Clonazepam in acute mania: time-blind evaluation of clinical response and concentrations in plasma.

This study was performed to evaluate the optimal doses and clinical efficacy of clonazepam as a first-line drug in acute mania, as well as to determine its effective plasma concentrations. Clonazepam was administered orally to 11 newly admitted inpatients. On day 0, the loading dose was titrated upward according to the clinical global impression; the maintenance dose was calculated with intent to maintain the plasma level that had been achieved after initial dose escalation. Clinically based dose adjustments were allowed on days 4 and 7. Manic symptoms were scored on days 0, 4 and 14 according to a time-blind procedure; clonazepam plasma levels were measured by HPLC. On day 14, there was a significant decrease in manic symptoms and 66.7% of the patients who completed the trial were markedly improved. Steady-state plasma levels of clonazepam were significantly correlated with daily doses (rs = 0.795, P < 0.005) and therapeutic concentrations ranged between 6.5-83.9 micrograms/l. At the onset of therapy, the clinically titrated loading dose resulted in plasma concentrations within the narrow range of 18.9-34.0 micrograms/l. These results support the potential value of clonazepam in the short-term management of acute mania; the initial control of agitation was achieved with plasma drug levels in a remarkably narrow range as compared with the further control of mania.

Correlation between methotrexate pharmacokinetic parameters, and clinical and biological status in rheumatoid arthritis patients.

OBJECTIVE: To determine the correlation between the pharmacokinetic (PK) parameters of methotrexate (MTX), clinical status and laboratory test results in rheumatoid arthritis (RA) patients. METHODS: 22 patients (4 M/18F, mean age: 50 +/- 12 years, mean duration of RA: 8.5 +/- 6.5 years, mean duration on MTX: 8 +/- 10 months) were included in a prospective study. The mean dose of MTX administered was 6 +/- 0.7 mg/m2 of body area/week. No patient received any nonsteroidal antiinflammatory drug (NSAID). Blood and urine samples were collected over 24 hours (9 blood samples). The MTX concentrations were assayed by fluorescence polarization immunoassay. Clinical parameters (Ritchie articular index, morning stiffness, joint pain count, joint swelling count), hematological, liver and renal function tests, and ESR were recorded. Correlations between the patients' PK parameters, laboratory tests and clinical status were carried out using Pearson's correlation coefficient test. RESULTS: A significant correlation was observed between the Ritchie articular index, morning stiffness and the area under the curve (p = 0.009 and p = 0.026, respectively). No correlation was found with the other parameters. CONCLUSION: These results suggest that when the patient's disease activity is higher, the AUC becomes more important, reflecting a greater body exposure to MTX.

A double-blind comparison of clonazepam and placebo in the treatment of neuroleptic-induced akathisia.

The present study was designed to investigate the efficacy of clonazepam in neuroleptic-induced akathisia. Twelve patients were treated during 2 weeks with clonazepam or placebo in a double-blind randomized design. Akathisia was scored by an independent rater before and after treatment, as well as 1 week after medication withdrawal. Clonazepam (0.5-2.5 mg/day) induced a significantly higher reduction in the akathisia scores than placebo (p < 0.05). One week after stopping the drug, there was a partial but significant relapse in the treated group as compared with controls, in whom the symptoms remained stable. In addition, the clinical improvement was significantly correlated with the daily dose of clonazepam (rs = 0.827; p < 0.002). These results support the potential usefulness of clonazepam in the treatment of neuroleptic-induced akathisia and suggest an optimal daily dose in the range of 10-40 micrograms/kg.

Therapeutic isoniazid monitoring using a simple high-performance liquid chromatographic method with ultraviolet detection.

