High doses of haloperidol in schizophrenia. A clinical, biochemical, and pharmacokinetic study.

The effects of high doses of haloperidol on clinical status and plasma neuroleptic and prolactin concentrations and CSF levels of homovanillic acid (HVA) and gamma-aminobutyric acid (GABA) were investigated in three paranoid schizophrenic patients over six weeks. The patients had been receiving haloperidol. Oral dosages were increased at weekly intervals from 10 to 200 mg/day and then reduced to 10 mg/day. The increase did not affect paranoid symptoms. Neurological side effects were slightly increased in two patients and moderately reduced in one. Plasma prolactin levels, initially high, increased when the dosage was increased to 100 mg/day but did not increase further. The CSF levels of HVA and GABA increased to day 7 but returned to initial values on day 28 in two patients; they were decreased to day 28 in one patient.

Placental transfer to diazepam and its disposition in the newborn.

Diazepam (DZ) placental transfer in pregnant women at term, following single or repeated drug administration by various routes, was evaluated. DZ and its metabolite N-demethyldiazepam (NDZ) were constantly present in umbilical cord plasma at concentrations comparable to the mother's shortly after drug administration. N-methyloxazepam (MOX) was detected in cord plasma only in a limited number of cases following chronic DZ treatment. Postmortem analysis of fetal tissue concentrations showed accumulation of NDZ in heart and lungs. Differences in NDZ concentrations between venous cord (VC) and arterial cord (AC) plasms suggest metabolic degradation of DZ in the fetus. The DZ apparent plasma half-life in the newborn was found to be longer (31 plus or minus 2 hr) than previously observed in infants and children. The low drug clearance appears to be linked to reduced urinary excretion of hydroxylated metabolites, suggesting limited capability to dispose of DZ in the newborn.

Betaxolol kinetics in hypertensive children with normal and abnormal renal function.

The kinetic and clinical profile of betaxolol--a beta 1-selective blocker with 80% to 90% bioavailability and a 16 to 20 hr t1/2--were studied in ten children aged 5 to 13 yr with chronic renal hypertension and mild to severe renal failure. An IV dose of 20 mg of betaxolol per 1.73 m2 body surface area (BSA) was followed by six daily oral doses. Six patients were maintained on combination therapy and four on betaxolol alone; two of these were newly treated. After the intravenous dose, t1/2 (mean +/- SE) was 19.9 +/- 1.7 hr, total clearance 0.30 +/- 0.03 l/kg/hr, and volume of distribution 8.2 +/- 0.7 l/kg. Clearance adjusted for BSA was 7.9 +/- 0.6 l/hr. The t1/2 correlated linearly to serum creatinine levels. After the last dose, peak concentration was 97.4 +/- 7.6 ng/ml, and t1/2 19.4 +/- 2.7 hr. Betaxolol 24-hr blood levels were twice as high as after the first dose. Blood pressure was reduced in two newly treated patients and two patients on combination therapy; previous responses were maintained in the others. The maximum effect was reached after the first dose and was maintained throughout the study week. Our results indicate that betaxolol disposition in children aged 5 to 13 yr with different degrees of renal failure is of the same order as that in young healthy adults, implying that there may be a higher rate of non-renal clearance. Renal failure-induced modification led to a doubling of the t1/2 in the most severe cases, again as in adult renal patients. There is an antihypertensive effect.

Further observations on carbamazepine plasma levels in epileptic patients. Relationships with therapeutic and side effects.

Plasma levels of carbamazepine, phenytoin and phenobarbital were monitored weekly over a period of 9 weeks in 20 epileptic patients unresponsive to treatment. No attempts were made to modify phenytoin and/or phenobarbital plasma levels; emphasis was on achieving carbamazepine plasma levels of 4 to 10 mug per milliliter. A remarkable drop in seizure frequency was attained within 2 to 3 weeks of monitoring, with carbamazepine plasma and concentrations within the desired range. Children disposed of the drug faster than adults. No effects of phenytoin and phenobarbital on carbamazepine plasma levels could be observed, while phenobarbital on carbamazepine plasma levels fluctuated remarkably without any relationship to carbamazepine levels. Transient leukopenia was present in most of the patients, while a significant reversible drop in red blood cells was observed in eight patients. The data reported confirm that with a careful monitoring of drug plasma levels, carbamazepine may exert a definite passive effect on seizure frequency in epileptic patients poorly responsive to therapy.

