[Rapid tranquilisation in adults†: algorithm proposed for psychopharmacological treatment]. / Agitation aiguë chez l'adulte†: proposition d'un algorithme de traitement psychopharmacologique.

Acute treatment of agitation in psychiatry is one of the urgent situations for which management recommendations are needed. Various existing international recommendations have been evaluated and adapted to our clinical practice and to the drugs available in Switzerland in order to propose a uniform management strategy in our hospital. This strategy includes a treatment choice algorithm with different options depending on the clinical situation and the possible route of administration. Dose recommendations for the oral and intramuscular routes, certain pharmacokinetic parameters, as well as risks of interactions and important warnings are also included in this clinical recommendation.

Le traitement aigu de l'agitation en psychiatrie fait partie des situations urgentes pour lesquelles des recommandations de prise en charge sont nécessaires. Diverses recommandations internationales existantes ont été évaluées et adaptées à notre pratique clinique ainsi qu'aux médicaments disponibles en Suisse afin de proposer une stratégie de prise en charge uniformisée au sein de notre hôpital. Cette stratégie inclut un algorithme de choix de traitement avec différentes options selon la situation clinique et la voie d'administration possible. Des recommandations de doses pour les voies orale et intramusculaire, certains paramètres pharmacocinétiques, ainsi que les risques d'interactions et des mises en garde importantes figurent également dans cette recommandation clinique.

[A rare cause of cyanosis: Sulphaemoglobinaemia related to thiocolchicoside (Miorel)]. / Une cause rare de cyanose: sulfhémoglobinémie imputable au thiocolchicoside (Miorel).

INTRODUCTION: An acquired abnormality of haemoglobin is among the many causes of cyanosis, especially in patients with no identified cardiorespiratory cause. CASE REPORT: A 50-year-old woman, suffering from amyotrophic lateral sclerosis, was hospitalised for dyspnoea. Physical examination revealed cyanosis that persisted despite oxygen therapy. Discordance between the reduced arterial oxygen saturation and normal arterial oxygen tension led to a search for a dyshaemoglobinaemia as a possible cause. Use of co-oxymetry with spectrophotometry revealed sulphaemoglobinaemia. Sulphaemoglobinaemia is due to irreversible incorporation of a thiol radical into the porphyrin ring of a haem group. This decreases the affinity of haemoglobin for oxygen and thus reduces oxygen carrying capacity. A drug-induced cause is often identified. However, no previously described cause for sulphaemoglobinaemia was identified in our patient. The patient was currently being treated with thiocolchicoside (Miorel((R))). Thiocolchicoside was suspected as the cause because its chemical structure contains an easily hydrolysable thiol radical. Withdrawal of thiocolchicoside led to regression of the sulphaemoglobinaemia. CONCLUSIONS: This report underlines the importance of searching for an acquired abnormality of haemoglobin (methaemoglobinaemia or sulphaemoglobinaemia) in patients with cyanosis resistant to oxygen, in the absence of any cardiorespiratory abnormality. This case is the first to suspect thiocolchicoside as a possible cause of sulphaemoglobinaemia.

Pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity.

OBJECTIVE: To examine the effect of cytochrome P450 (CYP) 2C19 activity on the single-dose pharmacokinetics and pharmacodynamics of etizolam. METHODS: The subjects were 21 healthy Japanese volunteers. The two mutated alleles (CYP2C19*2 and CYP2C19*3) causing absent CYP2C19 activity were identified by a polymerase chain reaction method. Twelve subjects were extensive metabolizers (EMs) with no or one mutated allele, and nine subjects were poor metabolizers (PMs) with two mutated alleles. The subjects received a single oral 1-mg dose of etizolam, and blood samplings and evaluation of psychomotor function were conducted up to 24 h after dosing. RESULTS: The PMs had significantly larger total area under the plasma concentration-time curve (287+/-74 vs 178+/-122 ng.h/ml, p<0.05) and longer elimination half-life (14.8+/-4.2 vs 10.5+/-3.9 h, p<0.05) of etizolam than the EMs. The area under the score-time curve from 0 to 8 h of the Stanford Sleepiness Scale was significantly larger in the PMs than in EMs (28.9+/-5.2 vs 22.9+/-6.9 score.h, p<0.05). CONCLUSION: The present study suggests that the single-dose pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity.

Induction of the metabolism of etizolam by carbamazepine in humans.

