Comparative pharmacokinetics of two diastereoisomers dexamethasone and betamethasone in plasma and cerebrospinal fluid in rabbits.

The two diastereoisomers dexamethasone (DXM) and betamethasone (BTM) were infused at two different doses (2, 10 mg.kg-1) in anesthetized rabbits. Samples of plasma and cerebrospinal fluid were collected over a 180-min period. Steroid concentrations were measured by high performance liquid chromatography. The terminal half life (85.7 +/- 20.8 min and 102.2 +/- 29.6 min for DXM; 117.6 +/- 19.8 min and 118.5 +/- 15.8 min for BTM) and the mean residence time (121.4 +/- 27.7 min and 146.1 +/- 41.3 min for DXM; 168.6 +/- 28.1 min and 172.2 +/- 20.6 min for BTM) were unchanged between the doses. Dose-dependent changes in the area under the curve normalized by the dose, then volume distribution and clearance were observed. The average percentage of DXM and BTM bound to plasma proteins were 78.1 +/- 11.5% and 88.3 +/- 5.1% respectively at the lower dose, and decreased significantly with 10 mg.kg-1. DXM appeared more rapidly in the CSF, the highest concentrations of DXM were obtained within 15 min after the end of the injection. The CSF levels were lower than that of plasma unbound and the passage through the blood-brain barrier was saturable. These results will complicate pharmacokinetic and pharmacodynamic analysis.

Influence of sex and oestrogen replacement on the disposition of dexamethasone in rats.

The disposition of dexamethasone (DXM, 2 mg/kg, iv) was studied in ovariectomized female rats treated with oestrogen (0.1 mg and 1 mg of oestradiol benzoate) and in male rats. Oestradiol replacement had no effect on body or liver weights or on the DXM pharmacokinetic parameters (CL, Vdss, AUC, MRT and t1/2) of the female groups. If the Vdss seemed slightly greater in male than in female rats, this difference disappeared after normalization based on body weight. In contrast, CL was greater in the male rats even after normalization. For all the animals, significant correlations were observed between body weight and Vdss (r = 0.731, P less than 0.001) or CL (r = 0.639, P less than 0.001). Terminal half life and MRT were negatively correlated with CL (r = -0.481, P less than 0.01 and r = -0.575, P less than 0.01, respectively) but not with Vdss. Although oestrogen replacement did not seem to affect the pharmacokinetics of DXM, the increase in the CL in male rats should be the main determinant observed between the sexes. These results are consistent with a slower metabolism found for various drugs metabolized by the cytochrome P-450 in female rats.

Increased iron content in rat myocardium after 5-fluorouracil chronic administration.

The isovolumic perfused rat heart model according to Langendorff has been used in order to characterize the changes occurring in the heart following 5-Fluorouracil (5-FU) administration. Preliminary published data pointed out that perfusion of isolated heart with 1 mg/l 5-FU failed to show any differences in contractility and oxygen consumption in comparison with the control group. However, when Wistar rats received 5-FU once a day (50 mg/kg, I.P.) for five consecutive days a consistent increase in oxygen consumption throughout the 80 min of perfusion associated with a decrease in the fractional extraction of oxygen and a lowered + dP/dt max were observed, without any drug added during the in vitro perfusion. Further investigation has been performed for a better understanding of the results observed after 5-FU pretreatment. Magnesium, potassium, calcium, copper and iron contents in the myocardium (at 0 min of perfusion) were measured by flame atomic absorption spectrophotometry. Iron levels were 20% higher in the 5-FU pretreated group than in the control group, whereas as no differences were observed for the other elemental concentrations. Both initial glycogen and ATP contents were respectively 42% and 29% higher in the pretreated than in the control group and alpha-hydroxybutyrate dehydrogenase release was lower after 40 min of perfusion in the pretreated group. However, 5-FU pretreatment increased net tissue water gain after 80 min of perfusion. Increases in mean oxygen partial pressure in the myocardium and in oxygen consumption associated with increased iron level might be candidates responsible for 5-FU induced cardiotoxicity through an increased in oxygen derived free radicals. Sympathetic over-stimulation or calcium overload do not appear to be involved in 5-FU induced cardiotoxicity.