Clincial pharmacokinetics in neonates.

Recent concern over toxic effects of drugs in newborns, infants and children have stressed the need for better knowledge of drug kinetics during development. The present review focuses on the available data on clinical pharmacokientics in the neonate. Despite the lack of systematic approaches on drug disposition during the first month of life, the body of data currently available indicates profound differences in drug disposition between neonates and older infants, children and adults. In terms of physiological and anatomical factors the neonate has to be considered as a 'unique drug recipient'. For all the specific variables which govern the drug kinetic pattern (absorption, blood esterase activity, plasma protein binding, metabolic degradation and renal excretion), there are clear difference between neonates and older infants and children. Such differences are not always unidirectional. In the case of absorption, they depend on the maturational stage, but more on the physico-chemical properties of the individual compound. Esterase activiy and renal excretion are also related to the physico-chemical properties of the drug, but are more clearly linked with the development stage. Plasma protein blinding is generally reduced, and depends on several factors, not all of which are as yet clearly identified and understood. Biotransformation activities are usually very low, but may be increased several-fold by exposure to inducing agents. Hydroxylating activity and conjugation with glucronic acid appear to be the two metabolic pathways which are most defective at birth, while sulphate and gylcine conjugation, and dealkylation activities are close to the adult pattern. The material reviewed is fragmentary and does not always permit a comparison of the data obtained in newborns with those reported for adults. Differences in the methodology used and in the kinetic criteria further complicate the matter. It is, however, clearly emerging that drug disposition may vary greatly in the newborn in relation to its developmental age. The reported differences may be relevant for clinical practice and stress the need for more detailed information on drug kinetics in the neonate. Such information may be achieved by carefully planned clinical trials, but more meaningfully, and more profitably for the individual patient, by a very carefully, well integrated monitoring of the neonate a risk. By such an approach, where drug plasma levels are related to drug effects and to the pathophysiological condition, the significance of various factors on drug disportion during development will be better clarified, thus allowing a more rational and safer therapy in the newborn.

Clinical pharmacology of the perinatal period and early infancy.

A consistent body of data, acquired in the last 20 years, indicates that at birth most of the physiological variables regulating drug kinetics are immature, thus conditioning modified kinetic profiles in the neonate. The situation may be greatly complicated by the possible 'in utero' exposure to agents capable of altering the activity of liver and/or kidney excretory functions, and/or the presence of severe pathological conditions capable of significantly altering regional or general haemodynamics. The different variables mature at different rates depending on the gestational age and physiopathological conditions. A review of the available information on drug kinetics in the neonate and early infancy is presented here. Therapeutic drug monitoring appears to be the only possible way to assure a safer therapy for at-risk populations.

Diurnal variations in steady-state plasma concentrations of valproic acid in epileptic patients.

Patients on long term valproate treatment exhibit unusual fluctuations in steady-state plasma levels of valproic acid. In order to delineate the underlying mechanisms of these fluctuations, 2 studies were undertaken. In the oral study, 6 epileptic patients received enteric-coated sodium valproate tablets (on a bid regimen for at least 1 month) and plasma levels were monitored on an hourly basis during 24 hours. In the intravenous study, 5 patients received first an intravenous bolus dose (800mg) of sodium valproate followed a week later by a combination intravenous loading dose/constant rate infusion for 36 hours. Plasma valproic acid concentrations were monitored hourly during the infusion study. In the oral study, valproic acid concentrations in all subjects continued to decay for 5 to 6 hours following the 8pm dose. The mean fluctuation in concentrations during 24 hours was 112.8 +/- 31.6%. Consecutive fasting levels were not reproducible. In the intravenous study, small but significant oscillations were present at steady-state; fluctuations ranged from 22 to 34%. However, no circadian rhythm was apparent. On the basis of these findings, it appears that the value of a single fasting sample during therapeutic monitoring of valproic acid is questionable. For an accurate evaluation of valproic acid plasma levels, an average concentration based upon several daily determinations should be performed.

