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Background: Current theoretical models of nicotine dependence assume a close relationship between use and dependence; however, previous data suggest that many daily smokers fail to develop nicotine dependence., Objectives: To determine what percentage of daily smokers fail to meet DSM-IV criteria for nicotine dependence within their lifetime, how non-dependence relates to duration and quantity of cigarette use, and whether other tobacco use and/or specific dependence criteria differentiate never-dependent and dependent smokers., Methods: Cross-sectional data collected via personal interview from a nationally representative sample of 8213 past year daily smokers were analyzed., Results: Approximately 39.4% of daily smokers never reached nicotine dependence. While the probability of remaining non-dependent decreased with smoking quantity and duration since the onset of daily smoking, a substantial portion of individuals (37.7%) who reported smoking >or=10 cigarettes per day and began smoking daily >or=10 years prior, remained never nicotine dependent., Conclusions: The absence of nicotine dependence in heavy daily smokers may result from limitations in the measurement of dependence and/or nicotine exposure. Alternatively, some individuals may be relatively resistant to becoming nicotine dependent despite extensive use. The latter explanation would have important implications for understanding the nature of nicotine dependence.

We have hypothesized that nicotine has two effects on reinforcement; it increases the probability of responses resulting in nicotine delivery (primary reinforcement) and enhances the apparent reward value of non-nicotine reinforcers (reinforcement enhancing effect). The present studies investigated two predictions generated by this hypothesis: (1) that the reinforcement enhancing effect will depend on apparent stimulus reward value and (2) that the temporal profile of this effect would depend on the pharmacological profile of nicotine. In Experiment 1, rats were trained to lever press for one of two audio-visual stimuli that differed in their intrinsic reinforcing value and then the effect of pre-session nicotine (0.4 mg/kg base) or saline injections was tested. The stimulus that supported very low rates of operant responding displayed smaller increases in responding after pre-session injections of nicotine. In Experiment 2 the effect of nicotine injected 5 min before the session was compared to the effect of nicotine injected 1h after the session using the more reinforcing stimulus condition from the first experiment. A control group received only vehicle injections. In contrast to nicotine injected just prior to the session, post-session injections of nicotine had no detectable effect on responding for the more reinforcing stimulus. These results indicate that the reinforcement enhancing action of nicotine depends on the intensity of the primary reinforcer and that enhanced reinforcement by nicotine depends on coincident access to a stimulus with reinforcing properties.

This study examined changes in rhythmic arm shaking and laterality biases in infants observed longitudinally at three points: just prior to, at, and just following reduplicated babble onset. Infants (ranging in age from 4 to 9 months at babble onset) were videotaped at home as they played with two visually identical audible and silent rattles presented at midline for 1.5 min each. Rate of rattle shaking increased sharply from the pre-babble to the babble onset session; but there was no indication that this increase was specific to the right arm. This finding suggests that the link between babble onset and increased rhythmic arm activity may not be the product of language-specific mechanisms, but is rather part of a broader developmental process that is also perceptual and motor.

In this study we examined early motor, vocal, and communicative development in a group of younger siblings of children diagnosed with autism (Infant Siblings). Infant Siblings and no-risk comparison later-born infants were videotaped at home with a primary caregiver each month from 5 to 14 months, with follow-up at 18 months. As a group, Infant Siblings were delayed in the onset of early developmental milestones and spent significantly less time in a greater number of postures, suggestive of relative postural instability. In addition, they demonstrated attenuated patterns of change in rhythmic arm activity around the time of reduplicated babble onset; and they were highly likely to exhibit delayed language development at 18 months.

The purpose of the study was to advance our understanding of resilience by studying multiple protective factors associated with positive adjustment among an ethnically diverse sample of 310 low-income boys followed prospectively from ages 1.5 to 12 years, using neighborhood quality to define risk status. The results indicated that child and family protective factors measured in early childhood were all significantly associated with positive adjustment at 11 and 12 years of age. However, these results were qualified by risk level, such that parent-child relationship quality was only significantly related to positive outcomes in the context of low levels of risk.

This study examined the effect of exemplar typicality on reaction time and accuracy of categorization. High-functioning children (age 9-12), adolescents (age 13-16), and adults with autism (age 17-48) and matched controls were tested in a category verification procedure. All groups showed improved processing throughout the lifespan for typical and somewhat typical category exemplars. However, individuals with autism responded more slowly than matched controls to atypical exemplars at all ages. The results are discussed in terms of potential differences in the type of processing that may be required for categorizing typical and atypical category exemplars. Parallels are also drawn to the results of previous studies on face processing in individuals with autism.

