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Purpose: The mechanisms of action of local anaesthetics and potassium channel agonists (PCAs) may interfere by acting in a direct or indirect manner on the same ion channels. In a previously reported study, the bupivacaine-induced mortality was shown to be modified in different ways by four PCAs tested (diazoxide (D), levcromakalim (L), nicorandil (N) and pinacidil (P)) since bupivacaine-induced mortality was increased by high doses of P and L, decreased by N and stayed unchanged by D. The present study was designed to document the changes in bupivacaine (B) local anaesthetic activity in mice after a single injection of one of the four PCAs (D, L, N and P)., Methods: Each PCA was tested at three different dosages. Controls received saline. The local anaesthetic activity was evaluated using sciatic nerve blockade. After injection of bupivacaine in the region of the sciatic nerve, the local anaesthetic activity was estimated as the loss of motor control of the injected limb., Results: PCA treatment increased (P = 0.0001) the time needed for recovery from bupivacaine-induced local anaesthesia. The area under the effect vs time curve, assessing the total anaesthetic effect, was greater for N (P = 0.0016) and P (P = 0.038) but not for L (P = 0.11). Compared with controls, the maximal effect (Emax) was less for D (P = 0.009) and N (P = 0.038) but not for L (P = 0.185) or P (P = 0.45) treated groups. The injection of the PCA in the region of the sciatic nerve of the right hindlimb did not induce any alteration of the motor activity of the injected limb., Conclusion: The four PCAs decreased the maximal local anaesthetic effect and increased the duration of action of bupivacaine.

Objectives: Assess the efficacy of an anesthesic cream for pacemaker implantations., Methods: Percutaneous anesthesia was studied in a series of permanent pacemaker transvenous implantations. The anesthesic cream composed of a mixture of lidocaine and prilocaine was applied precisely over operative areas after marking the skin. Percutaneous anesthesia should be applied 2 hours before entering the operating room., Results: This percutaneous local anesthesia was perfectly effective for simple replacement procedures. At first implantations, it was used alone in 4 out of 10 cases while intradermal injections were needed to anesthetize the deep layers in the other patients. Serum concentrations indicate very low levels which are tolerated very well., Conclusion: Alone or combined with lidocaine infiltration, the use of an anesthesic cream is safe and effective in transvenous pacemaker surgery.

Previous studies have reported interactions between potassium-channel agonists and bupivacaine. This study was designed to document possible changes in the pharmacokinetic behaviour of bupivacaine and its main metabolite, N-desbutylbupivacaine, in mice after a single 1 mg kg-1 intraperitoneal injection of nicorandil. The kinetic variables of bupivacaine were determined after a single 20 mg kg-1 intraperitoneal dose of bupivacaine in controls (group 1) and in nicorandil-treated mice (group 2). The maximal concentration in the serum (Cmax 0.618 +/- 0.051 vs 0.408 +/- 0.041 microgram mL-1 for group 1 vs 2, P = 0.01) and the area under the concentration curve (AUC 1.039 +/- 0.051 vs 0.758 +/- 0.072 microgram mL-1 h for group 1 vs 2, P = 0.013) of bupivacaine were significantly lower in nicorandil-treated mice, while CL (0.579 +/- 0.025 vs 0.815 +/- 0.079 for group 1 vs 2, P = 0.022) and Vd (0.506 +/- 0.054 vs 0.981 +/- 0.117 for group 1 vs 2, P = 0.1006) were increased in nicorandil-treated animals. The ratio of AUC for N-desbutylbupivacaine to AUC for bupivacaine, which may partially indicate the rate of metabolism, was higher in the presence of nicorandil (1.142 +/- 0.017 compared with 0.877 +/- 0.013, P = 0.0001). Our data may indicate an increased metabolism of bupivacaine in nicorandil-treated mice. These results do not explain the previously reported enhanced anaesthetic activity of bupivacaine in the presence of nicorandil, but may participate, at least in part, in the relative protective effect of nicorandil against the previously reported bupivacaine-induced toxicity.

Chronopharmacology studies the influence of time of administration of drugs. Numerous studies have report on the influence of time of administration on acute toxicity of drugs. Qualitative and quantitative responses of the organism to drugs have been described in different areas such as anaesthesiology, cardiology, oncology, endocrinology, gastroenterology, obstetrics, neurology, pneumology, psychiatry, rheumatology... in animals and in men. Underlying mechanisms of such variations involve temporal variations of the mode of action of the drug i.e. at the receptor level or temporal modifications of the kinetics of the drug. Absorption, distribution and drug protein binding, metabolism and elimination vary according to the moment of administration of the drug. Chronotherapy consists on the choice of the moment of administration of a drug in order to minimise its side effects and/or to emphasize its therapeutic effects.

