administrations of phytonadione in a surfactant solution (preparation a) and in an oleic acid solution (preparations b) greatly increased the bioavailability of phytonadione. The AUCs of preparations a and b were about 2.5 times larger than those of commercially available tablets A and C. This result well corresponded to the results of the dissolution test previously reported. The absorption of phytonadione from the gastro-intestinal tract was affected by food and the bioavailability was largely increased under non-fasted conditions. However, a large scatter was observed in the data, and it was found that the evaluation of the bioavailability of phytonadione preparations could not be done in non-fasted animals.

There is limited information available on the vitamin K intake of lactating mothers, concentration of vitamin K1 in breast milk, and the effect of long-term vitamin K1 supplementation of lactating mothers on the vitamin K1 concentration in breast milk. In a randomized study, we followed 20 mothers who received a daily oral vitamin K1 supplement (average 88 micrograms, supplemented group) and 16 mothers receiving no supplement (control group) from 4 throughout 91 days postpartum. Maternal vitamin K intakes (weighed dietary intake) at 4-6, 25-29 and 87-91 days postpartum ranged between 73 and 1735 micrograms/day. Differences between the groups were statistically not significant. Average intake exceeded the recommended dietary intake for lactating women of 55 micrograms/day by 670%. In the supplemented group, mean breast-milk vitamin K1 concentrations (HPLC) at 5, 26 and 88 days postpartum were 1.73 (SD 0.74), 1.36 (SD 0.81) and 1.67 (SD 2.01) ng/ml, respectively. Corresponding values in the control group were 1.44 (SD 0.57), 1.68 (SD 0.70) and 1.78 (SD 1.05) ng/ml. The latter were not statistically different from values in the supplemented group. Mean daily vitamin K1 intakes of infants breast-fed by supplemented mothers were 0.69 (SD 0.42), 0.93 (SD 0.51) and 1.25 (1.53) micrograms, respectively on days 5, 26 and 88. Corresponding values in the control group were 0.69 (SD 0.30), 1.07 (SD 0.58) and 1.31 (SD 0.95) micrograms and were statistically not different from values in the supplemented group. Average vitamin K1 intakes corresponded to 7-13% of the recommended dietary intake of 10 micrograms/d for infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Purpose: To present the diagnosis and management of superwarfarin ingestion, a cause of serious and prolonged coagulopathy., Methods: Specific identification of the anticoagulant was made by high-pressure liquid chromatography., Results: A 24 month-old child developed bruises and a prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) after receiving multiple doses of brodifacoum, a superwarfarin rodenticide. The coagulopathy was treated successfully with large doses of parenteral and oral vitamin K1; fresh frozen plasma was administered as a precautionary measure on two occasions. After the first 10 days of the child's hospitalization, the mother was identified as the source of brodifacoum, exemplifying the behavior described as Munchausen syndrome by proxy. Oral vitamin K1 was initiated and continued in an outpatient setting with tapering doses over nine months, using the PT as a guide for therapy., Conclusions: This report emphasizes the necessity of recognizing rodenticide poisoning and investigating its source. Frequent monitoring of the PT is essential to prevent hemorrhagic complications due to repeat exposure, inadequate vitamin K1 therapy, or noncompliance.

Cutaneous reactions to vitamin K1 injections are reported infrequently. Most previously reported cases have been associated with liver disease, primarily alcoholic cirrhosis and viral hepatitis. Four new cases are reported. One patient had polycythemia vera and the Budd-Chiari syndrome, the second such report in the literature. The other three patients had no known hepatic disease. The reactions consisted of erythematous plaques at the injection site without progression to sclerodermatous plaques. Histopathologic examination in three cases showed spongiotic changes and mononuclear infiltrates typical of cutaneous reactions to vitamin K1. In one instance a neutrophilic infiltrate was associated with the reaction site. Our findings support the observation that liver disease is not a necessary condition for the occurrence of vitamin K1 hypersensitivity.

