Origin of extracellular dopamine increase induced by lactic acid striatal perfusion monitored by microdialysis in the awake rat.

In previous studies we showed that a striatal lactic acid perfusion-induced lactacidosis produces a diphasic increase in extracellular dopamine (DA). In the present study, different pharmacological reagents were used to determine the origin of accumulated DA. Our data show that both DA accumulations were totally suppressed by tetrodotoxin and nicardipine, indicating a relationship with membrane depolarization and a Ca(2+)-dependent effect. The first DA peak was largely reduced by a specific inhibitor of DA uptake such as GBR-12935, and the second was totally suppressed by tyramine and reserpine and lowered and delayed by GBR-12935. These results compared to data in the literature suggest that the first increase in extracellular DA resulted mainly from a release of cytosolic DA by reversal of the DA transporter, while the second was mainly due to a release of vesicular DA by exocytosis. These data indicate that lactic acid perfusion helps clarify the mechanisms involved in this process and could be useful for the study of new treatments against the hyperactive dopaminergic reaction occuring during ischemia.

Using a WWW-based module for problem-based learning in a cardiovascular pharmacology course.

The authors have constructed a problem-based learning (PBL) computer program that makes full use of Internet facilities, and is aimed at providing a stimulating supplement to standard teaching practices. The authors report on students' reactions to this new method of teaching.

Pharmacokinetic and pharmacodynamic study of suriclone imipramine interaction in man.

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.

Assessment of the interaction between a partial agonist and a full agonist of benzodiazepine receptors, based on psychomotor performance and memory, in healthy volunteers.

Potential interactions between the imidazopyridine anxiolytic alpidem and the full benzodiazepine agonist lorazepam were assessed in a randomized, double-blind, four-way cross-over, placebo-controlled study in 16 healthy young male volunteers. Each volunteer received alpidem, 50 mg, or a placebo twice daily for 8 days with a 1- week wash-out interval. The interaction between alpidem, at the steady state, and a single oral dose of lorazepam 2 mg or a placebo was assessed after concomitant administration on days 7 or 9 of each treatment period. Psycho motor performance and cognitive function were evaluated before and 2, 4, 6 and 8 h post-dose, using objective tests [critical flicker fusion threshold (CFF), choice reaction time (CRT), digit-symbol substitution (DSST), body sway and short-term memory (Sternberg memory scanning)] and self-ratings [line analogue rating scales: (LARS)]. Long-term memory (delayed free recall and recognition of pictures) was assessed before the dose and 2 and 4 h post-dose. Pharmacodynamic interactions were evaluated by applying repeated measures ANOVA to a 2 x 2 factorial interaction model. Alpidem, 50 mg twice daily at the steady state, was free of any clinically relevant detrimental effects on skilled performance, information processing or memory. In contrast, a single 2 mg dose of lorazepam induced marked impairment of psychomotor performance and cognitive function (significant reductions in CFF and DSST and increases in CRT and body sway), as well as subjective sedation from 2 to 8 h post-dose, depending on the test used. In addition, lorazepam induced anterograde amnesia, characterized by a decrease in delayed free recall and recognition, and a deficit in short-term memory. Finally, alpidem 50 mg did not potentiate the detrimental effects of lorazepam 2 mg. On the contrary, alpidem significantly antagonized the lorazepam-induced CRT increase and anterograde amnesia, and produced similar trends on most of the other cognitive parameters; thus, the results obtained with the combination of alpidem and lorazepam consistently indicated less impairment than those measured after lorazepam alone. These results are consistent with the suggested partial agonsist properties of alpidem at the benzodiazepine receptor and indicate that such properties can be assessed in humans based on antagonism of the effects of a full agonist.

The effects of 600 mg of slow release caffeine on mood and alertness.