Background: Midazolam (MDZ) is used as an assessment of human cytochrome P450 3A (CYP3A) activity. A single blood measurement is used as a marker of its activity based on an observed correlation between MDZ clearance and the 1'-hydroxymidazolam (1'-OH-MDZ): MDZ plasma ratio is assessed at 0.5 h followig the intake of a single 7.5 mg oral dose of MDZ in healthy young volunteers. In addition, a 4-h plasma MDZ measurement has been found to be an excellent predictor of AUC and CYP3A activity., Objectives: The main aim of this study was to define a single-point blood sampling in healthy elderly volunteers. The secondary objective was to investigate the pharmacological effects of a low oral dose of MDZ (5 mg) and its potential psychometric changes., Methods: Eight healthy elderly Caucasian volunteers participated in a single-dose, open-label, non-comparative study. Each subject received a single 5 mg oral dose of MDZ. Plasma concentrations of MDZ and its major metabolite, 1'-OH-MDZ, were assayed over 12 h. Secondary assessments of critical flicker fusion (CFF), body sway and mini-mental state examination were also carried out during the 12-h post-administration period., Results: A moderate correlation was observed between MDZ clearance and the 1'-OH-MDZ: MDZ plasma concentration ratio at 9 h post-dosing (Rho=0.81; p=0.04), but an even better correlation (Rho=0.99; p<0.009) was found between MDZ AUC and MDZ plasma concentration at 6 h post-dosing, with the latter value corresponding approximately to the average mean residence time (MRT) determined in our trial. This study was well-tolerated despite a significant transitory decrease (relative to baseline) in cortical arousal at 1 h post-dosing, as assessed by CFF, and a non-significant decrease (relative to baseline) in balance and vigilance also measured at 1 h and assessed on body sway, compared to baseline values., Conclusion: Despite the small sample size, based on the results of healthy, elderly volunteers, a single MDZ plasma measurement taken at 6 h post-oral administration may represent an accurate marker of CYP3A phenotype. This single-time-point method could be used safely for predicting drug-drug or diet interactions and identifying individuals with genetic polymorphism that affect CYP3A activity.

Background: Alterations of hypothalamic-pituitary-adrenal (HPA) axis function and sympathetic-adrenal activity have been proposed as key factors in biological models of posttraumatic stress disorder (PTSD)., Methods: We examined neuroendocrine function in female survivors of intimate partner violence (IPV) with lifetime (current or remitted) PTSD (n=29) and in women who were exposed to IPV but never developed PTSD (n=20). Salivary cortisol was collected as a marker of HPA axis function at 1, 4, 9, and 11 h after awakening. Platelet epinephrine and norepinephrine were assayed as markers of sympathetic-adrenal activation., Results: Women with lifetime PTSD had significantly higher cortisol levels across the day compared to abuse-exposed participants without PTSD, after controlling for age, depression, severity, and latency of abuse. There were no significant group differences in levels of platelet catecholamines., Conclusions: Elevated cortisol levels may be a biomarker of IPV-related lifetime PTSD, reflecting long-lasting changes associated with trauma-exposure or possibly a reflection of risk for PTSD in women.

Rationale: Nicotine has two effects on reinforcement in traditional self-administration paradigms. It serves as a primary reinforcer by increasing the probability of behaviors that result in nicotine delivery. However, nicotine also potently enhances behaviors that result in the delivery of nonpharmacological reinforcers., Objectives: The present study sought to dissociate these two effects of nicotine on reinforcement., Methods: For one group of rats (2 lever), a nonpharmacological reinforcer [visual stimulus (VS)] was available for pressing one lever. Nicotine infusions were available for pressing a different lever. A second group (NIC + VS) received more traditional self-administration training; both the VS and nicotine were delivered for pressing a single active lever. Control groups received either nicotine infusions (NIC only) or VS presentations (VS only) for pressing the active lever., Results: Nicotine alone was a weak reinforcer; the VS alone was slightly more reinforcing than nicotine. When these two reinforcers were combined (NIC + VS), response rates were synergistically increased. For the 2-lever group, responding on the nicotine lever was weak, matching the response rates of rats receiving nicotine alone. However, responding on the VS lever was potently enhanced in this group; equaling the response rates for rats receiving both reinforcers for making a single response (NIC + VS)., Conclusions: These data indicate that the reinforcement-enhancing effects of nicotine are very potent even when only moderate quantities of the drug are self-administered. Moreover, they provide the first demonstration that the reinforcement-enhancing and primary reinforcing effects of nicotine can be dissociated behaviorally.

We investigated the stability in resting EEG across a 1- to 3-year interval in 49 adults (33 female and 16 male) with a history of unipolar depression (first onset prior to the age of 14) and 50 controls (33 female and 17 male) with no history of major psychopathology. Current depressive symptoms were quantified by self-report at both assessments. For the entire sample, EEG asymmetry in the alpha range was moderately stable (intraclass correlations between 0.39 and 0.61). Sex, history of depression, depressive symptom severity at Time 2, and change in symptom severity between Time 1 and Time 2 were unrelated to stability of EEG asymmetry. These findings support the view that resting frontal EEG asymmetry reflects a moderately stable individual difference in adults, irrespective of sex and history of depression.

Despite clear evidence of important genetic influences on schizophrenia, identifying the genes involved has been difficult because of the genetic complexity of the phenotype. The use of additional phenotypic measures that are more sensitive to the genetic liability than is the clinical diagnosis should enhance the power to detect small individual genetic effects. The present study assessed the neuropsychological performance of 30 male schizophrenia probands, 30 of their unaffected male siblings, and 20 well controls matched on age, sex, and education in order to identify measures that may be particularly sensitive to the genetic liability to schizophrenia and thus may be useful in gene mapping studies. Siblings showed impaired neuropsychological performance compared to controls on four out of the five measures used. Additional results suggested that Trails B was especially effective at discriminating index siblings from controls, thus supporting its potential utility as a candidate quantitative phenotype to aid in gene mapping studies of the disorder.

