The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABA-A alpha2,3 selective agonist, in comparison with lorazepam in healthy volunteers.

Benzodiazepines are effective short-term treatments for anxiety disorders, but their use is limited by undesirable side effects related to Central Nervous System impairment and tolerance development. SL65.1498 is a new compound that acts in vitro as a full agonist at the gamma-aminobutyric acid(A) 2 and 3 receptor and as a partial agonist at the 1 and 5 receptor subtypes. It is thought that the compound could be anxiolytic by its activation at the alpha2 and alpha3 receptor subtypes, without causing unfavourable side effects, which are believed to be mediated by the alpha1 and alpha5 subtypes. This study was a double-blind, five-way cross-over study to investigate the effects of three doses of SL65.1498 in comparison with placebo and lorazepam 2 mg in healthy volunteers. The objective was to select a dose level (expected to be therapeutically active), free of any significant deleterious effect. Psychomotor and cognitive effects were measured using a validated battery of measurements, including eye movements, body sway, memory tests, reaction-time assessments, and visual analogue scales. The highest dose of SL65.1498 showed slight effects on saccadic peak velocity and smooth pursuit performance, although to a much lesser extent than lorazepam. In contrast to lorazepam, none of the SL65.1498 doses affected body sway, visual analogue scale alertness, attention, or memory tests. This study showed that the three doses of SL65.1498 were well tolerated and induced no impairments on memory, sedation, psychomotor, and cognitive functions.

Pharmacokinetic and pharmacodynamic modeling of mizolastine in healthy volunteers with an indirect response model.

OBJECTIVE: The aim of this work was to model the pharmacokinetic and pharmacodynamic relationship of mizolastine, a new H1-receptor antagonist obtained from histamine-induced wheal and flare inhibition test. METHODS: Fifteen healthy volunteers participated in this double-blind crossover study and randomly received single doses of 5, 10, 15, and 20 mg of mizolastine and placebo at 1 week intervals. Simultaneous histamine tests and blood samples were performed before and at 9 different times up to 24 hours after each dosing. Pharmacokinetic and pharmacodynamic modeling were performed subject by subject for the 4 doses altogether by nonlinear regression. First, plasma concentrations were fit according to a two-compartment open model with zero order absorption and first order elimination. Then an indirect response model with inhibition of the formation rate was developed to describe the pharmacodynamic relationships between flare or wheal raw areas and plasma concentrations with the use of the pharmacokinetic parameters that were previously estimated. RESULTS: Mizolastine dose dependently inhibited the histamine-induced wheal and flare formation with a submaximum effect attained after 10 mg. The mean values of the pharmacodynamic parameters of apparent zero-order rate constant for the flare or wheal spontaneous appearance (k(in)), the first-order rate constant for the flare or wheal disappearance, the mizolastine concentration that produced 50% suppression of the maximum attainable inhibition of k(in), and the maximum attainable inhibition of the effect production were 14.1 cm2/h (coefficient of variation [CV], 32%), 0.68 h(-1) (CV, 24%), 21.1 ng/mL (CV, 77%), and 0.92 (CV, 8%), respectively, for the flare and 1.9 cm2/h (CV, 64%), 0.63 h-1 (CV, 39%), 43.9 ng/mL (CV, 68%), and 0.87 (CV, 12%), respectively, for the wheal inhibition. CONCLUSION: Pharmacokinetic and pharmacodynamic relationships of mizolastine were reliably described with the use of an indirect pharmacodynamic model; this led to an accurate prediction of the pharmacodynamic activity of mizolastine.

Flumazenil antagonizes the central effects of zolpidem, an imidazopyridine hypnotic.

