METHOTREXATE IN THE PLASMA AND CEREBROSPINAL FLUID OF CHILDREN TREATED WITH INTERMEDIATE DOSE METHOTREXATE

ABSTRACT. Rechnitzer, C, Scheibel, E. and Hendel, J. (University Clinic of Paediatrics, Rigshospitalet and Department of Clinical Chemistry, Finsen Institute, Copenhagen, Denmark). Methotrexate in the plasma and cerebrospinal fluid of children treated with intermediate dose methotrexate. Acta Paediatr Scand, 70:615,.–Serious complications can follow treatment with intermediate dose methotrexate of acute lymphoblastic leukemia in childhood. Toxicity has been shown to be correlated to plasma methotrexate concentrations. During intravenous infusions of methotrexate (500 mg/m²) the mean concentrations achieved 1 to 4¹/₂ hours after the start of infusion were 1.3×10^-7 mol/l in cerebrospinal fluid and 1.7×10^-5 mol/1 in plasma. At 72 hours after start of methotrexate infusion, plasma methotrexate concentrations were significantly higher in cases with symptoms of toxicity. In all the children who developed toxic symptoms 72-hour plasma methotrexate concentration was above 1×10^-7 mol/l. Assuming that leucovorin is given 48 hours after the start of methotrexate infusion, 72-hour plasma methotrexate is suitable for detection of patients at risk for toxicity. In children treated with intermediate dose methotrexate we therefore recommend estimating plasma methotrexate concentration 72 hours after the start of infusion, and instituting supplementary leucovorin when plasma methotrexate concentration exceeds 1×10^-7 mol/l.     

Inconsistent absorption from a sustained-release theophylline preparation during continuous therapy in asthmatic children

During routine monitoring of hospitalized children with asthma receiving a sustained-release theophylline formulation, we frequently observe unpredictable fluctuations in serum theophylline concentration (STC). We evaluated eight asthmatic patients (ages 4 to 17 years) with inconsistent STCs to determine the cause of this phenomenon. Only minimal variation in STC and therefore theophylline clearance was noted during a 24-hour period of continuous intravenous aminophylline infusion. However, marked variability in STC was observed when measured every 2 hours for 48 hours after 6 days of continuous therapy orally. In addition, the time required to reach peak and trough STCs varied from dose to dose. Inasmuch as clearance was shown to be constant, the variability was attributed to inconsistent theophylline absorption. Unpredictable fluctuations of STC secondary to variable absorption from this sustained-release theophylline preparation may occur in certain patients. Appreciation of this potential variability is necessary for the proper interpretation of STC measurements and subsequent dosage adjustment.     

Comparison of New Sustained-Release Theophylline (E-0686) and Theo-Dur

New sustained-release theophylline (E-0686) was administered to asthmatic children to study changes in serum theophylline level and its reproducibility. Results are as follows:

• 1) t-Max. of E-0686 was shorter than that of Theo-Dur, however, E-0686 could maintain a satisfactory serum theophylline level at 12 hours on a single dose.
• 2) A steady state was reached after three days on a multiple dose of E-0686. P-T difference of E-06 was 5.17 μg/ml, which could be sufficient for sustained-release theophylline.
• 3) Changes in serum theophylline level of E-0686 was highly reproducible.

     

SERUM CONCENTRATIONS OF THEOPHYLLINE IN CHILDREN FOLLOWING THE ADMINISTRATION OF DOSES GENERALLY RECOMMENDED:NEW DOSAGE REGIMEN REQUIRED

Abstract. Serum concentrations of theophylline following intravenous and oral administration of aminophylline were studied in asthmatic children, 2–17 years of age. The biological half-life (β) of theophylline varied between 165 and 495 min. The results revealed that an intravenous loading dose of 6 mg of aminophylline per kg body weight was necessary in order to obtain therapeutic concentrations in children who had not received the drug for the last 6 to 8 hours. The maintenance dose should be determined and controlled by use of serum concentration determinations. In a group of children receiving 5 mg of aminophylline per kg body weight 3 times a day orally, none had concentrations within the therapeutic range in the morning, and only 39% reached therapeutic levels 2 h after the morning dose. No correlation was found between the serum concentration of theophylline and the amount of drug given per kg body weight. The results show that theophylline concentration analysis is necessary to obtain adequate therapeutic levels in children without risking toxic effects.     