BACKGROUND: Caffeine is the most widely used psychostimulant. PURPOSE: This study evaluated the pharmacokinetics and effects of mood and alertness of a single oral administration of 600 mg of a slow release caffeine (SRC) on a large group of healthy subjects. METHOD: In this double-blind, parallel-group study, 120 young adult males were randomly assigned to either a caffeine group (CG, n = 100) or a placebo group (PC, n = 20). After a normal sleep, each subject took 600 mg of a SRC or a placebo. Circulating caffeine was determined by salivary caffeine assays after acetylation phenotype categorization. Mood, alertness and nocturnal sleep were evaluated by visual analog scales (VAS). RESULTS: This SRC was well tolerated probably due to its relative low plasmatic Cmax (10.37 micrograms.ml-1). Between CG and PG, there were no differences for alertness, contentedness and sleep quality of the night after treatment (N2) compared to the previous night (N1). VAS scores showed a decrease in calmness in the CG (p < 0.01). Sleep latency in N2 was significantly increased with caffeine (p < 0.01). Calmness, sleep onset latency, quality of sleep onset and overall rating of N2 compared to N1 were correlated with caffeine levels, which were only influenced by tobacco consumption. CONCLUSIONS: Although a single oral dose of 600 mg of a SRC is well tolerated, further evaluation must be done on alertness and pharmacokinetics with fatigued subjects and with females using oral contraceptives.

Pharmacokinetics of viloxazine hydrochloride in man.

The pharmacokinetic characteristics of a new antidepressant, viloxazine hydrochloride, were investigated in five males and five females to study sex differences. Plasma levels were determined over a period of 9 h after a single dose of viloxazine of 100 mg (expressed as base). The half life of the drug was in the range of 2.19 - 4.21 for females and 2.61 - 4.31 h for males. The maximum plasma levels occurred in 29 - 171 min of the oral dose for females and 54 - 155 min for males. They reached 1382 - 1769 ng/ml-l for females and 1108 - 2932 ng/ml for males. Pharmacokinetic data were not statistically different between males and females.

Adverse drug reaction monitoring and the Internet: evaluation of the use of the Internet by French Pharmacovigilance Centres and a non-exhaustive survey of websites of interest for collecting information about adverse drug reaction.

The Internet, indisputably the most important source of information obtainable in real time, was long essentially the domain of researchers in the USA, but has now become more accessible to French Pharmacovigilance Centres (CRPV) and pharmaceutical companies. A questionnaire was sent to every CRPV to determine how the Internet was perceived in terms of pharmacovigilance activities and existing Websites of particular value to CRPVs were investigated. Analysis of the questionnaires revealed that 66.7 per cent of CRPVs are connected to the Internet but do not use it fully; 94 per cent of connected CRPVs use it essentially for access to a bibliographic database such as Medline (88 per cent), and none subscribes to discussion lists concerning alert messages on problems related to drugs and therapeutics. Non-connected CRPVs do not intend to use the Internet because of financial considerations, lack of time or the assumption that it is not beneficial in everyday situations. Apparently, many French CRPVs are not sufficiently aware of the importance of the Internet for professional purposes. A non-exhaustive list of sites on the Internet providing information likely to be of use to Pharmacovigilance Centres in their everyday activities is included. The Internet offers far greater possibilities than research for bibliographic references on Medline and could improve the manner in which pharmacovigilance is practised.

[Follow-up of antidepressive therapy in psychiatric clinical practice]. / Le suivi thérapeutique des antidépresseurs en pratique clinique psychiatrique.

The therapeutic drug monitoring of antidepressant drugs is of interest to adapt dosage regimens to reduce the number of non-responder patients, to reduce drug side effects and to detect non-compliant patients. A therapeutic range is defined for many of these drugs and their linear or non-linear kinetics are important parameters in clinical practice to define the posology. Some patients, because of when there is drug biotransformation polymorphism, are exposed to drug accumulation a deficit in isoenzymes of cytochrome P450. The existence of these isoenzymes explains the possibility of non-linear kinetics and drug interactions.

[Drug interactions of cyclosporine. Literature review]. / Interactions médicamenteuses de la ciclosporine. Revue de littérature.

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.

