Evaluation in usual practice of the bevacizumab-FOLFIRI combination for the first-line treatment of patients with unresectable metastatic colorectal cancer treated in 2006: focus on resected patients and oncogeriatrics: AVASTIN OUEST cohort of the Observatory of Cancer of the Brittany and Pays de la Loire Areas (Observatoire dédié au Cancer Bretagne / Pays de la Loire).

BACKGROUND: In 2006, bevacizumab, a targeted therapy agent was combined with FOLFIRI for the firstline treatment of patients with unresectable metastatic colorectal cancer. METHODS/RESULTS: A study on a homogenous series of 111 patients from the Brittany and Pays de la Loire areas who received bevacizumab-FOLFIRI as first-line treatment in 2006 showed the following results: 51 responses, 29 stabilisations, 21 progressions and 10 cases of toxicity prior to assessment. Median overall survival (OS) was 25.1 months and median progression-free survival was 10.2 months. Surgery secondary to treatment tripled median OS which reached 59.2 months in resected patients versus 18.8 months in unresected patients. Comparison of patients aged more or less than 70 years showed no differences in terms of benefits or risks. CONCLUSION: Bevacizumab-FOLFIRI could be administered as part of a routine care protocol to elderly patients previously evaluated by a geriatric assessment and validated by a multidisciplinary staff.

En 2006, bevacizumab-FOLFIRI représente la thérapie ciblée administrable dès la première ligne chez les patients porteurs d'un cancer colorectal métastatique non opérable. Une série homogène de 111 patients colligés en région Bretagne et Pays de la Loire ayant reçu du bevacizumab- FOLFIRI en première ligne en 2006 révèle les résultats suivants: 51 réponses, 29 stabilités, 21 progressions et 10 toxicités avant évaluation. La médiane de survie globale (OS) est de 25,1 mois et la médiane de survie sans progression (PFS) de 10,2 mois. Dans le cas d'une chirurgie secondaire, l'OS médian triple de 18,8 mois chez les patients non réséqués versus 59,2 mois ceux réséqués. En comparant les sujets âgés de plus et de moins de 70 ans, aucune différence n'a été mise en évidence en termes de bénéfice ou de risque. Bevacizumab-FOLFIRI pourrait être administré en pratique courante chez les personnes âgées sous couvert d'une évaluation gériatrique et d'une approche multidisciplinaire.

Effect of grapefruit juice on digoxin pharmacokinetics in humans.

OBJECTIVES: Grapefruit juice is responsible for drug interactions mediated by intestinal cytochrome P4503A4 inhibition and possibly P-glycoprotein inhibition in enterocytes. Our main objective was to determine whether grapefruit juice alters the bioavailability of digoxin, a P-glycoprotein substrate. The secondary objective was to determine whether the magnitude of the pharmacokinetic interaction was influenced by P-glycoprotein genetic polymorphism. METHODS: Twelve healthy volunteers participated in this open randomized crossover study comparing the effect of grapefruit juice consumption (versus water) on the pharmacokinetics of a single oral dose of digoxin (0.5 mg). The P-glycoprotein genotype was determined according to MDR1 genetic polymorphism in exon 26 (C3435T). RESULTS: Grapefruit juice had no significant effect on the maximum plasma drug concentration (C(max)) of digoxin or the area under the plasma concentration-time curve (AUC) from time zero to 48 hours. However, there was a 9% increase in the digoxin AUC from time zero to 4 hours and from time zero to 24 hours (P =.01) during grapefruit juice administration. The digoxin renal clearance remained unchanged during both periods. No relationship between MDR1 C3435T genotype and early digoxin pharmacokinetic changes could be detected. CONCLUSION: The modest changes in digoxin pharmacokinetics observed during grapefruit juice ingestion do not support an important P-glycoprotein inhibition. Under our experimental conditions, grapefruit juice-mediated P-glycoprotein inhibition does not appear to play a relevant role in drug interactions, at least when assessed by use of digoxin disposition kinetics.

The reflex sympathetic dystrophy syndrome in patients who have had a spinal cord injury.

Patients suffering from a spinal cord injury often present with a pain syndrome. Although the reflex sympathetic syndrome is a common diagnosis in some forms of neurological disease such as patients with a stroke, it is less frequent in those with a spinal lesion. The authors report eight patients with reflex sympathetic dystrophy who had a spinal cord injury. The diagnosis and treatment are discussed along with a review of literature.

Determination of itraconazole and its active metabolite in plasma by column liquid chromatography.

