Additive effects of clonidine and antidepressant drugs in the mouse forced-swimming test.

In the mouse forced-swimming model, dose-dependent reversal of immobility was induced by the alpha-agonist clonidine given IP 30 min before testing. In addition, three preferential inhibitors of 5-HT uptake (citalopram, indalpine and fluvoxamine) had similar activity in the dose range 8-16 mg/kg as did the 5-HT1 agonist 8-OH-DPAT (1-4 mg/kg). Pretreatment with alpha-methyl-paratyrosine (100 mg/kg) did not prevent clonidine (1 mg/kg) action, suggesting that there was mediation by alpha post-junctional receptors. The effect of clonidine was unaltered by prazosin (2 mg/kg) and reversed by yohimbine (4 mg/kg) and 5-MeODMT (1 mg/kg), whereas it was potentiated by reserpine (2.5 mg/kg), methysergide (2 mg/kg) and ketanserin (8 mg/kg). Moreover, an ineffective dose of clonidine (0.06 mg/kg at 45 min pre-testing) made active subthreshold doses of various antidepressants (given at 30 min pre-testing): imipramine (4 mg/kg), amitriptyline (1 mg/kg), maprotiline (8 mg/kg), citalopram (2 mg/kg), indalpine, fluvoxamine and mianserin (4 mg/kg), viloxazine (2 mg/kg). Similar interactions were found with iprindole and nialamide (32 mg/kg), which were inactive alone up to 64 mg/kg, and 8-OH-DPAT (0.5 mg/kg) but not with major and minor tranquillizers. It is suggested that one effect of antidepressants might be the triggering of different relationships between alpha-2 and 5-HT mechanisms.

Influence of alpha stimulants and beta blockers on yohimbine toxicity.

1. Potentiation of yohimbine-induced sublethality has been largely used to predict antidepressant action. 2. Several products were tested in order to understand the mechanism of this toxicity better: an alpha-1 central stimulant (adrafinil); an alpha-2 central stimulant (clonidine); and 4 beta-blockers (propranolol, atenolol, penbutolol and metoprolol). 3. It was found that atenolol and adrafinil could not antagonize toxicity, whereas clonidine and the other 3 beta-blockers could. 4. It is suggested that a central beta-origin toxicity exists since only beta-blockers which cross the blood-brain barrier are capable of antagonizing this activity. 5. The fact that clonidine also antagonized this toxicity may be explained by the beta-antagonist action of this substance at the high doses used.

Effects of administration route on valproate pharmacokinetics in the rabbit.

The absorption of sodium valproate was studied in 5 rabbits. Each animal received the drug (70 mg/kg) via 3 routes: intravenous, gastric and duodenal. For the 2 extravascular routes, the absolute bioavailability F, maximal plasma concentrations Cmax, times to peak Tmax and absorption coefficients Kabs were the same. Absolute bioavailability was always close to unity. This indicated that valproic acid was absorbed from the intestine as well as from the whole gastrointestinal tract. The other pharmacokinetic parameters such as terminal plasma half-life, total clearance and volume of distribution remained unchanged whatever the route of administration.

Quantitative analysis of serum methohexital by GLC using capillary column and nitrogen-selective detection.

A gas chromatographic method for routine quantitation of methohexital in plasma samples is reported. One-step extraction in organic phase, the use of a fused silica capillary column, and nitrogen-selective detection permit simple, precise, and sensitive determination of methohexital in plasma. A linear relationship is described between peak height ratio and methohexital concentrations ranging from 0.125 to 50.0 micrograms/ml (r = 0.998). The sensitivity limit of the assay was 6 ng/ml in plasma. No interfering peak was observed with numerous other drugs. The procedure was successfully applied to the determination of pharmacokinetic parameters of methohexital after IV administration or continuous infusion in a child and an adult.

Pharmacokinetics of lidocaine and bupivacaine in retrobulbar and facial block.

Analgesia can be obtained during ophthalmic surgery by regional anesthesia using local anesthetic agents. As in other indications, neurological complications may occur, especially because the site of injection is close to the central nervous system. In order to evaluate the risk of retrobulbar and facial block obtained after 40 mg lidocaine and 20 mg bupivacaine injection, pharmacokinetics of both drugs was evaluated in plasma obtained from 11 patients. In addition, 3 cerebrospinal fluid samples were analyzed. Maximal plasma concentration was 0.73 +/- 0.33 micrograms.ml-1 for lidocaine and 0.19 +/- 0.06 micrograms.ml-1 for bupivacaine, obtained 24.7 +/- 23.0 min and 12.0 +/- 3.7 min after the end of injection, respectively. CSF/plasma ratio was in the range 0.05-0.26 for lidocaine and 0.56-1.33 for bupivacaine. In all patients, regional anesthesia was sufficient to perform surgery without any other analgesic drug. No sign of cardiovascular or respiratory toxicity was observed during the study.