We present a supercritical radiative shock experiment performed with the LULI nanosecond laser facility. Using targets filled with xenon gas at low pressure, the propagation of a strong shock with a radiative precursor is evidenced. The main measured shock quantities (electronic density and propagation velocity) are shown to be in good agreement with theory and numerical simulations.

Objective: To compare the pharmacokinetic parameters of sequential intravenous and subcutaneous teicoplanin in the plasma of surgical intensive care unit patients., Design and Setting: Prospective, randomized, crossover study in the surgical ICU of a university hospital., Patients: Twelve patients with a suspected nosocomial infection, a serum albumin level higher than 10 g/l, body mass index less than 28 kg/m(2), and estimated creatinine clearance higher than 70 ml/min., Interventions: Teicoplanin was first administered intravenously as a loading dose of 6 mg/kg per 12 h for 48 h and then continued at a daily dose of 6 mg/kg. On the fourth day patients were randomized in two groups according to the order of the pharmacokinetic studies., Measurements and Results: Serial plasma samples were obtained to measure teicoplanin levels. Compared with a 30-min intravenous infusion the peak concentration of teicoplanin after a 30-min subcutaneous administration occurred later (median 7 h, range 5-18) and was lower (16 micro g/ml, 9-31; vs. 73, 53-106). Despite large and unpredictable interindividual differences no significant differences between subcutaneous and intravenous administration were observed in: trough antibiotic concentrations (10 micro g/ml, 6-24; vs. 9, 5-30), the area under the teicoplanin plasma concentration vs. time curves from 0 to 24 h (AUC(0-24h); 309 micro g/ml per minute, 180-640; vs. 369, 171-955), the proportion of the dosing interval during which the plasma teicoplanin concentration exceeded 10 micro g/ml (96%, 0-100%; vs. 79%, 13-100%), and the ratio of AUC(0-24h) to 10 (77, 45-160; vs. 92, 43-239)., Conclusions: In critically ill patients without vasopressors a switch to the subcutaneous teicoplanin after an initial intravenous therapy seems to give comparable pharmacodynamic indexes of therapeutic success.

A previously developed pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to investigate the epileptogenic activity of norfloxacin as a representative antibiotic with concentration-dependent antimicrobial activity. Rats received an intravenous infusion of norfloxacin at a rate of 5 mg kg of body weight(-1) min(-1) over 30 min. Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion. An important delay was observed between concentrations of norfloxacin in plasma and the EEG effect. Indirect effect models failed to describe these data, which were successfully fitted by using an effect compartment model with a spline function to describe the relationship between effect and concentration at the effect site, as previously observed with imipenem. The robustness of the PK-PD model was then assessed by keeping the dose constant but increasing the duration of infusion to 120 and 240 min. Although this was accompanied by PK modifications, PD parameters did not vary significantly, and the PK-PD model still applied. In conclusion, the successful PK-PD modeling of the norfloxacin EEG effect in rats should be considered to predict and reduce the epileptogenic risk associated with this antibiotic as a representative fluoroquinolone (E. Fuseau and L. B. Sheiner, Clin. Pharmacol. Ther. 35:733-741, 1984).

The objective of this pilot study was to examine the relation between fluvoxamine (FVX) plasma concentrations, therapeutic response and side effects during a four-week treatment period. Twenty-two patients who met the DSM-IV criteria for major depression received 100 mg FVX during the first 2 days of treatment and then 150 or 200 mg/day. No clear relationship between plasma concentrations and side effects was detectable. A relationship between plasma concentrations and clinical efficacy was detectable after 21 days but not after 28 days of treatment. These preliminary results indicate that therapeutic drug monitoring might be useful for patients treated with FVX.

Psychological stress is known to affect immune function and to predict infectious disease susceptibility. However, not all individuals who are stressed develop disease. In the present article, we report on a series of studies from our laboratory describing interindividual variability of immune responses to psychological stress. In our initial series of experimental investigations, we demonstrated that acute laboratory stress alters both quantitative and functional components of cellular immunity. An examination of response variability revealed that individuals differ substantially in the magnitude of these immune responses. These differences were found to parallel (and be predicted by) interindividual variability in stress-induced sympathetic nervous system activation. Further investigation revealed that individuals vary consistently in the magnitude of their immune responses to stress, making it conceivable that individual differences in immune reactivity provide a vulnerability factor mediating relationships between stress and disease. In support of this possibility, we have recently reported initial evidence that individual differences in the magnitude of stress-induced reduction of immune function may be of clinical significance, being related to an immune response relevant for protection against infection, antibody response to hepatitis B vaccination.

Purpose: To investigate the norfloxacin-theophylline convulsant interaction in vivo, with an experimental approach distinguishing between pharmacodynamics and pharmacokinetics contributions to the observed effect., Methods: Male Sprague Dawley rats (n = 38) were infused each compound separately or in different combination ratios. Infusion was maintained until the onset of maximal seizures. Cerebrospinal fluid and plasma samples were collected for high performance liquid chromatography drug determination. The nature and intensity of the pharmacodynamics interaction between drugs was quantified with an isobolographic approach., Results: Isobolograms suggested a relatively marked antagonism between norfloxacin and theophylline at the cerebrospinal fluid (previously shown to be part of the biophase) and dose levels, but not at the plasma (free and total concentrations) levels. These apparent discrepancies could be explained by nonlinear distribution or/and distribution desequilibrium phenomenon., Conclusions: These findings showed that the quantitative isobolographic approach is appropriate to assess the nature and intensity of the pharmacodynamic interaction between two drugs when data are collected within the biophase, but that data interpretation outside the biophase can be risky due to further pharmacokinetic complexities, in particular slow or/and nonlinear diffusion into the biophase.