Zolpidem is a new imidazopyridine-hypnotic that selectively binds to the central omega 1-receptor subtype. A double-blind, randomized, three-way, crossover placebo-controlled study was carried out in nine healthy male volunteers to assess the possible antagonism of central nervous system--depressant effects of zolpidem by flumazenil. Subjects received zolpidem (0.21 mg/kg) or placebo, intravenously, followed 17 minutes later by flumazenil (0.04 mg/kg) or placebo. Vigilance and performance were assessed by a trained anesthetist with use of ciliary reflex, response to a verbal instruction, subjective sedation, a tracking task, and a free recall task. Zolpidem produced a clinically relevant hypnotic effect in five subjects and significantly impaired performance in all nine subjects up to 90 minutes after dosing. Flumazenil rapidly antagonized clinical sedation in the five subjects who were asleep and significantly reversed the performance decrement within 3 minutes, without any escape phenomenon. Flumazenil did not change zolpidem plasma concentrations, confirming the pharmacodynamic nature of the interaction. Flumazenil may thus be a safe and effective antidote in patients with zolpidem overdosage.

EEG profile of intravenous zolpidem in healthy volunteers.

Zolpidem is an imidazopyridine which binds specifically to the omega 1 receptor. Zolpidem demonstrated potent hypnotic activity at a dose of 10 mg. Pharmacodynamics and pharmacokinetics of zolpidem were studied after daytime administration in a randomised, double-blind, placebo-controlled, cross-over trial. Single doses of zolpidem (10 mg IV as a 3-min infusion and 20 mg orally) and placebo were firstly tested in 12 healthy young male volunteers. Two other doses (5 mg IV and orally) were then evaluated in 6 out of these 12 subjects. EEG (4 leads = Fp2-T4, Fp1-T3, T4-02 and T3-01), and Stanford Sleepiness Scale (SSS) were measured up to 5 h postdosing. Blood samples were also collected up to 24 h. The time course of the hypnotic activity of zolpidem, assessed by the score obtained on SSS, showed a similar profile whatever the route or the dose administered: slightly earlier onset after IV but sedative scores were reached at 30 min and the effect peaked between 1 and 1.5 h and lasted 4 h in both conditions. The EEG profile of zolpidem was characterised by a decrease of alpha activity and an increase in delta and in beta activity. The effect on beta activity was marked within the first hour and then disappeared. The time course of delta and alpha activities indicated a rapid onset (10 min after IV, 30 min after oral route) and a duration of 3-4 h. The amplitude of these relative EEG changes and their duration were independent of the route of administration and the dose administered. AUC and Cmax increased proportionally to the administered dose and elimination half life (2h), clearance and volume of distribution did not change according to the dose or the route of administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of histamine-induced skin wheal and flare after 5 days of mizolastine.

Mizolastine is a new, nonsedating antihistamine providing satisfactory symptomatic relief in allergic rhinitis and urticaria. The purpose of this study was to use inhibition of wheal and flare formation after 2-mu g intradermal histamine injections as a measure of the antihistamine effect of repeated doses of mizolastine. Eight volunteers were enrolled in this four-arm, double-blind, cross-over, randomized study. Three dose levels of once-daily mizolastine (5 mg, 10 mg, and 15 mg) were compared with placebo during 5-day dose periods. Histamine tests were performed before drug intake on days 1 and 5, and then 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours after drug intake on day 5. All 3 doses of mizolastine were more effective than placebo in suppressing wheal and flare reactions, and the antihistamine activity was highest at both the 10- and 15-mg dose levels. The effect on the flare reaction appeared within 1 hour, reached a maximum effect 4 hours after administration, and persisted for as long as 24 hours. The relative changes in wheal and flare areas were correlated with mizolastine trough plasma levels on day 5. Safety was satisfactory in all groups. This study confirms that mizolastine is a rapid and potent antihistamine; and its long-lasting effectiveness indicates that a once-daily regimen is acceptable for clinical use.

Pharmacodynamics and pharmacokinetics of two dose regimens of befloxatone, a new reversible and selective monoamine oxidase inhibitor, at steady state in healthy volunteers.