Lithium is the archetype of mood stabilizing drugs. Its narrow therapeutic index mostly accounts for the occurrence of acute intoxications. There is, however, growing evidence that lithium can induce long lasting neurological sequelae. These appear to be multifactorial, resulting mainly from overdosage, concomitant neuroleptic treatment, and hyperthermia. The most frequent clinical feature is a permanent cerebellar syndrome. As regards the few pathological data available, there is a striking loss of cerebellar Purkinje cells, which is present in all published neuropathological reports on this condition. It is suggested that lithium, cytokines, and neuroleptics synergize to disrupt calcium homeostasis in Purkinje cells, and to elicit calcium-mediated neurotoxicity. This model might help predict high risk clinical situations and define useful working hypotheses as well.

This study was designed to document possible changes in bupivacaine local anaesthetic activity in mice after a single injection of clonidine (0.1 or 1 mgkg-1, i.p.). The local anaesthetic activity was evaluated during 60 min, according to a previously reported technique, using sciatic nerve blockade by injection of bupivacaine in the area of the sciatic nerve. Clonidine pretreatment modified the local anaesthetic activity of bupivacaine dose-dependently. The time of recovery was higher for clonidine-pretreated mice (40.00 +/- 7.24 min, 0.1 mgkg-1 clonidine: 50.0 +/- 9.35 min, 1 mgkg-1 clonidine) compared with controls (27.22 +/- 1.21 min, P = 0.02). The maximal effect (Emax) was significantly lower for the pretreated group (1.15 +/- 0.13 units, 0.1 mgkg-1; 1.35 +/- 0.09 units, 1 mgkg-1) compared with the control group (1.72 +/- 0.13, P = 0.01). Our data indicate a significant decrease in the duration of anaesthetic activity of bupivacaine in clonidine-pretreated mice.

Previous studies have reported that clonidine pretreatment causes an increase in the local anaesthetic activity of bupivacaine. This study was designed to document possible changes in the pharmacokinetic behaviour of bupivacaine and its main metabolite, desbutylbupivacaine, PPX, in mice after a single, 0.1 mg.kg-1, injection of clonidine. Kinetic variables of bupivacaine were determined after a single 20 mg.kg-1 ip dose of bupivacaine in controls (Group I) and in clonidine (0.1 mg.kg-1 ip) pretreated mice (Group 2). The maximal concentration in serum (Cmax, 2.553 +/- 0.862 micrograms.ml-1 versus 0.962 +/- 0.141 microgram.ml01 for Groups 2 and 1, respectively, P = 0.01) and the area under the concentration curve (AUC, 3.530 +/- 0.330 micrograms.ml-1.hr-1 versus 1.755 +/- 0.252 micrograms.ml-1.hr-1 for Groups 2 and 1, respectively, P < 0.01) of bupivacaine were higher in clonidine pretreated mice while the Clearance (Cl) was decreased in clonidine pretreated animals (0.603 +/- 0.054 micrograms.ml-1 versus 1.264 +/- 0.447 micrograms.ml-1 for Groups 2 and 1, respectively, P < 0.01). The ratio of AUC PPX/AUC bupivacaine (which may partially indicate the rate of metabolism) was lower in presence of clonidine (0.220 +/- 0.019 against 0.425 +/- 0.033 for Groups 2 and 1, respectively, P < 0.01). Our data indicate decreased metabolism in the clonidine-treated mice which suggests altered hepatic metabolism of bupivacaine by clonidine. This may explain the previously reported enhanced anaesthetic activity of bupivacaine in the presence of clonidine.

A new regimen for postoperative analgesia after thoracic surgery is proposed. Eight children received an interpleural infusion using bupivacaine 0.1% in a regimen from 0.5 ml.kg-1.h-1 up to 1 ml.kg-1.h-1, for 48 h according to the pain scores. The plasma levels after 24 h and 48 h were measured as well as the pleural level and in two patients the free fraction of plasma bupivacaine and the plasma PPX (a metabolite of bupivacaine) and one patient the orosomucoid (main plasma protein involved in bupivacaine protein binding) were also measured pre and postoperatively. The results shows the safety of such a regimen, for two days of postoperative analgesia.