[Study of voluntary drug intoxication in an emergency unit]. / Etude des intoxications médicamenteuses volontaires reçues dans une unité d'accueil des urgences.

Voluntary drug intoxications are not systematically recorded. Main aspects of this important problem have been studied in the unit responsible for medico-psychological emergencies in the university hospital of Poitiers. Files of all patients admitted to the unit from January to December 1994 have been analysed and 598 patients were included in our study. Of these, 67 per cent were females. 31 per cent were 20 to 29 years old and for the most part unemployed (62.5 per cent). Drugs most commonly used are benzodiazepines (39 per cent), alone or often associated with alcohol (33 per cent). A fatal outcome was observed in one patient. In many cases (50 per cent) this was not the first episode of voluntary intoxication; 53 per cent of the patients were discharged from hospital after a psychiatric consultation. For many years, voluntary drug intoxication frequency has increased continually. All cases have a specific intention that we have to clarify in order to take effective preventive measures to prevent recidivism.

[Compliance, subdosage and overdosage of antidepressive agents in the first prescription in a hospital milieu]. / Observance, sous-dosage et surdosage des antidépresseurs lors de la première prescription en milieu hospitalier.

It is common clinical experience that depressed patients comply poorly with their treatment schedules. In a retrospective study, the authors studied the compliance with the tricyclic antidepressant treatment (TCA) in 1,023 in-patients and evaluated the frequency of the plasma levels under or above the therapeutic range, following a first prescription of TCA. To describe the adherence to the TCA regimen, the investigators have classified patients as either "compliant" or "bad compliant" on the basis of two different arbitrary dividing points: plasma levels of tertiary OR secondary amine lower than 20 ng/ml, or plasma levels of tertiary AND secondary amine lower than 20 ng/ml. The antidepressant plasma levels were measured, on steady state conditions, using a gas chromatographic method. The incidence of bad compliance ranged between about 2.5 and 10%, depending on the criteria used, the incidence of plasma levels under or above the therapeutic window ranged respectively between 26 and 54%-4 and 24%. The results from this study should encourage TCA plasma level measurements.

[Attitude of the clinican toward adverse effects of protease inhibitors]. / Attitude du clinicien face aux effets indésirables des inhibiteurs des protéases.

Since 1996, marketing of new drugs called protease inhibitors has revolutionized the treatment of patients suffering from AIDS. The side-effects of this new therapeutic family are quite well known but we wanted to evaluate the attitude of the clinician: can these adverse effects be corrected by symptomatic treatment, do they regress spontaneously or do they lead to an alternative PI therapy? We therefore carried out a retrospective survey in the Infectious Diseases Department of Poitiers Hospital consisting in research on files of patients (n = 70) treated in this department (hospitalization and consultation) for any clinical or biological abnormality attributable to the PI. For each drug we determined what sort of side-effects could be found and the position adopted by the clinician. For 30 patients the PI was stopped and for 21 of these cases because of drug toxicity (gastrointestinal, neurological, renal and metabolic effects). The biological anomalies are quite well tolerated and regress spontaneously in most cases.

Debrisoquine and dextromethorphan phenotyping and antidepressant treatment.

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.

[Cardiotoxicity of 5-fluorouracil. Clinical picture of 4 cases and a prevention proposal]. / Cardiotoxicité du 5-fluoro-uracile. Tableaux cliniques à propos de 4 cas et proposition de prévention.

5-fluoro-uracil (5-FU) cardiotoxicity has been often reported during chemotherapy. We collect four atypical cases of cardiac side effects in patients treated by 5-FU for head and neck tumors. We review the literature about the subject, and we propose criteria to detect patients with a high risk level, and to prevent this adverse effect incidence.

[Prospective study on admissions for iatrogenic adverse effects in the emergency service of hospital university center in Poitiers]. / Enquête prospective sur les admissions pour iatrogénie médicamenteuse dans le service d'accueil des urgences du centre hospitalier universitaire de Poitiers.