The epileptogenic activity of imipenem was investigated in rats with experimental renal failure induced by uranyl nitrate injection by using electroencephalogram (EEG) recording and a pharmacokinetic-pharmacodynamic model including an effect compartment. Results previously obtained with healthy rats were used to estimate the dose of imipenem required to induce an observable but nonlethal EEG effect on the assumption that only the pharmacokinetic parameters of the model would be affected by renal failure. Good agreement was observed between the predicted and observed effects.

The proconvulsant effect of biphenyl acetic acid (BPAA) on several fluoroquinolones (FQs) was investigated in vivo, by measuring drug concentrations in the biophase at the onset of convulsions. Male Sprague-Dawley rats (n = 134) were given BPAA orally, at various doses 1 h before starting FQ infusion, which was maintained until the onset of maximal seizures, when cerebrospinal fluid (CSF) and plasma samples were collected for drug concentration determination. The FQ-BPAA interactions in the biophase (CSF) were adequately described on most occasions by an inhibitory Emax effect model with a baseline effect parameter. The efficacy of the proconvulsant effect was characterized by the ratio of the CSF concentrations of FQs at the onset of convulsant activity when BPAA was absent (CCSF0, FQs) and as BPAA CSF concentrations tended toward infinity (CCSFbase, FQs). This ratio varied from 15 for enoxacin to 1.9 for sparfloxacin. The potency of the proconvulsant effect was characterized by the CSF concentration of BPAA corresponding to a proconvulsant effect half of its maximum. This parameter varied between 0.18 +/- 0.06 micromol/L with enoxacin and 15.0 +/- 12.1 micromol/L with sparfloxacin. The CSF diffusion of all FQs was apparently non-linear, as well as the plasma protein binding of BPAA, complicating interpretation of plasma data. The important variability in the proconvulsant effect of BPAA demonstrated in this study between various FQs suggests that in vitro gamma-aminobutyric acid (GABA) binding experiments conducted in the presence of BPAA are unlikely to be good predictors of FQ convulsant risk in clinical practice.

Background: Beta-2 agonists such as salbutamol are used, not only by asthmatic athletes to prevent exercise induced asthma, but also by non-asthmatic athletes as a potentially ergogenic agent. We have investigated whether inhaled salbutamol enhances endurance performance in non-asthmatic athletes., Methods: A prospective double blind, randomised, three way crossover design was used to study the effects of 200 microg and 800 microg inhaled salbutamol versus a placebo in 12 trained triathletes. The treatments were compared in three identical cycle ergometer sessions at 85% of the predetermined maximal oxygen uptake. Lung function, endurance time, metabolic parameters (glucose, potassium, lactate, free fatty acid, and glycerol), and psychomotor performance were evaluated., Results: Neither endurance time nor post-exercise bronchodilation were significantly different between the treatments. Metabolic parameters were affected by exercise but not by treatment., Conclusions: Inhaled salbutamol, even in a high dose, did not have a significant effect on endurance performance in non-asthmatic athletes, although the bronchodilating effect of the drug at the beginning of exercise may have improved respiratory adaptation. Our results do not preclude an ergogenic effect of beta2 agonists given by other routes or for a longer period.

A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was developed to investigate the epileptogenic activity of imipenem in rats. Initially, animals received an intravenous infusion of imipenem at a rate of 2.65 mg min(-1) for 30 min. Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion. A dramatic delay was observed between concentrations of imipenem in serum and the EEG effect; this effect was accompanied by tremors and partial seizures. Indirect-effect models failed to describe these data, which were successfully fitted using an effect compartment model. The relationship between effect and concentration at the effect site was best described by a spline function. The elimination rate constant from the effect compartment was severalfold lower than that from the central compartment. The robustness of the model was then confirmed after administering the imipenem dose over 60 and 90 min. In conclusion, the successful PK-PD modeling of the imipenem EEG effect in rats constitutes a major improvement for better prediction of the epileptogenic risk associated with this antibiotic.

The role of mdr1a-encoded P-glycoprotein on transport of several fluoroquinolones across the blood-brain barrier was investigated. In vitro, P-glycoprotein substrates were selected by using a confluent monolayer of MDR1-LLC-PK1 cells. The inhibition of fluoroquinolones (100 microM) on transport of rhodamine-123 (1 microM) was compared with P-glycoprotein inhibitors verapamil (20 microM) and SDZ PSC 833 (2 microM). Subsequently, transport polarity of fluoroquinolones was studied. Sparfloxacin showed the strongest inhibition (26%) and a large polarity in transport, by P-glycoprotein activity. In vivo, using mdr1a (-/-) and wild-type mice, brain distribution of pefloxacin, norfloxacin, ciprofloxacin, fleroxacin and sparfloxacin was determined at 2, 4, and 6 h following intra-arterial infusion (50 nmol/min). Brain distribution of sparfloxacin was clearly higher in mdr1a (-/-) mice compared with wild-type mice. Sparfloxacin was infused (50 nmol/min) for 1, 2, 3 and 4 h in which intracerebral microdialysis was performed. At 4 h, in vivo recovery (dynamic-no-net-flux method) was 6.5+/-2.2 and 1.5+/-0.5%; brain(ECF) concentrations were 5.1+/-0.2 and 26+/-21 microM; and total brain concentrations were 7.2+/-0.3 and 23+/-0.3 microM in wild-type and mdr1a (-/-) mice, respectively. Plasma concentrations were similar (18.4+/-0.7 and 17.9+/-0.5 microM, respectively). In conclusion, sparfloxacin enters the brain poorly mainly because of P-glycoprotein activity at the blood-brain barrier.