OBJECTIVE: To examine the effect of carbamazepine on the single oral dose pharmacokinetics of etizolam. METHODS: Eleven healthy male volunteers received carbamazepine 200 mg/day or placebo for 6 days in a double-blind, randomized, crossover manner, and on the sixth day they received a single oral 1-mg dose of etizolam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 24 h after etizolam dosing. Plasma concentration of etizolam was measured using high-performance liquid chromatography. RESULTS: Carbamazepine treatment significantly decreased the peak plasma concentration (17.5+/-4.1 ng/ml versus 13.9+/-4.1 ng/ml; P<0.05), total area under the plasma concentration-time curve (194.8+/-88.9 ng h/ml versus 105.9+/-33.0 ng h/ml; P<0.001), and elimination half-life (11.1+/-4.6 h versus 6.8+/-2.8 h; P<0.01) of etizolam. No significant change was induced by carbamazepine in the two pharmacodynamic parameters. CONCLUSIONS: The present study suggests that carbamazepine induces the metabolism of etizolam.

Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism.

OBJECTIVE: To clarify the involvement of cytochrome P450 (CYP) 3A4 in the metabolism of etizolam. METHODS: The effects of itraconazole, a potent and specific inhibitor of CYP3A4, on the single oral dose pharmacokinetics and pharmacodynamics of etizolam were examined. Twelve healthy male volunteers received itraconazole (200 mg/day) or placebo for 7 days in a double-blind randomized crossover manner, and on the 6th day they received a single oral 1-mg dose of etizolam. Blood samplings and evaluation of psychomotor function using the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 24 h after etizolam dosing. Plasma concentration of etizolam was measured by means of high-performance liquid chromatography. RESULTS: Itraconazole treatment significantly increased the total area under the plasma concentration-time curve (AUC; 213+/-106 ng rectangle h/ml versus 326+/-166 ng rectangle h/ml, P<0.001) and the elimination half-life (12.0+/-5.4 h versus 17.3+/-7.4 h, P<0.01) of etizolam. The 90% confidence interval of the itraconazole/placebo ratio of the total AUC was 1.38-1.68, indicating a significant effect of itraconazole. No significant change was induced by itraconazole in the two pharmacodynamic parameters. CONCLUSION: The present study suggests that itraconazole inhibits the metabolism of etizolam, providing evidence that CYP3A4 is at least partly involved in etizolam metabolism.

[Experimental pharmacokinetics of phenazepam during transdermal administration of the therapeutic phenaperkuten system]. / Eksperimental'naia farmakokinetika fenazepama pri primenenii transdermal'noi terapevticheskoi sistemy fenaperkutena.

The pharmacokinetics of fenazepam upon application of the transdermal therapeutic system (TTS) fenapercuten in various forms and under different conditions was studied in rabbits. The rate of the transdermal transfer of fenazepam from TTS to blood varied from 0.76 to 2.89 mg/(ml cm2). It was found that the drug transfer rate remains constant for 2-3 days. After removal of the TTS, fenazepam is eliminated within 3 days.

[Pharmacokinetic evaluation of the tablet dosage forms of gidazepam prepared by various technologies]. / Farmakokineticheskaia otsenka tabletirovannykh lekarstvennykh form gidazepama, prigotovlennykh po razlichnym tekhnologiiam.

The pharmacokinetics of gidazepam administered in tablets prepared using different technologies was studied in rabbits. The optimum properties (high relative bioaccessibility and low degree of dealkylation of the parent substance) were observed for the tablets fabricated using a solid disperse system.

Biokinetics of gidazepam, derivatives of peptideaminobenzophenones and their metabolites.