A gas-liquid chromatographic method for the simultaneous measurement in serum of bupivacaine, lidocaine, and their main metabolites, 2,6-pipecolylxylidide (PPX) and monoethylglycine xylidide (MEGX), respectively, is described. The procedure involves a one-step extraction and injection of the extract into a gas chromatograph equipped with a capillary column and nitrogen phosphorus detector under constant temperature conditions. Recovery of all components averaged 94%, with the lowest detection limit of 15 ng/ml for the four drugs. The precision within-series coefficients of variation ranged from 7.7% for bupivacaine, 8.6% for lidocaine, 10.2% for MEGX, and 15.8% for PPX. The interday coefficients ranged from 0.7 to 6.5%. Concomitant use of caffeine and carbamazepine may interfere with MEGX and bupivacaine determination, respectively. For this reason, in patients receiving one of these two drugs (or ingesting foods and beverages containing caffeine), the described method is not recommended.

Carboplatin (CBDCA) and oxaliplatin (I-OHP) are non-nephrotoxic platinum (Pt) compounds, which exert their main respective toxicities on the bone marrow and on the intestinal mucosa in mice. Plasma and red blood cell (RBC) drug dispositions were investigated in 324 male B6D2F1 mice after a single IV injection of CBDCA (72 mg kg-1) or I-OHP (17 mg kg-1). Since the toxicities of either drug largely depended upon circadian dosing time, such a pharmacokinetic study was performed following injection of either Pt complex at a time of low (16 h after light onset-HALO), intermediate (0 HALO) or high (8 HALO) toxicity. Pt concentrations in plasma ultrafiltrate (PUF) and in total plasma declined in parallel and became barely detectable by 2 h following CBDCA injection. Conversely, free Pt became undetectable 1 h after I-OHP injection, whereas sustained levels of total Pt were found 24 h post dosing. This suggested that I-OHP had a high binding affinity for plasma proteins. Mean values of t1/2 alpha and mean residence time (MRT) of free Pt for I-OHP (6.7 min and 9.7 min respectively) were half those of CBDCA (12.5 min and 18.1 min respectively). The two drugs had a similar initial volume of distribution (Vdi) of free Pt (10.5 mL) in mice. However, plasma clearance of I-OHP was twice as high (1.06 mL min-1) as that of CBDCA (0.58 mL min-1). Free Pt AUCs were eight to ten times lower for I-OHP than for CBDCA. In contrast, erythrocyte Pt AUCs were three to four times as high for I-OHP as for CBDCA. Circadian changes in pharmacokinetic parameters were large, yet limited to the initial distribution phase (C0, t1/2 alpha, Vdi) as well as mean residence time. The smallest Vdi and the fastest plasma elimination occurred when either drug was injected at 0 HALO. The largest Vdi and the longest elimination were however observed at 8 HALO for CBDCA and 16 HALO for I-OHP. No consistent relationship was found for both Pt complexes with regard to circadian changes in blood pharmacokinetics and in target organ toxicities. The major pharmacokinetics differences between CBDCA and I-OHP were related to both protein binding and RBC handling.

1. This study was designed to document the acute toxicity of two metabolites of bupivacaine, desbutylbupivacaine (2,6, desbutylbupivacaine; PPX) and pipecolic acid in mice. All the compounds were administered by the intraperitoneal (i.p.) route. 2. The mean convulsant activity was 100% for controls, 30, 100, 100, 100 and 90% for 400, 200, 150, 125 and 112.5 mg/kg i.p. of PPX, respectively, and 0% for the animals receiving pipecolic acid. 3. The acute induced mortality was 60% for bupivacaine control group (50 mg/kg/i.p.), 60, 30 and 0% for 800, 400 and 200 mg/kg of pipecolic acid, respectively, and 100, 90, 60, 80 and 10% for 400, 200, 150, 125 and 112.5 mg/kg i.p. of PPX, respectively. 4. The time to convulse was 158 +/- 16 s for bupivacaine, 230 +/- 30, 270 +/- 24, 255 +/- 21, 442 +/- 84 and 418 +/- 32 s for 200, 150, 125, 112.5 and 100 mg/kg i.p. of PPX, respectively; any pipecolic acid treated animal have convulsed. 5. In conclusion, the present study demonstrated that PPX is more toxic than expected since we found that its induced mortality was approximately three times that found for bupivacaine and its CNS toxicity was about two times that of bupivacaine.