Decreased deformability of red blood cells (RBC) in diabetes mellitus (DM) is considered to be linked to microcirculatory complications in this condition. As we found that phytomenadione increased RBC deformability in experimental animals, the question was raised, whether phytomenadione had the same effect on the RBC of diabetic patients. The study was performed in 10 patients with insulin-dependent diabetes mellitus, where the erythrocyte deformability was impaired. Patients received 10 mg/day phytomenadione i.m. for five days. Deformability was measured with policarbonate membranes (Nucleopore) with pore diameter 5 microns, under gravity. The results were expressed as the ratio (r) between the flow of 1.5 ml (r1) and 2 ml (r2) of RBC suspension and 1.5 ml of buffer. Phytomenadione increased the erythrocyte deformability in patients with diabetes mellitus, lowering the value r1 from 3.54 +/- 0.84 to 2.32 +/- 0.61 (p 0.02) and r2 from 7.80 +/- 2.41 to 4.65 +/- 1.07 (p 0.01). The values after treatment reached the range of healthy controls (r1 3.11 +/- 0.98, r2 6.52 +/- 3.04). The whole blood viscosity was significantly lowered after phytomenadione (5.28 +/- 0.58 mPas before, 4.64 +/- 0.74 mPas after, p < 0.02) with unchanged plasma viscosity, but significantly lowered internal viscosity of erythrocytes.

The metabolic basis for the high vitamin K requirement of chicks compared with rats was investigated. When chicks and rats were fed the same diet, containing 500 micrograms phylloquinone/kg, the total amounts of phylloquinone and its epoxide metabolite found in the liver and plasma were similar in both species. However, phylloquinone 2,3-epoxide was present in high concentrations in chick liver and serum but not in rat liver and serum. This metabolite of the vitamin is normally reduced by a hepatic vitamin K epoxide reductase. The activity of this enzyme in chicks was approximately 10% of that in rats, and the inability of chicks to effectively recycle the epoxide of vitamin K seems to be the major factor in its high requirement. Other species differences in vitamin K metabolism were observed. Much higher concentrations of bacterial menaquinones were present in rat feces compared with chick feces, but neither species had appreciable hepatic concentrations of menaquinones. Chicks, but not rats, were found to have a liver concentration of menaquinone-4 that exceeded that of phylloquinone. This vitamer was present even when its recognized precursor, menadione, was not present in the diet, and the data indicate that chicks convert phylloquinone to menaquinone-4 under the conditions of these experiments. The mechanism of this conversion was not established.

Vitamin K is an essential cofactor necessary for the production of clotting factors II, VII, IX, and X in humans and has recently been found to be an essential factor for many other proteins in the body. There are two sources of this essential vitamin, including vitamin K1, or phylloquinone which is primarily found in green leafy vegetables and vitamin K2 or menaquinone which is synthesized by certain intestinal bacteria. The precise contribution of the bacterially synthesized menaquinone to overall vitamin K requirements in man is unknown. This paper reviews the available literature regarding the production and liberation of menaquinones from bacteria, the animal experiments which have been done to examine the absorption of menaquinones and the indirect and direct evidence in humans regarding utilization of menaquinones. The preponderance of the evidence suggests that bacterially synthesized menaquinones, particularly in the ileum can and do play a significant role in contributing to vitamin K requirements in humans to prevent clinically significant coagulopathy, especially during periods of episodic dietary lack of the vitamin.