The pharmacodynamic equipotency of 2 dose regimens (5 mg twice daily versus 10 mg once daily) of befloxatone, a new reversible and selective monoamine oxidase A (MAO-A) inhibitor, after single and multiple doses for 6 days was examined in a randomized, double-blind, three-way crossover, placebo-controlled trial of 12 healthy volunteers. Plasma levels of the deaminated metabolite 3-4 dihydroxyphenylglycol (DHPG), as measured by high-performance liquid chromatography (HPLC) with coulometric electrochemical detection, were used as an index of MAO inhibition. A single dose of befloxatone produced a significant dose-related reduction in plasma DHPG levels, as shown by the decrease in the 24-hour area under the concentration-time curve (AUC0-24) of DHPG, which peaked 2 hours after administration and persisted over 24 hours. Both dose regimens provided equipotent extent and duration of MAO-A inhibition at steady state, suggesting a once daily dosage should be sufficient for most patients. The pharmacokinetic bioavailability at steady state of both dose regimens was also similar. The concentration-time effect curve after a single dose revealed a hysteresis corresponding to the delay necessary to elicit MAO inhibition and/or elimination of DHPG. The relationship between plasma levels of DHPG and/or elimination of plasma concentrations of DHPG and befloxatone after a single dose can be modeled using the Emax model with a mean EC50 of 4.75 ng/mL, and suggests the presence of a maximal response from the single dose. This model permits prediction of steady-state levels of DHPG.

Clinical pharmacology of befloxatone: a brief review.

Clinical pharmacology studies of befloxatone, a new selective reversible inhibitor of monoamine oxidase-A (MAO-A), have addressed safety, with special emphasis on tyramine interactions, and have also investigated pharmacokinetics (PK) and pharmacodynamics in terms of both MAO-A inhibition (using 3,4-dihydroxyphenylglycol, DHPG, as a pharmacological activity marker) and effects on psychomotor and cognitive function, in young and elderly healthy volunteers. Clinical and laboratory safety data were satisfactory in healthy volunteers given single doses of up to 160 mg or repeated doses of up to 80 mg/day for 7 days. Tyramine interaction studies showed that the expected potentiation of the tyramine pressor effect occurred with a safety margin that was so wide as to make dietary restrictions unnecessary with dosages of up to 20 mg once daily in clinical settings. Absorption was rapid (tmax = 2 h), terminal halflife was about 11 h, and PK parameters increased linearly with the dose. Befloxatone induced a dose-dependent decrease in plasma DHPG levels from 2.5 mg upwards, and a 10-mg dose provided sub-maximal activity (80% DHPG decrease) of 24 h duration. No sedative or stimulant effects were detected using several batteries of psychometric tests. Befloxatone was devoid of deleterious effects on memory in young volunteers, and exhibited the EEG profile of a non-sedative antidepressant. In summary, available clinical pharmacology studies confirm that befloxatone is a safe and potent RIMA with no potential for inducing deleterious CNS effects.

Pharmacokinetic and bioavailability of diltiazem sustained-release: influence of food and time of administration.

Diltiazem is a calcium channel blocking agent known to be effective in the treatment of angina pectoris, hypertension and supraventricular arrhythmias. To improve the conditions of diltiazem administration in the treatment of hypertensive patients, a sustained-release formulation (Mono-Tildiem LP 300 mg) allowing a single daily oral administration has been developed. The aim of the present study was to first evaluate the influence of food intake and second to evaluate those of the time of administration on the pharmacokinetic parameters and the bioavailability of this sustained-release formulation. The influence of these factors was investigated over two different open, randomized, cross-over studies in 12 healthy volunteers. Although a significant decrease in Tmax and an increase in Cmax occurred when diltiazem sustained-release was administered with food intake, AUC0-48, and therefore the fraction absorbed, were not modified either by concurrent food intake or by different times of administration. The minor modifications of pharmacokinetic parameters of diltiazem sustained release observed were unlikely to induce any clinical consequence.

New metabolic and pharmacokinetic characteristics of thiocolchicoside and its active metabolite in healthy humans.

