[Is therapeutic drug monitoring (TDM) in paediatric patients necessary?]. / Czy konieczne jest prowadzenie u dzieci terapii monitorowanej stezeniem leku we krwi (TML)?

There is increasing discussion about the clinical usefulness of routine TDM of selected drugs in paediatrics. Routine TDM is performed as a way to individualize dosing requirements so as to achieve "therapeutic" concentrations in all patients, independently of age and individual drug response. The therapeutic ranges established for most drugs are based upon studies performed in adults. Extrapolation of these ranges to paediatric patients, especially to neonates, is questionable because drugs disposition and pharmacodynamics differ in this population compared to adults. The scepticism of the value of routine TDM in paediatric patients concerns antiepileptic drugs and digoxin. Recently also the value of vancomycin TDM in neonates has been the subject of discussion, resulting in new recommendation for dosing schedule in this age group. Therapeutic monitoring of methotrexate, especially administered in high doses in anticancer therapy is not questioned. Aminoglycosides have an extremely important role in paediatric antimicrobial therapy. They are still frequently used in the neonatal period. The rationale for monitoring of aminoglycosides is a narrow therapeutic range resulting in risk of oto- and nephrotoxicity, and large inter- and intra-subject variation in pharmacokinetics. Routine TDM is not recommended for paediatric patients (other than neonates) with normal renal function and without chronic illnesses associated with changes in pharmacokinetics of aminoglycosides. In these patients the peak and trough concentrations are within the therapeutic range using standard dosing regimes. Therapeutic monitoring of aminoglycosides is still obligatory in neonates, especially in premature and low birthweight neonates because of particularly wide inter-patient and intra-patient pharmacokinetic variability and risk of oto- and nephrotoxicity.

[Pharmacokinetic and therapeutic monitoring of gentamicin serum concentration in neonates]. / Badania nad farmakokinetyka I terapia monitorowana stezeniem gentamycyny we krwi u noworodków.

Pharmacokinetic analysis of gentamicin in 355 neonates hospitalized in the Clinical Dept. of Neonatology of the National Institute of Mother and Child in Warsaw was performed. The patients' group consisted of 119 premature and 236 full-term neonates, who were receiving gentamicin i.v. in the mean doses 4.461 +/- 0.921 ing/kg and 4.706 +/- 0.676 mg/kg, respectively. With use of the non-compartmental method, the following pharmacokinetic parameters were measured: biological half-life (t 0.5), elimination rate constant (k el), area under the curve (AUC), volume of distribution (V d) and total clearance (C T). Results differ considerably in term and preterm neonates and amount to: 11.25+/- 3.40 h-1, 0.0673 +/- 0.02 h-1, 233.7+/- 95.44 ug h/ml, 1.22 +/- 0.79 l/kg, 0.086 +/- 0.077 l/h/kg - for premature neonates versus 8.19 +/- 2.58 h, 0.089 +/- 0.02 h-1, 157.5 +/- 60.2 ug h/ml, 0.637 +/- 0.316 l/kg, 0.060 +/- 0.042 l/h/kg for full- term neonates. The analysis of pharmacokinetic parameters suggests that these findings may be already used as a preliminary basis of gentamicin population pharmacokinetics in both groups of neonates. The obtained results confirm that monitoring of gentamicin serum concentration helps to improve the treatment of neonates with this antibiotic. It was also found that the use of the dosing schedule of gentamicin with the dose intervals 36 or 48 h should guarantee adequate Cmax and Cmin without the need of routine monitoring of each patient in the premature neonate group.

[Preliminary evaluation of individualized use of large doses of methotrexate for treatment of osteosarcoma in children and adolescents]. / Wstepna ocena zastosowania indywidualizowanych duzych dawek metotreksatu w leczeniu miesaka kosciopochodnego u dzieci i mlodziezy.

To improve the final treatment results in children with osteosarcoma, we applied after French DD-11 protocol HD MTX increasing with the younger age of patients, modified next on the basis of maximal serum drug concentrations (Cmax) as feed-back dosing. Toxic side effects were analysed according to WHO grading correlated with MTX elimination. We administered 39 HD MTX courses in 13 patients with osteosarcoma: aged 7-20 yrs (median 12 yrs). We performed 301 measurements of MTX concentration using the method of fluorescence polarisation. Therapeutic Cmax of 1000 microM/L and higher were obtained in 20 courses, the mean of lower values was 770 microM/L. We modified the next MTX doses in 23.7% of courses. Drug elimination was good in the majority of cases: in 34 of 39 courses at 24 hrs, in 36 of 39 at 48 hrs. Nevertheless, III and IV degree toxic side-effects accompanied about half of the courses and could not be predicted by MTX serum level measurements. HD MTX therapy with monitoring MTX serum levels proved feasible with acceptable toxicity. Therapeutic MTX levels were obtained in about 60% of cycles in patients with a favourable course of the disease in comparison with 25% in patients with an unfavorable course but the beneficial effect of age-tailored MTX and feed-back dosing on the treatment results will be possible to assess in the next 3 years.