Sprague-Dawley rats were given daily subcutaneous doses of sodium warfarin (100 mg/kg) and vitamin K1 (10 mg/kg) for up to 12 weeks, starting on the day after birth. This dosing regimen creates an extrahepatic vitamin K deficiency while preserving the vitamin K-dependent processes of the liver. Control rats received either vitamin K1 only or were untreated. All rats survived without any signs of hemorrhage. The warfarin-treated rats developed a marked maxillonasal hypoplasia associated with a 11-13% reduction in the length of the nasal bones compared with controls. The length of the posterior part of the skull was not significantly different from controls. In the warfarin-treated rats, the septal cartilage of the nasal septum showed large areas of calcification, not present in controls, and abnormal calcium bridges in the epiphyseal cartilages of the vertebrae and long bones. The ectopic calcification in the septal cartilage may have been the cause of the reduced longitudinal growth of the nasal septum and the associated maxillonasal hypoplasia. It is proposed that (1) the facial features of the human warfarin embryopathy are caused by reduced growth of the embryonic nasal septum, and (2) the septal growth retardation occurs because the warfarin-induced extrahepatic vitamin K deficiency prevents the normal formation of the vitamin K-dependent matrix gla protein in the embryo.

Objective: To assess unexpected associations between childhood cancer and pethidine given in labour and the neonatal administration of vitamin K that had emerged in a study performed in the 1970 national birth cohort., Design and Setting: 195 children with cancer diagnosed in 1971-March 1991 and born in the two major Bristol maternity hospitals in 1965-87 were compared with 558 controls identified from the delivery books for the use of pethidine during labour and administration of vitamin K., Main Outcome Measures: Odds ratios for cancer in the presence of administration of pethidine or of intramuscular vitamin K. Both logistic regression and Mantel-Haenszel techniques were used for statistical analyses., Results: Children of mothers given pethidine in labour were not at increased risk of cancer (odds ratio 1.05, 95% confidence interval 0.7 to 1.5) after allowing for year and hospital of delivery, but there was a significant association (p = 0.002) with intramuscular vitamin K (odds ratio 1.97, 95% confidence interval 1.3 to 3.0) when compared with oral vitamin K or no vitamin K. There was no significantly increased risk for children who had been given oral vitamin K when compared with no vitamin K (odds ratio 1.15, 95% confidence interval 0.5 to 2.7). These results could not be accounted for by other factors associated with administration of intramuscular vitamin K, such as type of delivery or admission to a special care baby unit., Conclusions: The only two studies so far to have examined the relation between childhood cancer and intramuscular vitamin K have shown similar results, and the relation is biologically plausible. The prophylactic benefits against haemorrhagic disease are unlikely to exceed the potential adverse effects from intramuscular vitamin K. Since oral vitamin K has major benefits but no obvious adverse effects this could be the prophylaxis of choice.

As part of a metabolic study aimed at inducing a subclinical vitamin K deficiency in healthy adults, we designed a diet containing less than 10 micrograms/day of vitamin K-1 (phylloquinone). Two-day menus were constructed from a vitamin K-1 food database developed in our laboratory. This diet offers palatability and provides nutrient adequacy; that is, it meets the Recommended Dietary Allowances for protein and all other vitamins and minerals. An interesting feature of the diet is that the vitamin K-1 level can be kept very low while still fulfilling a large range of energy needs (1,800 to 3,400 kcal/day). The diet proved useful in altering apparent nutritional status for vitamin K-1; after ingestion of the diet for 6 days, plasma concentrations of vitamin K-1 decreased by 80% and fell below the established normal range. Given the well documented drug-nutrient interaction between vitamin K and warfarin--a vitamin K antagonist routinely used in the management of thromboembolic diseases--the dietary information presented in this report may provide useful information for patients undergoing warfarin therapy.

The hepatic turnover of phylloquinone and menaquinone-9 (MK-9) and their relative efficacy in satisfying the dietary requirement for vitamin K were compared in male rats. Rats fed 1.1 mumol phylloquinone/kg diet had higher initial liver and serum vitamin K concentrations than rats fed an equimolar amount of MK-9. The initial rate of hepatic turnover of phylloquinone was two to three times as rapid as that of MK-9. After about 48 h of vitamin K restriction there were no significant differences in hepatic vitamin K concentration of rats fed phylloquinone or MK-9. Phylloquinone was much more effective than MK-9 in maintaining normal vitamin K status at low dietary concentrations (0.2 mumol/kg diet), whereas at high dietary concentrations (5.6 mumol/kg diet) they were equally effective.