Itraconazole is a new triazole antifungal agent. Active orally, this drug is effective against a wide range of fungal pathogens that includes Aspergillus species, and its use in leukemic and AIDS patients is currently on the increase. Oral itraconazole absorption presents up to threefold interindividual variation in man and is reduced in AIDS patients. Consequently an individual itraconazole adjusting dosage is necessary to ensure adequate clinical antifungal activity. Itraconazole undergoes extensive metabolism and the main isolated metabolite, hydroxyitraconazole, is found in plasma at concentrations 2-3-fold higher than parent drug and presents in vitro the same antifungal activity. At present, despite the contribution of this metabolite to the overall activity of the drug, no well-documented assay was reported in the literature for the codetermination of itraconazole and hydroxyitraconazole in plasma. Due to the wide variety of coadministered drugs to patients receiving itraconazole, the purpose of the developed method was to obtain a specific assay sensitive enough for itraconazole therapeutic monitoring. Therefore, a three-step liquid-liquid extraction procedure following by reversed-phase chromatography and spectrofluorimetric detection was performed. This assay allowed determination of 20 ng/ml of both itraconazole and its active metabolite with an acceptable precision using a 0.5-ml plasma sample; no analytic interference was encountered from 45 coadministered drugs tested.

Cyclosporine in whole blood: drug monitoring difficulties and presentation of a reliable normal-phase liquid chromatographic assay.

Monitoring of cyclosporine (CsA) in whole blood is complicated by the important intra- and interindividual variabilities in its pharmacokinetics and by its narrow therapeutic range. Consequently, an individual CsA adjusting dosage is necessary to ensure adequate immunosuppression without major toxic effects. This can be achieved by several methods of drug determination, including immunoassays and high-performance liquid chromatography (HPLC). Despite the use of specific monoclonal antibodies, immunoassays tend to overestimate (at least slightly) CsA blood levels due to a certain percentage of cross-reactivity with drug metabolites; so, at the present time, HPLC remains the reference method. The main problems of CsA analysis by liquid chromatographic (LC) methods depends on its physicochemical properties: a low detection wavelength and the need to use the LC column at a high temperature. A sensitive assay for the determination of CsA in whole blood has been developed using C8 solid-phase column extraction followed by normal-phase LC of the sample. This assay allowed determination of 25 ng/ml CsA in whole blood with an acceptable precision (intra- and interassay variabilities ranged from 7.7 to 10.4%, respectively n = 5). Standard curves constructed daily over the concentration range 25 to 400 ng/ml showed good reproducibility [coefficient of variation (CV) = 5.3%; n = 5] and the assay was linear up to 1,000 ng/ml. A chromatographic run was achieved in 5 min and no late eluting peak was observed. This method has proven to be reliable from the French interlaboratory cyclosporine quality assessment scheme and has been used routinely over 2 years to determine residual blood concentrations of liver transplant recipients.

Rapid and sensitive liquid chromatographic assay of mefenamic acid in plasma.

Mefenamic acid (MA) is a nonsteroidal antiinflammatory analgesic agent widely used clinically. A simple and sensitive liquid-chromatographic assay has been developed for the quantitative determination of MA in human plasma. A reverse phase, 10-microns cyano column (25 x 0.4 cm), a mobile phase of water-acetonitrile-methanol-17 M acetic acid (69:15:15:1 by volume), and an ultraviolet detection (290 nm) are used for the separation of MA and internal standard (methyl-clonazepam). MA and internal standard are extracted from acidified plasma into diethyl ether and after evaporation of the organic phase, the residue is redissolved in methanol. Calibration curves are linear in the range 0.05-3.20 micrograms/ml, and at the plasma level corresponding to the quantification limit (0.05 microgram/ml) coefficients of variation are 7.5% and 10.2% for repeatability and reproducibility studies, respectively. This assay was successfully used in the study of pharmacokinetics of MA in human plasma after a single oral administration of a low MA dose.

[Adjusting the dosage of netilmicin from two measurements. Program validation]. / Adaptation des posologies de la nétilmicine à partir de deux points. Validation d'un programme.

The aim of this study is to give to clinicians a well validated usefull tool allowing an increase of safety in the monitoring of netilmicin. During the first administration of the drug, two plasmatic concentrations are measured, and input in a preprogrammed hand-held calculator. A posology and a rythm of administration are returned by the calculator. After six days of this dosage regiment, the peak and the valley concentrations are compared with those previously given by the computer as values at equilibrium. No significant difference can be observed. There is no change in plasmatic creatinine level from the first to the sixth day of treatment. So, a preprogrammed hand-held computer can be convenient and safe to monitor netilmicin.