Pharmacokinetics and effects of propranolol in terminal uraemic patients and in patients undergoing regular dialysis treatment.

Propranolol blood and plasma levels were measured after a single oral dose of 40 mg in patients with chronic renal failure, in patients undergoing regular dialysis treatment, and in healthy volunteers. Peak levels were observed in all cases within 1.5 to 3 hours. However, peak blood and plasma concentrations of propranolol in the chronic renal failure group were 2- to 3-fold higher (161 +/- 41 ng/ml) than those observed in the dialysis patients (47 +/- 9 ng/ml) and in the healthy volunteers (26 +/- 1 ng/ml). The apparent plasma clearance was also significantly reduced in the patients with chronic renal failure. The data suggest a reduced hepatic extraction in chronic renal failure patients. A significant increase in the fraction of the dose available to the systemic circulation was also found, together with a modification of apparent plasma half-life and volume of distribution in regular dialysis patients during the dialysis day as compared with the after-dialysis day. No extraction of propranolol by the dialyzer was noticed. Marked fluctuations in propranolol blood concentrations were also observed in patients on regular dialysis following continuous propranolol treatment. The suppressive effect of propranolol on plasma renin activity did not fully correlate with the hypotensive effect of the drug. On the basis of the reported data, propranolol should be used with great caution and at low doses in chronic renal failure.

Uptake of desipramine by the rat vas deferens.

1. Determinations of desipramine in the isolated rat vas deferens were carried out in order to study the uptake of the drug and to evaluate how this may correlate with the effect on noradrenaline (NA)-induced contraction.2. Vasa deferentia, in contact with concentrations of desipramine of 1 ng-25 mug/ml for 10 min accumulated the drug about 6-fold in respect to the medium. When the time of contact was prolonged to 4 h, desipramine (200 ng/ml) was concentrated about 100-fold. The uptake was not saturable and it was not affected by the presence of imipramine, cocaine, ouabain, dinitrophenol and iodoacetate.3. No metabolic process is involved although the accumulation of desipramine is temperature dependent. The release of desipramine from the vas deferens is exponential and it is not affected by the presence of plasma in the medium.4. No clear correlation was found between tissue concentration of the drug and the potentiation of noradrenaline responses, probably because of the high non-specific binding of the drug to tissue components which may mask specific binding sites for NA resulting in potentiation. However, the concentration of desipramine seems to correlate with the inhibition of NA effect which occurs at high doses of desipramine.

Plasma nortriptyline and cardiac responses in young and old rats.

1. The relationship between plasma concentrations and cardiac effects of nortriptyline was studied in anaesthetized young and old rats. 2. Nortriptyline was administered by two consecutive intravenous infusions which resulted in a peak plasma concentration followed by steady state values. Increasing infusion rates were followed by proportional increases in the drug plasma concentrations ranging from 0.15 to 6.0 microgram/ml. 3. In young rats, nortriptyline induced an increase in the heart rate, a right rotation of the electrical axis and a prolongation of the PQ interval. Heart rate changes were not correlated with nortriptyline plasma concentrations, while significant correlations were found for the other two parameters. Plasma concentrations inducing 20% increase of the PQ interval and 40 degrees rotation of the electrical axis were 1.65 microgram/ml respectively. Arrhythmias occurred at concentrations higher than 5.2 microgram/ml. 4. Nortriptyline caused more severe cardiac effects in old than in young animals. However, plasma concentrations of nortriptyline in old rats were two to five times higher than those found in young rats at similar infusion rates. A higher concentration of the drug at its sites of action seems to be responsible for the more severe cardiac toxicity of nortriptyline observed in old rats.

Correlation between desipramine levels and (-)-noradrenaline uptake and chronotropic effect in isolated atria of rats.