Absorption characteristics of once-a-day slow-release theophylline preparation in children with asthma

The single- and multiple-dose absorption characteristics of a new sustained-release theophylline preparation, which has been formulated for once per day dosing in adults, were investigated in children aged 8 to 14 years. Four single doses were studied, each dose separated by 1 week. During steady state the preparation was given once daily in the morning for 1 week, and serum theophylline concentration was determined through two dosing intervals (48 hours). The product showed excellent sustained-release characteristics and consistent absorption profiles, which were not affected to any clinically important extent by the intake of various meals. After single doses, only 77% to 91% of the product was absorbed during the first 28 hours after dosing. However, bioavailability was complete both after single doses and during steady state. Eight of 14 children had steady-state fluctuations in serum theophylline levels of less than 90% when given doses once daily. Steady-state day-to-day variations in serum theophylline profiles were small in all patients except one, in whom differences up to 33 mumol/L (6 micrograms/mL) were seen (8 hours after dosing). We conclude that this formulation is completely absorbed at a sufficiently slow and consistent rate to permit acceptable fluctuations in absorption with once daily dosing for many, but not all, patients. However, it should not be used in very young children until bioavailability has been studied in this age group.     

Theophylline pharmacokinetics in children,comparing sustained release spheres (Theo-Dur sprinkle) with elixir

A new sustained release theophylline preparation (Theo-Dur Sprinkle, TDS) was given b.i.d. and a theophylline elixir t.i.d. to eight children with bronchial asthma, 4–10 years of age, in an open study with a randomized cross over design. The serum concentration curves of theophylline were compared. The individual theophylline dose was close to 20 mg/kg body weight per day. On day 3 of each regimen, blood samples were taken 11 times over 24h. There were great differences between morning concentrations of theophylline, with a range from 0.9–10.7 mg/l in children given elixir, while corresponding values for children given TDS were 4.1–19.3 mg/l. Fluctuation during a dosing interval was 276% for elixir but only 54% in the case of TDS. The morning theophylline levels on two consecutive days did not differ significantly when the children were treated with TDS. The bioavailability of theophylline from TDS was 94% (range 54%–121%). Parents prefered TDS in seven of the eight cases. TDS showed satisfactory sustained release properties but the study confirmed the need for individually tailored dosage of theophylline based on monitoring of symptoms and serum concentrations.Abbreviations TDS Theo-Dur sprinkle - HPLC a liquid chromatographic method - AUC area under concentration curve - C_max maximum-theophylline concentration - C_min minimum theophylline concentration Subsidiary of AB Astra, Sweden     

ALPHA FETOPROTEIN LEVELS IN NEONATAL HYPERBILIRUBINAEMIA

Abstract. Ikonen, R. S., Lindgren, J., Niemi, E., Sorto, A. E., Seppälä, M. and Ruoslahti, E. (Department of Paediatrics, Central Hospital of Tampere; Department of Bacteriology and Immunology, University of Helsinki; Department of Paediatrics, Central Hospital of Satakunta, Pori; Department of Obstetrics and Gynecology, University Central Hospital, Helsinki, Finland and Division of Immunology, City of Hope National Medical Center, Duarte, California, USA). Alpha fetoprotein levels in neonatal hyperbilirubinaemia. Acta Paediatr Scand, 69:59, 1980.—Serum alpha fetoprotein (AFP) levels were studied in 15 neonatally hyperbilirubinaemic children and 15 controls matched for sex and gestational age. All children were born between 38 and 40 weeks of gestation. During the first seven weeks of postnatal life hyperbilirubinaemic children had serum AFP concentrations over twice as high as controls. At the age of 5–7 days the mean (± S.E.M.) serum AFP values were 52.4.i-5.8 mg/I for hyperbilirubinaemic children and 24.8 ± 4.3 mg/l for controls ( p < 0.001). At 20–25 days of age they were 7.28 ± 1.10 and 2.75 ± 0.45 mg/I, respectively ( p < 0.001), and at 40–49 days 1.39 ± 0.21 and 0.46 ± 0.07 mg/l ( p < 0.001). However, no correlation was found between serum bilirubin and AFP concentrations in hyperbilirubinaemic children     