The effects of 5-fluorouracil on contractility and oxygen uptake of the isolated perfused rat heart.

Clinical cardiotoxicity related to 5-fluorouracil (5-FU) simulates either myocardial ischemia or left ventricular dysfunction. In order to characterize the changes occurring in the heart following 5-FU administration, the isovolumic perfused rat heart model according to Langendorff has been used. Particular emphasis was laid on contractility and oxygen uptake. Perfusion of isolated hearts with 1 mg/L 5-FU for 80 minutes failed to show any differences in contractility and oxygen consumption in comparison with the control group. On the contrary, 5-FU pretreatment of Wistar rats (50 mg/kg I.P. for 5 consecutive days) led to a decrease in inotropism without any change in maximum relaxation rate. The most significant finding was the consistent increase in oxygen consumption throughout the 80 minutes of perfusion (p less than 0.05) associated with a decrease in the fractional extraction of oxygen. Mean coronary flow was consistently increased in the 5-FU-pretreated group. Lactate release and CK Leakage did not differ in the two groups. In the 5-FU-pretreated group the ratio of oxygen consumption to rate-pressure product remained significantly elevated throughout 80 minutes of perfusion in comparison with the control group (p less than 0.05). Inappropriately high oxygen uptake could be a reflection of cellular metabolic disturbances responsible for post-ischemic dysfunction.

Combination chemotherapy with cisplatin, etoposide and gallium chloride for lung cancer: individual adaptation of doses.

Twelve inoperable lung cancer patients were treated with a combination chemotherapy of cisplatinum (CDDP) and etoposide (VP16), as a continuous infusion for 5 days, every 21 days, and with a daily oral administration of GaCl3. Dosages of CDDP and VP16 were adapted in order to obtain an area under the curve (AUC) of 80,000 micrograms l-1.h for plasma total platinum and of 200 mumol.l-1 h for plasma VP16 during each 120 h infusion. GaCl3 was given at the dosage of 400 mg/24h from the time of diagnosis at least until the evaluation after 3 courses of chemotherapy. An objective response was observed in 5 non small cell (NSCLC) lung cancer patients (group 1) and 3 small cell (SCLC) lung cancer patients (group 2). In the other 4 patients with a NSCLC no partial response was noted (group 3). No significant difference in area under the curve (AUC) was noted between the 3 groups, either for plasma total platinum (group 1 = 89,598 +/- 20,843 micrograms l-1.h; group 2 = 88,081 +/- 15,431 micrograms l-1.h; group 3 = 83,820 +/- 13,455 micrograms l-1.h), or for VP16 (group 1 = 227 +/- 41 mumol.l-1 h; group 2 = 217 +/- 29 mumol.l-1.h and group 3 = 211 +/- 30 mumol.l-1.h). The maximal plasma Ga concentrations were 244 +/- 34 micrograms/l in group 1, 112 +/- 57 micrograms/l in group 3 (p less than 0.005) and 243 +/- 132 micrograms/l in group 2. It was then decided to increase the dose of GaCl3 in the further non-responding patients. In 6 responders, 3 additional courses of this combination chemotherapy could have been given without major toxicity, allowing a much more important decrease in the tumor volume in 4 of them. This schedule of treatment should permit the chemotherapy to continue for longer than 6 courses, in order to improve the survival time.

Pharmacokinetics and brain distribution of zolpidem in the rat after acute and chronic administration.

The pharmacokinetics of zolpidem were studied after single dose, administered for either 7 or 28 days to rats. Thirty minutes after the last dose, animals were killed and the brain removed. The highest concentrations in plasma, which were observed at the first sampling time (0.5 h) were 2341 +/- 540 (day 0), 1956 +/- 325 (day 7) and 2908 +/- 1369 ng mL-1 (day 28). Corresponding AUC values of 1742 +/- 488, 1583 +/- 422 and 2683 +/- 1249 ng mL-1 h were found. MRT increased significantly from 0.46 +/- 0.06 h on day 0 to 0.67 +/- 0.02 h on day 28. The cerebral levels showed no significant change during the chronic administration (766 +/- 285, 685 +/- 171 and 887 +/- 264 ng g-1, respectively). No modification of the principal kinetic parameters was detected up to the 28th day of treatment.

