High inducibility of mouse renal CYP2E1 gene by tobacco smoke and its possible effect on DNA single strand breaks.

Several studies have shown in humans an association between renal carcinoma and cigarette smoking. Cigarette smoke contains numerous cytochrome P450 inducers and substrates. In the present study we investigated the effect of cigarette smoke on the regulation of murine cytochrome P450 expression in kidney and its possible role in the induction of single strand breaks in DNA.

Diabetes in the indigenous population of the Commonwealth of the Northern Mariana Islands.

Diabetes prevalence and complications rates were examined for the indigenous population of the Commonwealth of the Northern Mariana Islands in the western Pacific. Diabetes is common, with 4% of the population and 11% of adults having diagnosed diabetes. Diabetes is more common among females and islanders of Carolinian descent.

Plasma concentrations and pharmacokinetics of idebenone and its metabolites following single and repeated doses in young patients with mitochondrial encephalomyopathy.

Objective: The pharmacokinetics and tolerance of idebenone after single or repeated doses have been studied in young patients with mitochondrial encephalomyopathy.

Results: No significant adverse effects were noted. In 3 out of 7 patients idebenone induced overall stimulation and improvement in arousal.

[In utero measurement of the umbilical cord in full term pregnancy].

Objective: The length of the umbilical cord varies widely from one pregnancy to another. Although its average length is 50 cm, this measurement could vary from as little as 20 cm to more than one metre. The purpose of our study was to evaluate, in utero, the length of the umbilical cord during the third trimester of pregnancy knowing the propagation velocity of the pressure wave along the cord.

[Individual dose adjustment of high-dose methotrexate in clinical practice].

Since its discovery in 1948 the clinical applications of methotrexate have widened; and in order to overcome resistances to methotrexate, the concept of high-dose methotrexate has been proposed. The use of rescue by folinic acid, as well as rapid dosage of MTX coupled with pharmacokinetic studies, have permitted us to administer an optimum dose of drug, with maximum therapeutic effects, but with reduced toxicity. Individual adaptation of posology, calculated using the test dose or according to population pharmacokinetic with a Bayesian method of parameter estimation (which allows us to adjust the dose of high-dose methotrexate during its infusion) permits control of inter and intra-individual variations of this drug.

Evaluation of saccadic eye movements as an objective test of recovery from anaesthesia.

Saccadic eye movements have been previously used to assess residual effect of anaesthetics, but this test is seldom compared to other psychomotor tests. The aim of the present study was to validate saccades as a recovery index in relation to frequently referred subjective and psychometric tests. Eight healthy subjects were tested before and after intra-muscular injection of either placebo or 0.

Dosage adjustment of high-dose methotrexate using Bayesian estimation: a comparative study of two different concentrations at the end of 8-h infusions.

Bayesian estimation (BE) of pharmacokinetic parameters enables the clinician to adjust the dosage of high-dose methotrexate (HDMTX) to correct the inter- and intraindividual variation of concentrations that are responsible for severe toxicity. In this study of 672 HDMTX infusions, we validated an approach that consisted of reaching as nearly as possible a theoretical concentration of 5.10(-4) M or 10(-3) M at the end of an 8-h infusion by adjusting, when necessary, the dosage at the 6th h.

Glucuronidation of propofol in microsomal fractions from various tissues and species including humans: effect of different drugs.

This in vitro study was conducted to evaluate propofol glucuronidation and the effect of concomitantly administered drugs in various species. Propofol glucuronidation was studied in microsomal fractions from rat, rabbit, and human livers. Extrahepatic metabolism was investigated using lung and kidney microsomes.

Comparative effects of antifungal agents on zidovudine glucuronidation by human liver microsomes.

Zidovudine (ZDV) is extensively metabolised by the liver to an inactive glucuronide (GZDV). Since ZDV is often administered with antimycotic drugs, we studied the effect of six systemic antifungal agents on the in vitro glucuronidation of ZDV by human liver microsomes. 5-fluorocytosine and itraconazole had no inhibitory effect whereas amphotericine B, ketoconazole, miconazole and fluconazole inhibited in vitro GZDV formation (Ki values were 0.

[Quantification and monitoring of vascular resistance in the lower limbs by the Doppler method (animal model)].

