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1. We previously reported circadian variations of pharmacokinetic parameters of lidocaine in the rat after a single 50 mg.kg-1. I.M. dose of this drug administered at four different fixed time points of a 24-hours period (i.e.: 10.00, 16.00, 22.00 or 04.00 h). As diurnal variations of membrane permeability was one of the suggested hypothesis, we investigated this possibility through the search of an eventual influence of the hour of administration of lidocaine on its intraerythrocytic passage. 2. Plasmatic and intraerythrocytic levels of lidocaine were determinated during 6 hours after each administration (10.00, 16.00, 22.00 or 04.00 h). 3. Our data show a circadian variation of the intraerythrocytic passage of lidocaine higher intraerythrocytic levels of this drug are observed when lidocaine is administered at 22.00 h; at this time the red blood cell level of the drug represent 73,6% of the plasmatic level. 4. The circadian variation of the intraerythrocytic passage of lidocaine in the rat may reflect circadian variations of membrane permeability, explaining in part the circadian fluctuations of lidocaine pharmacokinetics.

Seven asthmatic patients were given a single placebo tablet in a first test session and then in two subsequent double blind sessions they randomly received 400 mg bevantolol or 100 mg atenolol, with at least 2 days between each of the sessions. Neither beta-blocker had any significant effect on FVC as compared to the placebo. FEV 1, however, was significantly lower 2 and 3 h after atenolol or bevantolol; there was no significant difference between the effects of the two drugs on FEV 1. Peak expiratory flow rate was reduced by bevantolol but not by atenolol, the difference reaching significance after 3 h. Fenoterol inhalation at the end of each test session always enhanced pulmonary performance, but to a lesser extent after bevantolol than after placebo or atenolol. A slower heart rate was recorded 2, 3, and 4 h after bevantolol and 3 and 4 h after atenolol; the mean 2-h value was significantly lower with atenolol than with bevantolol. No patient suffered any adverse effect. Bevantolol may be slightly less selective than atenolol.

Certain accidents related to local anaesthesia during bronchial fibroscopy may be due to overdosage of local anesthetic drugs. In view of the various techniques employed, the various doses used and the different serum levels obtained, we decided to study the passage of lidocaine into the systemic circulation during bronchial fibroscopy in order to confirm that the doses required for good anaesthesia are not toxic. We studied the kinetics of lidocaine on 10 occasions in 9 patients. All patients had normal renal, hepatic and cardiac function. The anaesthetic was administered in standardized doses (by pharyngo-laryngeal spray of a 5% solution followed by injection via a laryngeal syringe and finally by the operating lumen of the fibroscope with a 1% solution). The total dose of anaesthetic was administered at the beginning of the examination in order to avoid contamination of the aspirated secretions after connection of the traps. The mean dose administered was 9.2 +/- 0.5 mg/kg (range of 380 to 800 mg). The maximal serum levels never attained toxic levels (9 mcg/ml). The highest levels (7 mcg/ml and 5.7 mcg/ml) were observed in a patient with a bronchial epithelioma, normal biochemistry and normal liver ultrasonography, who died two months later with hepatic metastases. The mean maximal serum levels for this group of patients was 2.8 +/- 0.6 mcg/ml between the 5th and 45th minute, which is equivalent to anti-arrhythmic doses (therapeutic level of 1.2 to 5 mcg/ml). The levels obtained are not negligible, but they achieve very good quality anaesthesia with a good margin of safety, apart from the one case with hepatic metastases.

The study of the acute toxicity of two barbiturics anaesthetics (pentobarbital and thiopental) shows the newborn period a higher susceptibility of the young rat, probably due to an immaturity of biotransformations enzymatic systems or to an increased blood-brain-barrier permeability.

This experiment was carried out upon the male-adulte-AF SPF-Wister Rat, anesthetized by the use of pentobarbital-Na at the only dosage of 40 mg/kg/IP and put under artificial ventilation. The animals were divided into two groups: Group I, "diurnal animals" curarized between 10 a.m and 4 p.m; Group 2, "nocturnal animals" curarized between 9 and 12 p.m. Four drugs of the curarimimetic (pachycurare, non-depolarizing) type: gallamine, D-tubocurarine, pancuronium and AH-8165 were studied at doses presenting the same activity. The total curarizing effect measured by the surface defined by the curve of curarization within ten mns was constantly and significantly lowered in "nocturnal animals": a 25 p. 100 diminution with gallamine, 20 p. 100 diminution with D-tubocurarine, 27 p. 100 diminution with pancuronium, 19 p. 100 diminution with AH-8165. The hypothesis is that this diminution in the action of curarizing substances may be, to a great extent, in keeping with the rise of their metabolism -- the hepatic enzymatic activity being, in the rat, a nocturnal animal, definitely increased during the night.

