Nefopam hydrochloride compatibility and stability with selected proton pump inhibitors in bionolyte G5 injection for intravenous infusion.

BACKGROUND: The use of extemporaneously prepared admixtures of drugs must be supported by documentation of their chemical stability. OBJECTIVE: To assess the physical compatibility and the chemical stability of nefopam hydrochloride, a centrally acting non-opioid analgesic, when admixed with selected proton pump inhibitors (omeprazole, esomeprazole or pantoprazole), in bionolyte G5 injection for intravenous infusion. METHOD: Admixtures were assessed for periods of up to 72 h after storage at ambient temperature without protection from light and at +4 degrees C protected from light. A preparation was considered stable if the compounds of the mixture retained at least 90% of their original potency during the storage. Triplicate samples of nefopam and the selected proton pump inhibitors as well as the following mixtures (nefopam/omeprazole, nefopam/esomeprazole and nefopam/pantoprazole) were prepared in the concentrations required, in polypropylene bottles of bionolyte G5 injection. The physical compatibility was assessed by visual observation at each sampling interval. The chemical stability of the drugs was evaluated by high-performance liquid chromatography and by measurement of pH values. RESULTS: During refrigerated storage, nefopam as well as the selected proton pump inhibitors, when prepared separately in bionolyte G5 injection maintained chemical stability for up to 7 days. At ambient storage conditions, the protons pump inhibitors maintained chemical stability for 24 h, but thereafter their concentrations decreased significantly at day 1. Nefopam maintained chemical stability for up to 72 h at +25 degrees C. Nefopam/omeprazole and nefopam/esomeprazole mixtures in bionolyte were physically incompatible with the mixtures exhibiting a black colour. They underwent rapid and extensive loss, making the combination unacceptable within minutes of mixing. However, the nefopam/pantoprazole mixture was compatible over the study period, but with a reduced duration of the stability. CONCLUSION: Within the limits defined above, nefopam and the selected proton pump inhibitors may be prepared separately in advance in bionolyte G5 injection. The nefopam/pantoprazole mixture was stable for a short period, while the nefopam/omeprazole and the nefopam/esomeprazole mixtures were incompatible and unusable, immediately upon admixture.

Provision of information on regulatory authorities' websites.

BACKGROUND: Several organizations have raised concerns about the excessive secrecy maintained by regulatory authorities around the world, in particular in the European Union, France, UK, Canada and Australia. However, limited research has assessed the provision of information by regulatory authorities. This study aimed to assess the type and availability of information provided on the regulatory authorities' websites. METHODS: Regulatory authorities' websites in six countries (USA, Canada, UK, France, Australia and New Zealand) and at the European level (European Medicines Evaluation Agency) were surveyed by two reviewers between October 2005 and March 2006. The survey instrument included 16 criteria organized in 3 domains: information on marketed drugs, information on assessment of drugs and information on drug safety. RESULTS: There was a great variability in the level of information provided. Several medicine agencies did not provide basic information on marketed drugs, such as the summary of products' characteristics. Information on registration dossiers was scant on most websites except that of the US Food and Drug Administration. The European Medicines Evaluation Agency, the French agency and the Canadian agency released public assessment reports that contained only summarized information of registration data. Only one country, Canada, provided full access to pharmacovigilance data. The periodic safety update reports that companies have to provide regularly to regulatory authorities were not available in any country. CONCLUSION: Information on which regulatory authorities base their decisions for licensing new drugs and the rationales behind these decisions were often not publicly available.

Compatibility of nitroglycerin, diazepam and chlorpromazine with a new multilayer material for infusion containers.

The stability and compatibility of three drugs: nitroglycerin, diazepam and chlorpromazine, with a new multilayer infusion bag were studied. The study was carried out comparatively with PVC bags with which these drugs are incompatible. The drugs were diluted in 5% dextrose or in 0.9% sodium chloride isotonic solutions. Solutions were stored during 8 or 48 h with or without any protection against light. Remaining concentrations of drug were determined by high-performance liquid chromatography (HPLC) during the storage. The admixtures were also monitored for precipitation, color change and pH. Whatever the isotonic solution used, the loss of drugs is in discredit of the use of PVC bags for their storage. So, these three drugs would not be stored in PVC bags. In multilayer bags, no loss of drugs and no color change were detected throughout the storage period. pH values were stable during the same storage period. These three drugs were compatible with multilayer bags in all tested conditions for 8 or 48 h. The leaching of the plasticizer di-(2-ethylhexyl) phthalate (DEHP), that is incorporated into PVC to make the bags soft and pliable was not detected in the three drug solutions during storage period. Our study confirms that these three drugs are incompatible with PVC bags, on the contrary the new materiel tested was proved to be interesting for drug storage.

Evaluation of the direct toxicity of trioctyltrimellitate (TOTM), di(2-ethylhexyl) phthalate (DEHP) and their hydrolysis products on isolated rat hepatocytes.