In rabbits with experimental hypocoagulation induced by phenylin, the use of a new dosage form of vitamin K1 for intravenous injections in does of 1 and 5 mg/kg led, in contrast to vicasol in a dose of 0.4 mg/kg, to an increase of the prothrombin index after 2 hours and to its complete normalization after 4 hours. Intravenous injection of vitamin K1 into intact animals did not entail any changes in the activated partial thromboplastin time, thrombin and prothrombin time, in the content of fibrinogen and products of its biotransformation, antithrombin III activity, and fibrinolytic activity or in the count of platelets and their aggregation capacity.

Reversal of the anticoagulant effect of warfarin in patients with no active haemorrhage can be achieved by administration of intravenous vitamin K1. Currently recommended doses of intravenous vitamin K1, for this purpose often result in subsequent difficulties in anticoagulation. We observed the response to low dose intravenous vitamin K1 in patients requiring reversal of anticoagulant therapy. Ten consecutive patients received 1 mg and 21 further patients received 0.5 mg of intravenous vitamin K1. In 50% of the patients who received 1 mg of vitamin K1 the INR (International Normalised Ratio) fell below 2 at 24 h whereas in patients who received 0.5 mg the INR fell below 5.5 in all subjects after 24 h and in none did it fall below 2.0. No patient had any thrombotic or haemorrhagic complications and no difficulty was encountered in re-establishing anticoagulant control after 24 h. We recommend 0.5 mg of vitamin K1 as an effective and convenient method of predictable and fine control of oral anticoagulant therapy.

Liver and serum concentrations of vitamin K active compounds were measured in two groups of (deficient and normal) broilers after administration of phylloquinone 1 mg/kg. Assays were performed by HPLC after extraction and purification of these compounds. The only menaquinone found in the chicken was menaquinone-4. In the deficient group, the chickens exhibited hepatic concentrations of vitamin K1, vitamin K1 epoxide and menaquinone-4 markedly lower than those of the control group. After administration of phylloquinone, vitamin K and vitamin K epoxide levels fell sharply. There is no hepatic storage of vitamin K comparable to that of vitamin A. However, while menaquinone levels were found to be stable in the control group, they rose significantly in the deficient group after vitamin K injection. The question is: is there a transformation of vitamin K into menaquinone and/or is there a preferential utilization of one of the vitamin K active compounds?

Ten patients with large inoperable desmoid tumors in various body locations were treated with testolactone. Four tumors (40%) responded with major regressions, i.e., more than 50% reduction in volume. Eight patients received nonsteroid anti-inflammatory drugs (indomethacin, sulindac, or sulindac with warfarin and vitamin K1 [Mephyton]) for periods of 2 to 91 months. There was one major regression, one partial regression, and three instances of tumor growth arrest over periods up to 8 years. Seven patients were treated with nonsteroid anti-inflammatory drugs concurrent with or after testolactone or tamoxifen. There were five major regressions and one partial regression with extensive central necrosis of an enormous intra-abdominal tumor. The last patient has been treated for only 12 months, with no change in tumor volume. It appears that estrogens function as growth factors for desmoid tumors, and that minimization of these effects inhibits tumor growth in some, but not all, cases. In those instances where antiestrogens were not effective as single agents, the tumors usually responded to subsequent nonsteroid anti-inflammatory drug therapy. Withdrawal of estrogen may be followed by inhibition of transcription of genes that support tumor cell proliferation, and sulindac and indomethacin may augment these effects by inhibiting prostaglandin and cyclic AMP synthesis and the activity of protein kinase C. Warfarin may function as a protonophore to acidify the cytoplasm and prevent the alkalinization that is necessary to initiate DNA synthesis and cell cycle progression, again an impairment of the transcription process.

