Administration Of Vitamin K1 Research Articles

Pharmacokinetics and Safety of a New Solution of Vitamin K1(20) in Children with Cholestasis

SummaryIn cholestatic diseases, the absorption of fat‐soluble compounds, including vitamin K1(20), is low and periodic administration of vitamin K1(20) is often necessary. Due to the low absorption of vitamin K1(20) from the Konakion formulation, late hemorrhagic disease of the newborn also occurs especially after oral vitamin K1(20) prophylaxis with Konakion. We investigated the pharmacokinetics and the safety of a new formulation of vitamin K1(20) in a mixed micelles (MM) solution. Compared to the old formulation (Konakion) using Cremophor EL as a solubilizer, the higher vitamin K1(20) levels (as measured by HPLC) in serum obtained after oral administration of the MM formulation clearly demonstrate a superiority of this new formulation. Additionally, the elimination of Cremophor EL as well as of propylene glycol from the formulation avoids possible adverse effects associated with intravenous or intramuscular administration. Furthermore, in most cases, the discomfort of parenteral injections can be overcome by simple oral administration even in children with severe cholestasis.

Effective Reversal of Warfarin-lnduced Excessive Anticoagulation with Low Dose Mtamin K1

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.

Two Cases of Idiopathic Vitamin K Deficiency in Infancy who Failed to be Prevented

Two cases of Idiopathic vitamin K deficiency in infancy we experienced recently are reported. The first case was admitted to Kanagawa Children's Medical Center at 62 days of age, because of intracranial hemorrhage due to vitamin K (VK) deficiency. She fell ill in spite of prophylactic administration of oral VK at her birth and 6 days after birth. She exhibited hyperbilirubinemia and elevation of serum transaminase. It was suspected that Cytomegalovirus (CMV) infection was related to her liver dysfunction, because IgM antibody to CMV was increased and CMV was isolated from her urine and breast milk of her mother. The second case was admitted at 31 days of age, and made a diagnosis of subdural hemorrhage and hemothorax due to VK deficiency. He had not received VK administration prophylacticaly, because his Normotest was normal at 6 days of age. He exhibited slight elevation of serum transaminase on admission. However CMV infection could not be elucidated in this case. We think that liver dysfunction plays important role in the onset of VK deficiency in infancy.The prophylactic administration of VK during the neonatal period has been carried out widely in Japan, and a remarkable decrease of intracranial hemorrhage due to Idiopathic VK deficiency in infancy has been reported. It is important to study the cases that failed to be prevented, for making a plan to prevent VK deficiency in infancy furthermore.

The Third Nationwide Survey in Japan of Vitamin K Deficiency in Infancy

The occurrence of hemorrhagic disease due to vitamin K (VK) deficiency beyond the neonatal period has come under investigation in Japan. In 1980 the 1st nationwide survey was conducted in Japan by Nakayama and others, and was followed by the 2nd nationwide survey in 1985 by Hanawa. The present survey was designed to further monitor the incidence of this disease in Japan during the 3-year period from July 1985 to June 1988. Questionnaires were sent to 1,315 hospitals having more than 200 beds, located throughout Japan. Responses were received from 775 hospitals, for an answer rate of 58.9%. The total number of reported cases was 175, including 129 idiopathic type, 28 secondary type and 18 near-miss type. In this survey it was revealed that the incidence rate of the idiopathic type of vitamin K deficiency in infancy (VKDI) has decreased remarkably, to about one-fourth that reported in the first survey. The declining incidence rate of VK deficiency in Japan is considered to be the result of ever more widespread prophylactic administration of VK during the neonatal period, as most occurrences of VK deficiency in infancy are preventable by prophylactic administration of VK from the neonatal period. However, in 16 cases of the idiopathic type of VK deficiency found in the present survey, VK had been administered at least once during or after the neonatal period. This shows the heterogeneity of this condition.

Maternal Administration of Vitamin K Does Not Improve the Coagulation Profile of Preterm Infants