This study was designed to document possible changes in bupivacaine kinetics in rats after exposure to cigarette smoke. Rats (n = 15) were exposed to cigarette smoke (Borgwaldt type Hamburg II) for ten minutes per day during four days (C) or eight days (B); controls (A) were used simultaneously without exposure to cigarette smoke. After bupivacaine 20 mg.kg-1 ip at day 4 (C) or day 8 (B), blood was sampled (0.5 ml of blood collected by puncture at the retro-orbital sinus 0.25, 0.5, 1, 2, 4, 6 and 8 hours after administration) and bupivacaine and its main metabolite i.e., desbutylbupivacaine (PPX) were determined by gas liquid chromatography. The sensitivity of the method was 15 ng.ml-1 and the reproductibility was < 6%. Serum bupivacaine concentrations were plotted against time and the pharmacokinetic variables were determined assuming a two compartment open model: Cmax, Tmax were derived directly from individual data. The beta phase elimination half-lives (T1/2 beta), the area under the serum concentration curve (AUC0 infinity), the total plasma clearance (Cl) and the total volume of distribution (Vd) were calculated. These variables were assessed according to non-linear fitting method. Cigarette smoking exposure did not change the pharmacokinetic variables of bupivacaine.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of the present work was to document the possible influence of the time of administration of brewer's yeast on a model of fever previously reported. Forty male Wistar AF IOPS rats were recorded every hour for 24 h; 2 days later, five groups (four animals each) were injected subcutaneously (neck) at 09:00 or 20:00 h with four different doses of brewer's yeast (group A, 2.5 g/kg; group B, 2 g/kg; group C, 1.5 g/kg; group D, 1 g/kg) or with the equivalent volume of saline (group E, controls). Rectal temperature was recorded every hour for 24 h with an electronic thermometer with a thermistor probe inserted rectally. All data were quantified (means +/- SEM) and compared by analysis of variance (two ways). The circadian variations of temperature were assessed by cosinor analysis. Brewer's yeast-induced fever was statistically significant since increases of 01.04 to 0.77 degrees C and of 0.47 to 0.73 degrees C were observed compared with matched controls after the morning and the evening administration, respectively. A significant circadian rhythm of temperature was detected (p < 0.001) in controls before and during the experiments and in the differently treated groups. The effect of brewer's yeast was different according to the hour of its administration: after morning injection, the mesor of the circadian rhythm was significantly increased as compared with controls and the acrophase was significantly shifted in proportion to the dose. Concerning the evening dosing, the amplitude and the mesor of the circadian rhythm were increased and the acrophase was significantly shifted. During the 4 h following injection, brewer's yeast may induce hyper- or hypothermia.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of the study was to evaluate the penetration of ciprofloxacin into bronchial secretions from mechanically ventilated patients with nosocomial bronchopneumonia. For this purpose, in each patient studied, simultaneous serial blood and bronchial secretion samples were obtained over a 12-h period on days 2 and 4. Eight patients were included in the study. Ciprofloxacin was given at a dose of 200 mg over 30 min by using an automatic pump. Ciprofloxacin was measured by high-performance liquid chromatography. Peak levels of drug in serum were 2.95 +/- 1 mg/liter on day 2 and 2.43 +/- 0.7 mg/liter on day 4. Peak and trough levels in bronchial secretions were 0.95 +/- 0.51 and 0.21 +/- 0.12 mg/liter, respectively, on day 2 and 0.76 +/- 0.17 and 0.18 +/- 0.14 mg/liter, respectively, on day 4. The ratios of peak concentrations in bronchial secretions/serum were 0.32 +/- 0.11 and 0.33 +/- 0.06 on days 2 and 4, respectively. The ratios of the area under the concentration-time curve from 0 to 12 h (AUC0-12) for bronchial secretions/those for serum were 0.66 +/- 0.40 and 0.55 +/- 0.30 on days 2 and 4, respectively. A significant positive correlation was found on day 4 between the AUC0-12 for serum and the AUC0-12 for bronchial secretions. No significant correlations were found between peak values in serum and bronchial secretions.

The aim of this study was to document possible alterations of bupivacaine pharmacokinetic behaviour in rats during hyperthermia. Two groups of Wistar AF IO PS male rats (Group A = normothermic controls, Group B = hyperthermia-induced animals) received a single 20 mg.kg-1 ip dose of bupivacaine. Two other groups (Group C = normothermic controls without bupivacaine, Group D = hyperthermia-induced animals without bupivacaine) received, under the same experimental conditions, an equivalent volume of saline. Hyperthermia-induced animals (Groups B and D) were placed in a water-bath at 40 degrees C. Bupivacaine or saline were administered (Group B and D) four hours after the beginning of the experiment and blood samples were obtained by retro-orbital sinus puncture 0.25, 0.5, 1, 2, 4 and 8 hr after administration. Bupivacaine and its main metabolite, 2,6 desbutylbupivacaine (PPX) were assayed according to a gas liquid chromatographic method. The Cmax, Tmax, t1/2, Cl, Vd and AUC were determined according to a two compartment open model. Our data have demonstrated a decrease in clearance of bupivacaine (5.85 +/- 0.23 ml.hr-1 and 4.59 +/- 0.35 ml.hr-1 for groups A and B, respectively, P < 0.05, and, Tmax of PPX during hyperthermia (0.24 +/- 0.03 hr and 0.15 +/- 0.0 hr for Groups A and B, respectively, P < 0.05). In conclusion, hyperthermia induces a decrease in bupivacaine clearance in rats which may be of importance in clinical practice.

