Pharmacokinetic study of fentiazac and its main metabolite hydroxyfentiazac in the elderly.

The pharmacokinetics of fentiazac (F, CAS 18046-21-4) and hydroxyfentiazac (OH-F) were estimated in 12 elderly (> 76 years). After an oral single dose of 200 mg F, the plasma and urine profiles were determined using high-performance liquid chromatography with a fluorescence detection. When compared to results obtained in young adults, the maximum plasma concentrations (5.4 +/- 1.9 mg/l) and-the time to reach them were identical. The terminal half-life (7.0 +/- 9.1 h) was longer, due to a slight increase of the apparent volume of distribution and a decrease of the elimination clearance. The findings suggest that the dosage regimen of this drug should be decreased in the elderly. Moreover, the variability of the pharmacokinetics being larger, individual adaptation of the daily dose should be performed.

COR3224--a new antidepressant: pharmacokinetics and metabolism in rat.

COR3224 is a new 2-amino-2 oxazoline derivative with antidepressant properties. The distribution, excretion and metabolism of radiochemically labelled 14C-COR3224 has been investigated in the rat after intravenous injection. The compound was widely distributed and rapidly excreted. Hydroxylation and sulphate conjugation are involved in the COR3224 elimination.

[Transplacental passage of doxorubicin]. / Passage transplacentaire de la doxorubicine.

The transplacental passage of doxorubicin, an anthracycline used for lymphoproliferative disorders and breast cancer, was studied by in vitro perfusion of term human placenta. Placentas from women with uncomplicated pregnancy were collected immediately after vaginal delivery and put into a 37 degree C thermostatically-controlled hood. A cotyledon was chosen and placed into the perfusion chamber; fetal and maternal compartments of the isolated lobe were thus perfused with separated "open" circuits. Perfusion of fetal surface of the placenta was started immediately at a flow rate of 6 ml/mn and then so was the perfusion of the intervillous space at a rate of 12 ml/mn. Perfusion medium used was Earle's solution. Antipyrine, to validate experience, and doxorubicin were added to the maternal perfusate. Samples were collected from arterial inflow and venous outflow respective of the maternal and fetal compartment and timed measurements of the fetal venous return were used to calculate flow rates. After a stability study of doxorubicin solutions under experimental conditions, the transplacental transfer of doxorubicin was then investigated for three doses: 3 mg/l, 30 mg/l and 150 mg/l. The global transfer value is low (2.96% +/- 0.75%) and doesn't seem dose-dependent. Adriamycinol, a plasma doxorubicin metabolite, has not been found even for the greatest concentration. The low transfer value can explain the rarity of fetal accidents in clinical reports.

[In vitro study of the transplacental passage of chloroquine sulfate]. / Etude in vitro du passage trans-placentaire du sulfate de chloroquine.

The authors, by performing in vitro perfusion on six human placentas, have studied the passage of chloroquine sulphate into the placenta. The drug levels were recorded by high performance liquid chromatography (HPLC). The placental perfusions lasted one hour and drug passage into placental tissue was low (14.21%) which seems to be due to the high degree of fixation of chloroquine on placental tissue.

[Pharmacokinetics of apalcillin in pediatrics]. / Pharmacocinétique de l'apalcilline en pédiatrie.

Apalcillin is a semi-synthetic broad-spectrum penicillin which is particularly active against Pseudomonas. Pharmacokinetic studies were carried out after slow (3 mn) intravenous administration of a single dose of 20 or 30 mg/kg in five categories of infants: premature, dysmature, full term newborn up to 8 days of age, infant aged 8 days to 1 month and infant beyond 1 month. Elimination half-lives in these five groups are respectively: 6.83, 5.44, 5.01, 2.28 and 1.28 hours. A decrease in elimination half-life and increase in total clearance are observed as the infant matures. Renal clearance represents a quarter of total clearance suggesting than there is considerable extrarenal clearance. Pharmacokinetic findings beyond one month of age are comparable to those demonstrated in adults. The dysmature infant is characterized by a significantly lower steady-state distribution volume (p less than or equal to 0.025) as compared to the full term neonate. From these results the recommended dosage is: 20 mg/kg twice daily for premature, dysmature and full term neonates up to 8 days, 30 mg/kg twice daily for infants from 8 days to one month of age, and 30 mg/kg three or four times a day for infants above one month of age.

[Transplacental transfer of 5 antibiotics by in vitro human placental perfusion]. / Etude du passage transplacentaire de cinq antibiotiques par perfusion in vitro du placenta humain.