Plasticizers are added to polyvinyl chloride (PVC) to confer flexibility to the polymer. Di(2-ethylhexyl) phthalate (DEHP) is the most commonly used of them. However, due to its non covalent bond to the PVC, DEHP tends to vaporize easily. A significant exposure has been recorded in dialyzed patients since medical tubings. Most animal species metabolize DEHP rapidly into monoethylhexyl phthalate (MEHP) and 2-ethylhexanol (2-EH). Because of the suspected toxicity of DEHP, an alternative plasticizer, trioctyltrimellitate (TOTM) has aroused increasing interest. The aim of this study was to determine on isolated rat hepatocytes in vitro, the direct hepatotoxic potential of both DEHP and TOTM and their hydrolytic products. To evaluate the possible toxic liver risk resulting from exposure to DEHP and TOTM, isolated rat hepatocytes were incubated with either DEHP, TOTM, MEHP or their common metabolite (2-EH) for 3 hours. Cell viability was periodically estimated thanks to trypan blue tests (15 - 180 min). The activity of lactate dehydrogenase (LDH) was also monitored (1h, 2h, 3h). The results obtained with trypan blue test and with direct LDH activity measurements, were satisfactorily correlated. Hepatocytes treated with both plasticizers and metabolites on the one hand, and the controls (untreated suspension) on the other hand, showed important differences as for cell viability. The acute toxicity on hepatocytes is mainly due to MEHP. Among DEHP, TOTM, MEHP, 2-EH and after intraperitoneal injection of those compounds, only DEHP and MEHP were able to induce a significant hydrogen peroxide (H2O2) production by the rat hepatocytes. These observations enable us to confirm the hypothesis according to which DEHP and MEHP cause an imbalance between the synthesis and the degradation of H2O2. Our results suggest a short-term in vitro cytotoxicity of MEHP. Even if trypan blue and LDH tests offered good results and were easily branded, further assays as well as MTT-tests should performed in order to confirm the cytotoxicity of the compounds tested.

Induction of propranolol metabolism in isolated rats hepatocytes treated by di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate (MEHP).

Blood lines of polyvinyl chloride (PVC) for hemodialysis usually contain di(2-ethylhexyl) phthalate (DEHP) as a plasticizer. Previous studies show that 1 mg/kg of this plasticizer can leach into the blood during one dialysis session. It is rapidly metabolized in the liver. Mono(2-ehtylhexyl) phthalate (MEHP), its main metabolite can be detected as well. After oral administration to rodents, both compounds caused a variety of adverse biological effects such as testicular atrophy, peroxisome proliferation and hepatic peroxisomal enzyme induction. Male wistar rats were treated intraperitoneally by DEHP and MEHP using twice the dose of that involved in human exposure during a dialysis session. Propranolol metabolism by hepatocytes was investigated after fresh isolation from treated and untreated rats by means of reverse phase HPLC. The choice of propranolol as a substrate was made because of its rather quick liver metabolisation. Phenobarbital was chosen in the study as a reference of enzymatic inducer to evaluate the inducing effect of DEHP and MEHP. Propranolol was metabolized by the hepatocytes of both treated and untreated rats. Hepatocytes isolated from rats treated by phenobarbital, MEHP and DEHP were shown to have a higher speed constant of metabolism indicating a rapid metabolism of propranolol. Under these conditions, in fact, propranolol metabolisation was found to be respectively 6, 2.7, 2 times faster than the propranolol metabolisation of untreated rats. The hypothesis that DEHP and MEHP are enzymatic inducers, particularly cytochrome P450 (CYP) inducers of the xenobiotics metabolism on the intact liver after IP administration has become been found to be valid. The results obtained in this study confirm the value of isolated hepatocytes as an in vivo drug metabolism predictive model.

[Clinical trials in Alzheimer disease. Comments on the project of FDA's guidelines]. / Essais cliniques dans la maladie d'Alzheimer. Commentaires sur le projet de recommandations de la FDA.

The draft guidelines for the clinical evaluation of antidementia drugs give an important series of advice on all trials phases: the main objective, in the present state of knowledge, is to improve memory. patients must have a confirmed dementia, and other causes than Alzheimer diseases must be excluded by appropriate investigations. They should not be too severely ill, but they should be institutionalized, at least during the first phase of treatment, the placebo controlled trial and the dose-effect relationship are necessary, the cross-over trial is not advised, the treatment duration should be at least 3 to 6 months, two strictly independent evaluations are necessary: cognitive tests, and clinical global impression based only on interviews of the patient, the file must contains at least 1000 cases with at least 300 cases treated 3-6 months with at least the median dose.

[Drug flow. Good manufacturing practices, good clinical practices]. / Circuit du médicament. Bonnes pratiques de fabrication, bonnes pratiques cliniques.

On a worldwide basis, the drug development circuit in clinical trials undergoes a general movement towards improvement which is sensitive to the degree of quality. The methods used to achieve this are found at the interface of Good Manufacturing Practices (GMP) and Good Clinical Practices (GCP). They consist primarily of two types, for which examples are given here: strengthening of controls (verification of the resemblance of test drugs in double-blind comparison by a "jury" and computerized systems of drug accountability), improvement in "compliance with therapy at the site of investigation" (use of more "intelligent" drug packages and labels).