[Pharmacokinetics of dexamethasone administered orally in obese patients]. / Pharmacocinétique de la dexaméthasone par voie orale chez le sujet obèse.

Dexamethasone pharmacokinetics was studied after oral administration of two Décadron tablets in six healthy controls and in eight obese patients whose weight was at least 20% above that of the ideal body weight. The absorption (0.30 +/- 0.09 h and 0.29 +/- 0.08 h) and elimination (4.52 +/- 0.57 h and 3.71 +/- 1.05 h) half-lives were not significantly different. Maximum plasma concentrations were similar (11.95 +/- 1.00 micrograms/l and 10.93 +/- 0.94 micrograms/l) but the lag-time was significantly higher in the obese patients (0.49 +/- 0.12 h and 0.13 +/- 0.04 h). A positive correlation was observed between the AUC and the total body weight (r = 0.738, p less than 0.01). Mean predexamethasone cortisol level was significantly lower in the obese patients (189.20 +/- 52.7 micrograms/l and 256.90 +/- 58 micrograms/l). The pharmacokinetics modifications were not sufficient to explain the increased false positive frequency in the dexamethasone suppression test of the hypothalamic-pituitary-adrenal axis in obesity.

[Chronopharmacokinetics of dexamethasone in young subjects]. / Chronopharmacocinétique de la dexaméthasone chez le sujet jeune.

Dexamethasone chronopharmacokinetics was studied in six young subjects 20 to 30 years old. The randomized cross-over study consisted of evening (11.00 p.m.) or morning (08.00 a.m.) dose separated by a period of one week. After the evening administration of the drug, only Tmax (1.77 +/- 0.74 à 11.00 p.m. and 0.99 +/- 0.64 à 08.00 a.m.) and Cmax/Tmax were higher than those determined at 08.00 a.m. This difference might be related to a cyclic variation of the absorption phase of dexamethasone. Thus, in our study, the time of administration has only a weak effect on the pharmacokinetics of dexamethasone.

[The acetylator polymorphism in a Khmer population: clinical consequences]. / Polymorphisme d'acétylation dans une population khmère: conséquences cliniques.

The great variability of slow acetylator (SA) and/or rapid acetylator (RA) frequency is mainly due to ethnic-racial origin. Using the urinary elimination ratio of three metabolites of caffeine--acetylamino formylamino methyluracil (AFMU) to AFMU + 1-methyl urate (1U) + 1-methyl xanthine (1X)--we settled the acetylation phenotype in 54 independent subjects of Khmer and 70 independent subjects of Caucasian origin. Using DNA from peripheral leucocytes, we determined by PCR, in 32 Khmer and 122 Caucasian subjects, the frequencies of wild-type alleles (NAT-2 *4) and of mutated alleles (NAT-2 *5A, *6A, *7A). The frequency of SA was respectively 28 per cent and 61 per cent in Khmer and Caucasian subjects. The antimode of the distribution of the ratio was different in the two populations: 0.07 in Khmers and 0.18 in Caucasians showing a reduced acetylation capacity in the Khmer population in spite of a higher frequency of RA. The frequencies of alleles were also different between the two populations. Between Khmers and Caucasians respectively: *4: 48.4-23.8 per cent *5A: 15.6-44.2 per cent. *6A: 29.7-32.0 per cent. *7A: 6.3-0 per cent. These differences might be taken into account to define a therapeutic strategy in the treatment of tuberculosis by isoniazide.

[Value of determining dexamethasone in the rapid adrenal suppression test]. / Intérêt du dosage de la dexaméthasone dans le test de freination rapide surrénalienne.

During the dexamethasone suppression test (DST), we evaluated the relationship between the 8 a.m. dexamethasone (DXM) level and the pharmacokinetics of this corticoid after the oral administration of a single dose at midnight of DXM (1 mg) in 7 healthy subjects. The half-life time of the terminal phase for DXM was 283 min +/- 132 min (mean +/- s.d.). The 8 a.m. DXM level, which is positively correlated with the DXM half-life time, is useful for the interpretation of the DST. On the other hand, no correlation was observed between the 8 a.m. plasma cortisol and DXM levels in 21 healthy subjects. However, the negative correlation between the dose of DXM/kg and post-DXM cortisol level suggests the possibility of adjusting the dose of DXM in obese patients.