The obesity-induced kinetic changes have been studied only from twenty years, despite the frequency of such a pathological state; thus many work need to be done in this area. The tissular distribution of drugs may depend on the obesity-induced changes in the body composition taking into account the degree of drug liposolubility. Some other factors such as protein binding and regional blood flow may also be involved in tissular diffusion of drugs in obesity. Drug binding to albumin does not seem to be modified in obesity. On the contrary, the protein binding of some basic drugs is increased because of the rise of the plasma alpha 1 glycoprotein acid levels in obesity. Although the cardiac output and the total blood volume are increased in obese patients, the blood flow recalculated according to the adipose tissue weight, is less than in non obese subjects: this point could reduce the diffusion of some lipophilic drugs. More complex are the obesity induced changes in the hepatic clearance of drugs: some reactions such as oxydo-reduction and acetylation do not vary, some others such as sulfoconjugation or glucuronoconjugation are increased. The renal clearance is increased for drugs totally eliminated by glomerular filtration and for drugs which are both filtrated and secreted. According to the liposolubility characteristic of a drug and its clearance, one can calculate the loading dose and the maintenance dose.

We have investigated the possible influence of time of day on the activity of flumazenil on lignocaine-induced toxicity in mice. The circadian pattern of the period of latency for convulsions and the induced mortality for lignocaine alone and for lignocaine plus flumazenil was not statistically significant (cosinor or analysis of variance) but the influence of flumazenil on lignocaine-induced toxicity was circadian-time dependent (F = 27.8, P = 0.0001).

Our aim was to document possible alterations of theophylline pharmacokinetics in rats during fever. Two groups (group A = normothermic controls, group B = fever-induced animals) of Wistar AF IOPS male rats were injected at 19 30 h either with 2 g/kg of brewer's yeast subcutaneously (20% w/v) or with the equivalent volume of saline. Twelve hours later at 07:30 h the two groups received a single 12 mg/kg/IP dose of theophylline. Blood samples were obtained by retro-orbital sinus puncture 0, 0.25, 0.5, 1, 2, 4, 8, 12, 16 and 24 hours after administration. A third group of 10 male IOPS rats (group C) were used under the same experimental conditions in order to determine the influence of brewer's yeast-induced fever on biological parameters. Cmax, Tmax, Cmax/Tmax, T 1/2, Cl, Vd and AUC were determined according to a one-compartment open model. Our results confirm the fever-induced decrease in total plasma proteins and albumin but do not demonstrate any significant change in theophylline pharmacokinetic parameters.

This study was designed to document possible changes in bupivacaine kinetics in mice after a single 1 mg/kg injection of flumazenil. After a single 20 mg/kg i.p. dose of bupivacaine, C max, Vd, Cl and AUC were not significantly modified by flumazenil; even if T max was shown to be significantly shorter when flumazenil was associated, bupivacaine bioavailability did not seem to be modified and thus may not be involved in the explanation of previously reported increasing bupivacaine-induced mortality by flumazenil.

The purpose of this study was to investigate the influence of calcium channel blockers on bupivacaine-induced acute toxicity. For each of the three tested calcium channel blockers (diltiazem, verapamil and bepridil) 6 groups of mice were treated by two different doses, i.e. 2 and 10 mg/kg/i.p., or an equal volume of saline for the control group (n = 20); 15 minutes later, all the animals were injected with a single 50 mg/kg/i.p. dose of bupivacaine. The convulsant activity, the time of latency to convulse and the mortality rate were assessed in each group. The local anesthetic-induced mortality was significantly increased by the three different calcium channel blockers. The convulsant activity of bupivacaine was not significantly modified but calcium channel blockers decreased the time of latency to obtain bupivacaine-induced convulsions; this effect was less pronounced with bepridil.

The aim of this study was to investigate the possible influence of the time of administration on bupivacaine (B), etidocaine (E), and mepivacaine (M) protein and tissue (brain and heart) binding. For each anesthetic agent, a single dose of B (20 mg/kg), E (40 mg/kg), or M (60 mg/kg) was administered intraperitoneally at 10:00, 16:00, 22:00, and 04:00 h. Blood and tissue samples were collected 15 min after drug administration. This study documents significant circadian variations in protein and tissue binding of the three local anesthetic agents. We did not demonstrate a temporal relationship between the respective free and tissue levels. Thus, the temporal variations of free plasma, brain, and heart levels do not seem to be involved in the temporal changes of induced mortality.