1. The uptake of unlabelled and [(14)C]-desipramine was studied in rat isolated atria incubated in a medium containing concentrations of desipramine ranging from 200 pg/ml to 2 mug/ml. The uptake was found to be dose- and time-dependent. Equilibrium was not reached after 2-3 h of incubation unless concentrations of desipramine higher than 1 mug/ml were used.2. The washout curves of atria previously loaded with desipramine showed that the drug is slowly released and that this release is not influenced by its initial tissue concentration.3. The binding appeared to be at non-specific sites and not at sites where noradrenaline is stored since atria taken from rats treated with 6-hydroxydopamine accumulated the drug at the same rate as control atria.4. The inhibition of (-)-noradrenaline uptake and the potentiation of the chronotropic response to (-)-noradrenaline is correlated with the concentration of desipramine in atria for tissue levels of the drug ranging from 0.01 to 1 mug/g. Higher tissue levels show less potentiation of the effect of (-)-noradrenaline or even inhibition of the maximal response to (-)-noradrenaline. These concentrations of desipramine (> 7 mug/g) markedly depressed the atrial rate.5. The results show that despite the accumulation of desipramine by unspecific sites, concentrations of desipramine in the tissue are correlated with the pharmacological response. Furthermore a gradual shift from potentiation to inhibition of noradrenaline response can be obtained with the same bath concentrations of desipramine by increasing the time of incubation.

Plasma concentrations and cardiotoxic effects of desipramine and protriptyline in the rat.

1 Desipramine and protriptyline were administered to anaesthetized rats by two consecutive intravenous infusions in order to obtain a peak level (first infusion) followed by lower steady state concentrations (second infusion) (Wagner, 1974). Theoretical plasma level time courses were confirmed experimentally.2 Desipramine and protriptyline were measured in atria and ventricles. Increasing infusion rates led to proportional increases in plasma and atrial concentrations. The tissue/medium ratio ranged from 57 to 21 for desipramine and from 43 to 11 for protriptyline according to the time of determination during infusions.3 Heart rate changes, deviation of the electrical axis of the heart and prolongation of atrioventricular conduction were recorded at fixed times during infusion.4 Positive chronotropic effects were noted at plasma concentrations ranging from 0.035 to 0.1 mug/ml for desipramine and from 0.04 to 1.2 mug/ml for protriptyline. At higher plasma concentrations the positive chronotropic effect decreased and bradycardia developed. Both drugs induced right rotation of the electrical axis of the heart. Threshold plasma levels giving 40 degrees rotation were 1.35 mug/ml (desipramine) and 1.75 mug/ml (protriptyline). Atrioventricular conduction was prolonged at threshold plasma concentrations of 2.2 mug/ml for desipramine and 3.6 mug/ml for protriptyline.5 Desipramine is more cardiotoxic than protriptyline. This difference is discussed in relation to the plasma and heart concentration of the two drugs.

Prevalence of nightmares and their relationship to psychopathology and daytime functioning in insomnia subjects.

A representative sample of 5,622 subjects between 15 and 96 years of age from the noninstitutionalized general population of France were interviewed by telephone concerning their sleeping habits and sleep disorders. The interviews were conducted using the Sleep-Eval knowledge-based system, a nonmonotonic, level 2 expert system with a causal reasoning mode. Questions investigated nightmares, based on the Diagnostic and Statistical Manual, fourth edition (DSM-IV), definition, psychopathological traits, and included 12 other groups of information, including sociodemographics, sleep-wake schedule, daytime functioning, psychiatric and medical history, and drug intake. The data from 1,049 subjects suffering from insomnia were considered for this analysis. Bivariate analyses, logistic regression analysis using the method of indicator contrasts for the investigation of independent variables, and calculation of significant odds ratios were performed. Nightmares were reported in 18.3% of the surveyed insomniac population and were two times higher in women than in men. The following factors were found to be significantly associated with nightmares 1) sleep with many awakenings, 2) abnormally long sleep onset, 3) daytime memory impairment following poor nocturnal sleep, 4) daytime anxiety following poor nocturnal sleep, and 5) being a woman. There was a strong association between the report of nightmares in women and the presence of either a depressive disorder, anxiety disorder, or both disorders together. When the effects of major psychiatric disorders were controlled for, nightmares were significantly associated with being a woman, feeling depressed after a poor night's sleep, and complaining of a long sleep latency. Nightmares can lead to a negative conditioning toward sleep and to chronic sleep complaints. Considering the frequency of nightmares in an adult insomniac population and the significant relationship between nightmares and certain subgroups, nightmares should receive more attention in patients, especially women complaining of disrupted sleep, as high rates of psychiatric disorders were found in this specific group.