Hospital admissions resulting from an adverse drug reaction have been studied in the emergency unit of the university hospital in Poitiers during a 27-day period. This prospective study consisted in documenting all observations considered as an ADR by the medical practitioner in charge of the patient. There were 1235 hospital admissions to the emergency unit during the study period. Thirty-one (2.5 per cent) of admissions were considered to be drug-related. Women were more often affected than men. Patients with ADR were classified taking into account the type of pathology and the drug responsible for the effect. Dermatological and gastrointestinal reactions were predominant. Antibiotic and analgesic drugs were the most common drug groups implicated in causing an ADR.

Medications exposure during pregnancy. A study in a university hospital.

To collect informations about drugs prescribed during pregnancy in France we carried out a retrospective survey from august to december 1989. This study was based on a questionnaire at delivery for 225 women. Socio-economic status, obstetrical past history and patterns of prescribing medications were studied. 99.5% of the women were found to have used drugs during pregnancy with a mean of 6.84 medications per woman. There was no influence of age, geographic origins, number of previous pregnancies on drug consumption; socio-professional status was also found to have a poor correlation with drug intake. Patterns of prescribing were compared to those of a previous French study made in 1976: changing pattern of prescribing were found for progestatives, corticoids, neurotropes, aspirin and beta adrenergic agents. We also pointed out that self-administered drugs decreased from 25.9 to 17.9%. This evaluation supports the need of further epidemiological studies in our country.

[Pharmacokinetic factors and resistance to antidepressant treatment]. / Facteurs pharmacocinétiques et résistance aux traitements antidépresseurs.

A number of treatment failures occurring during antidepressant treatment may be related to the pharmacokinetics of the drug used. In fact, numerous factors are able to modify the fate of the antidepressant in the body. These factors may involve the absorption, distribution, biotransformation or elimination of the drug. The reality of these problems is illustrated by a number of clinical case reports. Such modifications lead to a variation in the quantity of drug available to exert its antidepressant action at the sites responsible for the pharmacodynamic effects. This raises the possible value of defining, and then using in practice, the therapeutic zone of the plasma concentrations of the antidepressant used, below and above which a poor therapeutic response is likely. Modern analytical techniques actually allow the routine analysis of plasma concentrations of a number of antidepressants, resulting in a more rational approach to drug therapy and a decrease in the number of depressions resistant to antidepressant treatments.

[Clinical pharmacokinetics of viloxazine chlorhydrate. Practical implications]. / Pharmacocinétique clinique du chlorhydrate de viloxazine. Implications pratiques.

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.

[Dexamethasone test: suppressors and non-suppressors, what's the difference?]. / Test à la dexaméthasone: suppresseurs et non suppresseurs, quelle différence?

In sixty-six depressed in-patients, 20 of them showed marked resistance to suppression after dexamethasone. The authors found no difference between the two subgroups of suppressors and non suppressors, when considering the following parameters: age, sex, duration of illness, number of prior episodes, family history, intensity of depression, response to antidepressant treatment, relapses, diagnoses. Furthermore the normalization of DST after a 28 day treatment did not systematically correlate with a good clinical improvement.

[Clomipramine and desmethylclomipramine: relationship between plasma levels and clinical effect (author's transl)]. / Clomipramine et desméthylclomipramine. Relation entre les concentrations plasmatiques et l'effec clinique.

Pharmacokinetic can perhaps explain that about 30% of depressed patients do not respond to tricyclic antidepressants. Studies of the relationship between the pharmacokinetic and pharmacological effects of the tricyclic antidepressants are particularly important. Clomipramine is a tricyclic antidepressant widely used. But there are disparities in various findings on relationship between plasma levels of this drug and clinical effect. Forty in-patients, with an endogenous or exogenous depressive syndrome, received clomipramine orally. In 19 patients treated by 75 mg per day of clomipramine, there was a great interindividual variability of the plasma levels at the 28 day treatment. A comparison of clinical response with plasma levels of clomipramine and desmethylclomipramine, showed a significant negative linear correlation at day 28.