Thiocolchicoside (TCC) has been prescribed for several years as a muscle relaxant drug, but its pharmacokinetic (PK) profile and metabolism still remain largely unknown. Therefore, we re-investigated its metabolism and PK, and we assessed the muscle relaxant properties of its metabolites. After oral administration of 8 mg (a therapeutic dose) of 14C-labelled TCC to healthy volunteers, we found no detectable TCC in plasma, urine or faeces. On the other hand, the aglycone derivative obtained after de-glycosylation of TCC (M2) was observed and, in addition, we identified, as the major circulating metabolic entity, 3-O-glucuronidated aglycone (M1) obtained after glucuro-conjugation of M2. One hour after oral administration, M1 plus M2 accounted for more than 75% of the circulating total radioactivity. The pharmacological activity of these metabolites was assessed using a rat model, the muscle relaxant activity of M1 was similar to that of TCC whereas M2 was devoid of any activity. Subsequently, to investigate the PK profile of TCC in human PK studies, we developed and validated a specific bioanalytical method that combines liquid chromatography and ultraviolet detection to assay both active entities. After oral administration, TCC was not quantifiable with an lower limit of quantification set at 1 ng/mL, whereas its active metabolite M1 was detected. M1 appeared rapidly in plasma (tmax=1 h) and was eliminated with an apparent terminal half-life of 7.3 h. In contrast, after intramuscular administration both active entities (TCC and M1) were present; TCC was rapidly absorbed (tmax=0.4 h) and eliminated with an apparent terminal half-life of 1.5 h. M1 concentration peaked at 5 h and this metabolite was eliminated with an apparent terminal half-life of 8.6 h. As TCC and M1 present an equipotent pharmacological activity, the relative oral pharmacological bioavailability of TCC vs. intramuscular administration was calculated and represented 25%. Therefore, to correctly investigate the PK and bioequivalence of TCC, the biological samples obtained must be assayed with a bioanalytical method able to specifically analyse TCC and its active metabolite M1.

Pharmacokinetics and pharmacodynamics of zolpidem following repeated doses in hemodialyzed uraemic patients.

Zolpidem, an imidazopyridine derivative, is a chemically novel, non-benzodiazepine hypnotic agent. Many uraemic patients complain of sleep disorders and ask for hypnotic medication which is well tolerated both clinically and biologically in such patients. We studied the pharmacokinetics and pharmacodynamics of zolpidem in 12 end-stage renal patients regularly treated by hemodialysis three times a week. Zolpidem (10 mg) was given orally for 14 or 21 days. Pharmacokinetic and pharmacodynamic evaluations were repeated at the end of the study on day 14 or day 21. Cmax, Tmax, t1/2 and the area under the curve were not modified in hemodialyzed patients. After daytime dosing, zolpidem induced the same level of sleepiness after the first and last dose and was well tolerated as a hypnotic agent after the night-time dosing. From these results, it can be said that zolpidem may be administered safely to patients with severe renal impairment without any modification of the dosage regimen.

Effects of mizolastine, a new antihistamine, on psychomotor performance and memory in elderly subjects.

The effects of a single 10 mg dose of the new H1 antihistamine mizolastine on psychomotor performance and memory in the elderly were assessed in a double-blind, cross-over, placebo-controlled study in 15 elderly female volunteers aged 66-77 years, using clemastine 2 mg as a positive control. Objective (critical flicker fusion, choice reaction time, digit symbol substitution, immediate and delayed free recall) and subjective (linear analogue rating scales) assessments were done on each test day before the dose, then 4 and 8 h post-dose. Plasma samples were also collected. A single oral dose of mizolastine within the range of recommended daily therapeutic dosages (10 mg) failed to induce subjective drowsiness and produced no detrimental effects on psychomotor performance or on short-term and long-term memory in the elderly subjects. In contrast, 2 mg clemastine induced significant impairments (decrease in critical flicker fusion, increase in recognition reaction time) in comparison with placebo and mizolastine, although it did not impair memory. The pharmacokinetic profile of mizolastine in the elderly study subjects was similar to that observed in healthy young volunteers. Therefore, it can be concluded that mizolastine 10 mg could be used safely in elderly out-patients as it preserves functions involved in activities of daily living.