In order to demonstrate possible modifications of circadian rhythms of plasma proteins in elderly, we measured every four hours during 28 hours in 14 aged (greater than 60 years) subjects orosomucoid, alpha-1-antitrypsin (AAT) and ceruleoplasmin (Cp). A circadian rhythm of the 3 proteins was significantly detected: the 24 hour mean values of orosomucoid and AAT were higher in elderly compared to young subjects but not difference was detected concerning Cp. As far as acrophase and amplitude of these rhythms were concerned no statistical differences were found between elderly and young subjects.

The influence of menstrual cycle on drug kinetics is not largely documented. Concerning theophylline it was of interest to investigate whether or not the kinetics of this drug is modified throughout the oestrous cycle. Though the kinetics of this drug was assessed in adult Wistar female rats at different stages of the oestrous cycle: proestrous (P), oestrous (O) and diestrus (D). Our preliminary data clearly indicate statistically significant differences (p less than 0.01) of theophylline kinetic parameters such as elimination half-life: 8.70 +/- 0.60 h (P), 4.61 +/- 0.16 h (O) and 5.01 +/- 0.85 h (D), area under concentration versus time curve (AUC): 214.61 +/- 3.58 micrograms.h/ml (P), 128.64 +/- 9.64 micrograms.h/ml (O) and 165.57 +/- 23.86 micrograms.h/ml (D). These results agree with clinical data reported on the influence of estroprogestative drugs on theophylline kinetics in women (higher elimination half-life and lower clearance). In order to explain some of our findings the possible variations of theophylline protein binding and metabolism throughout the oestrous cycle are under investigation.

Three regimens of sustained-release theophylline (SRT), Theostat were administered to 12 male patients with chronic obstructive pulmonary disease in a randomized cross-over trial. Each 7-day treatment consisted of: treatment A--8 mg/kg at 0700 hr and 4 mg/kg at 1900 hr, treatment B--6 mg/kg at 0700 hr and 6 mg/kg at 1900 hr, treatment C--4 mg/kg at 0700 hr and 8 mg/kg at 1900 hr. Peak expiratory flow (PEF) was recorded each day at 0700, 1100, 1500, 1900 and 2300 hr and theophylline plasma levels were determined on the 7th day of each treatment sequence. Cosinor analysis of the data revealed significant circadian rhythms in PEF for each treatment: the mesor (24-hr average) was significantly higher with C and acrophases (phi, peak time of PEF rhythm) were located at 1426 hr for A and 1425 hr for C; a shift of the acrophase to an earlier timing was detected for B (phi = 0958 hr. These findings suggest that an unequal, twice-daily SRT dosing with the greater amount of drug at night may be beneficial in the treatment of COPD.

Determination of urinary delta-amino levulinic acid (ALA) is now systematically used in occupational health to detect an excessive exposure to lead in professionally exposed workers. However, to determine whether circadian changes of the urinary excretion of ALA alter the significance of the test, we quantified the ALA levels in the urine of 19 healthy young adults. Urine samples were taken every 3 hr between 0700 and 2300 hr and ALA levels were determined by a spectrocolorimetric method. The data indicated that the 24-hr mean ALA level was: 1.81 mg/g creatinine. The peak values (2.24 +/- 0.24) were obtained between 1400 and 1700 hr whereas the lowest ALA levels were found between 2200 and 0300 hr. Cosinor analysis revealed a significant circadian rhythm while no significant difference could be found according to sex. Possible explanations of our findings are discussed.

For chronopharmacokinetic investigations on bupivacaine in mice we needed a gas liquid chromatographic (GLC) method with flame ionization detection, sufficiently sensitive, linear and precise: thus we describe in this paper a GLC method adapted from previous findings of Desh and al. A single extraction procedure involving methylene chloride was used with mepivacaine as internal standard. Under the conditions of the assay used, retention times were 3.3 minutes and 6.3 minutes for mepivacaine and bupivacaine, respectively. Repeatability and recovery of the method were good and standard calibration curves were linear in the concentration range studied. The assay described herein has been used to study single dose kinetics of bupivacaine in mice. The method herein described is more sensible and more rapid for the determination of bupivacaine than previous GLC methods.