The pharmacokinetics and tissue penetration of cefotetan were studied after a single injection of 2 g given intravenously for antimicrobial prophylaxis to 16 consecutive patients undergoing colorectal surgery. Concentrations in tissue greater than or equal to the MIC for 90% of the main pathogens tested were considered adequate. The elimination half-life at beta phase was 4.6 +/- 1.4 h, the total body clearance was 0.75 +/- 0.19 ml/kg/min, and the volume of distribution was 260 +/- 71 ml/kg. At the time of incision (33 +/- 16 min after the injection), cefotetan concentrations were 14.2 +/- 7 micrograms/g in abdominal-wall fat, 16.4 +/- 1 micrograms/g in epiploic fat, and 163 +/- 62 mg/liter in serum. At the time of surgical anastomosis (151 +/- 54 min), cefotetan concentrations were 33.3 +/- 6 micrograms/g in the colonic wall and 73 +/- 34 mg/liter in serum. Upon closure of the abdomen (216 +/- 76 min), cefotetan concentrations were 6.3 +/- 3 micrograms/g in abdominal-wall fat, 6.1 +/- 4 micrograms/g in epiploic fat, and 64 +/- 38 mg/liter in serum. Cefotetan tissue penetration was 10% into abdominal and epiploic fat and 46% into the colonic wall. Levels in tissue were compared with the MIC for 90% of the most frequently encountered pathogenic germs (Staphylococcus aureus, Bacteroides fragilis, and Escherichia coli). Adequate concentrations in tissue were obtained up to anastomosis but not upon closure. The authors therefore recommend the injection of an additional dose of 1 g before closure in order to ensure optimal efficacy throughout the surgical procedure.

Theophylline levels in plasma, erythrocytes and cantharides-induced blister fluid (BF) have been correlated with peak expiratory flow (PEF) in asthmatic patients. Nine asthmatic men received an IV infusion of 240 mg theophylline at a constant rate for 30 min. The theophylline concentrations in erythrocytes and blister fluid were 37% and 78% of those in plasma. There was not a strong correlation between erythrocyte or blister fluid penetration and the clinical effect of theophylline.

This study was designed to document possible changes in caffeine kinetics in female rats both according to the stage of the oestrous cycle and in castrated animals. After a single 12 mg/kg ip dose during proestrus, oestrus, dioestrus, or 15 days after castration, the plasmatic clearance of caffeine varied significantly with higher values during oestrous. The other pharmacokinetic parameters did not vary significantly.

The purpose of this study was to investigate the effect of a constant infusion rate of terbutaline on circadian bronchial peak expiratory flow rate (PEFR), heart rate and arterial pressure in patients with asthma exacerbation. Fifteen hospitalized asthmatic patients (6 females and 9 males, mean age 43.3 years, mean weight 67.0 kg) were included in this study. In order to reach the desired plasma concentrations of terbutaline immediately, a pharmacokinetic simulation was done. Based on the predicted values thus obtained, an initial 5-min bolus dose of 2.94 micrograms/kg was given to all patients at 7 a.m., i.e. at the beginning of the study. Over the following 24 h (7 a.m. to 7 a.m.), 33 micrograms/kg of terbutaline was infused intravenously at a constant rate with an electric pump. Since severe acute asthma requires corticosteroids, a 40-mg injection of methylprednisolone was given to all patients at 7 a.m. PEFR, heart rate, systolic arterial pressure, side effects and plasma terbutaline levels were recorded at 7 and 10 a.m., 1, 4, 7 and 11 p.m., and 3 and 7 a.m. the following morning. Terbutaline had a significant favorable effect on asthma exacerbation but no circadian rhythm was found in PEFR. Although terbutaline was infused at a constant rate, plasma levels depended on circadian variations.

The aim of the study was to evaluate, in clinical conditions, the penetration of ciprofloxacin into bronchial secretions. Eight patients were included in the study. They presented with nosocomial pneumonia and were under controlled mechanical ventilation. Ciprofloxacin was given at a dose of 3 mg/kg over 30 min. Serial bronchial and blood samples were obtained over a 12 hour period on day 2 and 4. Ciprofloxacin was measured by HPLC. Serum peak levels were 2.95 +/- 1 mg/l on day 2, and 2.43 +/- 0.7 mg/l on day 4. Bronchial peak and through levels were 0.95 +/- 0.51 mg/l and 0.21 +/- 0.12 mg/l, respectively, on day 2, and 0.76 +/- 0.17 mg/l and 0.18 +/- 0.14 mg/l, respectively, on day 4. The ratio of bronchial/serum peak was 0.32 +/- 0.11 and 0.33 +/- 0.06 on day 2 and 4, respectively. The ratio of AUC 0-12 h in the bronchial secretions/AUC 0-12 h in the serum samples was 0.66 +/- 0.04 and 0.55 +/- 0.27 on day 2 and 4, respectively.