[The effect of fenoterol (partusisten) on cAMP and cGMP concentrations, acetylcholine esterase and choline acetyltransferase activities in rat placenta]. / Wplyw podawania fenoterolu (partusisten) na stezenie cAMP i cGMP, aktywnosci acetylotransferazy cholinowej i esterazy acetylocholinowej w lozysku szczura.

Several observations indicate a possible role of the placental cholinergic system in the modulation and maintenance of placental function and subsequently fetal growth and development. We have investigated the effect of Partusisten (1 mg/kg p.o., twice daily, since the 15th to the 20th day of gestation) on cAMP and cGMP concentrations, acetylcholine esterase and choline acetyltransferase activities in rat placenta. The obtained results show that Partusisten increased cAMP concentration and decreased cGMP concentration (see Tab. 1; Fig. 1, 2). Choline acetyltransferase activity was elevated (Tab. 2; Fig. 3) whereas Partusisten had no effect on acetylcholine esterase activity (see Tab. 2; Fig. 4). The results indicate disorders in placental cholinergic system after chronic Partusisten administration to pregnant rats. On the other hand, the marked increase in choline acetyltransferase activity suggested the high adaptability of placenta.

[Diurnal fluctuations in plasma carbamazepine level in children with epilepsy]. / Dobowe wahania poziomów karbamazepiny w osoczu u dzieci z padaczka.

After determination of carbamazepine level in plasma by means of gas chromatography 23 profiles of 24-hour concentrations were plotted in children aged from 20 months to 15 years treated for epilepsy. In 12 of them monotherapy was given (Amizepin-Polfa in a mean daily dose of 18.7 mg/kg) while polytherapy was given to 11 children (mean daily dose was 21.1 mg/kg). Considerable fluctuations of the level of the drug were found in the plasma over 24 hours in various children, and individual differences after the administration of carbamazepine alone or with other drugs. The 24-hour fluctuations of total carbamazepine in the plasma and individual differences are due, probably, to pharmacokinetic factors due to physiological differences between patients and were correlated more to the age of the child than to the administered dose.

[Carbamazepine dosage and its blood serum level in children]. / Dawkowanie karbamazepiny a jej poziom w surowicy krwi u dzieci.

Evaluating in 62 children aged from 4 months to 14 years (mean age 3 years 7 months) the correlation between the carbamazepine dosage (carbamazepine was given as the only drug in 21 cases, and as one of several drugs in 41) the authors failed to find a simple correlation. Nevertheless, most children receiving the "proper" doses had therapeutic plasma carbamazepine levels. Moreover, it was found that carbamazepine dose increase over 25 mg/kg daily caused on further rise of its plasma level.

[Pharmacokinetics of 6-mercaptopurine in rats during postnatal development]. / Farmakokinetyka 6-merkaptopuryny u szczurów w czasie rozwoju osobniczego.

It was shown that 6-MP pharmacokinetics in rats was age-dependent. The distribution processes were mainly influenced by age of animals. 6-MP total distribution volume (VD) increased from 26.4 ml in 2 week old animals to 60.2 ml and 55.5 ml in 4-week-old and adult rats, respectively. However, the relative volume of distribution (delta, per cent of body weight) decreased from 1019 ml/kg in 2 week old rats to 317 ml/kg in adult rats. Similar relationships between total body clearance and the age of animals were observed. One may suspect that the changes in the distribution processes are connected both with the increased extracellular water content and the changed protein binding in young animals.

[Pharmacokinetics of nitrofurantoin in the bodies of pregnant rats]. / Farmakokinetyka nitrofurantoiny (NTF) w ustroju szczurów ciezarnych.

The investigation of nitrofurantoin (NTF) pharmacokinetics in pregnant rats was undertaken to estimate its cumulation in the fetus unit. It was found that pharmacokinetics of NTF is dose-dependent in non-pregnant rats. The biological half-life time increased from 0.24 to 0.41 and 0.72 h for NTF doses 10.20 and 40 mg/kg, respectively. The elimination of NTF was diminished in pregnant rats. The pharmacokinetic analysis revealed a possibility of strong NTF accumulation in the pregnant rats (increased K12/K21 ratio). Taking into account increased renal function in pregnancy, one may suspect that decreased elimination of NTF was rather caused by its significant cumulation in the changed tissue compartment.

[Serotonin concentration in the rat fetal brain in experimental intrauterine dystrophy]. / Stezenie serotoniny w mózgu plodów szczura w doswiadczalnie wywolanej dystrofii wewnatrzmacicznej.