The main objective of this study was to compare the cerebrospinal fluid (CSF) diffusion of imipenem and meropenem at steady state, following intravenous infusions at various rates in rats. A preliminary experiment was conducted to estimate the elimination half-lives of these two carbapenem antibiotics, and then to evaluate the infusion duration necessary to reach steady state. CSF diffusion of imipenem was essentially linear over the wide range of infusion rates (66-1,320microg min(-1)) and corresponding steady-state plasma concentrations (11.7-443.0 microg mL(-1)). Conversely the CSF diffusion of meropenem was saturable, with a predicted maximum CSF concentration equal to 1.3 microg mL(-1). Extrapolation of these data to the clinical situation may not be possible since the rats had normal blood-brain and blood-CSF barriers whereas patients with diseases such as meningitis may not. However, it is suggested that the observed differences in the diffusion characteristics of imipenem and meropenem may be partly responsible for their differences in toxicity and efficacy at the central level.

Fluoroquinolones (FQs) are associated with a low incidence of central nervous system (CNS) side effects, possibly leading to convulsions, especially when co-administered with nonsteroidal anti-inflammatory drugs (NSAIDS). Although the in vivo pro-convulsant activity of NSAIDS is essentially unknown, the convulsant potential of FQs is traditionally evaluated by in vitro gamma-aminobutyric acid (GABA) binding experiments in the presence of 4-biphenyl acetic acid (BPAA), the active metabolite of fenbufen. The aim of this study was therefore to investigate the BPAA-norfloxacin convulsant interaction in vivo. Male Sprague-Dawley rats (n = 27) were given BPAA orally, at various doses 1 h before norfloxacin infusion, which was maintained until the onset of maximal seizures, when cerebrospinal fluid (CSF) and plasma samples were collected for analysis. An inhibitory E(max) effect model with a baseline effect parameter was fitted to the norfloxacin versus BPAA concentrations in the CSF, previously shown to be part of the biophase. This model includes three parameters: the concentrations of norfloxacin in the absence of BPAA (C(CSF0, Nor)), and when BPAA concentration tends toward infinity (C(CSFbase, Nor)), and the BPAA concentration for which half of the maximal effect is observed (C(CSF50, BPAA)). The maximal proconvulsant effect of BPAA is given by the C(CSF0, Nor) / C(CSFbase, Nor) ratio, estimated to approximately 6 in this study. Derived models were developed in plasma to account for the non-linear CSF diffusion of norfloxacin and protein binding of BPAA. In conclusion this study has shown that the convulsant interaction between norfloxacin and BPAA in rats, can be adequately characterized by modelling of the CSF concentrations of the two drugs at the onset of activity, following their administration in various proportions.

Imipenem and meropenem CSF diffusion was comparable in DBA/2 mice but only imipenem induced convulsions, not related to CSF concentration.

The in vivo convulsant activities in rats of five representative fluoroquinolones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were compared. The experimental approach allowed distinction between the drugs' ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the highest intrinsic convulsant activities had the lowest levels of diffusion in CSF and vice versa. This in vivo approach provides information complementary to that of in vitro experiments and should be recommended for early preclinical assessment of a new FQ's epileptogenic risk.

The epileptogenic potential of pefloxacin and norfloxacin, two quinolone antibiotics, was investigated in vivo in three different animal species by measuring drug concentrations in cerebrospinal fluid (CSF), which is part of the biophase, at the onset of convulsions. Interestingly, the pefloxacin-to-norfloxacin concentration ratios in CSF were virtually constant across the species (7.0, 6.6, and 6.0 in mice, rats, and rabbits, respectively), suggesting that this approach could be used to predict the relative epileptogenic potential of quinolones in humans.

Purpose: A new mathematical approach was developed to quantify convulsant interaction between pefloxacin and theophylline in rats., Methods: Animals received each compound separately or in different combination ratios. Infusion was stopped at the onset of maximal seizures. Cerebrospinal fluid (CSF) and plasma samples were collected for HPLC drug determination. The nature and intensity of the pharmacodynamic (PD) interaction between drugs was assessed with a new modeling approach which includes (a) data transformation to create an essentially error-free X-variable and (b) estimation of an interaction parameter a by fitting a nonlinear hyperbolic model to the combination data with unweighted nonlinear regression., Results: Drug disposition to the biophase was linear within the range of administered doses. The estimates of a suggested a Loewe antagonistic interaction between pefloxacin and theophylline at the induction of maximal seizures in rats. Similar intensity of PD interaction was observed at the dose and biophase level (alpha was -0.415 +/- 0.069 and -0.567 +/- 0.079, respectively)., Conclusions: The suitability of the proposed model was assessed by Monte Carlo simulation. This new mathematical approach enabled the characterization of the Loewe antagonistic nature of the PD (convulsant) interaction between pefloxacin and theophylline, whereas previously used methodologies failed to do so.