The potential for 20 g olestra/d to affect vitamin K status was assessed in a 6-wk study involving 202 free-living subjects. Functional prothrombin [Simplastin (S)-Ecarin (E) assay] concentrations and classical clotting times were unaffected by olestra. Initial S:E values were 0.80 and 0.79 for the olestra and placebo groups, respectively, compared with a value of 0.92 for normal reference plasma. At week 6 the value was 0.81 for both groups. Mean phylloquinone serum concentrations, expressed as differences from baseline, were not significantly different between groups. Weekly food diaries indicated that the average phylloquinone intake of the subjects was low, approximately 60 micrograms/d. Sensitive measures of vitamin K status were unaffected in a population where any significant decrease in phylloquinone bioavailability should have been reflected in those measures, indicating that 20 g olestra/d in the diet did not affect vitamin K status.

Serum concentration of vitamin K1 and activity of vitamin-K-dependent factors II, VII, IX and X were determined before and after vitamin K1 administration in infants. The babies received vitamin K1 intramuscularly or orally. 12 hours after vitamin K1 treatment the mean concentration was increased in the groups receiving vitamin K1 intramusculary or orally, respectively. Serum level of vitamin K1 fell exponentially, the mean half life was about 30 hours in both groups. Activity of vitamin K-dependent clotting factors did not change significantly after intramuscular or oral vitamin K1 administration during the first four-five days of life. It was no direct correlation between the concentration of vitamin K1 and the activity of vitamin-K-dependent clotting factors. This study suggest that oral administration of vitamin K1 is as effective as the intramuscular route.

Seventy-eight women at earlier than 35 weeks' gestation with premature rupture of membranes and/or preterm labor were randomly assigned to receive either 10 mg vitamin K1 intramuscularly (IM) or no treatment. If delivery did not occur within 4 days, the dose of vitamin K1 was repeated. Women whose pregnancies continued beyond 8 days received 20 mg of vitamin K1 orally every day until the end of the 34th week or until delivery, whichever occurred earlier. The median maternal plasma vitamin K1 level was significantly higher in treated than in untreated subjects (11.592 versus 0.102 ng/mL; P less than .001). The median cord plasma levels were 0.024 ng/mL in the treated group and 0.010 ng/mL in the controls, a significant difference (P = .046). Median plasma vitamin K1 levels were comparable in mothers receiving the drug by the IM route only and by both the IM and oral routes (10.533 versus 11.928 ng/mL; P = .460). The infants of the latter group, however, had significantly higher median cord plasma levels (0.42 versus 0.017 ng/mL; P less than .001). There was no correlation between cord plasma vitamin K1 levels and gestational age or duration of maternal supplementation with vitamin K1. We conclude that, in preterm pregnancies, vitamin K1 crosses the placenta slowly and to a limited degree.

A 28-year-old woman in labor developed a severe anaphylactoid reaction, necessitating acute cesarean section, with subsequent neonatal death, after receiving 10 mg of phytomenadione (Konakion) by the intramuscular route. Allergologic investigations revealed no type I reaction against the drug, and the symptoms were considered to be caused by drug-induced intolerance. Prophylactic administration of phytomenadione to the infant rather than to the parturient is recommended.

In 23 female and male healthy volunteers the pharmacokinetic behaviour of [3H]phenprocoumon and [3H]phytomenadion was investigated. The time-dependent changes in plasma radioactivity and the amount of urinary excretion were measured. Under simultaneous administration of phytomenadion (PHY) in daily doses of 10 mg, the elimination of phenprocoumon (PPC) was not altered (t0.5 beta 141.4 h, CUE50 20.4% of administered dose) as compared with data of previous investigations, while its anticoagulant effect was inhibited. PHY in doses of 10 mg was absorbed quickly and eliminated with a mean half-life of 60.6 h at a total body clearance (Cltot) of 9.3 ml/min and a renal clearance (Clren) of 1.9 ml/min. Under the co-administration of PPC the vitamin was eliminated with a half-life time of 23.1 h (Cltot 16.7 ml/min) and the amount of excreted radioactivity was enhanced (26.3% of administered dose; Clren 4.5 ml/min) as compared with the data of PHY without co-medication. From the experiments it is concluded that (1) PHY inhibits the action of PPC without influencing its pharmacokinetics, and (2) that PPC distinctly changes the pharmacokinetics of PHY and diminishes its pharmacodynamic action as measured by changes in the prothrombin complex activity.