Simultaneous measurement of isoniazid and its main acetylated metabolite acetylisoniazid in human plasma is realized by high-performance liquid chromatography. The technique used is evaluated by a factorial design of validation that proved to be convenient for routine drug monitoring. Plasma samples are deproteinized by trichloroacetic acid and then the analytes are separated on a microBondapak C18 column (Waters). Nicotinamide is used as an internal standard. The mobile phase is 0.05 M ammonium acetate buffer (pH 6)-acetonitrile (99:1, v/v). The detection is by ultraviolet absorbance at 275 nm. The validation, using the factorial design allows one to: (a) test the systematic factors of bias (linearity and matrix effect); (b) estimate the relative standard deviations (RSDs) related to extraction, measure and sessions assay. The linearity is confirmed to be within a range of 0.5 to 8 microg/ml of isoniazid and 1 to 16 microg/ml of acetylisoniazid. This method shows a good repeatability for both extraction and measurement (RSD INH=3.54% and 3.32%; RSD Ac.INH=0.00% and 5.97%), as well as a good intermediate precision (RSD INH=7.96%; RSD Ac.INH=15.86%). The method is also selective in cases of polytherapy as many drugs are associated (rifampicin, ethambutol, pyrazinamide, streptomycin). The matrix effect (plasma vs. water) is negligible for INH (3%), but statistically significant for Ac.INH (11%). The application of this validation design gave us the possibility to set up an easy and suitable method for INH therapeutic monitoring.

A double Weibull input function describes the complex absorption of sustained-release oral sodium valproate.

The pharmacokinetics of valproic acid after oral administration of sustained-release formulations were studied in 12 healthy volunteers. The objective of the present study was to find an appropriate mathematical model to describe the complex drug intake process. The concentration of valproic acid in plasma was measured by HPLC. For each subject, during the input process a double peak phenomenon was observed, the plasma concentrations were fitted according to a single or a double Weibull input function, and then a first-order elimination rate was used to describe the observed data. The Weibull model was considered as an approximation of the overall process. The mean peak plasma concentration, 34.6 +/- 8.9 mg/L, was reached after 8.6 +/- 2.7 h. A single Weibull function adequately described the observed data for three subjects; the mean Weibull parameters were td (the time necessary to transfer 63% of the administered drug into the systemic circulation) of 7.87 +/- 3.53 h and gamma (shape) of 1.16 +/- 0.66. A double Weibull input function was used for nine subjects; the mean Weibull parameters were td1 = 2.35 +/- 1.18 h and td2 = 9.36 +/- 4.47 h and gamma 1 = 1.77 +/- 2.27 and gamma 2 = 3.68 +/- 3.26. The mean half-life value of the elimination phase was 14.4 +/- 4.6 h.

Statistical analysis of performance of a liquid chromatographic assay of anticonvulsants involving solvent-demixing extraction and reciprocal internal standardization.

Analysis of variance both factorial and nested was used to validate a HPLC method intended for routine clinical assay of ethosuximide, phenobarbital, phenytoin and carbamazepine. Drugs were salted out, together with the solvent, from 0.5 ml acetonitrile-deproteinized plasma samples with 80-90% recovery. The acetonitrile extraction solution contained a known amount of all four drugs. This added amount of any drug was used when absent from plasma as an internal standard for those present and when present as a calibrator. Results showed that assay precision was acceptable (CV 6%) over and above the therapeutic range when additions did not exceed the lower therapeutic plasma level and if as many replications were made as there were drugs to assay. In return for some loss of sensitivity, reciprocal internal standardization provides increased assay reliability owing to the usual availability of more than one internal standard and to easier identification of interfering chromatographic peaks.

Performance analysis of a rapid HPLC determination with the solvent demixing extraction of HIV antiproteases and efavirenz in plasma.

A rapid and simple high-performance liquid chromatographic method without internal standardization is evaluated for the drug-level monitoring of most marketed antiproteases and efavirenz. Following plasma deproteinization with acetonitrile, the analytes are extracted into the solvent while it is demixed by the addition of a saturating amount of neutral salt. The organic supernatant is diluted by half with water up to the polarity of the mobile phase before being injected. The isocratic mobile phase is unbuffered water-acetonitrile (52:48), and the stationary phase is LiChrospher 100 RP-8 (5 microm). Analytes are eluted between 4 min (amprenavir and indinavir) and 20 min (nelfinavir). A spreadsheet program including analysis of variance (ANOVA) and regression is used for both the overall validation of milligrams-per-liter determinations and the performance evaluation of analytical steps from chromatographic raw data. Extraction shows acceptable 5% repeatability and nearly 100% recovery, although it is somewhat concentration-dependent. The calibration function is better fitted by bilogarithmic than arithmetical regression, and the ANOVA of raw data is found quite predictive of the quality of the final determinations.

Pharmacokinetics of an indomethacin pro-drug: apyramide after intravenous administration in dog.