Theophylline absorption in young asthmatic children receiving sustained-release formulations

Theophylline absorption from sustained-release formulations intended for administration every 8 hours and every 12 hours was examined in children ages 2 to 6 years during multiple dosing intervals. By generally applied measurements, including mean serum theophylline concentration, bioavailability over a single daytime dosing interval, and percent change in serum theophylline concentration over a single dosing interval, the preparations did not differ. However, over multiple dosing intervals, the 8-hour preparation varied in rate and extent of absorption, with subsequent large variations in serum theophylline concentrations. The 12-hour preparation, on the other hand, was completely bioavailable during each dosing interval, although the rate of absorption did differ from day to night, and was associated with generally acceptable changes in serum concentrations. Thus, analysis of dose-to-dose absorption was required to reveal the differences between the two study preparations. This indicates that traditional analysis of a single daytime dosing interval may be inadequate in the evaluation of preparations of sustained-release theophylline.     

COPPER DEFICIENCY AND HYPOCALCEMIC RICKETS IN A SMALL-FOR-DATE INFANT

ABSTRACT. A case of copper deficiency associated with hypocalcemia, radiological features of rickets and hyperparathyroidism is described in a small-for-date infant (gestational age 39 weeks, B.W. 1240 g). Neonatal serum copper (Cu) levels were found between 223 and 138 μmol/l. She was given daily 2 400 U of vitamin D₂ and a load dose of 80 000 IU at the age of 55 days. At the age of 79 days, X-rays of the legs and wrist showed spread, cupped and frayed metaphyses. Serum Ca was 1.35 mmol/1, P=0.99 mmol/1 with high alkaline phosphatases (A.P.) 590 II/ml. But plasma level of 25 hydroxycholecalciferol (25-OH-CC) was normal = 10.8 ng/ml. Serum Cu was low=3.14 μmol/l and serum immunoreactive parathormone (iPTH) level was elevated: 520 μlEq/ml (N±100). Administration of vitamin D₂ (15 mg) induced an immediate normalization of serum Ca, normal serum iPTH (68 μlEq/ml) in one month, normal X-rays in two months and normal A.P. in four months. Serum Cu and ceruloplasmin levels increased slowly without any supplementation to subnormal levels at the age of eight months (14.9 and 1.65 μmol/1. Serum Cu concentrations were found to be normal (16.0–33.7 μmol/1) in five children with hypocalcemic rickets. These results suggest a role of Cu deficiency in the occurrence of this transient vitamin D-resistant rickets.     

Adrenal Function in Asthmatic Children Treated with Inhaled Budesonide

Bisgaard, H., Pedersen S., Damkjær Nielsen M and Østerballe O. (Department of Paediatrics, University Hospital of Copenhagen, County of Gentofte, Copenhagen; Department of Paediatrics, County Hospital of Kolding; Department of Clinical Physiology, University Hospital of Copenhagen, County of Glostrup, Copenhagen; Department of Paediatrics, County Hospital of Viborg, Denmark). Adrenal function in asthmatic children treated with inhaled budesonide. Acta Paediatr Scand 80: 213, 1991
The effect of the inhaled topical steroid budesonide on adrenal function was evaluated in 33 children (aged 7–15 years) with moderate bronchial asthma. The trial was designed as a prospective single-blind study of the effect of budesonide in daily doses of 200 μg through 400 μg to 800 μg in three randomized consecutive periods of 8 weeks. The unstimulated diurnal production of cortisol was assessed by measurement of free cortisol in 24-hour urine samples at the end of each period. No significant dose-related suppression was found. The cortisol production did not differ significantly during treatment with 800 μg budesonide as compared to treatment with 200 μg budesonide (95% confidence interval: 74%–112%). It is concluded, that budesonide is a topical steroid with a favourable ratio between topical and systemic effects in asthmatic children.     

