The link between sunshine and phototoxicity of sparfloxacin.

AIMS: To test the association between reporting rates for sparfloxacin-induced phototoxicity and sunlight u.v. exposure, and the effects of regulatory action. METHODS: The reporting rates for phototoxicity with sparfloxacin to the French Pharmacovigilance System or to the Drug Manufacturer were compared with concurrent national mean u.v. exposure obtained from Météo-France, before and after the regulatory restrictions and warnings. RESULTS: There were 371 severe phototoxic reaction reports during the first 9 months of marketing (reporting rate of 0.4 per thousand treated patients), approximately four to 25 times that reported for other fluoroquinolones. The reporting rate correlated highly (r = 0.873, P < 0.001) with the mean monthly u.v. exposure from sunlight (from Météo-France). Regulatory action including warnings for physicians, and restricted indications dramatically decreased the number of reports, but not the reporting rate. CONCLUSIONS: This is the first demonstration of a strong association between sunlight exposure in a population and drug-induced phototoxicity. Regulatory action had no effect on the reporting rate (individual exposed patient risk), though it solved the public health issue.

Adverse drug reactions with fluoroquinolones.

The French system of drug surveillance has analysed the notifications of adverse drug reactions (ADRs) to fluoroquinolones since they were launched. Their frequency ranges from 1/15,000 to 1/208,000 case per days of treatment. Cutaneous diseases and tendon disorders predominate in France whereas cutaneous effects and neuropsychiatric disorders are predominant in the UK; tendon disorders take up only the 5th position. Among the most unexpected ADRs are the following: -shock represents 33 of the anaphylaxis reactions which range from 1/5.6 x 10(6) to 1/4.4 x 10(5) case per days of treatment. -acute renal failure is rare: one case/80,000 patients treated by ciprofloxacin to 1/320,000 by norfloxacin. The pathophysiology is not well known. Tendon ruptures represent 81 cases for 921 notifications of tendon disorders which are related in decreasing order to pefloxacin 1/23,130 case per days of treatment, ofloxacin, norfloxacin and ciprofloxacin 1/779,600 case per days of treatment. Age and corticosteroids increase the risk of tendon rupture.

Penetration of pefloxacin and its desmethyl metabolite into the uroepithelium after a 800-mg single oral dose in human patients.

Penetration of pefloxacin into the uroepithelium was studied in 20 patients (10 men and 10 women) receiving a single oral dose of 800 mg. Samples of serum, urine, and uroepithelium were taken 1.8 h (mean) after the dose. Pefloxacin and its active metabolite, norfloxacin, were assayed by liquid chromatography, and the microbiologically active compounds were quantified by a microbiological assay. Both procedures were correlated (r > 0.7); nevertheless, slight differences detected in concentrations depended on the levels of norfloxacin achieved in the biological samples. The serum and tissue concentrations were higher than the concentration of bactericide (4 micrograms.ml-1), except in one case. The uroepithelium concentration of pefloxacin was proportional to the serum concentration (r = 0.79). The urinary concentrations ranged from 1.2 micrograms.ml-1 to 82.4 micrograms.ml-1. The mean norfloxacin/pefloxacin ratios were 3% in serum, 8% in uroepithelium, and 44% in urine. The mean uroepithelium/serum concentration ratios were 1 for pefloxacin and 2.3 for norfloxacin. This result shows that, at a time close to that of the maximum concentration, there is good penetration of pefloxacin and norfloxacin into the uroepithelium.

Double-blind randomized multicentre trial of acamprosate in maintaining abstinence from alcohol.

A prospective placebo-controlled, randomized double-blind study of Acamprosate at two dose levels in alcohol-dependent patients followed up for 12 months was performed. After detoxification, each of the 538 patients included was randomly assigned to one of three groups: 177 patients received placebo, 188 received Acamprosate at 1.3 g/day (low dose group) and 173 received 2.0 g/day (high dose group) for 12 months. This was followed by a single blind 6 month period on placebo. The patients' mean age was 43.2 +/- 8.6 years. Their mean daily alcohol intake was high (nearly 200 g/day) and of long duration (9.5 +/- 7.1 years). Abstinence figures followed the order high dose > low dose > placebo. The difference was significant at 6 months (P < or = 0.02) but not at 12 months (P = 0.096). The number of days of continuous abstinence after detoxification was 153 +/- 197 for the high-dose group versus 102 +/- 165 for the placebo group (P = 0.005), with the lose-dose group reporting 135 +/- 189 days. Clinic attendance was significantly better in the Acamprosate groups than in the placebo group at 6 months (P = 0.002) and 12 months (P = 0.005). During the 6-month post-treatment period, no increased relapse rate or residual drug effect was observed. The side effect profile for Acamprosate was good compared with controls with only diarrhoea being reported more frequently (P < 0.01). This study confirms the pharmacological efficacy of Acamprosate and its good acceptability. As an adjunct to psychotherapy, this study supports the inclusion of Acamprosate in a strategy for treating alcoholism.