Lack of effect of mizolastine on the safety and pharmacokinetics of digoxin administered orally in repeated doses to healthy volunteers.

The effects of mizolatine, a new H1 receptor antagonist, on safety and pharmacokinetics of digoxin were studied in a double-blind placebo-controlled crossover study. After administration of digoxine alone (0.25 mg o.d. for 7 days), 12 healthy young male volunteers (23+/-2 years) received either placebo and digoxin (0.25 mg o.d.) or mizolastine (10 mg o.d.) and digoxin (0.25 mg o.d.) during 7 days. The assessment criteria consisted in hemodynamic and ECG parameters recordings and the pharmacokinetics of digoxin during the last day of coadministration (day 14). No difference between the 2 treatment groups was evidenced on ECG, hemodynamic, and clinical and laboratory safety parameters. No change in AUC and tmax was recorded. No clinically relevant effect of mizolastine on the digoxin pharmacokinetics was found. However, a statistically significant increase in digoxin Cmax (3.03+/-0.18 nmolxl(-1) vs 2.52+/-0.19 nmolxl(-1), p < 0.05) and Cmin (0.99+/-0.08 nmolxl(-1) vs 0.87+/-0.07 nmolxl(-1), p=0.05) occurred after the coadministration vs digoxin alone. It can be concluded that mizolastine and digoxin at therapeutic dosages can be safely coadministered.

The pharmacokinetics of idraparinux, a long-acting indirect factor Xa inhibitor: population pharmacokinetic analysis from Phase III clinical trials.

BACKGROUND: Idraparinux, a long-acting synthetic pentasaccharide, is a specific antithrombin-dependent inhibitor of activated factor X that has been investigated in the treatment and prevention of thromboembolic events. OBJECTIVES: To characterize the population pharmacokinetic profile of idraparinux in patients enrolled in van Gogh and Amadeus Phase III clinical trials. PATIENTS AND METHODS: Idraparinux was administered once-weekly subcutaneously at a dose of 2.5 mg, or 2.5 mg (first dose) and then 1.5 mg for patients with severe renal insufficiency (creatinine clearance<30 mL min(-1)). A population pharmacokinetic model was developed using data from 704 patients with acute deep-vein thrombosis or pulmonary embolism, 1310 patients suffering from atrial fibrillation, and 40 healthy subjects. Potential covariates analyzed included demographics (age, sex, weight and ethnicity), and serum creatinine and creatinine clearance determinations. RESULTS: A three-compartment model best described idraparinux pharmacokinetics, with interindividual variability on clearance, central volume of distribution, and absorption rate constant; residual variability was low. Typical clearance, central volume of distribution, absorption rate constant and volume of distribution at steady-state were 0.0255 L h(-1), 3.36 L, 1.37 h and 30.8 L, respectively. Peak concentration was reached at 2.5 h. The terminal half-life was 66.3 days and time to steady-state was 35 weeks. At steady-state, exposures were similar for patients without and with severe renal impairment receiving adjusted-dose. Creatinine clearance was the most important covariate affecting idraparinux clearance. The particular characteristics of idraparinux--rapid onset of action and long-acting anticoagulant effect--offer interesting clinical perspectives currently under investigation with idrabiotaparinux, the reversible biotinylated form of idraparinux.

Determination of vincamine in human plasma using automated high-performance liquid chromatography.

A specific and sensitive high-performance liquid chromatographic method for the quantitative determination of vincamine at therapeutic concentrations in plasma is described. The column was packed with Spherisorb ODS 5 micrometer, and the mobile phase was acetonitrile-potassium phosphate (0.02 M, pH 2.3) (50:50) with a flow-rate of 10 ml/min. Detection was at 230 nm. Using automated large-volume injection of a non-eluting solvent (0.02 M potassium phosphate) the method was capable of the analysis of a large number of samples daily. The coefficient of variation of the procedure was 4.8% at a plasma vincamine concentration of 10 ng/ml

Treatment of persistent fetal circulation syndrome of the newborn. Comparison of different doses of tolazoline.