Transplacental transfer of 5 semi-synthetic penicillins which act on Gram + and Gram - bacteria were studied by in vitro perfusion of the human placenta. These penicillins were: amoxicillin, apalcillin, mezlocillin, piperacillin and ticarcillin. Placental transfer of these 5 antibiotics varies between 5 and 7% of the maternal concentration. Amoxicillin 7,62% - apalcillin 5,66% - mezlocillin 5,4% - piperacillin 7,37% - ticarcillin 4,86%. The reasons for such low transfer and the clinical repercussions of these results are discussed by the authors.

Pharmacokinetics of apalcillin in intensive-care patients: study of penetration into the respiratory tract.

A pharmacokinetic study of apalcillin was performed in 12 patients in an intensive-care unit. All received a single dose of 30 mg/kg in a 30 min infusion followed by 90 mg/kg/day for four days; six patients (group A) were treated by intermittent administration for two days (30 mg/kg in 30 min infusion, three times daily), followed by continuous infusion for the next two days; six other patients (group B) first received continuous infusion followed by intermittent infusion. Serial serum specimens were collected after the first infusion and on the third and fifth days of treatment. Bronchial secretions were taken simultaneously via an endotracheal tube or the tracheostomy cannula, in order to study the penetration of the drug into the respiratory tract. Assays were performed by a microbiological method. A mean serum peak value of 87.1 +/- 6.13 mg/l 5 min after the end of the first injection was followed by a slow decrease in serum levels and a residual value of 6.29 +/- 3.21 mg/l (8h). Intermittent administration resulted in a mean serum peak of 79.56 +/- 12.35 mg/l whereas after continuous infusion, a steady state of about 30 mg/l was obtained. No significant difference was found between pharmacokinetic parameters for the two groups. In bronchial secretions, a mean peak value of 5.8 mg/l was attained by the second hour. Decreased levels in bronchial secretions measured after three or five days treatment were possibly related to a decrease in inflammation.

[Pharmacokinetics of apalcillin. Study of linearity]. / Pharmacocinétique de l'apalcilline. Etude de la linéarité.

Apalcillin is a new semi-synthetic penicillin active on the positive Gram bacteria, and on the enterobacteria, with a particular activity on Pseudomonas and Acinetobacter. The linearity study of the pharmacokinetic was carried out on 26 subjects who were given increasing doses (500, 1 000, 2 000, 3 000 mg) of apalcillin by the venous route. The dosages carried out by the HPLC and bacteriological methods, show a good correlation between the two methods. The serum concentrations, 5 mn. after injection, were respectively 72 micrograms/ml (500 mg); 145 micrograms/ml (1 g) ; 221 micrograms/ml (2 g) ; 290 micrograms/ml (3 g). Urinary excretion is around 20 %, and this, regardless of the dose. The dose increase seems to have no effect on the pharmacokinetic parameters, calculated on the basis of a bi- compartmental model. The areas under the time serum concentrations, increase proportionally, to the dose : 61 (500 mg) ; 146 (1 g) ; 285 (2 g) ; 367 (3 g) - micrograms/ml X h. the linear regression between the AUC (y) and the applied doses (X) is : y = 0,12 X + 14,27 ; r = 0,9046 ; n = 69. The correlation between the AUC and the doses is significant (p less than 0,001). The results obtained show that increasing the dosage has no effect on apalcillin pharmacokinetics, which appear linear.

[Pharmacokinetic study of apalcillin after infusion]. / Etude pharmacocinétique de l'apalcilline après perfusion.

Apalcillin is a new semi-synthetic penicillin of the uridino-penicillin group. The study comprises two groups of 6 subjects receiving 1 g and 2 g respectively of apalcilline by a two-hour infusion. The assays done by HPLC and microbiology show a good correlation between the two methods. The serum concentrations at the end of the infusion are: 32,2 micrograms/ml-1 (1 g) and 62,7 micrograms/ml-1 (2 g). The modelisation of the serum curves has been realized according to an open model with two compartments. A phase of rapid distribution is observed: t 1/2 alpha of 19.5 mn (1 g), 8.96 mn (2 g) followed by a phase of longer elimination: t 1/2 beta of 1.17 h (1 g), 1.15 h (2 g). The distribution volume at the steady-state is: 14.19 l (1 g), 14.76 l (2 g). This volume, much greater than the plasmatic volume, allows to suppose a good tissular diffusion of apalcilline. The urinary concentrations of the twelve first hours are: 182.64 micrograms/ml (1 g), 323 micrograms/ml (2 g). The urinary elimination during the 24 hours following the administration is: 18.58% (1 g), 16.47% (2 g).