Rapid gas-chromatographic assay of bupivacaine in plasma.

A method for estimating bupivacaine concentration in human plasma by capillary gas-chromatography using solid injection and nitrogen-specific detection is described. Etidocaine, another anilidetype local anesthetic was used as internal standard and added to the sample before single-step extraction with diethylether. This method demonstrates high sensitivity (6 ng/ml plasma) and combines selectivity, rapidity, and simplicity. Results of this procedure correlate well with those obtained by an HPLC method.

Pharmacokinetics of high-dose melphalan in adults: influence of renal function.

BACKGROUND: The pharmacokinetics of melphalan were studied in 20 patients with multiple myeloma, primary amyloidosis or lymphoma after IV dose of 140 mg/m2 infused over 30 minutes (two patients were treated with a higher dose). MATERIALS AND METHODS: Six patients received melphalan alone, 8 received melphalan combined with total body irradiation, 2 received busulphan plus melphalan and 4 received the BEAM association (BCNU + etoposide + high dose aracytine + high dose melphalan). Creatinine clearance was measured immediately before the infusion of melphalan, and 9 blood samples were taken to monitor elimination kinetics. RESULTS: Pharmacokinetic parameters (CIT, Vdss, t1/2) and areas under the curve (AUC) were comparable to those obtained by Ardiet et al after rapid IV injection. For all patients, AUC, CIT, Vdss, t1/2 beta and MRT were significantly correlated with creatinine clearance; the different pharmacokinetic parameters calculated showed great interindividual variations. CONCLUSIONS: Renal insufficiency did not lead to a large decrease in melphalan clearance compared to interindividual variations in systemic clearance.

Quantitation of amphotericin B in plasma by second-derivative spectrophotometry.

A method is described for determining amphotericin B in plasma using second-derivative spectrophotometry after deproteinization. The assay was based on the absorbance at 407.5 nm. The second-derivative spectrum recorded between 350 and 450 nm allowed identification of the analyte and showed absence of drug interference. Only bilirubin interfered at high concentration (> or = 50 mumol l-1. The linear concentration ranges were 0.05 -5.0 mg l-1 (r = 0.999, slope = 2.731, intercept = 0.008). Between-day CV < or = 9.7%, within-day CV < or = 5.5%, analytical recovery close to 100% were suitable for clinical investigations. This method provides better specificity than direct absorbance, is simpler and faster than a high performance liquid chromatography assay and can be used routinely by any laboratory possessing a spectrophotometer with a derivative accessory.

Effects of administration route on pharmacokinetics of viloxazine in the rabbit.

The absorption of viloxazine chlorhydrate was investigated in ten rabbits. Each animal received the drug (15 mg/kg) by three routes: intravenous, gastric and duodenal. Viloxazine plasma concentrations were low when administered by gastric and duodenal routes compared to those after intravenous injection. Concentrations to peak were 1-2 times higher after duodenal than gastric administration. Times to peak were 23.0 +/- 4.7 min after gastric administration and 9.5 +/- 5.4 min after duodenal administration. A better absorption of viloxazine after administration occurred in the duodenum than in the stomach; these results agree with viloxazine pKa = 8.13. The other pharmacokinetic parameters such as half-life, clearance and volume of distribution where the same irregardless of the administration route.

Effects of administration route on pharmacokinetics of aspirin in the rabbit.

The absorption of aspirin used in the form of lysine acetylsalicylate was studied in the rabbit. Each animal received the drug by three routes: intravenous, gastric and duodenal. Plasma concentrations of acetylsalicylic acid (ASA) and salicylic acid (SA) were compared. ASA plasma concentrations obtained after gastric or duodenal administration were low compared to those after intravenous injection. Concentrations were 2 to 5 times higher after gastric than duodenal administration. SA plasma concentrations were lower at the beginning of the experiment for gastric than for duodenal administration; after 90 min the concentrations were similar. A better absorption of aspirin (as lysine acetylsalicylate) after administration occurred in the stomach than in the duodenum, but the amount of ASA which reached the central compartment was quite poor.

[Clinical data on COX-1 and COX-2 inhibitors: what possible alerts in pharmacovigilance?]. / Les inhibiteurs de COX-1 et COX-2, données cliniques: quelles alertes possibles en pharmacovigilance?