The effect of maternal administration of vitamin K1 on cord blood prothrombin time, activated partial thromboplastin time, activity of factors II, VII, and X, and antigen levels of factors II and X in infants less than 35 weeks' gestation was evaluated. Pregnant women in preterm labor were randomly assigned to receive 10 mg of vitamin K1 intramuscularly or no injection. If delivery did not occur in 4 days, the dose of vitamin K1 was repeated. Women who continued their pregnancy 4 days beyond the second dose received 20 mg of vitamin K1 orally daily until the end of the 34th week of gestation. The birth weights of infants ranged from 370 to 2550 g and gestational age ranged from 22 to 34 weeks. The prothrombin time, activated partial thromboplastin time, factors II, VII, and X activity, and factors II and X antigen levels were not statistically different in either group of infants. Intraventricular hemorrhage occurred in 25 of 51 control infants and 25 of 47 vitamin K-treated infants. More control infants had grade III intraventricular hemorrhage on day 1 (P = .032), but on day 3 and 14 of life, the severity of intraventricular hemorrhage was comparable in both groups. Infants in whom an intraventricular hemorrhage developed were significantly smaller, younger, and more critically ill than infants without intraventricular hemorrhage. Administration of vitamin K1 to pregnant women at less than 35 weeks' gestation does not improve the hemostatic defects nor does it reduce the incidence or severity of intraventricular hemorrhage in their infants.

Maternal-fetal transport of vitamin K 1 and its effects on coagulation in premature infants

We conducted a prospective study to determine (1) the maternal-fetal vitamin K1 transport in premature infants after vitamin K1 was given to the mothers antenatally and (2) the vitamin K1 effects on blood coagulation in the babies. Women in labor at less than or equal to 34 weeks of gestation were randomly selected to receive antenatal vitamin K1, 5 mg given intramuscularly (vitamin K1 group), or no vitamin K1 (control group). Eight infants, including one set of twins, were in the vitamin K1 group and six in the control group. Vitamin K1 concentrations were higher in the vitamin K1 group than in the control group (p = 0.06). Activated partial thromboplastin time was prolonged, and factor II coagulation activity and factor II antigen were proportionately decreased in cord plasma in both groups. The average ratio of factor II coagulation activity to antigen was not decreased in either group. Protein induced by vitamin K absence-II (PIVKA-II) was not detectable in any cord plasma sample in either group. These findings support previous reports that the decreased vitamin K-dependent coagulation activity in premature infants is the result of reduced synthesis of precursor proteins, rather than the result of vitamin K deficiency, and suggest that additional vitamin K1 is not likely to improve coagulation activity. Among those infants who underwent cranial ultrasonography, all four in the vitamin K1 group and one of five in the control group had mild intraventricular hemorrhage. Studies of a larger number of patients are necessary before it can be established that maternal antenatal administration of vitamin K1 results in improvement of coagulation and the prevention of intraventricular hemorrhage in premature infants.

An investigation of the pharmacological response to vitamin K1 in the rabbit.

1. The relationship between pharmacological response and disposition of a dose of vitamin K1 (10 mgkg-1, i.v.) in normal rabbits and in rabbits treated with the coumarin anticoagulant brodifacoum, has been studied. 2. High performance liquid chromatography (h.p.l.c.) with electrochemical detection (EC) was used to determine concentrations of vitamin K1 in plasma, whole liver homogenate, and liver microsomes. 3. After intravenous administration of vitamin K1, plasma concentrations of the vitamin declined in a tri-exponential fashion. There were no differences between the two groups over the first 24 h of the experiment. However, between 24 h and the end of the study, plasma concentrations of vitamin K1 in the presence of brodifacoum were significantly (P less than or equal to 0.05) below those of vehicle-treated rabbits. 4. Seventy-two hours after administration of vitamin K1, plasma concentrations of the vitamin were not different from normal. 5. Three hours after administration of vitamin K1, the concentrations of the vitamin in whole liver were 46.6 +/- 4.3 micrograms g-1 in the presence of brodifacoum, and 32.8 +/- 6.4 micrograms g-1 in the absence of brodifacoum; and were significantly (P less than or equal to 0.05) greater than normal (127.7 +/- 44.3 ng g-1). Likewise, microsomal concentrations of vitamin K1 (4.00 +/- 2.38 micrograms mg-1 protein, and 2.65 +/- 1.01 micrograms mg-1 protein, in the presence and absence of brodifacoum, respectively) were significantly (P less than or equal to 0.01) greater than normal (16.0 +/- 3.5 ng mg-1 protein). 6 In conclusion, there appears to be no direct effect of coumarins on clearance of vitamin K1 from either plasma or liver; the need for large doses of vitamin K1 during coumarin poisoning is due to a greatly increased requirement for the vitamin.

Solubilization of vitamin K1 by bile salts and phosphatidylcholine-bile salts mixed micelles.