The concentration of serotonin (5-hydroxytryptamine, 5-HT) was determined in the brain of fetal rats with experimental intrauterine growth retardation (IUGR). IUGR was induced using the procedure of Wigglesworth. On the 17th day of gestation, the uterine artery supplying one uterine horn was ligated. The artery of the opposite uterine horn was left untouched (control). On the 22nd day the fetuses were delivered by C-section. 5-HT was determined by fluorometric method. Statistical analysis employed the paired Student t-test. The average body weight of the IUGR fetuses was 3.15 g, whereas control fetuses 4,50 g. The mean concentration of 5-HT was 10,4% lower in IUGR fetal brains. The mean 5-HT brain concentration in IUGR was 155 micrograms/g of tissue, whereas in control the mean concentration was 173 micrograms/g of tissue. The difference between these brain concentrations was significant (p less than 0,005). We conclude that reduction in maternofetal blood flow in the 3rd trimester of gestation results in decreased concentration in the brain of 5-HT.

Experimental and clinical pharmacokinetics of nitrofurantoin in the early period of life.

The investigation of pharmacokinetics showed age-dependent rate of nitrofurantoin elimination in rats. Nitrofurantoin half-life of 0.41 hr in adults was prolonged to 0.95 hr in 2-weeks-old rats. Nitrofurantoin excretion rate was decreased in children younger than 2 years. Older children excreted in urine 44.32 +/- 16.07 and younger 25.07 +/- 5.7 per cent of the given dose of nitrofurantoin, indicating the lower capacity for nitrofurantoin elimination via kidneys.

[The effect of biseptol and sodium salicylate administration on the concentration of serotonin and histamine and mono- and diamine oxidase activities in rat placenta]. / Wplyw podawania biseptolu i salicylanu sodu na stezenie serotoniny i histaminy oraz na aktywnosc oksydazy monoaminowej i dwuaminowej w lozysku szczura.

It is known that two biogenic amines:serotonin and histamine, as well as the enzymes connected with their metabolism (mono- and diamine oxidase), play very important role in human and animal fetal development. We have investigated the effect of Biseptol and sodium salicylate administered to pregnant rats on the concentrations of serotonin and histamine and activities of the above mentioned enzymes in placenta. The obtained results showed that the administration of Biseptol has no influence on the serotonin concentration, whereas the administration of sodium salicylate caused slight increase of serotonin concentration in rat placenta. The activity of monoamine oxidase was elevated after administration of both drugs (Tabl. I, Fig. 1). The administration of Biseptol decreased the histamine concentration and caused the marked increase of DAO activity. The sodium salicylate administration to the pregnant rats didn't influence on the histamine concentration, whereas it caused parallel twofold increase of DAO activity (Tabl. II, Fig. 2).

[Serotonin concentration in the placentas in experimental intrauterine growth retardation]. / Stezenie serotoniny w lozyskach w doswiadczalnie wywolanej dystrofii wewnatrzmacicznej.

A number of investigators have shown that 5-hydroxytryptamine (5-HT) administration to pregnant animals produces changes in the placenta and leads to death of the fetuses. It has been well known that 5-HT is the most potent umbilical-placental vasoconstrictor and that its administration affects the nutritional function of the placenta. In view of these results it seemed desirable to determine 5-HT concentration in the placenta in experimental intrauterine growth retardation. IUGR was induced on the 17th day of gestation in pregnant rats by ligating the uterine artery of one horn as described by Wigglesworth with the opposite horn left untouched (control). On day 22, fetuses were delivered by C-section. 5-HT was determined by a fluorometric method. Statistical analysis employed the paired Student t-test. Average weight of IUGR fetuses was 3,05 g, whereas control fetuses 4,48. The mean concentration of 5-HT was 11% higher in IUGR fetal placentas. The mean placental concentration in IUGR was 247 micrograms/g of tissue, whereas in control the mean concentration was 222 micrograms/g of tissue. The difference between these placental concentrations was significant (p less than 0,01). We conclude that decreased blood supply to the pregnant rat uterus results in increased concentration in the placenta of 5-HT.

Effect of prolonged acetylcholinesterase inhibition on postnatal brain development in rabbit. I. Level of serotonin in different brain regions.

Studies were performed on young rabbits treated with dichlorvos (organophosphorus pesticide) 9 mg/kg/day by oral gavage. Pesticide was given for 10 days starting on the 6th day of life or as a single dose on the 16th day of life. Animals were sacrificed 30 min, 3 und 24 h after treatment. The spinal cord and the brain were removed and 6 regions (neocortex, hippocampus, basal ganglia, mesencephalon, brain stem, cerebellum) were isolated. Acethylcholinesterase activity was estimated by biochemical and histochemical methods. The concentration of serotonin in brain regions was determined. Acute and prolonged intoxication with dichlorvos inhibited acethylcholinesterase activity. As revealed the histochemical studies, single dose decreased activity of enzyme mainly in neuropil. Prolonged intoxication decreased the acethylcholinesterase in neuropil and in neurons. The single dose of dichlorvos caused the increase of serotonin concentration in all brain regions. After prolonged intoxication the decrease of serotonin concentration in brain stem, mesencephalon and hippocampus for 78, 74, 41% respectively was observed. The cholinergic-serotonergic link is discussed.