Initial experiences with "Oranienburg" slow-release theophylline in asthma therapy of children and adolescents

Experiences in 50 patients show that Theophyllin retard Oranienburg (280 mg theophylline) could be used as an effective bronchospasmolytic drug on conditions of mono- and combination-therapy. Advantages of this preparation are improvement of the compliance and an undisturbed night-sleep in patients. However an optimum dosage is hardly maintained in children by the present dose of a single tablet of 280 theophylline content. The effectiveness in therapy of childhood asthma could be improved by stronger sustained release effect and different doses of tablets.     

Lactate and pyruvate concentrations in capillary blood from newborns

Using high pressure liquid chromatography on strong cation exchange column, we analyzed capillary blood from 141 healthy full-term newborns for lactate and pyruvate concentrations. Total range of lactate was 367–3245 μmol/l and reference interval (mean ± 2 SD) was 260–2212 μmol/l. Total range of pyruvate was 10–141 μmol/l and reference interval (10th/90th percentile) was 12–71μmol/l.     

THE EFFECT OF DIETARY γ-TOCOPHEROL ON SERUM TOCOPHEROLS IN FORMULA-FED INFANTS

ABSTRACT. Jansson, L., Holmberg, L. and Jakobsson, I. (Department of Paediatrics, University of Lund, Malmö General Hospital, Malmö, Sweden). The effect of dietary γ-tocopherol on serum tocopherols in formula-fed infants. Acta Paediatr Scand, 70:297, 1981.–The levels of α-, β- and γ-tocopherol were determined in two formulas (Nutramigen± and Soja-semp±) and in 20 infants fed either of these formulas. The y-tocopherol concentration in Nutramigen was 22.8±1.9 µmol/l; and that in Soja-semp 3.7±0.5 µmol/l. This difference was reflected in the serum tocopherols of the infants, since in the 10 infants fed Nutramigen, γ-tocopherol accounted for 16.7 ± 7.9% of the total tocopherols compared to 4.2±1.8% in the 10 infants fed Soja-semp. The study shows that γ-tocopherol accumulates in the serum of infants fed large amounts of it. The serum γ-tocopherol level should therefore be taken into account, when estimating the vitamin E status in humans, especially when the intake of γ-tocopherol is high.     

PROMOTION OF BREAST FEEDING: EFFECT ON NEONATES OF CHANGE OF FEEDING ROUTINE AT A MATERNITY UNIT

Abstract. Verronen, P., Visakorpi, J. K., Lammi, A., Saarikoski, S. and Tamminen, T. (Department of Clinical Sciences, University of Tampere, and Department of Obstetrics and Gynaecology, Central Hospital of Tampere, Finland). Promotion of breast feeding: effect on neonates of change in feeding routine at a maternity unit. Acta Paediatr Scand, 69: 279, 1980.—The effect on the health of neonates of a change in neonatal routine care, including general rooming-in, breast feeding on demand and avoidance of supplementary bottle feedings was studied in conjunction to a breast feeding campaign at a maternity unit. There was an accentuated weight loss in the neonatal period during ad libitum breast feeding. The mean serum bilirubin of clinically jaundiced infants was slightly higher on a 4-hourly feeding schedule with supplementary bottles than on the new regimen. There was a similar high (32–33%) incidence of bilirubin levels >205 µmol/l (12 mg/100 ml) in both groups. The incidence of spontaneous hypoglycaemia did not differ in the two groups. The new feeding regimen was thus considered safe. Infants at risk for hypoglycaemia were given supplementary bottles and were excluded from the study     