The solubilization of vitamin K1 by bile salts (sodium deoxycholate, sodium cholate and their corresponding glycine conjugates) and phosphatidylcholine (egg)-bile salt mixed micelles has been investigated. The solubilization curves were not always linear with increasing bile salts, but the vitamin was appreciably solubilized in the region below their CMCs. In the bile salt solutions (20 mM, phosphate buffered saline, pH 7.5, ions strength 0.2), the solubilized vitamin ranged from 0.3 to 0.9 mM. With increasing phosphatidylcholine, the amount of vitamin solubilized was dramatically increased; at the molar ratio of 1:1 (both 20 mM), the amount of vitamin solubilized was about 25-30 times more than by the corresponding bile salts alone. There is a possibility that exogenous phospholipid given orally as liposomal forms assists the solubilization of vitamin K1, in the intestine. This characteristic is suggested as being responsible, in part, for the enhanced recovery of blood coagulation after oral administration of liposomal vitamin K1 to warfarin-treated rabbits.

Malabsorption of Liposoluble Vitamins in a Child with Bile Acid Deficiency

SummaryA male born to first cousins presented at 12 months with hypocalcemic convulsions, rickets, epistaxis due to vitamin K deficiency, and extremely low serum levels of beta‐carotene and vitamin A. Liver function was altered moderately (glutamic‐oxaloacetic transaminase, 55 U/L; glutamic‐pyruvic transaminase, 37 U/L; lactate dehydrogenase, 255 U/L; alkaline phosphatase, 437 U/L). To correct the deficiencies, 8000 IU vitamin D/day, 10,000 IU vitamin A/day, and intramuscular administration of vitamin K1 were required. At 9 years, he presented signs of neuromuscular affection, and the serum vitamin E level (measured for the first time) was extremely low. Classic lipid malabsorption syndromes (abetalipoproteinemia, chronic cholestasis, mucoviscidosis, coeliac disease, Whipple's disease) were excluded by appropriate examinations. Composition of duodenal bile acids was characterized by undetectable levels of cholic acid metabolites, and only chenodeoxycholic acid metabolites were present. Serum total bile acid concentration was normal, with an atypical low cholic acid/chenodeoxycholic acid ratio and abnormal presence of 3β‐OH‐δ5‐cholenic acid and 6‐OH‐bile acids. Urinary bile acid composition was also characterized by elevated 6‐OH‐bile acids. Known enzymopathies of the bile acid synthetic pathway were excluded (cerebrotendinous xanthomatosis, cerebro‐hepato‐renal syndrome of Zellweger, coprostanic acidemia). Bile acid pool sizes were determined by using stable isotopes: cholic acid pool size [2.90 (N, 32 ± 16) μM/kg] and chenodeoxycholic acid pool size [10.8 (N, 32.6 ± 9.9) μM/kg] were extremely low; fractional turnover rates of both bile acids were in a normal range. Treatment with chenodeoxycholic acid markedly improved the absorption of fat soluble substances and normalized hepatic function. A partial enzyme defect in the metabolism of the steroid nucleus is proposed.

Enantiomers of warfarin and vitamin K1 metabolism.

The effect of the individual enantiomers of warfarin at steady state (1 mg daily) was investigated in five healthy volunteers. Both enantiomers produced a significant increase in prothrombin time, but the increase with S warfarin (1.8 +/- 0.8 s, mean +/- s.d.) was greater than with R warfarin (1.0 +/- 0.3 s), despite lower steady state plasma concentrations of S warfarin, due to its more rapid clearance. Following the administration of vitamin K1, the maximum plasma concentration and area under the plasma concentration time curve values for the metabolite vitamin K1 2,3-epoxide were greater after S warfarin than after R warfarin. The greater anticoagulant potency of S warfarin is reflected by a greater degree of inhibition of vitamin K1 epoxide reductase.

Vitamin K1 metabolism in relation to pharmacodynamic response in anticoagulated patients.

The disposition of, and pharmacological response to, a single intravenous dose of vitamin K1 (10 mg) was studied in eleven patients on daily warfarin therapy. The pharmacokinetics of vitamin K1 in patients were similar to those reported previously in healthy volunteers, terminal half-life 1.7 h. All patients had been taking warfarin for at least 3 months. Steady state warfarin plasma concentrations ranged from 0.5 to 1.4 micrograms ml-1. Prothrombin complex activity ranged from 15 to 28.5%. There was considerable inter-individual variation in pharmacodynamic response as expressed by prothrombin complex activity (PCA) and Factor VII. The maximum values for PCA and Factor VII were reached at 24-96 h and 24-48 h, respectively, after the administration of vitamin K1. Vitamin K1 (10 mg) has a long duration of action (greater than 168 h) in terms of clotting factor synthesis in patients on steady state warfarin. All the patients on warfarin had measurable levels (CPmax 0.3-1.2 micrograms ml-1) of vitamin K1 2, 3-epoxide. There was a significant correlation between the pharmacodynamic response as expressed by change in % PCA and the AUC for vitamin K1 2,3-epoxide (P less than 0.05).