[The risks of pyrimethamine-sulfadoxine combination in the prenatal treatment of toxoplasmosis]. / Les risques de l'association pyriméthamine-sulfadoxine dans le traitement anténatal de la toxoplasmose.

Some of the alternative treatments to avoid termination of pregnancy in cases where the fetus is affected by toxoplasmosis is to treat it as soon as the diagnosis has been made. The authors who already have experience of using pyrimethamine with sulfadoxoine (Fansidar) in the post-natal treatment of congenital infection, thought after reviewing the literature that this association of drugs would be harmless if applied during pregnancy. The principal risk that arises in the fetus is the teratogenicity of each of the components of pyrimethamine and sulfadoxine and also their associations. In animals pyrimethamine can increase the frequency of cleft palates probably because of its antifolinic action but there is no formal proof that it is teratogenic in human beings. Furthermore, the theoretical risk of karnicerus in the new born using the Sulfonamide has not been demonstrated. In the mother the main but rare risk (1 in 75,000) seems to be for the production of severe skin lesions such as Lyell and Stevens-Johnson which could be brought about by sulfonamides, but not particularly sulfadoxine.

[Bone and blood levels of azlocillin after intra-arterial injection in the dog]. / Taux osseux et sanguins de l'azlocilline après injection intra-artérielle chez le chien.

Pharmacokinetic values of azlocillin--a semisynthetic penicillin of the ureidopenicillin family--were determined in dogs after injection of the drug into the right femoral artery by measuring plasma concentrations in the right femoral artery and left femoral vein and tissue concentrations in ipsi- and contralateral bones. Two different doses of azlocillin were administered, one group of dogs receiving 100 mg X kg-1 by fast (1 min) bolus injection and the other group receiving 250 mg X kg-1. The drug was assayed by high performance liquid chromatography in reverse phase, which proved to be the simplest, most rapid and most sensitive method. Changes in plasma and bone tissue concentrations after intra-arterial injection were interpreted as order one kinetics with a two-compartment open model. Following the 100 mg/kg dose, concentrations versus time corresponded to the following equations: --Arterial blood (mg/l) = 7570 e-0.15 t (min) + 240 e-0.017 t --Venous blood (mg/l) = 553 e-0.13 t + 222 e-0.016 t --Bone tissue (micrograms/g) = 15 e-0.0115 t (elimination phase). Distribution and elimination constants were identical in arterial and venous blood. Distribution half-life was 5 +/- 1 min in arterial blood and biological half-life was 42 +/- 11 min. However, bioavailability was comparatively lower in veins due to higher levels in arteries during the distribution phase. Bone tissue concentrations were much lower than plasma concentrations and were identical on both sides despite high arterial levels on the ipsilateral side during the distribution phase. Bone concentrations diminished rapidly and elimination kinetic values were the same in bone and in plasma. It is concluded that bone tissue concentrations of azlocillin after intra-arterial injection are highest during the distribution phase.

[Demethylation and blood dosage of antidepressive imipramine drugs. Preliminary note]. / Déméthylation et dosage des antidépresseurs imipraminiques dans le sang. Note préliminaire.

The ability to demethylate the classical imipraminic antidepressants is a key factor for the immediate and long-term management of long cycles primary unipolar depressions. These are preliminary observations concerning two different cases of a well-demethylating patient, and a badly-demethylating one.

[Plasma levels of clomipramine and declomipramine in patients with depression: a study of its correlation with therapeutic efficacy]. / Concentrations plasmatiques de clomipramine et de déclomipramine chez des patients atteints de dépression: recherche de corrélations avec l'efficacité thérapeutique.

Twenty four in-patients with an endogenous or non endogenous depressive syndrome (9 and 15, respectively) were treated in hospital for 21 days with various dosages regimens of clomipramine. Plasma concentrations of clomipramine and demethylclomipramine were determined once a week in blood samples. Therapeutic effects were assessed with Hamilton Rating Scale. At day 21, optimal therapeutic effect was observed when the sum of clomipramine and demethylclomipramine plasma levels was situated between 200-400 ng/ml.