The effects of two doses of tolazoline have been compared in 2 groups of newborns suffering from the persistent fetal circulation syndrome. The effects on PaO2 and AaDO2 were similar in the 2 groups who received either a bolus of 1 or 0.5 mg X kg-1 tolazoline, followed by a continuous infusion of 1 or 0.5 mg X kg-1 X h-1. The observed changes did not differ significantly from those previously observed in babies treated with 2 mg X kg-1. A rise in PaO2 and a reduction in AaDO2 were usually observed shortly after the bolus injection and at plasma levels between 1.5 and 4 micrograms X ml X -1. A progressive rise in plasma level over time occurred after 1 mg X kg-1 (and in the previous study of 2 mg) but not with 0.5 g/kg tolazoline. The elimination half-life of tolazoline in 6 patients was 5 to 13 h. The data suggest that continuous infusion of tolazoline is not necessarily required and that the dose of 0.5 mg/kg is more appropriate and safer than the higher doses usually proposed.

Population pharmacokinetic analysis and optimization of the experimental design for mizolastine solution in children.

Mizolastine is a second generation antihistamine agent approved in Europe for the treatment of allergic rhinitis and skin conditions for which Sanofi-Synthélabo is developing a pediatric solution. Our objective was to design the population pharmacokinetic (PK) study of mizolastine pediatric solution in children. A bioavailability study of this solution compared to the marketed tablet was performed in 18 young volunteers. These PK data were analyzed by nonlinear regression using a two-compartment open model with zero-order absorption. From the estimated parameters, we designed population PK studies in two groups of children: 6 to 12 years and 2 to 6 years, respectively. To compare several population designs and to derive the optimal ones, we used the determinant of the Fisher information matrix of the population characteristics using a first-order expansion of the model. We have evaluated a "reference" population design with 10 samples (from 0.25 to 36 hr after drug intake) per child in 6 children, which could not be implemented in practice for ethical reasons. We then derived optimal population designs with 1, 2, 3, 4, or 5 samples per child and a total of 60 samples. Finally, the designs that were implemented in the population PK study were "compromise" population designs with 60 samples; one defined for 20 children 6 to 12 years old, and one with 24 children 2 to 6 years. In the older group, the population design involved 8 children with a catheter from which 6 samples at time 0.25, 0.5, 0.75, 2, 3, and 6 hr after drug intake are collected, and 12 children with only one sample at time 8, 12, 24, or 36 hr. In the younger group, the population design involved 15 children with a catheter who are divided in three groups with four samples at different times from 0.25 to 6 hr after drug intake, and 12 children with only one sample at time 8, 12, 18, or 24 hr. The expected average increase of variances of these designs compared to the reference design were 1.6 and 1.8 for the older and younger group, respectively, which was decided to be acceptable. Better population designs would have involved three groups of children with five samples per child but could not be implemented in practice. The data of the PK study in children 6 to 12 years were available and were analyzed using NONMEM. A total of 53 concentrations were obtained in 18 children. The same two-compartment model with zero-order absorption was used. The interindividual variability in children was small. The estimated population parameters in children 6 to 12 years, were 0.28 L/kg for Vc/F, 0.10 L/hr per kg for CL/F, 0.53 hr-1 for lambda 1, 0.076 hr-1 for lambda 2, and 0.49 hr for Tabs. These values were close to the median values observed in young volunteers when standardized to 70 kg; notably, CL/F in L/hr per kg was similar, so that a dose of 0.15 mg/kg o.d. for mizolastine pediatric solution should give an equivalent area under the curve to a 10 mg o.d. tablet in adults.