Results of a comparative study of biokinetics of two prodrugs gidazepam (I) and the derivative of peptideaminobenzophenone, 2-N-carbobenzylglycyl-glycylamido-5-bromobenzophenone (II) and their main physiologically active metabolite-7-brom-5-phenyl-dihydro-3H-1,4-benzodiazepine (III) were investigated in mice. It was shown earlier that I undergoes intensive N1-desalkylation with the formation of a metabolite: (III) and products of its further oxidation. Metabolism of II is characterized by hydrolysis of the peptide fragment and subsequent intramolecular condensation resulting in the formation of III, its oxi- and metoxylated derivatives and other minor metabolites. The difference between kinetics of 14C-contents in organs and tissues of mice following administration of prodrugs I, II and their metabolite III are demonstrated: In the first two cases no rapid distribution phase of I and II was detected; maximal levels of III were achieved faster (0.25-0.35 min) and its elimination proceeded with higher rates. For all substances the organs and tissues studied are not "stores" of slow exchange of 14C-material between serum and brain and are essentially different. After administration of I and II, the relationship between 14C-contents in brain and serum change demonstrating a loop over the whole period of the experiment which allows to suggest that serum acts as the central compartment, whereas brain is a peripheral compartment of a kinetic scheme of distribution of prodrugs in mice. Following administration of III, we observed a linear relationship between serum and brain 14C-contents which did not depend on the experimental time. This finding suggests that the studied biosubstrates act as one (central) compartment of a kinetic scheme of distribution of III. It is demonstrated that the peculiarities of their pharmacologic action of prodrugs are explained by the nonlinearity of the processes of their biotransformation and specific of biokinetics.

Atypicality of several antipsychotics on the basis of in vivo dopamine-D2 and serotonin-5HT2 receptor occupancy.

An in vivo receptor binding technique was used to evaluate the binding profiles of typical and atypical antipsychotic drugs to striatal dopamine-D2 and frontal serotonin-5-HT2 receptors in a rat brain using more specific ligands than those previously employed. [3H]-YM-09151-2 or [3H]-ketanserin was injected into the tail vein 10 minutes after administration of test drugs. One hour after the ligand injection, radioactivities in the striatum, frontal cortex, and cerebellum were counted to obtain receptor occupancies by the test drugs. Higher ratios of potency in occupying 5-HT2 versus D2 receptors were found for clozapine, RMI-81512, and tiospirone compared to haloperiodol and pimozide. Zotepine, mosapramine, and clocapramine produced ratios that fall between these two groups. Chlorpromazine was exceptional as a typical antispychotic by these criteria. Relatively strong antagonism of 5-HT2 receptors by atypical antipsychotics was confirmed by this in vivo measure of receptor binding using more selective ligands than those used in previous studies.

Disposition of asarone after intravenous administration to rabbits assessed using HPLC.

A simple and sensitive high-performance liquid chromatography (HPLC) method for the determination of asarone in rabbit plasma has been developed. Up to 0.1 mL of plasma containing asarone was deproteinated by acetonitrile, which contained an internal standard (indomethacin). The supernatant was injected into a Nucleosil 7C18 column using acetonitrile-water-triethylamine (55:45:0.1 v/v, pH 5.4-5.5, adjusted with orthophosphoric acid) as the mobile phase and UV detection at 257 nm, followed by UV spectrum identification (between 200 and 380 nm) with a photodiode array detector. The method is rapid, easily reproduced, selective and sensitive. It was applied to pharmacokinetic studies of asarone in rabbit, after 5, 10, or 20 mg kg-1 intravenous administration. Rapid distribution followed by a slower elimination phase was observed from the plasma concentration-time curve. The plasma disposition at each dose fitted well to a two-compartment open model and the terminal disposition became much slower as the dose was increased, suggesting a nonlinear dose-dependent plasma asarone disposition.

Open-loop feedback control of serum bentazepam concentrations and Bayesian estimation in multiple dosage regimens in patients.

The time course of serum levels of bentazepam was studied in 10 patients receiving anxiolytic agent orally at a dose of 25 mg on multiple dosage regimens with dosage intervals of 8 and 12 h. Using the methods of "open-loop feedback control", no linear regression programs and Bayesian estimation, it was possible to establish the best estimates of the pharmacokinetic parameters corresponding to the single-compartment model for each patient from all their data relating to the serum levels obtained after the first dose and after multiple dosing with different regimens. The application of the Kruskal Wallis test showed that there were only statistical differences for the absorption constant, determined with and without Bayesian estimation. However, no statistically significant differences were found on comparing the experimentally obtained serum levels with the corresponding theoretical values calculated independently for each patient from the parameters established with and without Bayesian estimation. As population pharmacokinetic parameters of bentazepam, the following were established: Ka = 2.330 +/- 0.665 l/h; Vd = 1.209 +/- 0.546 l/Kg and Ke = 0.160 +/- 0.118 l/h, corresponding to a mean value for the elimination half-life of 4.33 h.

Pharmacokinetic study of iminodibenzyl antipsychotic drugs, clocapramine and Y-516 in dog and man.