The purpose of this investigation was to compare the convulsant activity of two quinolones differing, respectively, by the presence (pefloxacin) or absence (norfloxacin) of a methyl group on the piperazine moiety at the position 7 of their parent nuclei and consequently by their lipophilicity. An in vivo model was used, which can distinguish between ease in reaching pharmacological receptors at the central nervous system level, and ability to interact with these receptors. Male Sprague-Dawley rats (approximately 230g-300g) received an i.v. infusion of pefloxacin or norfloxacin at one of four different rates: 480, 960, 1440 and 1920 micromol/hr, until the onset of maximal seizures. This occurred after an average of 12.7 to 69.4 min. We found enough evidence to suggest that in these conditions the contribution of pefloxacin metabolites, including norfloxacin, to its convulsant activity was negligible. Doses of pefloxacin and concentrations in cerebrospinal fluid and plasma (total and unbound) at the pharmacodynamic endpoint were all independent of infusion rate, whereas only cerebrospinal fluid concentrations of norfloxacin were independent of infusion rate. The overall cerebrospinal fluid concentration of norfloxacin (47.3 +/- 9.9 micromol/liter) was about 8-fold lower than that of pefloxacin (380 +/- 27 micromol/liter), indicating that on average the "intrinsic convulsant activity" of norfloxacin is 8-fold greater than that of pefloxacin. However, total doses of pefloxacin and norfloxacin at the onset of maximal seizures were in the same order of magnitude (1500-2000 micromol/kg), suggesting that the higher ability of the more lipophilic pefloxacin to reach central nervous system compensates for its lower intrinsic convulsant activity.

The effect of tamoxifen on the pharmacokinetics of theophylline was investigated in male Sprague-Dawley rats. The oral administration of tamoxifen at a dose equal to 40 mg kg-1 48 h before the intravenous injection of theophylline 10 mg kg-1, significantly (P < 0.05) increased the clearance of theophylline by 39%, with no apparent effect on the volume of distribution. As a consequence, the elimination half-life of theophylline was significantly (P < 0.05) shortened in the tamoxifen-treated rats (3.56 +/- 0.39 h vs 5.25 +/- 0.48 h) as well as its mean residence time (5.04 +/- 0.60 h vs 7.50 +/- 0.75 h). Although these data cannot be directly extrapolated to the clinical situation, they provide experimental support to suggest that more attention should be paid to the potential risk of pharmacokinetic interactions in the presence of tamoxifen.

The purpose of this study was to compare the nephrotoxicity of gentamicin and vancomycin alone and in combination. Thirty-two male Sprague-Dawley rats were randomized into 4 groups of 8 animals. Each group received 200mg/kg gentamicin (G) i.m., or 300 mg/kg vancomycin (V) i.v., or an association of 200 mg/kg gentamicin + 300 mg/kg vancomycin (i.m. and i.v., respectively), or 0.9% NaCl solution i.m. and i.v. (controls). To determine AAP, GGT, and NAG enzyme excretions, urine samples were taken over 24-h periods before and after the start of the experiment. A single renal cortical sample was obtained at necropsy for quantitation of antibiotic levels. No significant modifications of urinary excretions of creatinine and enzymuria were noted during the 24-h period before each drug administration or in controls. AAP, GGT, and NAG excretions were significantly increased after G and G + V injections (p < 0.001), whereas only AAP and GGT were statistically higher in rats receiving V (p < 0.05). NAG elimination (mean +/- SD) was higher in G + V (16.0 +/- 0.2 IU/mmol creatinine/24 h; p < 0.001) than g (8.8 +/- 0.6) or V (1.7 +/- 0.2). Surprisingly, mean vancomycin cortical levels decreased in the combination (827 +/- 131 vs. 1964 +/- 23 micrograms/g for V alone; p < 0.001), whereas gentamicin concentration was unchanged (826 +/- 66 vs. 839 +/- 28 micrograms/g for G alone). Determination of enzymuria allowed the nephrotoxicity of the antibiotics to be graded in the following order: vancomycin + gentamicin > gentamicin > vancomycin.

The time course of arterial plasma lidocaine concentration, following an epidural anaesthesia via the sacrococcygeal or the S4-S5 trans-sacral approach, was studied in nine healthy piglets (7.8 +/- 1.3 weeks). Plasma lidocaine concentrations were measured for up to six hours after administration (5 mg/kg). Peak plasma concentration was 1.83 +/- 0.17 mg/l. Pharmacokinetic parameters determined from an independent compartment model were not different from those observed after an epidural administration of lidocaine via the sacrococcygeal space in children, except for a wide variability in the time taken to reach the maximum concentration (27.3 +/- 7.4 min) and a shorter half-life of elimination (82.8 +/- 7.0 min). The total body clearance of lidocaine was similar in piglets (17.3 +/- 1.6 ml/min/kg) to that in children. The shorter half-life of elimination was therefore attributed to a smaller volume of distribution in piglets (2.0 +/- 0.2 l/kg).

Cytochrome P450 IID6 has got typical features (genetical polymorphism, competitive inhibition, saturability) which can be at the origin of pharmacokinetic modifications of molecules using it for their metabolism. In the field of pharmacology, many molecules are substrates or inhibitors of this cytochrome. They are presented. The results of a study of the dextromethorphan variation test performed before and after 28 days of clomipramine therapy with depressed patients are explained. They show a significant decreasing of the cytochrome P450 IID6 oxidation capacities between both of these times. A patient has passed from the phenotype "effective metabolizer" to the one of "poor metabolizer" with clomipramine.

