Plasma vitamin K1 and PIVKA-II after oral administration of mixed-micellar or cremophor EL-solubilized preparations of vitamin K1 to normal breast-fed newborns.

BACKGROUND: Vitamin K1 prophylaxis in neonates is required for prevention of vitamin K1 deficiency bleeding. Although intramuscular administration of vitamin K1 is safe, this invasive method is not generally accepted. We therefore examined the pharmacokinetics of two orally administered vitamin K1 preparations in normal, fully breast-fed newborns. METHODS: Within 1 hour of birth, each baby was randomized to a 2 mg dose of either a conventional Cremophor EL-solubilized preparation of vitamin K1 (Konakion drops, F. Hoffmann-La Roche, n = 16), or a new mixed-micellar preparation of vitamin K1 (Konakion MM, F. Hoffmann-La Roche, n = 14). The concentrations of vitamin K1, des-gamma-carboxyprothrombin (PIVKA-II), and total bound bilirubin were measured in plasma samples taken at 24 hours, 4 days, and 24 days after birth. RESULTS: The median concentration of plasma vitamin K1 was higher at all three time points in the group that received the mixed-micellar preparation, but the difference was only significant (p < 0.05) at 4 days. At 24 hours and 4 days, PIVKA-II was detectable in a significantly lower proportions of infants receiving the new mixed-micellar preparation than those receiving the Cremophor EL preparation (21% vs. 75% at 24 hours, p < 0.05 and 14% vs. 50% at 4 days, p < 0.05). None of the infants in the study had detectable PIVKA-II levels 24 days after birth. CONCLUSIONS: Our results suggest that when given orally, the mixed-micellar preparation is superior to the conventional formulation because it increases plasma vitamin K1 concentrations to higher levels, suggesting superior bioavailability, and decreases PIVKA-II concentrations more efficiently, suggesting a faster pharmacodynamic response.

Pharmacokinetics and tolerance of intravenous and intramuscular phylloquinone (vitamin K1) mixed micelles formulation.

1. The pharmacokinetics and tolerance of phylloquinone(vitamin K1) mixed micelles formulation (Konakion MM) were evaluated, in normal human adult volunteers (n = 30) using an open randomized crossover design protocol following a 10 mg intravenous or intramuscular injection. 2. Blood samples were collected for up to 12 h after the intravenous and up to 72 h after the intramuscular injections and the phylloquinone(vitamin K1) levels determined by reversed phase h.p.l.c. with fluorometric detection after post-column electrochemical reduction. 3. Konakion MM was well tolerated after either route of administration. Pharmacokinetic analysis of plasma phylloquinone(vitamin K1) concentration vs time profiles revealed that in one-fifth of the subjects systemic availability of intramuscular phylloquinone (vitamin K1) was below 65%. 4. Our data suggest that due to sustained, but irregular and unpredictable absorption of the phylloquinone(vitamin K1) from the depot site, the intramuscular route of Konakion MM administration is not suitable and thus not recommended. 5. Konakion MM i.v. is indicated to be well tolerated and effective in antagonizing coumarin-type-anticoagulants like Marcoumar.

Vitamin K1 concentration in breast-fed neonates after oral or intramuscular administration of a single dose of a new mixed-micellar preparation of phylloquinone.

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).

[Arrhythmogenic ventricular dysplasia or Uhl's disease?]. / Dysplasie ventriculaire arythmogène ou maladie d'Uhl?

Uhl's anomaly and arrhythmogenic right ventricular dysplasia are characterized by an analogous morphologic lesion which can be attributed to a major or minor expression of the same genetic disorder. The clinical diagnosis of arrhythmogenic dysplasia is not always easily established. A 23-year-old patient is discussed who showed extrasystolic arrhythmia, electrocardiographic signs of myocardial impairment and syncopes, the latter proving fatal. The segmental absence of myocardial tissue in the right ventricle is associated with interstitial sclerosis of the left ventricular myocardium. Subsisting myocardial fibers might be at the origin of a conduction slowdown creating an intraventricular reentry mechanism. The diagnosis should be considered in young subjects, more frequently males, with some years' history of palpitations, malaise with or without syncopes, and nonspecific electrocardiographic signs such as retarded activation of right cavities (S wave in derivations I and V6, possible right bundle block) and, during ventricular tachycardia, signs of delayed activation of left chambers, a right axis or an extreme deviation to the left.