The pharmacokinetics of apyramide, an ester of indomethacin and acetaminophen (paracetamol), were determined after intravenous administration to nine beagle dogs. Indomethacin and its pro-drug, apyramide, were extracted from acetonitrile-precipitated plasma by a solvent-demixing procedure and the concentration of these two drugs was measured by a reversed-phase liquid chromatographic assay. The kinetic evolution with time of plasma levels of apyramide and of indomethacin resulting from enzymatic hydrolysis was compared with values obtained for indomethacin injected in equimolar dose. Plasma levels of apyramide quickly decreased and the mean (+/- SD) half life was 0.15 +/- 0.08 h. For metabolic indomethacin, the mean (+/- SD) area under curve was 12.36 +/- 4.80 mg.h/l and the mean (+/- SD) half life of terminal phase was 16.71 +/- 9.46 h. After administration of indomethacin, these values were 17.60 +/- 4.12 mg.h/l and 7.89 +/- 2.20 h, respectively.

[Corneal and lens deposits due to treatment by phenothiazine type neuroleptics]. / Dépôts cornéens et cristalliniens dus aux traitements par neuroleptiques de type phénothiazine

The authors have studied the corneal and lens lesions which appeared following a prolonged treatment by phenothiazines. They examined 186 patients: 147 took phenothiazines of which 35 of them presented anterior segment alterations. It seems that all phenothiazines can be held responsible for the apparition of these lesions. At this point the authors evaluated the global dose of the various phenothiazines which were administered. The threshold at which the association of these lesions seem to appear, seems to be situated around 300 gr. The total quantity of phenothiazines which are absorbed seems to be a good measure of the risk of ocular toxicity. In the case of one patient they observed that his visual keenness was lowered due to the importance of his corneal and lens lesions.

Liquid chromatographic assay of heptaminol in serum and its oral pharmacokinetics in the dog.

In order to investigate the pharmacokinetics of heptaminol in dogs, a high-performance liquid chromatographic assay of the drug was devised and it was evaluated in a general purpose validation design through analysis of variance. Heptaminol and its internal standard n-propylamine were salted out from plasma together with acetonitrile, the previously proposed "solvent demixing " extraction procedure. Both amines were derivatised in acetonitrile with the o-phthaldialdehyde, 2-mercaptoethanol procedure of Roth. The adducts were quantitated by reversed-phase high-performance liquid chromatography on Radial-Pak cartridges with ultraviolet detection. Peak height ratios were linearly related to concentrations up to 250 mumol l-1 with a 2% coefficient of variation. Sensitivity was 3.5 mumol l-1 (signal-to-noise ratio of 5). Means of the usual pharmacokinetic parameters in four dogs were: elimination half-life 3.75 h, apparent distribution volume 2.18 l kg-1 and total clearance 0.402 l kg-1 h-1, similar to the results obtained in humans by other authors using radiolabelled heptaminol .

Performance analysis of a reversed-phase liquid chromatographic assay of lamotrigine in plasma using solvent-demixing extraction.

A reversed-phase column liquid chromatographic assay is described and validated for lamotrigine, a new anticonvulsant drug. The drug and its internal standard were extracted from plasma into acetonitrile according to a previously described solvent-demixing procedure, separated on LiChrospher 100CN, and measured by ultraviolet absorption at 280 nm. The assay performance was evaluated through analysis of variance and of regression with our usual validation design. The method detects ca. 2 ng (55 micrograms/l x 30 microliters) and shows a linear response with a constant 5% coefficient of variation from 1 to 10 mg/l. It is easy and robust, and seems well suited to therapeutic drug monitoring.

[Use of a volatile substrate to explore oxidative metabolism of xenobiotics in the rabbit lung]. / Utilisation d'un substrat volatil pour explorer le métabolisme oxydatif des xénobiotiques par le poumon chez le lapin.

A demethylation breath test was modeled in rabbits receiving 14C-anisole either by the intravenous route or by inhalation. The exhalation rate of 14CO2 was measured in a metabolic cage. The modeling hypothesis involved two metabolic compartments: a "central" compartment receiving the infusion, and a "pulmonary" compartment receiving the inhalation. The modeling succeeded in identifying a highly significant metabolic contribution of the lungs following inhalation of the substrate.