Objective: To assess the pharmacokinetics and clinical tolerance of a 33% cocaine solution administered topically for intranasal surgery., Study Design: Clinical prospective open trial., Patients and Methods: Twelve ASA I patients scheduled for intranasal surgery were sedated with midazolam 2 mg and fentanyl 50 micrograms. Topical anaesthesia was obtained with aqueous 33% cocaine HCl 360 mg, lidocaine HCl 140 mg, adrenaline 0.04 mg and naphazoline 0.4 mg. Venous blood samples were taken before cocaine application and 15, 30, 45, 60, 90, 120, 150, 180, 240 min later. The plasma was immediately separated and the samples were frozen. The concentration of cocaine was measured by HPLC. Potential cardiotoxic and neurotoxic effects were clinically monitored., Results: The mean dose of cocaine applied was 5.85 +/- 1.3 mg.kg-1 and the dose actually delivered was 4 +/- 1.5 mg.kg-1. The Cmax was 859 +/- 503 ng.mL-1 after a Tmax to 47 +/- 17 min. The mean elimination half-life was 87 +/- 19 min (mean +/- SD). The total clearance and the volume of distribution were respectively 4,521 +/- 1,858 mL.min-1 and 568 +/- 273 L. No clinical evidence of toxicity was found., Conclusions: This study shows that it is possible to perform major intranasal surgery under topical anaesthesia with a concentrated solution (33%) of cocaine at a high dose (6 mg.kg-1). These results differ completely with data obtained in addicts.

Rifampin is an enzymatic inducer known to increase steroid metabolism. We studied two patients with giant cell arteritis in whom rifampin caused nonresponsiveness to prednisone treatment. A prednisone pharmacokinetics study was done. When rifampin-prednisone treatment must be used in giant cell arteritis, we propose increasing the prednisone dosage to 2 mg/kg per day.

Suriclone is a novel cyclopyrrolone exhibiting anxiolytic activity. Twelve healthy Caucasian male volunteers participated in the study. A single dose of suriclone 0.4 mg, imipramine 75 mg, suriclone 0.4 mg + imipramine 75 mg, or placebo was given according to a 4 x 4 Latin-square design in order to assess the effect of drug association on pharmacokinetics and psychomotor performances. Visual analogue scale ratings, critical flicker frequency, choice visual reaction time, and Pauli, picture memory and Sternberg tests were performed before and 1.5, 6 and 9 h after drug administration. Suriclone, with the exception of the Pauli test, had no effect on psychomotor performances. The imipramine-suriclone association appeared to disturb some performances (no statistical significance), probably due to the effect of imipramine. Blood samples were collected for determination of imipramine and suriclone plasma levels respectively by high-performance liquid chromatography and radioimmunoassays. Suriclone AUC, Cmax and Tmax were not affected by imipramine, and reciprocally.

The possibility of a pharmacokinetic interaction between amitriptyline and toloxatone (a new MAOI-A) has been studied in 17 depressed in-patients. Amitriptyline and its demethylated and hydroxylated metabolites in blood and urine were measured at steady state after the administration of amitriptyline with and without toloxatone in steady state. The metabolic status of patients was determined using the dextromethorphan phenotyping test. There was only a minor pharmacokinetic interaction between amitriptyline (AMT) and toloxatone, with a small increase in the AMT/NT (nortriptyline) plasma ratio: 0.68 before and 0.78 after toloxatone. The urinary excretion and plasma levels of AMT and its metabolites were not affected by the co-therapy. Three of the patients were poor metabolisers, but this did not predict the magnitude of the drug interaction. The interaction does not justify plasma level monitoring of amitriptyline as the change in pharmacokinetics was so small.

The aim of this study was to compare nephrotoxicity of the combinations amikacin/vancomycin and amikacin/teicoplanin. Eighteen male Wistar rats were divided into 3 groups of 6 animals each. The first group received 50 mg.kg-1 of amikacin (i.m. route) and 100 mg.kg-1 of vancomycin (i.p. route). The second group received 50 mg.kg-1 of amikacin (i.m. route) and 40 mg.kg-1 of teicoplanin (i.p. route). The third group received an isotonic solution of sodium chloride. The antibiotics were injected for a period of 6 days. Urine samples of animals were taken 24 h before the beginning of the experiment, then every day, throughout the duration of the treatment (6 days), continuing for an additional 3 days following completion of the administration of the drugs. There were no significant modifications in the urinary excretions of alanine aminopeptidase and the creatinine between the 3 groups; but in the group receiving amikacin/teicoplanin, we observed between days 3 and 8 an increase in the excretion of N-acetyl-beta-D- glucosaminidase when compared to the group receiving amikacin/vancomycin (p < or = 0.05) and to the control group (p < or = 0.01).

The cyclosporine is widely used as an immuno-suppressive agent in association with others drugs. Its narrow therapeutic range requires frequent monitoring. We suggest a literature review of suspected or confirmed drug interactions. The classification is presented as: absorption interactions; pharmacokinetic interactions in antiinfectious, anticonvulsants, cardiovascular drugs, H2 antagonists agents, hormonotherapy; pharmacodynamic interactions associated to increased cyclosporine nephrotoxicity.