Adverse effects of NSAIDs are serious, mainly related to gastrointestinal bleeding, and throughout the world cause about 260,000 hospitalizations and 26,000 deaths a year, but each day at least thirty million patients take NSAIDs. Selective COX-2 inhibitors (i.e. celecoxib, rofecoxib) have demonstrated in clinical trials better gastrointestinal tolerability but their safety in patients with active ulcer, cardiovascular or renal disease has still to be further investigated. When their long-term safety has been established by pharmacovigilance studies they could be prescribed in the at-risk population or for other indications, including pre-term labour, colorectal cancer and Alzheimer's disease, provided they have shown efficacy and safety in controlled trials.

[Cutaneous side effects of ketoprofen gels: results of a study based on 337 cases]. / Kétoprofène gel et effets secondaires cutanés: bilan d'une enquête sur 337 notifications.

Ketoprofen gels, since their introduction on the French market (1989), have been responsible for various cutaneous side-effects (essentially photosensitization and contact eczemas). A study conducted by the French drug surveillance system detected 337 cases. Analysis showed that the frequency of cutaneous adverse events was from 0.008/1000 to 0.023/1000 according to the commercial gel. The sex ratio was well distributed, and the population was young (30-40 years) and athletic. Treatment lasted about 7 days, and the appearance of the side-effect was sometimes quite delayed relative to discontinuance of treatment. Reactions were severe in 40 per cent of cases. The factors favourable to side-effects were essentially exposure to the sun (one-third of cases) and occlusive dressing. No particular predisposing conditions were noted, although 2.6 per cent and 8.5 per cent of cases respectively involved earlier sensitization by a topical NSAID. The side-effect lasted about 16 days. The course was usually favourable but hospitalization was required in about 10 per cent of cases. Photoallergological testing indicated photosensitization to ketoprofen. These results led the National Commission of the French drug surveillance system to request a modification in the indications for the prescription of the ketoprofen gels.

A 2-year evaluation of questions concerning "Drugs--Pregnancy" at the CRPV in Nantes March 1992--March 1994. / Bilan de 2 années du suivi des questions "Médicaments--Grossesse" au CRPV de Nantes entre Mars 1992 et Mars 1994.

Since 1990, the 'Centre Regional de Pharmacovigilance' of Nantes has systematically monitored pregnant women exposed to drugs. To increase physicians' participation in this study (34 per cent), the protocol was modified in 1992. Phoned answers are confirmed by mail. At the supposed time of the delivery, the physician receives a questionnaire about the outcome of pregnancy. A second letter and phone call are planned. With this method, 89 per cent of the pregnancies were fully documented between March 92 and March 94. Answers are classified according to the type of the practice. Pregnancy outcome is studied according to the drugs and the moment of exposure during pregnancy. Quality of the information, motivation of the physicians, and the benefits and difficulties of this method are discussed.

[Evaluation of drug consumption by hospitalized patients. Prospective survey]. / Evaluation de la consommation médicamenteuse des sujets hospitalisés. Enquête prospective.

Drug use was assessed in a prospective 6-month study carried out in the Department of General Medicine V and Rheumatology of the Nantes Regional Hospital Center. An attempt was made to evaluate consumption as realistically as possible, and a judgment was made based on the consensus of the medical team as to whether the prescription was justified or not. The mean number of drugs consumed by each patient was 2.8; 60% being prescribed for cardiovascular and neuropsychiatric purposes. As 33% of the prescriptions were considered unnecessary, it would appear that use was excessive in these hospitalized patients.

[Iatrogenic disease. Prospective study, relation to drug consumption]. / Pathologie iatrogène. Enquête prospective, lien avec la consommation médicamenteuse.

The role of drug use in iatrogenic pathology was studied prospectively in a hospital department. It wa s found that patients received an average of 2.8 drugs and that 30% of the prescriptions were unnecessary. During this six-month study of all patients admitted to a general medicine and rheumatology department, there were 67 iatrogenic accidents affecting 12.3% of the population: 41.8% of the accidents were directly responsible for hospitalization, 35.4% were due to therapy initiated during hospitalization and 32.8% occurred during the hospital stay but were the result of earlier treatment. Moreover, 26% of the accidents were related to what was considered to be unnecessary therapeutics. This study shows that elevated iatrogenic pathology was due to excessive drug use. However, the degree of severity of the adverse effects varied considerably, and some could have been easily avoided.

[Use of the CD-ROM "Tox-Didact" for teaching of toxicology and pharmacology]. / Application du CD-ROM 'Tox-Didact' à l'enseignement de la toxicologie et de la pharmacologie.