The pharmacokinetics of vitamin K1 was studied in 21 newborn infants. 11 neonates had received no parenteral loading dose prior to the study (group I), while 10 had been injected 5-10 mg vitamin K1 at birth (group II). At postnatal age 2-9 h, 1 mg of vitamin K1 was injected intravenously, and small samples of blood (less than or equal to 500 microliter) were collected at different times during 6 h. Serum vitamin K1 and its epoxide were assayed by high-performance liquid chromatography (HPLC). In both groups, the disappearance curve showed two exponential components: a fast distribution component during the 1st h and a slower elimination component during the next 5 h. In group I, the plasma half-life of the first component was between 18 and 52 min (median 23 min), and the half-life of the second was between 67 and 179 min (median 109 min). Both half-lives were significantly higher in group II. The volumes of distribution were suggestive of distribution into plasma during the first phase and roughly into the extracellular water for the second component. Epoxide was detected in most patients 15 min after vitamin K1 injection, and after 3 h its concentration was higher than the concentration of vitamin K1. These data suggest that the kinetics of vitamin K1 in neonates is not very different from that in adults. The newborn infant is able to oxidize vitamin K1, a phenomenon in keeping with the gamma carboxylation of glutamic acid.

Vitamin K1 (5 mg/kg of body weight/day divided for several 5-day regimens) was effective in preventing bleeding diathesis in diphacinone-poisoned dogs. Diphacinone, a vitamin K-inhibiting rodenticide, was given 2.5 mg of diphacinone/kg of body weight orally in divided doses 2 times daily for 3 days. One dog was given 5.0 mg of warfarin/kg in 2 divided doses for 3 days. Hemograms and biochemical profiles were performed every other day. A pancreatic exocrine function test was performed before and after administration of diphacinone and warfarin. All dogs were monitored, using routine coagulation screening tests and assays of coagulation factors II, VII, IX, and X. When laboratory results or clinical illness indicated hemorrhage, diphacinone-treated dogs were given 5.0 or 2.5 mg of vitamin K1/kg in divided doses 3 times a day for 5 days. The warfarin-treated dog was given 2.5 mg of vitamin K1/kg of body weight in divided doses 3 times a day for 5 days. Of the diphacinone-treated dogs, 1 dog (given 2.5 mg of vitamin K1/kg) required 3 vitamin K regimens and 2 dogs (given 5.0 mg of vitamin K1/kg) required only 2 vitamin K regimens. The warfarin-treated dog required only 1 vitamin K1 regimen. Bleeding was observed in the diphacinone-treated dogs up to 2 weeks after treatment. The vitamin K-enzyme complex was inhibited in diphacinone-treated dogs for approximately 30 days, as indicated by routine coagulation screening tests and coagulation factor inhibition. Hepatic dysfunction was not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Cutaneous hypersensitivity to vitamin K1 injection has been reported once in North America. This case and most of the others in European literature have been associated with alcoholic liver disease. We report six patients who developed persistent skin hypersensitivity reactions at the site of vitamin K1 injection. These cases are the first reported to occur in liver disease associated with primary biliary cirrhosis, chronic myeloid leukemia, amyloidosis, and preeclampsia. Patch and intradermal skin tests demonstrated a hypersensitivity that seems to have an immune basis and is restricted to fat-soluble vitamin K1. This finding suggests that patients with any type of liver disease may be at risk for vitamin K hypersensitivity and that the hypersensitivity may be a marker of liver disease.