The object of this study was to define and validate a non-invasive method of evaluation and monitoring of vascular resistances in the leg. Blood flow velocity was measured by Doppler ultrasound in an animal model (ewe) with similar blood flow characteristics in the lower limb as man and allowing access to the required invasive measurements for validation of the method (pressure and flow). Vascular resistances distal to the measuring point (femoral, for example) were assessed using the resistance index R = D/S, S being the peak systolic deflection and D that of diastolic reflux of the Doppler spectral analysis of flow in the femoral artery.

Lack of correlation between pharmacokinetics and efficacy of low dose methotrexate in patients with rheumatoid arthritis.

Objective: To determine if the variability in the efficacy of methotrexate (MTX) in rheumatoid arthritis (RA) is correlated with its pharmacokinetics.

Methods: MTX pharmacokinetics was evaluated in 46 patients with RA starting a weekly intramuscular low dose MTX treatment. The patients were divided into 32 responders and 14 nonresponders to MTX according to the clinical response in the 6 months after the pharmacokinetic study.

Estrogen and progesterone receptors in breast cancer microsamples simultaneously quantified by enzyme-ligand immunoassay.

A new method (enzyme-ligand immunoassay, ELIA) is described for the estimation of estrogen (ER) and progesterone (PR) receptors in microsamples of human breast cancer tissue. The technique, based on the nonisotopic measurement of receptor-bound estradiol and progesterone, involves three steps: (a) simultaneous saturation of active receptors with their respective authentic ligands, (b) heat treatment of the cytosol to release the steroids from their cognate receptors before or after absorption with dextran-coated charcoal, and (c) measurement of both steroids present in the cytosol by a modified competitive-inhibition enzyme immunoassay. The useful range of the method was 10-4000 pmol/L for ER and 6.

Evaluating motor recovery early after stroke: comparison of the Fugl-Meyer Assessment and the Motor Assessment Scale.

This study compared the measurements of the Motor Assessment Scale (MAS) to that of the Fugl-Meyer Assessment (FMA), a reliable and valid test for motor function in stroke patients. Thirty-two patients (20 men, 12 women) with a mean age of 60 years, and a mean time since stroke of 64.5 days, were tested with the FMA and MAS on two consecutive days.

Dose optimization of gallium chloride, orally administered, in combination with platinum compounds.

An individual dose adaptation for cisplatin (CDDP), etoposide and gallium chloride (GaCl3) was proposed to improve the efficacy of this combination chemotherapy and avoid its toxicity. A clinical study was performed in 28 non small cell lung cancer patients, to verify this hypothesis. CDDP and etoposide were administered as continuous infusions every 3 weeks and GaCl3 orally during and between the CDDP-etoposide sequential infusions.

[Status epilepticus in an asthmatic child].

Background: Chronic administration of theophylline can be used for treating asthma; it may represent a severe risk when some other drugs are prescribed by unaware physicians.

Case Report: A 4 yr-8-mo-old boy was admitted suffering from status epilepticus which occurred 3 hours after vomiting. This patient had asthma and was given sustained-release formulation of theophylline and, independently by another physician, two anti-H1 drugs: ketotifen and mequitazine.

Effect of cigarette smoke on hepatic and pulmonary cytochromes P450 in mouse: evidence for CYP2E1 induction in lung.

Pulmonary and liver microsomes of male NMRI mice were used to study the inductive effect of cigarette smoke on various cytochrome P450 isoforms implicated in precarcinogen and premutagen bioactivation. The enzymatic activities catalyzed by CYP1A1, CYP2B, CYP2C, CYP2D, CYP2E1 and CYP3A were induced in liver microsomes. Immunoquantification of lung and liver CYP1A1, 2E1 and 3A demonstrated that 1) CYP1A1 was induced in lung and liver, 2) CYP3A subfamily was induced in liver and not detected in lung, 3) CYP2E1 was slightly induced in liver whereas its pulmonary expression was more largely increased (6.

Improvement of cyclosporin A-induced cholestasis by tauroursodeoxycholate in a long-term study in the rat.