Serum vitamin K1 concentration and vitamin K-dependent clotting factor activity in maternal and fetal cord blood

The serum concentration of phylloquinone (vitamin K1) was measured in 34 healthy mothers and in the arterial cord blood of their newborn infants. In addition, the activities of factor II and of factors VII plus X were determined simultaneously in 16 paired maternal and fetal bloods. The serum vitamin K1 concentration was similar to that of control subjects in 27 mothers: 9.03 ± 4.9 μg/L (mean and SD), with a simultaneous concentration of 10.4 ± 5.3 μg/L in cord blood. Six mothers exhibited high serum vitamin K1 concentrations from 40 to 240 μg/L (median, 82) and the concentration in cord blood ranged from 25 to 115 μg/L (median, 71). One mother had a normal concentration of vitamin K1: 9 μg/L while no vitamin K1 was detectable in the serum of her infant. The activity of factor II and factors VII plus X was 7% and 7%, respectively, in this infant and 100% in the mother. All other mothers showed normal factor II and factors VII plus X activity, while the median activity was 47% (28%–56%) for factor II and 65% (35%–100%) for factors VII plus X in cord blood. These data suggest that vitamin K1 can cross the placental barrier but not in every case. Therefore the systematic administration of vitamin K1 to the newborn infant seems to be required to prevent the occurrence of the hemorrhagic disease.

Antimicrobial therapy in dialysis patients. I. Penicillins and cephalosporins.

Antibiotic therapy, using penicillins or cephalosporins, is frequently required in patients on maintenance hemodialysis. Points to consider are dose adjustment for drugs which are excreted via the kidney, drug dialysability, and cumulation with frequent occurrence of side reactions, neurotoxicity and bleeding being the clinically most important ones. For third-generation cephalosporins with N-methylthiotetrazole side chain, impaired intrahepatic vitamin K metabolism may cause problems of hemostasis which can be avoided by dose adjustment and prophylactic administration of vitamin K1.

Coagulation recovery after warfarin-induced hypoprothrombinaemia by oral administration of liposomally-associated vitamin K1 to rabbits.

The effect of liposomally-associated vitamin K1, administered orally, was investigated using rabbits with warfarin-induced hypoprothrombinaemia, and evaluated in comparison with other dosage forms of the vitamin, including a vitamin K1 emulsion, the physical mixture of the emulsion with empty liposomes, polyoxyethylene hydrogenated castor oil (HCO-60)-stabilized emulsion and the vitamin solubilized by HCO-60. The effect on blood coagulation recovery of each preparation was estimated as the time required for the prothrombin complex activity to return to 60% (TPCA60). The coagulation recovery time of the liposomal preparation was much faster than that of the other preparations and it was compared with the response to intravenous administration in which the vitamin was considered to be 100% available. The TPCA60 for the intravenous administration was 1.9 h, that for the oral liposomal preparation was 6.2 h, HCO-60 solubilized vitamin 13.6 h, HCO-60 stabilized emulsion 19.6 h, the physical mixture 17.8 h and plain emulsion 18.2 h. The vitamin K1 dose was maintained at 12 mg kg-1 in each instance.

Cyclic interconversion of vitamin K1 and vitamin K1 2,3-epoxide in man.

The disposition of a single intravenous bolus dose of 10 mg vitamin K1 and vitamin K1-2,3-epoxide were studied in two healthy subjects without and with 12 h pretreatment dose of phenprocoumon (0.4 mg/kg). For each compound administered alone the plasma concentration-time profile was adequately fitted by a biexponential equation, with an average terminal half-life of 2.0 and 1.15 h for the administered vitamin K and its 2,3-epoxide respectively. While vitamin K1 was measurable in plasma following administration of vitamin K1-2,3-epoxide, the epoxide was not detectable following administration of vitamin K1. Following pretreatment with phenprocoumon and after intravenous administration of vitamin K1, both the average half-life and area under the plasma concentration-time profile of vitamin K1 were marginally reduced to 1.5 h and 1.76 mg l-1 h respectively, while the plasma concentration of vitamin K1-2,3-epoxide was readily measurable and its half-life markedly prolonged to 14.7 h. Following pretreatment with phenprocoumon and after oral administration of vitamin K1-2,3-epoxide, no vitamin K1 was detectable in plasma and the half-life of the epoxide was 13.8 h. Based on area considerations the data suggest that either phenprocoumon does more than just inhibit the reduction of vitamin K1-2,3-epoxide to vitamin K1, or that the simple model describing the interconversion between vitamin K1 and its epoxide is inadequate. The same conclusion is drawn from the analysis of comparable data in dogs, obtained by Carlisle & Blaschke (1981).