Tox-Didact is a multimedia teaching software package for initial training, continuing training and self-learning of toxicology and pharmacology. This software covers a large part of toxicology in its acute and chronic pathology using several approaches: drugs (salicylics, paracetamol, lithium ...); toxins (lead, methanol, carbon monoxide ...); drug addiction and doping (cocaine, heroin, LSD, amphetamines ...); systemic targets (kidneys, skin, liver ...). Tox-Didact is currently composed of 39 modules in validation, each tackling the diagnosis, biological surveillance, treatment, prevention and documentation of a real clinical case. Each module is organized around four types of questions, requiring a choice either (drug, symptom, formula ...) or an open response. Each validated answer is analysed by software which then comments on or corrects it. The essential points which characterize this software are: its multidisciplinarity (toxicology, pharmacology, semiology ...), its reliability (validated by experts), its simplicity of use. It is modular and offers an interactive teaching approach. The objective is to create a portable multimedia tool operational with all computer systems (IBM PC, Macintosh). This program is sustained by the Région des Pays de la Loire and by the Multimedia Resource Office of the French Ministry of National Education.

Warning! One buflomedil may hide another one!

A 75-year-old woman experienced fever and convulsions. She was treated for diabetes mellitus, angina pectoris and also for arteritis with Buflomedil Merck (3 tab/d). Further investigations failed to find any aetiology. Buflomedil dosage was elevated to 6.3 mg/l (N = 4-4.5 mg/l). The drug was discontinued and there was no recurrence of symptoms. There was no evidence of error in dosage or interaction. A failure of the generic product was suspected. Only a pharmacist solved the problem. Fonzylane (buflomedil) had recently been switched to Buflomedil Merck. The patient misunderstood the change and took both drugs! Our purpose is not to report a known effect but to emphasize the importance of extending the information given to the patient and the risk of misuse of the generic product.

[Determination of plasma retinol and alpha-tocopherol by HPLC]. / Dosage du rétinol et de l'alpha-tocophérol plasmatique par CLHP.

Retinol (vit A) and alpha-tocopherol (vit E), the active compounds of vitamins A and E, were assayed by reversed-phase high performance liquid chromatography (HPLC) (C18) with UV absorbance detection at 280 nm. Plasma was deproteinized and liquid-liquid extraction performed with hexane. After evaporation, the residue was dissolved in organic solvents (ether:methanol 25:75, V/V). Standard curves were prepared by adding known amounts of standards to plasma. The use of acetonitrile in the mobile phase (acetonitrile:methanol:water 64.5:33:2.5, V/V) avoided interference peaks, giving a total run time of 8 min. Analyte stability required that samples be treated in the dark. Analytical performance was good: recovery around 100%, detection limits 0.015 mg/l for vit A and 0.030 mg/l for vit E, linear range 2 mg/l for vit A and 20 mg/l for vit E, no recorded interference, and between-run and within-run precision with coefficients of variation < 11%. Analytes were stable at room temperature for 24 h (vit A) and 48 h (vit E) in plasma stored in the dark for one month at -20 degrees C. The standard solution containing both vit A and vit E increased vit A stability. Plasma concentrations (mg/l) for vit A and E were respectively: 0.63 +/- 0.17 and 9.61 +/- 3.1 in adults (n = 29), 0.39 +/- 0.17 et 7.10 +/- 2.41 in children 0 to 15 years (n = 21). This method allows regular monitoring of patients with cystic fibrosis to check for retinol and alpha-tocopherol deficiencies. The usefulness and results of the method are discussed in terms of previous studies.

[Neutropenia caused by acenocoumarol associated with hairy cell leukemia]. / Neutropénie à l'acénocoumarol associée à une leucémie à tricholeucocytes.

We report the case of a woman splenectomized to treat her hairy cell leukemia (at the moment in remission) 11 years before the detection of neutropenia. The neutropenia began just after the treatment of pulmonary embolism by acenocoumarol. The neutropenia disappeared quickly after substitution of acenocoumarol by fluindione. We discuss the attribution of the neutropenia to acenocoumarol and the part played by hairy cell leukemia.

[French system of drug surveillance]. / Le système francais de pharmacovigilance.

The French drug surveillance system is characterized by: a network of thirty one regional drug surveillance centres, located to provide convenient proximity to health care professionals; a causality assessment method, compulsory for all persons involved in drug surveillance, to assess the causal relationship between an adverse effect and one or more drugs; if necessary, an additional evaluation of the causal relationship will be performed using pharmaco-epidemiology methods; a Technical committee and a National Commission of Drug Surveillance which centralize and assess all the data in order to provide a consensual advice to the relevant authorities on necessary measures, to prevent, or reduce a drug related adverse effect; in the case of an inquiry, the drug surveillance department of the pharmaceutical company and the network of regional drug surveillance centers will pool their data with the aim to exchange information and ideas.