The choice of dosing of osteoporosis drugs should lie upon appropriate studies, indicating particularly the minimal efficient dosing which is, in this area, of a particular importance. Because of technical difficulties in the realisation, very few studies have been reported at the present time. From a practical point of view, the good choice of dosing of anti osteoporotic drugs must be studied from dose-response relationship curvus at the beginning of phase III clinical studies. From literature, it appears that the supposed optimal dosing of anti osteoporotic drugs have frequently been assessed empirically or from studies with patent methodological errors. Such studies should be on the contrary, prospective in parallel groups, randomized, double-blinded, using a pertinent, validated and more sensitive criteria of response.

Because a eutectic mixture of lidocaine and procaine (EMLA cream) is used to treat pain in children who are undergoing venipuncture for screening clinical presurgery laboratory tests, this study was designed to investigate the influence of the time of application of EMLA cream on lidocaine transcutaneous absorption in children. The same phenomenon was also studied in rats. Local application of EMLA (right and left cubital fossae) was performed 1 hour before venipuncture in two groups of children (0.5 g/kg body weight at two sites), at 08:15 or 16.15 h; blood samples were performed 1 h later. Two groups of five rats each received 12 mg/kg lidocaine at 07:30 or 19.30 h by application to the back skin. Blood samples were collected 0.5, 1, 1.5, 2, 3, and 4 h after application. Plasma lidocaine levels were assayed according to an immunoenzymatic method (Abbott). Our data indicate that the lidocaine plasma levels were significantly different: higher in the evening for the children or in the morning for the rats. The plasma level of the local anesthetics (LA) represents an elimination route and thus may be inversely correlated to the skin amount of the LA.

The temporal variation in the NADPH-dependent lipid peroxidation and glutathione-S-transferase activity and in the concentration of cytosolic and microsomal proteins and in reduced glutathione of rat liver were investigated at 0100, 0500, 0900, 1300, 1700, and 2100 in male Sprague-Dawley rats synchronized to a 12-hr light-dark cycle. Highly significant time-dependent variations were obtained in the microsomal rate of lipid peroxidation, and in the concentration of reduced glutathione and cytosolic and microsomal protein. The maximal mean values for the lipid peroxidation, for the concentration of reduced glutathione, and of cytosolic and microsomal proteins were obtained at 1300, 0900, 0100 and 2100, respectively, whereas the corresponding minimal values were determined at 0100, 1700, 0900, and 1700. There was no temporal variation in the glutathione-S-transferase activity of rat liver. The temporal variation in microsomal peroxidation and in the concentration of reduced glutathione exhibited a characteristic circadian rhythm. There was no reverse relationship between the daily variation in the rate of microsomal lipid peroxidation and the hepatic concentration of reduced glutathione.

Our study investigated the differential effects of continuous or unequal day-night terbutaline dosing on circadian bronchial patency, heart rate, and arterial pressure in severe acute asthma. Forty-five hospitalized asthmatic patients (19 women and 26 men, mean age 45.4 years, mean weight 63.5 kg) were included in this multicenter study. Three groups of patients (corresponding to three dosing schedules) were randomized; the three groups were comparable, since no statistically significant difference was detected in the age, weight, or peak expiratory flow values at the beginning of the study. In order to reach immediately the concentrations of terbutaline corresponding to the desired unequal day-night concentrations, a theoretical pharmacokinetic simulation was done to predict the outcome in terms of the plasma concentrations after the three dosing regimens; the results of this simulation allowed us to calculate the initial bolus dose to be given over 5 min to groups A, B, and C, i.e., 1.47, 2.94, and 4.41 micrograms/kg, respectively. This bolus was given to all patients at 0700 h, the beginning of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of ofloxacin was studied in 12 intensive care patients, 6 of whom being under mechanical ventilation. All patients had a creatinine clearance greater than 60 ml/min/1.73 m2 and they were given 3 mg/kg. IV ofloxacin within 30 mn, with a twice daily regimen for 7 days. Pharmacokinetic studies were performed on day 1 (D1) and 7 (D7). Between D1 and D7 a significant increase in T 1/2 beta, AUC and blood levels were observed together with a decrease in total body clearance. Creatinine clearance was not modified between D1 and D7 but ofloxacin renal clearance was considerably altered. Abnormalities in ofloxacin renal tubular secretion may account for the drug cumulation which was observed during repeated administration in intensive care patients.