Effects in man of progabide on prolactin release induced by haloperidol or domperidone.

The effects of progabide, a GABA receptor agonist, on haloperidol-induced and domperidone-induced hyperprolactinaemia have been studied in man. There was a moderate inhibition by progabide of the rise in prolactin after domperidone. No such effect was found after haloperidol. The results support the view that in man, as in animals, GABA agonists have an inhibitory effect on prolactin release, probably at the level of the hypothalamus and anterior pituitary.

Kinetics of distribution of amphetamine in cats.

The distribution and metabolic fate of amphetamine were studied in cats. In the brain, high levels of drug were detected in the grey matter structures at short intervals after administration, while at longer intervals distribution between white and grey matter areas was more uniform. In peripheral tissues the greatest concentration of the drug was seen in the highly vascularized organs. Para-hydroxy-amphetamine was found in minimal amounts in the liver and kidneys and only at trace quantities in the brain.

Regional distribution of diazepam and its metabolites in the brain of cat after chronic treatment.

Repeated administration of diazepam leads to remarkable accumulation of N-desmethyldiazepam in white matter structures and in subcortical areas such as thalamus, hypothalamus, and hypophysis. Diazepam and the hydroxylated metabolites were present in lesser amounts. The distribution pattern of diazepam and N-desmethyldiazepam offers a rationale for its efficacy in inhibiting seizures spreading and for the lack of effect on primary foci discharges.

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)

Comparison of single-dose pharmacokinetics of imipramine and maprotiline in the elderly.

Pharmacokinetic profiles of imipramine and a newer tetracyclic antidepressant, maprotiline, were studied in elderly (75-83 years of age) subjects who were given a single oral dose of 125 and 175 mg, respectively, of these drugs. The apparent elimination half-life of imipramine was 20.8-34.9h (means 26.4h), its biovailability (F) was 40-64% (means 57%), and the apparent plasma clearance was from 0.27-0.57h/kg (mean 0.41h/kg). Maprotiline had a longer half-life (mean 31.5h range 20.6-51.8h, but its bioavailability (mean 50%) and plasma clearance (mean 0.49h/kg) values were in the range similar to those seen after imipramine. It appears that the elimination half-life of imipramine is longer and its plasma clearance is markedly reduced in elderly subjects when compared to values reported in young adults. Subjective clinical side effects were minimal with the two drugs. However, alterations in heart rate, blood pressure, or electrocardiogram occurred in all subjects. This suggests that caution should be exercised before initiating and during the treatment of elderly patients with these antidepressant drugs.

Effect of amphetamine and fenfluramine on brain noradrenaline and MOPEG-SO4.

I.p. administration of d-amphetamine sulphate and fenfluramine-HCl at various doses induced significant modifications of brain noradrenaline (NA) and MOPEG-SO4 (3-methoxy-4-hydroxyphenylethyleneglycol) in the rat. Both drugs induced a decrease in brain noradrenaline but the two compounes seem to interact with the central noradrenergic system through a different mechanism. The decreased levels of noradrenaline after 1-fenfluramine administration were paralleled by increased MOPEG-SO4 levels. The d-isomer of fenfluramine was less active than the l-isomer. Amphetamine was considerably more effective than l-fenfluramine in reducing NA concentration. However, in spite of the long lasting effect on noradrenaline levels the i.p. administration of amphetamine did not lead to an increased MOPEG-SO4 concentration suggesting a more complex interaction with the noradrenergic system.

Brain distribution of propranolol in the rat.

The distribution and kinetics of D,L-propranolol in rat brain were examined after an intravenous injection of the drug. Measurements in brain areas and blood were performed by means of a sensitive and specific gas liquid chromatographic method. The disappearance rate in cortical areas paralleled that in blood. However D,L-propranolol decreased at a slower rate in hypothalamic and medullary nuclei. Since propranolol is believed to have central hypotensive effects, its retention by certain central nuclei involved in blood pressure regulation is of interest.