A 63-year old man developed a delayed cutaneous reaction at the sites of intramuscular injections of a phytonadione (vitamin K) preparation. The patient was tested with the drug and its components by intradermal and epicutaneous application. Sensitivity to the pure phytonadione and not the other components of the preparation was documented by patch tests.

Dicumarol poisoning was reproduced by feeding naturally spoiled, sweet clover hay, which contained a minimum of 90 ppm dicumarol. Vitamin K1 administered IM was effective in treating the disease at dosages of 1.1, 2.2, and 3.3 mg/kg of body weight. Vitamin K3 treatment by various routes and dosages was ineffective.

The relationship between dietary phylloquinone, serum and liver concentrations of phylloquinone, and various indices of vitamin K adequacy have been studied in male rats fed a purified diet containing various levels of phylloquinone. In excess of 500 micrograms phylloquinone/kg diet was needed to prevent the most sensitive signs of vitamin K deficiency. Liver phylloquinone concentrations were shown to be correlated with dietary phylloquinone intake. Serum phylloquinone was not correlated with either diet or liver concentration of phylloquinone and did not increase with increased dietary intake until the liver contained sufficient vitamin to maintain optimal synthesis of vitamin K-dependent proteins. Because of the rapid loss of vitamin from the liver, prior ingestion of a high level of vitamin K had little influence on liver vitamin K concentrations beyond the first 2 d of a deficient period. When rats consumed a diet containing 500 micrograms phylloquinone/kg diet in 3 h, liver and serum phylloquinone concentrations fluctuated drastically following this feeding period. During the subsequent 24-h period, liver phylloquinone concentrations decreased to a level that would not support maximal activity of the hepatic vitamin K-dependent carboxylase.

The efficacy and tolerability of a conventional vitamin K1 preparation containing polyoxyethylated castor oil as solubilizer were compared with those of a new compound containing mixed micelles as solubilizer in 30 patients. A statistically significant increase in the thrombotest was detected after treatment in both groups. No hematological or chemical toxicity was observed during the observation period. One patient had an anaphylactoid reaction after intravenous injection of the mixed micelles preparation. Intradermal testing yielded positive results. The authors conclude that intravenous administration of vitamin K preparations should be reserved for acute emergencies.

The effects of vitamin K on hemorrhagic death induced by dietary butylated hydroxytoluene (BHT) were studied. Male Sprague-Dawley rats were given BHT or two phenolic antioxidants (2,4,6-tri-tert-butylphenol and 2,5-di-tert-butylhydroquinone) in combination with a 24% casein basal diet. The levels of the phenols were chosen to nearly equal LD50 (40 days). Hemorrhagic death, hemorrhage and a decrease in prothrombin index caused by 1.20% BHT were prevented by simultaneously adding phylloquinone (0.68 mumole/kg/day). Phylloquinone also inhibited the effect of the related phenolic antioxidants. Ten nanomoles of phylloquinone injected into the femoral vein on day 3 of feeding 1.2% BHT increased the prothrombin concentration from 28% of normal to 100% of normal within 18 to 24 hours. Phylloquinone oxide also prevented hypoprothrombinemia due to BHT. These results suggest that BHT-induced hemorrhagic death may be caused by direct and/or indirect vitamin K deficiency, and its mechanism may be different from those of warfarin.

Clinical use of antibiotics containing a N-methyl-thiotetrazole (NMTT) side chain has been reported to be associated with an increased incidence of a vitamin K-responsive hypoprothrombinemia. Administration of NMTT to rats decreased the activity of the liver microsomal vitamin K epoxide reductase, increased the liver ratio of vitamin K epoxide to vitamin K, and decreased the rate of metabolism of injected vitamin K epoxide. These responses are the same as those observed following the administration of coumarin anticoagulants. In contrast to the effect of coumarin anticoagulants, NMTT did not inhibit the vitamin K epoxide reductase in vitro. These data suggest that the hypoprothrombinemia which has been observed following use of these antibiotics results from the inactivation of the liver vitamin K epoxide reductase by NMTT or a NMTT metabolite.