Influence of food intake on the pharmacokinetics of a sustained release formulation of sodium valproate.

The effect of food intake on the pharmacokinetics of DEPAKINE CHRONO 500 mg (Sanofi, France), a sustained release formulation containing 333 mg sodium valproate and 145 mg valproic acid, was studied in 12 young healthy female volunteers. Relative to fasting conditions (F), when the tablet was given at the midpoint of the breakfast (NF), the maximum concentration (F: 34.6 +/- 8.9 micrograms ml-1 and NF: 40.9 +/- 7.3 micrograms ml-1; p = 0.014) and the mean cumulative amount absorbed up to time 6 h (F: 76.3 +/- 11.8% and NF: 90 +/- 10.4%; p = 0.0099) were significantly increased. Nevertheless, the extent of absorption (F: 46.7 +/- 9.9 mg l-1; NF: 48.7 +/- 7 mg l-1) was not significantly affected. There was no change in the area under the curve (1129 micrograms.h ml-1), in the mean residence time (28 h), or in the elimination half-life (16 h). On the basis of this study, the question as to whether DEPAKINE CHRONO should be administered to subjects in the fasting or non-fasting state would not appear to be a major consideration when deciding on the regimen.

[Stereoselective protein binding of non-steroidal anti-inflammatory agents. Pharmacological implications]. / Fixation protéque stéréosélective des anti-inflammatoires non stéroïdiens. Implications pharmacologiques.

Non steroidal anti-inflammatory drugs (NSAIDs) contain a chiral carbon alpha to carboxyl function. Except for naproxen, chiral NSAIDs are marketed for clinical use as racemate, ie an equimolar mixture of the two enantiomers R(-) and S(+). However, in vitro studies have shown that the anti-inflammatory activity exists almost solely in the S form. The unbound fraction is able to diffuse into tissues and to reach sites of action. It represents also the pharmacological active form. Stereoselective protein binding studies carried out at various concentrations of NSAIDs and albumin are used to evaluate the free fraction of the active enantiomer. Two optical isomers do not interact in the same manner with proteins and this binding stereoselectivity depends on NSAID and experimental conditions. Thus, it seems difficult to predict the in vivo free concentration of each enantiomer and protein binding experiments should be achieved taking into account the physiopathological parameters which influence this biological process. This enantioselectivity is determinant for the pharmacokinetic properties and could be responsible of the parameters variation obtained for each enantiomer. It could explain the variability in response to NSAIDs too. In fact, the anti-inflammatory effect is directly function of the free concentration of the S isomer. To correlate the NSAID dose with its activity, it should be better to determine this free fraction in the site of action, in particular in the synovial fluid. But the clinical response, as for example the antalgic effect, remains very far from the pharmacological activity, ie the cyclooxygenase inhibition.

Determination of zopiclone in plasma using column liquid chromatography with ultraviolet detection.

A reversed-phase liquid chromatographic method with ultraviolet detection for the determination of zopiclone in plasma is described. It is rapid, sensitive, reproducible and linear over a wide range. The method was used to study plasma zopiclone concentrations in a case of acute intoxication after oral ingestion of 300 mg of the drug. The plasma level was 1600 ng/ml 4.5 h after the dose and the elimination half-life was 3.5 h.

Plasma and cerebrospinal fluid concentrations of paracetamol after a single intravenous dose of propacetamol.

Since the antipyretic and probably the analgesic effects of paracetamol are, at least in part, centrally mediated, its plasma and cerebrospinal fluid (CSF) concentrations were measured in 43 patients with nerve-root compression pain. Each subject was given a short i.v. infusion of 2 g propacetamol, a prodrug which is hydrolysed to paracetamol within 7 min. Single blood and CSF samples were drawn concomitantly in each patient at intervals between 20 min and 12 h. Maximum CSF drug concentrations were observed at the 4th hour, subsequent concentrations exceeding those in plasma. The elimination half-life of paracetamol calculated from pooled data was shorter in plasma (2.4 h) than in CSF (3.2 h). The time-course of paracetamol in CSF may parallel that of analgesic effect.