The aim of this study was to investigate the possible influence of the time of administration on etidocaine acute toxicity and kinetics in mice. Different groups of adult male NMRI mice maintained under controlled environmental conditions (lights on 06.00-18.00) were injected at one of the following times: 10.00, 16.00, 19.00, 22.00, 01.00 and 04.00 h with four doses of etidocaine at each time point to establish the acute toxicity (LD 50). To assess chronokinetics, a single 40 mg kg-1 i.p. dose of etidocaine was given to adult male NMRI mice at four fixed times: 10.00, 16.00, 22.00 and 04.00 h. Etidocaine serum levels were determined by GLC. The data showed significant 24 h variations of the Cmax only (highest value = 9.64 +/- 1.31 micrograms mL-1 at 10.00 P less than 0.05; amplitude, (maximum-minimum) mean x 100 = 84%) Vd, (amplitude = 59.7%), alpha and beta phase elimination half-lives (amplitude = 52 and 35%, respectively), clearance (amplitude = 23%) and AUC infinity 0 (amplitude = 22%) were not found to be significantly time dependent. Etidocaine kinetics in brain were determined similarly; a significant temporal variation was found for the elimination half life (amplitude, 161.9%) and AUC (amplitude, 133.2%) but not for Cmax. These data demonstrate a temporal pattern of etidocaine kinetics similar to those reported previously for other local anaesthetic agents, bupivacaine and mepivacaine. The temporal changes in etidocaine induced acute toxicity may result in part from its chronokinetic changes.

Twenty children undergoing surgery received a lumbar block using 0.4 ml/kg mepivacaine 2.0%. They were randomized into two groups, one of which received midazolam 0.4 mg/kg rectally as premedication. Midazolam administration did not significantly influence the plasma concentrations of mepivacaine.

The effect of menstrual cycle on the pharmacokinetics of theophylline has been studied in 9 female asthmatic patients. At three different times during the cycle (first, tenth and twentieth days) each subject received an i.v. infusion of 240 mg theophylline. Significant changes were found in the kinetics of theophylline according to the menstrual cycle. The maximum plasma drug concentration, minimum mean residence time, and minimum elimination half-life were observed at mid-cycle. The lowest clearance was observed at D 20. The AUC and volume of distribution did not vary significantly during the cycle.

Regarding interrelationships between epilepsy, antiepileptic drugs and neuroendocrinological events, sodium valproate effects on estrous cycle of the rat have been performed by daily vaginal smears for twenty one days with 200, 100, 20 and 10 mg per kg bodyweight. Our data showed that sodium valproate did not significantly modify the evolution of estrous cycle even if intracerebral GABA content increase has been reported to influence hormonal secretions.

Cyclic variations in circulating hormone levels and the associated physiological changes during the menstrual cycle may modify the pharmacokinetics of drugs. So gastric acidity or gastrointestinal motility variations may alter drug absorption; plasma protein concentration changes may also modify drug binding. Finally biotransformations and elimination may be changed during the menstrual cycle. The few studies on menstrual changes in pharmacokinetics are often conflicting and this factor needs to be better documented.

The aim of this study was to investigate the possible influence of the time of administration on mepivacaine acute toxicity and kinetics in mice. Four different groups of adult male NMRI mice maintained under controlled environmental conditions (lights on: = 0600-1800 h) were injected at one of the following times: 1000, 1600, 1900, 2200, 0100 and 0400 h with one of four doses of mepivacaine at each time point to establish the acute toxicity (LD50). To assess chronokinetics, a single 60 mg kg-1 i.p. dose of mepivacaine was given to adult male NMRI mice at four fixed times: 1000, 1600, 2200 and 0400 h. Mepivacaine plasma concentrations were determined by GLC. Our data showed significant 24 h variations in the following parameters: Highest tmax value = 0.366 +/- 0.073 h at 1000 h (P less than 0.005, amplitude, maximum-minimum/mean x 100, = 184%), highest Cmax/tmax ratio = 177.17 +/- 9.49 at 2200 h (P less than 0.005, amplitude = 192%), highest Vd = 0.842 +/- 0.23 L kg-1 at 2200 h (P less than 0.005, amplitude = 158%) and highest beta phase elimination half-life = 5.408 +/- 1.36 h at 2200 h (P less than 0.025, amplitude = 145%). Cmax (amplitude = 15%), AUC infinity 0 (amplitude = 24%) and clearance (amplitude = 23%) were not significantly time-dependent. These data demonstrate a temporal pattern of mepivacaine kinetics similar to those reported previously for bupivacaine. The temporal changes in mepivacaine-induced acute toxicity may result in part from its chronokinetic changes.