Cyclosporin A is an essential immunosuppressive drug, but it is potentially toxic to the kidney and liver. Ursodeoxycholic acid, a hydrophilic bile acid, has been reported to improve cholestasis in liver disease in man. The purpose of this work was to examine whether tauroursodeoxycholate could reduce cyclosporin A-induced hepatic or renal injuries in the rat.

Pharmacokinetics of a single oral dose of clobazam in patients with liver disease.

The pharmacokinetic effect of a single oral in dose of 20 mg clobazam was studied in 15 patients with liver disease and in 6 healthy volunteers. Plasma concentrations of clobazam and its main metabolite, norclobazam, were measured by gas liquid chromatography. Clobazam was rapidly absorbed.

Predictive performance of two software packages (USC*PACK PC and Abbott PKS system) for the individualization of amikacin dosage in intensive care unit patients.

Many dosing methods (nomogram, pharmacokinetic methods, Bayesian methods) can be used for the individualization of amikacin dosing. Among these methods, it is now well known that the Bayesian method provides a rapid and accurate means for individualizing dosage requirements for patients with diverse pharmacokinetic profiles. However, one problem has not been fully resolved.

Abbott PKS system: a new version for applied pharmacokinetics including Bayesian estimation.

Abbott Laboratories has developed a new software package (Abbottbase pharmacokinetic system or PKS package) that employs the principles of pharmacokinetics to assist clinical pharmacologists and clinicians in designing dosage regimens. This software, which runs on IBM PC compatibles, allows Bayesian estimation of individual pharmacokinetic parameters. The aim of the present study was to validate this new system in routine clinical practice for amikacin (40 intensive care unit patients) and theophylline (20 patients).

Determination of acitretin in the skin, in the suction blister, and in plasma of human volunteers after multiple oral dosing.

Several HPLC methods for quantification of acitretin and its 13-cis isomer in biological fluids have been described. Only limited data are available on determination of this drug in skin samples. Our objective was to improve the sensitivity and selectivity of existing methods to measure drug in small skin samples from humans treated with acitretin.

Monitoring of pefloxacin serum concentrations in intensive care unit patients: comparison of a new immunoassay with high-performance liquid chromatography.

Serum quinolone concentrations are not routinely measured in clinical practice. However, in order to optimize quinolone treatment, monitoring of serum concentrations could sometimes be useful particularly in critically ill patients. A new enzyme-linked immunosorbent assay (ELISA) that permits direct determination of pefloxacin in serum is described.

Pharmacokinetics of intrapleural recombinant interleukin-2 in immunotherapy for malignant pleural effusion.

Background: The authors measured pharmacokinetic parameters before, during, and after immunotherapy by continuous intrapleural infusion of recombinant interleukin-2 (rIL-2) and correlated the resulting data with clinical effects in nine patients with malignant pleural effusion.

Methods: The underlying disease was malignant mesothelioma in five patients and adenocarcinoma in four patients. Continuous intrapleural infusion of rIL-2 was performed for 5 days at 21 x 10(6) IU/m2/day.

Pharmacokinetics of high-dose methotrexate in adult osteogenic sarcoma.

The pharmacokinetics of 222 infusions of high-dose methotrexate (MTX) with leucovorin rescue were studied in 22 adults with osteosarcoma. To reduce the variability of plasma concentration, we individualized dose regimens using a Bayesian method to reach a concentration of 10(-3) M MTX at the end of an 8-h infusion. The mean concentration observed at the end of the infusion was 1016 +/- 143 mumol/l.

[The kinetics of IL-2 after pleural administration in the treatment of neoplastic pleurisy].

The half-life of interleukin-2 (IL-2) is short after intravenous bolus injections (6 to 10 minutes) and elevated doses are necessary for its anti tumour action on account of severe side-effects which limit its use. Studies have shown good tolerance and efficacy of elevated doses of recombinant IL-2 after intrapleural administration in the treatment of neoplastic pleurisy. After a phase one study to determine the maximum tolerated dose (24 x 10(6) IU/m2 per day), we have studied the pharmacokinetics of 21 x 10(6) IU/m2 per day of recombinant IL-2 administered as a continuous intrapleural infusion over 5 days in 6 patients who presented with a neoplastic pleurisy (3 had malignant mesotheliomas and 3 had adeno-carcinomas of unknown primary site).