[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.

[Are the cytostatic drugs and their metabolites, excreted by patients during chemotherapy, hazardous for the family environment?]. / Czy leki cytostatyczne i ich metabolity, wydalane przez pacjentów poddawanych chemioterapii, stanowia zagrozenie dla srodowiska rodzinnego?

In recent years the problem concerning adverse effects of excreted drugs and their active metabolites on other people and the environment has been found to be an important aspect of clinical pharmacology and environmental health. It is commonly known that antineoplastic drugs are hazardous to medical personnel who handle them, but cytostatics administered during ambulatory care are always transferred via the patient's organism to his home and hypothetically generate potential risk to other family members. The patient s home is a sub-set of the family environment where genetically determined predisposition to neoplastic disease could additionally appear. This could intensify the effect of exogenous factors responsible for carcinogenesis (e.g. cytostatics), and increase late consequences (e.g. mutations). To assess the risk the authors elaborated an algorithm for hazard identification and assessment of consequences of the hazard. Preliminary results indicated passage a/significant amounts of excreted cytostatics and their metabolites to the natural, hospital and also family environment. After excretion, mutagenic properties of these drugs were still observed. Chemical inactivation of the excreta of patients on chemotherapy completely eliminates or strongly reduces their mutagenicity. At the present time it is difficult to assess the total risk level of cytostalic drugs and their metabolites excreted by patients on chemotherapy, for their home environment. Risk identification based on dose-response and exposure assessment, will allow to determine the health, social and economic hazards and to establish standards of procedures with regard to the risk factor.

[Pharmacokinetics of methotrexate and therapeutic drug monitoring in children with osteosarcoma. Computer simulation using a pharmacokinetic model]. / Farmakokinetyka metotreksatu a monitorowanie terapii stezeniem leku u dzieci z miesakiem kosciopochodnym. Symulacja komputerowa z zastosowaniem modelu farmakokinetycznego.

The pharmacokinetics of methotrexate (MTX) and the therapeutic drug monitoring (TDM) in children treated-with high-dose of MTX (HD MTX) have been discussed. The pharmacokinetics of MTX was studied in 15 children (54 courses) with osteosarcoma, treated with HD MTX (8, 10 and 12 g/m2; 4 h i.v. infusion). Pharmacokinetic analysis was performed by standard non-compartmental methods and using two-compartment nonlinear model with coexistence of additional, parallel linear route of elimination from the central compartment. This proposed model can be used for computer simulation and prognosis of the serum-level curve course depending on the simulated dosage, enhanced diuresis and simulated kidney or liver insufficiency during the dose individualisation. The usage of the pharmacokinetic model for computer simulations may improve the understanding of MTX kinetics and can optimalise dosage regimens for the next cycles of chemotherapy.

[Monitoring high dose methotrexate therapy (HD MTX) in children with osteosarcoma and computer simulation using a pharmacokinetic model]. / Monitorowanie terapii wysokimi dawkami metotreksatu (HD MTX) u dzieci z miesakiem kosciopochodnym a symulacja komputerowa z zastosowaniem modelu farmakokinetycznego.

The pharmacokinetics of methotrexate (MTX) was studied in 15 children with osteosarcoma, treated (54 courses) with high-dose methotrexate (8, 10 i 12 g/m2; 4 h i.v. infusion). Pharmacokinetic analysis was performed by standard non-compartmental methods and using two-compartment nonlinear model with coexistence of additional, parallel linear route of elimination from central compartment. The model was used for computer simulation and prognosis of the serum-level curve course depending on the simulated dosage, enhanced diuresis and simulated kidney or liver insufficiency during the dose individualization. The usage of the pharmacokinetic model for computer simulations may improve understanding of the MTX kinetics and can optimise dosage regimens for the next cycles of chemotherapy.

[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.

[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.

[45Ca2+ uptake by rat thymocytes in the presence of blood serum of patients with cystic fibrosis]. / Wychwytywanie 45CA2+ przez tymocyty szczura w obecnosci surowicy krwichorych na zwlóknienie torbielowate (CF).

The results of examination of 45Ca2+ (uptake by freshly prepared) thymocytes from rat in the presence of blood serum from CF patients and healthy persons as differentiating agent are presented. The presence of the factor responsible for enhanced Ca uptake in the blood serum of CF patients was found in our experimental system. That factor was absent in the blood serum of rats chronically treated with reserpine. This is in agreement with previous findings that this factor was related to the basic genetic defect in CF(6). Very efficient influx of 45Ca2+ into the rat thymocytes (up to 6,2%) being accompanied by increased calcium uptake in the presence of serum factor of CF patients in comparison with control serum of healthy persons should be underlined.

[Effect of drugs on cyclic AMP levels in the tissues of animals at different stages of ontogenesis. I. Experimental studies on the effect of adrenomimetic drugs on cyclic AMP concentration in the brain of 7-day-old and adult rats]. / Wplyw leków na stezenie cyklicznego AMP w tkankach zwierzat w róznych okresach rozwoju osobniczego. I. Badania doswiadczalne nad wplywem leków adrenomimetycznych na stezenie cyklicznego AMP w mózgu szczurów 7-dniowych i doroslych.

The purpose of the investigations was the comparison of the adrenergic receptors excitability in brain of 7-days-old and adult rats after adrenaline and isoprenaline administration. The excitation was evaluated biochemically by measurement of the beta receptor-mediated increase in brain cAMP concentration. There was no significant difference in brain tissue cAMP concentration of 7-days-old and adult rats in physiological conditions. The concentration of cAMP in brain of adult rats was not affected after administration both adrenaline and isoprenaline. On the contrary, the concentration of cAMP in brain of 7-days-old rats was significantly increased after each of two examined drugs, indicating that blood-brain barrier is permeable for catecholamines at this age.

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.

[Binding capacity of some drugs to plasma proteins of newborns in comparison with adults (author's transl)]. / Bindungskapazität der Serumeiweisskörper von Neugeborenen und Erwachsenen für einige Arzneimittel.

Comparative studies on binding capacity of some drugs to plasma proteins of newborns and adults were carried out. Plasma from the newborn and adult rabbits as well as human from 4 sources: a) from healthy adults, b) from cord blood, c) from 5 days old newborns, and 6 month old infants were used for the experiments. For methodological reasons in the first part of our studies we have chosen: two sulfonamides - sulfamethazine and sulfamethoxasole, chlorpromazine and sodium salicylate. In the experiments two different techniques were used 1) equilibrium dialysis, 2) ultrafiltration. On the basis of the results obtained in animals as well as in human beings it was noted that the degree of drug binding to plasma proteins in newborns was different from that observed in adults, it may be higher or lower according to the drug used. The knowledge of this fact is of great importance, and should be taken into consideration in the calculation of proper dosage of various drugs in the newborns and infants.