The effectiveness of recombinant human erythropoietin (r-HuEpo)

Based on in vitro work with rat liver, we recently suggested that the peroxisomal fraction is most important for the oxidation of 3a,7a,12a-trihydroxy-5,8-cholestanoic acid (THCA) into cholic acid. The cerebro-hepato-renal syndrome of Zellweger is a fatal recessive autosomal disorder, the most characteristic histological feature of which is a virtual absence of peroxisomes in liver and kidneys. This disease offers a unique opportunity to evaluate the relative importance of peroxisomes in bile acid biosynthesis. A child with Zellweger syndrome was studied in the present work. In accordance with previous work, there was a considerable accumulation of THCA, 3a,7a,12a,24-tetrahydroxy-5,6-cholestanoic acid (24-OH-THCA), 3a,7a,12a-trihydroxy-27-carboxymethyl-5#6-cholestan-26-oic acid (C2-dicarboxylic acid), and 3a,7a-dihydroxy-5#-cholestanoic acid in serum. In addition, a tetrahydroxylated 51e-cholestanoic acid with all the hydroxyl groups in the steroid nucleus was found.3H-Labeled 5W-cholestane-3a,7a,12a-triol was administered intravenously together with 14C-labeled cholic acid. There was a rapid incorporation of 3H in THCA and a slow incorporation into cholic acid. The specific radioactivity of 3H in THCA was about one magnitude higher than that in cholic acid. The conversion was evaluated by following the increasing ratio between 3H and 14C in biliary cholic acid. The rate of incorporation of 3H in cholic acid was considerably less than previously reported in experiments with healthy subjects, and the maximal conversion of the triol into cholic acid was only 15-20%. About the same rate of conversion was found after oral administration of 3H-THCA. Both in the experiment with 3H-5W6cholestane-3a,7a,12a-triol and with 3H-THCA, there was an efficient incorporation of 3H in the above unidentified tetrahydroxylated 5#-cholestanoic acid. There was only slow incorporation of radioactivity into 24-OH-THCA and into the C2-dicarboxylic acid. From the specific activity decay curve of "'C in cholic acid obtained after intravenous injection of 14C-cholic acid, the pool size of cholic acid was calculated to be 24 mg/M2 and the daily production rate to 9 mg/M2 per d.This corresponds to a reduction of -85 and 90%, respectively, when compared with normal infants. It is concluded that liver peroxisomes are essential in the normal conversion of THCA to cholic acid. In the Zellweger syndrome this conversion is Address correspondence to Dr. Pedersen, Institute for Nutrition Research.Received for publication 9 January 1984 and in revised form 12 October 1984. defective, and as a consequence the accumulated THCA is either excreted as such or transformed into other metabolites by hydroxylation or side chain elongation. The accumulation of THCA, as well as the similar rate of conversion of 5#-cholestane-3a,7a,12a-triol and THCA into cholic acid, support the contention that the 26-hydroxylase pathway with intermediate formation of THCA is the most important pathway for formation of cholic acid in man.

SUMMARY Twenty three children with recurrent supraventricular tachycardia were treated with flecainide. Twenty one of these received intravenous treatment during an attack (2 mg/kg over 10 minutes). The tachycardia was terminated in 17. After an intravenous bolus of flecainide, blood samples were drawn at regular intervals for analysis of flecainide concentration over 48 hours. Pharmacokinetic variables were calculated-median terminal half life 7 5 hours, median volume of distribution 6-2 1/kg, and median plasma clearance 7-2 ml/min/kg. There was a significant correlation between half life and age. Twenty of the children received long term treatment with an oral preparation offlecainide to prevent further attacks. Twelve had no further attacks and 16 were considered to have good control. Two children suffered potentially serious arrhythmogenic effects soon after the start oforal treatment and flecainide had to be stopped. During oral treatment regular blood samples were drawn and plasma concentrations were analysed to assess the therapeutic range. This did not differ substantially from that proposed in adults (400-800 Mg/l). Eight children were electively withdrawn from oral flecainide to see whether they really needed it. Blood samples for measurement offlecainide concentration were drawn after their last oral dose. Pharmacokinetic variables were calculated: time to maximum concentration 2 hours, median terminal half life 7 9 hours. For the combined data from patients receiving intravenous and oral treatment there was a significant correlation between elimination halflife and age. An intravenous dose of2 mg/kg over at least 10 minutes and an initial oral dose of 6 mg/kg/day in three divided doses is recommended. Treatment should be started in hospital so that children in whom the drug may be arrhythmogenic can be identified and plasma concentrations measured to identify patients in whom lack of efficacy is caused by underdosage.Flecainide is a new class lc antiarrhythmic drug that has recently been introduced into paediatric practice. It acts on the fast sodium channel. It slows conduction throughout the conduction system and has its greatest effect on the His bundle. The refractory period of most tissues is only slightly prolonged except that ofaccessory pathways, where this effect is more pronounced.' In adults flecainide was highly

Plasma erythropoietin (erythropoiesis stimulating factor(s), ESF), PCV and body weight were measured in normal mice from birth until the age of 70 d. Low but detectable ESF activity was present at birth, following by undetectable levels 12-48 h after birth. Thereafter the ESF level rapidly increased. Peak levels were obtained 15-20 d after birth. During the same phase an increased growth velocity occurred, coincident with decreased PCV levels. A fall to undetectable levels in plasma ESF activity coincided with decelleration of growth 40-50 d after birth. In small litters (four pups per litter) growth velocity and PCV levels were significantly higher than in large litters (16 pups per litter) 8 and 15 d after birth. The plasma ESF activity, however, did not differ between the two groups. Prohibiting suckling for a period of 16 h did not change the plasma ESF level. The hypothesis is put forward that growth directly or indirectly stimulates ESF production.