The correlation between debrisoquine and dextromethorphan oxidation polymorphism was studied in 16 depressed in-patients. There was a close correlation between both phenotypes (r = 0.81 p less than 0.0017). During a treatment with amitriptyline during two weeks there was no significant modification of the dextromethorphan polymorphism. In the same way, the association of amitriptyline and toloxatone during two other weeks did not change this polymorphism in a significant way, even if there was a non significant shift towards higher values of the dextromethorphan metabolic ratio.

Pharmacokinetic data of an antidepressant agent: Apparent half-life (T1/2 elim), time of peak plasma concentration (Tmax), bioavailability, have a major contribution to determine optimal dosage in accordance with a low modification of steady-state levels. Viloxazine is a second generation antidepressant drug with a short apparent half-life (T1/2 elim: 2 to 5 h (3.4 h), which requires once a day 3 h i.v. infusion or three intakes of 100 mg oral standard formulation. The recent development of a new 300 mg slow-release form seems justified by a best compliance. Pharmacokinetic properties [Tmax = 3 to 9 h (5.2 h), T1/2 term = 6 to 7 h], suggest once a day dosage without risk of accumulation in chronic treatment. The relationships between plasma levels and the clinical improvement were not clear in literature. The recent therapeutic use of a 300 mg slow-release tablet has not permitted to change precedent findings.

Plasma and ascitic fluid concentrations of ofloxacin were determined in 12 cirrhotic patients after a single dose and repeated 200 mg oral doses. The single dose kinetics were compared to those obtained in 12 healthy volunteers. Mean plasma elimination half-life was 11.6 h in cirrhotics and 7.0 h in controls. Mean total clearance was 2.3 times lower in patients than in controls, due to a significant decrease of renal clearance of the drug, unrelated to creatinine clearance. Mean apparent volume of distribution was 1.2 l/kg in patients and 1.8 l/kg in controls. Estimated by the ratio of AUC in peritoneal fluid and plasma, ascitic fluid penetration was 80% after the first oral dose. Ascitic fluid concentrations equaled corresponding plasma concentrations after 10 h, without pronounced accumulation of ofloxacin in ascites. We may conclude that, in cirrhotic patients with normal serum creatinine, a significant impairment of renal tubular handling of ofloxacin could be observed and led to a delayed elimination half-life of the drug. Because of its broad spectrum of activity, low side-effect profile, and large ascitic fluid penetration after oral administration, ofloxacin appears to be a new therapeutic approach of severe infections in cirrhotic patients, in particular spontaneous bacterial peritonitis.

The pharmacokinetic study of quinupramin was developed on healthy volunteers, after cross-over administrations of three doses (2.5 and 7.5 mg P.O. and a 2.5 mg intravenous bolus dose). A specific and sensitive Gas chromatographymass spectrometry (GC-MS) method was applied to the determination of Quinupramin in plasma and urine. The calculated kinetic data for Quinupramin indicated a good bioavailability for the oral doses (2.5 and 7.5 mg). The coefficient of bioavailability (F) was found to be (0.75), with small individual variations. After oral administration, the area under experimental points of the curves (AUC 0 leads to infinity): 43.7 +/- 10.2 (S.E.M.) and 132.5 +/- 8.3 ng.ml-1.h, respectively, were proportional to doses. Blood levels (CMAX) were about 1.1 and 3.4 ng.ml-1 at 3 hours, for oral doses of 2.5 and 7.5 mg. The pharmacokinetic of Quinupramin was not dose-dependent. The high value of the apparent volume of distribution (A.V.D.) 34.2 +/- 4.8 l.kg-1 after bolus I.V., indicated a very high distribution of Quinupramin, as for all anti-depressants in a deep compartment (CNS). The apparent terminal half life of elimination was very high: 33.5 h (+/- 2.7 S.E.M.) for 2.5 mg bolus I.V. and 28.8 h (+/- 5.01 S.E.M.), 33.1 (+/- 3.2 S.E.M.) for 2.5 mg and 7.5 mg oral doses respectively. The lack of metabolism for Quinupramin, demonstrated by many authors, explained the absence of interindividual variations of bioavailability. The renal elimination (CLr) after bolus I.V. was 2.6% of the dose, after 72 h. Many variations of plasma concentrations illustrated a predominant biliary excretion. The decline in plasma Quinupramin concentrations (Ct) was fitted to a bi-exponential equation, using least-square regression analysis, for the three formulations.

Especially because of their physico-chemical properties, and in particular of their lipo-solubility, it was interesting to compare the tissue distribution of two beta 2 sympathomimetics: the clenbuterol and the salbutamol. The study was realised after a direct intravenous administration of clenbuterol chlorhydrate (5 micrograms/kg) and one of salbutamol sulfate (50 micrograms/kg) given to a dog. In a first time, the determination by mass-spectrometry of the two drugs in the plasma allows the pharmacokinetic study in dogs. After a three days wash out, this same experience was repeated. The animals are sacrificed and the assays of the two beta 2 sympathomimetics were effected in lung, bronchial, muscle, heart and brain tissue samples. The tissue distribution was different for clenbuterol and salbutamol and had to be considered as factors of selectivity in the sympathomimetic beta 2 activity. Nervous central diffusion of clenbuterol is higher than salbutamol but cardiac distribution is very important for salbutamol.