Factor V Deficiency and Its Reversal With Gluten Restriction

Hemorrhagic manifestations in patients with celiac disease are uncommon and, when present, are usually due to a deficiency of the vitamin K-dependent clotting factors. A patient with celiac disease was seen with a severe bleeding diathesis associated with deficiencies of factor V. The deficiencies of vitamin K-dependent clotting factors were rapidly reversed with parenteral administration of phytonadione. Factor V levels returned to normal levels only after gluten restriction.

Post-natal development of factor IX.

Post-natal development of clotting activity and of antigen level of Factor IX was evaluated in 111 healthy, breastfed, newborn infants, aged 1-30 days. Of these, 80 had received at birth 2 mg of vitamin K1 orally. Factor IX clotting activity was determined by one-stage assay and antigen level by electroimmunoassay. On the 1st day both antigen level and clotting activity were low and the ratio was 1.01. There was a significant postnatal increase of the two activities of Factor IX during the first three days of life; thereafter both remained constant. No statistical difference inFactor IX activity was found with oral administration of vitamin K1 after the birth. During the first month of life both clotting activity and antigen level of Factor IX were low as compared to adult values. There was no correlation with age. The Factor IX protein of newborns did not show molecular heterogeneity by crossed-immunoelectrophoresis.

COVERT ANTICOAGULANT INGESTION: STUDY OF 25 PATIENTS AND REVIEW OF WORLD LITERATURE

Twenty-five patients with covert ingestion of oral anticoagulant drugs were studied. Most of the patients were women who were either connected with the medical profession or were previously treated with antigoagulants. The most common findings were ecchymoses, hematuria, and a markedly prolonged prothrombin time. The anticoagulant drug was identified in the plasma of all 25 patients. Most patients responded promptly to administration of vitamin K1. The most common motives were malingering and suicide. The world literature was reviewed for covert ingestion of oral anticoagulant drugs and 48 other cases were found. The correct diagnosis is important to focus the physician's attention on the psychiatric rather than the somatic aspects of the disorder.

The Influence of the Thyroid Function on the Metabolic Rate of Prothrombin, Factor VII, and Factor X in the Rat

The influence of the thyroid function on the metabolic rate of prothrombin, factor VII, and X was studied in the rat. Disappearance rates of the three coagulation factors were measured after synthesis had been blocked with appropriate doses of warfarin, and reappearance rates were assessed upon induction of synthesis by high doses of vitamin K1 injected into rats displaying coumarin induced hypocoagulability. No statistically significant difference in the disappearance and production rates of any of the factors could be found between normal euthyroid rats and thyroxin-treated hypothyroid rats proven to be euthyroid. The differences between the two euthyroid groups and the hypothyroid group were highly significant, however: hypothyroidism results in an approximately 50% decrease of the metabolic rates of the three coagulation factors under study. The reappearance of the three factors, under euthyroid as well as hypothyroid conditions, showed a biphasic pattern: in the first two hours after vitamin K1 administration to warfarin treated rats, a rapid reappearance was observed, to the same extent for all three factors, in hypo- as well as euthyroid rats. This finding suggests that in vitamin K1 deficiency an intracellular accumulation of precursor proteins (PIVKAs) occurs, which after rapid conversion into biologically active coagulation factors by vitamin K1 are shed into circulation. The subsequent phase of reappearance is much slower and reflects the synthesis rate of coagulation enzymes. It is characteristic for each factor and clearly slower in hypothyroid rats than in euthyroid rats. From this an influence of thyroid function on the synthesis rate of the protein moiety of coagulation factors can be inferred. An apparent difference between disappearance and reappearance rate of the coagulation factors in the plasma, particularly pronounced for factors VII and X in euthyroid rats, could theoretically be explained as the consequence of the model used for derivation of these rates.

Clotting factor deficiencies in rats fed a modified iodine-deficient diet.

Fatal hemorrhages were found to occur in rats after 3–4 weeks of feeding a commercial iodine-deficient (Remington) diet corrected for iodine deficiency. Hematological investigation revealed a markedly prolonged one-stage prothrombin time in these rats, and reduced circulating levels of two vitamin-dependent clotting factors, factors VII and X. Cold exposure (5 °C) afforded partial protection to the Remington-fed rats: decreased incidence of deaths and partial correction of the clotting time. Complete correction or prevention of the clotting defects was obtained with the administration of vitamin K1, suggesting either an insufficient supply or an inadequate absorption of vitamin K in the Remington-fed rats.