Pharmacokinetic analysis of mizolastine in healthy young volunteers after single oral and intravenous doses: noncompartmental approach and compartmental modeling.

This paper presents the analysis of the kinetics of a new antihistamine, mizolastine, in 18 healthy volunteers, from concentrations measured after an intravenous infusion and two different oral administrations: tablet and capsule. Two approaches were used to analyze these data: (i) a noncompartmental approach implemented in PHARM-NCA; (ii) a compartmental modeling approach implemented in a new S-PLUS library, NLS2, which allows the estimation of variance parameters simultaneously with the kinetic parameters. For the compartmental modeling approach, two-compartment open models were used. According to the Akaike criterion, the best model describing the kinetics of mizolastine after oral administration was the zero-order absorption model. The kinetic parameters obtained with PHARM-NCA and NLS2 were similar. The estimated duration of absorption was greater for the tablets than for the capsules (with means equal to 1.13 hr and 0.84 hr respectively). After an intravenous infusion, the mean estimated clearance was 4.9 L/hr, the mean lambda 2-phase apparent volume of distribution was 89.6 L and the mean terminal half-life was 12.9 hr.

Effect of seizures on brain phenobarbital concentration in newborn piglets.

Phenobarbital (PB) brain and blood concentrations were measured together with brain and blood pH in newborn piglets before and at the end of seizure activity induced by pentylenetetrazol or bicuculline. Seizures induced a significant elevation of arterial blood pressure and profound changes in the blood gases and in the acid-base balance, with a marked reduction in brain tissue pH. Despite an intense brain acidosis, however, and a significant rise in blood/brain [H+] gradient, phenobarbital brain concentrations were not reduced during seizures but, on the contrary, were increased in 7 of 11 piglets. These data suggest that contrary to the pH partition hypothesis, brain uptake of PB is concomitantly increased during seizures and brain acidosis.

Regional cerebral blood flow during bicuculline-induced seizures in the newborn piglet: effect of phenobarbital.

The changes in cerebral blood flow (CBF) during and after bicuculline-induced seizures were studied by the radioactive microsphere technique in 12 newborn, urethan-anesthetized piglets, 6 piglets pretreated with phenobarbital (10 mg/kg) and 6 without phenobarbital. The mean arterial blood pressure (MABP), PaO2, PaCO2 and the cerebral tissue pH (CtpH) were measured. CBF was increased during seizure, more in basal ganglia (98 and 106% in the control and phenobarbital group, respectively) than in brainstem, cerebellum and cortex. 15 min after seizure, CBF has returned to preseizure values. There was no significant difference at any time between the control and phenobarbital group. The increase in CBF was correlated with an increase in MABP (r = 0.753, p less than 0.01), suggesting a loss of cerebral autoregulation. CBF was significantly correlated with PaCO2 before and after seizure, but not during seizure. Finally, the increase in CBF was significantly correlated with an early increase in CtpH (r = 0.570, p less than 0.05), suggesting that brain acidosis is not involved in the pathogenesis of the increased CBF during seizures.

To nurse when receiving acebutolol: is it dangerous for the neonate?

The concentrations of acebutolol and of its main active metabolite diacetolol in milk and plasma were studied in 7 hypertensive mothers treated with acebutolol, a cardioselective beta-adrenoceptor blocking agent. Clinical monitoring on their newborn babies was also done, as well as measurement of plasma level of the drug in them. The ratio between milk and plasma concentrations ranged from 1.9 to 9.2 for acebutolol and from 2.3 to 24.7 for diacetolol, and in any given milk sample, the diacetolol concentration was always higher than that of acebutolol. In a newborn infant, plasma concentrations of the two transplacentally acquired substances was raised when breast feeding started and remained high. Clinical signs of pharmacological beta-blockade were observed. Evaluation of the iatrogenic risk shows that pharmacologically active amounts of acebutolol might be received by a neonate if the daily maternal dosage exceeds 400 mg/day and/or renal function in the mother is impaired.