Low-dose theophylline in childhood asthma: a placebo-controlled, double-blind study

Regular anti-inflammatory treatment is essential in treating persistent asthma. Most commonly, inhaled corticosteroids (ICS) are used. However, especially in children, there is concern about the long-term safety of ICS such that doses should be kept to a minimum. The use of theophylline has decreased because of frequent side-effects in therapeutic doses. In adults, there have been reports about an immunomodulatory effect of low-dose theophylline. To study the clinical and immunomodulatory effect in children, 36 patients (mean age 12.5 SD 2.4 years) with moderate, persistent asthma on regular ICS were recruited into a placebo-controlled, double-blind study. After a 6-week run-in period, patients received either theophylline 10 mg/kg bodyweight or placebo for 12 weeks. Diary cards, lung function, peripheral blood lymphocyte subpopulations and serum eosinophil cationic protein (sECP) were assessed. In the treatment group, mean serum theophylline was 7.1 mg/l. There was no change in symptoms or use of rescue medication. Mean (SD) peak expiratory flow (PEF) increased from 86% (24) to 95% (18) predicted. sECP decreased from 43.2 μg/l (32.5) to 26.5 μg/l (16.9) (p = 0.02). Lymphocyte subpopulations did not change. The study failed to show a beneficial clinical or an immunomodulatory effect of theophylline when used in low doses. These results do not support a more important role of theophylline in the long-term treatment of moderate childhood asthma.     

ESTIMATION OF FREE THYROXINE INDEX IN THE NEWBORN USING MICRO-METHODS

Abstract. Rogowski, P., Siersbæk-Nielsen, K. and Mølholm Hansen, J. (Medical Department E, the Obstetrical Department, and the Department of Clinical Chemistry, Frederiksberg Hospital, Copenhagen, Denmark). Estimation of free thyroxine index in the newborn using micro-methods. Acta Paediat Scand, 63: 201, 1974.–Thyroid function in the newborn has been studied with the purpose of establishing normal values for total plasma thyroxine, T-3 test and free thyroxine index in the neonatal period using new micro-methods. Total thyroxine determinations were carried out using the Sephadex column method (Tetralute®) which requires 25 to 50 µ1 plasma. The unbound TBG binding sites were evaluatid using a T-3 Sephadex retention test (Trilute®) requiring 50 μl plasma. Free thyroxine index were calculated as the product of the two tests. 202 fullterm newborns were examined in the period 19 to 71 hours after birth and the normal range (95 % limits) for plasma thyroxine were found to be 9.2–26.0 μg/100 ml. Normal values for the T-3 test varied between 42.5 and 64.9 % and free thyroxine index values between 510–1378 arbitrary units. The mean values of total thyroxine, T-3 test and free thyroxine index were found to be significantly increased compared with cord blood and adult mean values indicating a physiological thyroid hyperfunction in the neonatal period. The new thyroid function tests used in the present study were found to be technical simple and are suggested to be used whenever thyroid diseases in the newborn are suspected.     

Iodine status in neonates in Denmark: regional variations and dependency on maternal iodine supplementation

Nøhr SB, Laurberg P, Børlum K-G, Pedersen KM, Johannesen PL, Damm P, Fuglsang E, Johansen A. Iodine status of neonates in Denmark: regional variations and dependency on maternal iodine supplementation. Acta Pàdiatr 1994;83:578–82. Stockholm. ISSN 0803–5253
Iodine status of 147 neonates born in five different regions of Denmark was evaluated in relation to the iodine content of breast milk and iodine supplementation taken by the mother. Approximatcly two-thirds of the women had not received iodine supplementation. They had low iodine concentrations in breast milk and urinary iodine concentrations of the neonates at day 5 were low. The median values (milk/urine) were 33.6/31.7 μ/l (Randers 22/26, Ringkøbing 29/16, Aalborg 36/31, Århus 54/41 and Copenhagen 55/59 μg/l). Higher values were found in the group where tablets containing iodine had been taken (milk/urine: 57.0/61.0 μ/1). In general, the values are low compared with internationally recommended levels. We suggest that mothers without autoimmune thyroid disease should receive iodine supplementation in the form of vitamin/mineral tablets containing iodine (150 μg per tablet).     