The pharmacokinetic properties of the iminodibenzyl antipsychotic drugs clocapramine (CCP, 3-chloro-5-[3-(4-carbamoyl-4-piperidino piperidino) propyl]-10, 11-dihydro-5H-dibenzo[b, f]azepine) and Y-516 (3-chloro-5-[3-(2-oxo-1, 2, 3, 5, 6, 7, 8, 8a-octahydroimidazo [1,2-a] pyridine-3-spiro-4'-piperidino) propyl]-10, 11-dihydro-5H-dibenzo[b, f]azepine) were investigated in dog and man. Dogs were administered CCP and Y-516 intravenously, intraperitoneally, and orally, and the concentrations of the parent drugs and their metabolites in the plasma and urine were determined. Half-life (t1/2) was approximately the same by all three administration routes, being approximately 5 h for CCP and 3 h for Y-516. Bioavailability following oral administration was 0.16 +/- 0.01 (mean +/- SD, n = 3) for CCP and 0.29 +/- 0.07 for Y-516. The fractions of dose absorbed following oral administration were 0.43 +/- 0.07 and 0.79 +/- 0.24, and the fractions of dose metabolized in the liver due to the first-pass effect were 0.63 +/- 0.05 and 0.63 +/- 0.04 for CCP and Y-516, respectively. Y-516 was detected in the plasma after intraperitoneal and oral administration of CCP. The ratio of the AUC of Y-516 to that of CCP was 0.06 following intraperitoneal administration and 0.40 following oral administration. This indicated that while the metabolism of CCP into Y-516 may occur partly in the liver due to the first-pass effect, it occurs mostly within the gastrointestinal tract itself or its mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Thin-layer chromatographic screening method for the tranquillizers azaperone, propiopromazine and carazolol in pig tissues.

A procedure is described for the detection of azaperone, propiopromazine and carazolol in pig muscle, liver and kidney tissue. The method comprises extraction from an alkaline tissue homogenate with diethyl ether, followed by cleaning up and concentration of the extract on a silica gel solid-phase extraction column. Two-dimensional thin-layer chromatography on a silica plate was used for the detection of the tranquillizers. Detection levels were 25 micrograms kg-1 for propiopromazine, 50 micrograms kg-1 for azaperone (or its metabolite azaperol) and 125 micrograms kg-1 for carazolol. In pigs treated with the usual doses the presence of propiopromazine and azaperol could be established in kidney tissue 8 h after administration, whilst in injection sites all three tranquillizers could be detected.

Comparative study of the pharmacokinetics of zuclopenthixol decanoate and fluphenazine decanoate.

Seventeen outpatients were treated with depot neuroleptics, zuclopenthixol decanoate in Viscoleo or fluphenazine decanoate in sesame oil, with dosage intervals of 3 weeks. During the 4th, 6th, and 8th dosage interval blood samples were drawn in oxalated tubes. Plasma concentrations of the active neuroleptic drugs, zuclopenthixol and fluphenazine, were determined by high performance liquid chromatography. The concentrations indicated some interindividual as well as intraindividual variations. For zuclopenthixol the maximum concentration was most often seen at day 7 after injection, whereas the kinetics of the fluphenazine concentrations was more variable. There was an indication of more fluctuation in the 4th dosage interval than in the 8th dosage interval, possibly due to the fact that steady state has not yet been achieved at the 4th dosage interval.

Absorption of intramuscularly administered [14C]haloperidol decanoate in rats.

When [14C]haloperidol decanoate, an ester of haloperidol and decanoic acid, was given intramuscularly to rats, levels of total radioactivity and haloperidol decanoate in medial iliac and hypogastric sacral lymph nodes nearest to injection sites were the highest in examined lymph nodes and plasma. These lymph node levels became maximum 16 days after administration and declined gradually with half-life (around 14 days) similar to those of plasma total radioactivity, haloperidol decanoate and haloperidol. However, when the labelled ester was given intravenously, plasma total radioactivity disappeared far more rapidly. Much more radioactivity was found in hind limbs whose femoral muscles had been injected than in other body parts, even at late stages after administration. Haloperidol alone was found in the brain after [14C]haloperidol decanoate was given either intramuscularly or intravenously. It was concluded that haloperidol decanoate injected in rat femoral muscle was rate-limitedly distributed in lymph circulation and that the absorbed ester did not penetrate the brain through the blood-brain barrier but formed haloperidol did.