Increased lipid peroxidation in children with autoimmune diseases

To examine the role of oxidative damage in children and adolescents with autoimmune diseases, we compared blood serum levels of the lipid peroxidation (LPO) products 4-hydroxynonenal (HNE) and malondialdehyde (MDA) in 22 children with systemic lupus erythematosus (SLE), 13 children with focal type of scleroderma, and 21 healthy controls. In order to study the influence of disease activity in SLE on serum LPO product levels, the SLE group was divided into one group with active disease ( n = 11) and one group with non-active disease ( n = 11) according to SLEDAI-score, 15.1 and 1.8, respectively. SLE patients with active SLE (146 ± 14nmol/l, median 145nmol/l) have significantly higher HNE levels compared to controls (61 ± 10nmol/l, median 52nmol/l), whereas the MDA serum levels are similar to those of the control group, 1.94 ± 0.18μmol/l (median: 2.02μmol/l) and 1.58 ± 0.11 μmol/1 (median: 1.52 μmol/l), respectively. Children with SCL had HNE and MDA levels similar to the control group.     

Clinical Experience with Genotropin Worldwide: An Update March 1987

Gunnarsson, R., and Wilton, P. (Medical Department, KabiVitrum Peptide Hormones, Stockholm, Sweden). Clinical experience with Genotropin worldwide: an update March 1987. Acta Paediatr Scand [Suppl] 337:147, 1987.
The efficacy and safety of Genotropin (recombinant somatropin, KabiVitrum AB, Sweden) was analysed in 199 children with hGH deficiency, comprising a combined series of four current multicentre trials. Stimulation of linear growth from pretreatment height velocities of 3–4 cm/year to about 10 cm/year was observed after 6 and 9 months of treatment. Statistical analysis revealed significantly greater height velocities (by 2–3 cm/year) when the weekly dose of the hormone was given in 6–7 injections rather than in 3 injections. Immunogenicity seems to be very low, with only about 2% of the children having detectable antibodies during treatment.     

PLACENTAL TRANSFER OF MATERNAL ANTI-RABBIT IgG CAUSING FALSELY ELEVATED TSH LEVELS IN NEONATES

Abstract. Larsson, A., Hedenborg, G. and Carlström, A. (Department of Paediatrics, Karolinska Institute, St. Göran's Children's Hospital, and the PKU Section, Department of Bacteriology, National Bacteriological Laboratory, Stockholm, and the Department of Clinical Chemistry, Karolinska Institute, Danderyd's Hospital, Danderyd, Sweden). Placental transfer of maternal anti-rabbit IgG causing falsely elevated TSH levels in neonates. Acta Paediatr Scand, 70:699,.–Two infants were found to have markedly increased TSH levels, 104 and 154 mU/l of plasma, respectively, in a routine screening programme for congenital hypothyroidism. The recall limit used was 50 mU/l of plasma. On follow-up, both infants were clinically euthyroid and had normal serum T₄ and T₃. The elevated TSH levels were confirmed only with some commercial radioimmunoassay kits–but not with others. Similar results were obtained in TSH assays of samples from their mothers, who had no other biochemical or clinical evidence of thyroid dysfunction. Both mothers had intense contact with rabbits over long periods. The apparent TSH activity was found to be associated with the IgG fraction. It was neutralized by the addition of normal rabbit serum to the samples and was caused by antibodies to rabbit immunoglobulin. The activity was eliminated from the circulation of both infants with a half-life of approximately one month. Apparently, the heterophilic antibodies were of maternal origin and were transferred to the foetus via the placenta. Infants with so-called transient hyperthyrotropinaemia identified in screening programmes have to be reevaluated to exclude false TSH elevations of this type.