[The role of the packaging in terms of safety and good use of medicines]. / Les missions du conditionnement en terme de sécurité et de bon usage du médicament.

The pharmaceutical packaging is an essential constituent of medicinal products because it guarantees its stability and integrity. It is sometimes an intrinsic part of the pharmaceutical form itself. Furthermore, the pharmaceutical packaging has always been an essential information medium for patients (labelling, leaflet) but also for professionals (such as pharmacists, other pharmacy staff or nurses) at the time of drug delivery. Of course, the information delivered to the patient through the packaging has to be in accordance with the Marketing Authorization terms. Besides, this information is included in the drug Marketing Authorization (annexes II and III). The information delivered has to be clear because patients generally refer to the leaflet when no professional is available for advice. An easy-to-use pharmaceutical packaging also guarantees the good use of medicinal products and promotes patient compliance (for example, pack and calendar blisters). It is also a safety guarantee when it uses specific methods, such as single-dose packaging (particularly in hospital setting) or safety caps for children. The drug leaflet must clearly mention utilisation for some difficult use forms (case of medicinal products for asthma or insulin pens). Lastly, the pharmaceutical packaging also helps to recognize the drug, which in itself is part of the safety process all along the supply chain. Indeed, drug packaging's major role is to avoid confusion with other drugs among professionals and patients alike.

[Regulations on gases for medical use in France]. / Situation réglementaire des gaz à usage médical en France.

In 1989, a European directive extended the definition of proprietary medicinal products, and consequently the necessity to hold a marketing authorization (MA), for all industrially manufactured products, including medicinal gases. In France, the directive 89/341/CEE was transposed in the French law on December 8(th), 1992 and France was the first Member State to implement provisions for the obtention of MAs for gases for medical use. Since then, France has stayed at the forefront in this area. Following the inclusion of gases in the scope of pharmaceutical products, gases require on MA obtained following the same methods as for drugs and be manufactured and distributed in authorized sites. Moreover, the European directive has led the French authorities to classify gases according to their use. Gases for medical use are thus considered either as medicinal products or as medical devices.

Comparative pharmacokinetics and bioavailability of two oral formulations of thiocolchicoside, a GABA-mimetic muscle relaxant drug, in normal volunteers.

The comparative pharmacokinetic and bioavailability profile of two different formulations (tablets and capsules) of thiocolchicoside was investigated in 8 healthy male volunteers after administration of single oral 8 mg doses. Plasma samples were assayed by a capillary gas chromatography--mass spectrometry (GC-MS) method following enzymatic hydrolysis of thiocolchicoside to its aglycone (3-demethylthiocolchicine) and no attempt was made to account for the possible occurrence of hydrolysis in vivo. Irrespective of the formulation used, the drug was rapidly absorbed from the gastrointestinal tract, peak levels of about 17 ng/ml being detected within 1 h in most subjects. Elimination was rapid, with mean MRT values of 5-6 h. All kinetic parameters showed considerable interindividual variability but none differed significantly between the two formulations. Relative to the tablet formulation, the oral bioavailability of the capsule formulation was 1.06 +/- 0.39.

[Hepatic transport of mitoxantrone in relation to multiple resistance]. / Transport hépatique de la mitoxantrone en relation avec le phénomène de résistance multiple.

We have examined the effect of cyclosporin A on transport processes (uptake, efflux, binding) of mitoxantrone in isolated rat liver cells. Accumulation and binding of mitoxantrone was rapid with or without cyclosporin A. The initial uptake was linear over a wide concentration range (1 to 1000 microM). For the first 100 s, the rate of uptake is constant. The uptake clearance ranged from 12.53 +/- 3.9 to 33.77 +/- 15.1 nl.min-cell-1 for different extracellular concentrations of mitoxantrone. Also cyclosporin A did not modified this coefficient. Initial binding of mitoxantrone to cell plasma membrane was estimated and it was modified by different extracellular concentrations of mitoxantrone but not by cyclosporin A. Respectively at 60 seconds it accounted to 79.6% and 81.6% of the total transport. Influx of mitoxantrone was not temperature sensitive. We next examined the efflux of mitoxantrone from cells that were preloaded with drug. Initial efflux was rapid for the first 5 minutes. Cyclosporin A slightly decrease this efflux (7%). The data suggest that the mechanism of uptake of mitoxantrone is passive diffusion and that cyclosporin A a p-glycoprotein 170 inhibitor agent has only a weak effect on efflux.

In vitro acid decalcification of human surface enamel pretreated with toothpaste slurries.

An in vitro caries-like challenge of human tooth enamel treated with inorganic fluoride (NaF) and organic fluoride (aliphatic and aromatic amine fluorides) toothpaste slurries has been investigated. The results revealed that the organic fluoride-containing toothpastes affected positively the resistance of tooth enamel to demineralization.

Comparison of in vivo antibacterial activity of hydro-alcoholic solutions of hexamidine and of chlorhexidine.

Samples of cutaneous flora were obtained from the antecubital fossa of 20 healthy volunteers before and after treatment with hydro-alcoholic solutions of chlorhexidine (CHX) and of hexamidine (HXM). Percentage reductions in bacterial flora were statistically greater (p less than 0.001) after CHX (99 to 100%) than after HXM (about 70 to 90%). Furthermore, CHX had a smaller disturbing effect upon the natural balance of the bacterial population than HXM with a more rapid return towards the initial proportions of the different organisms one hr after treatment.

Controlled trial of the action of a toothpaste containing nicomethanol hydrofluoride in the treatment of dentine hypersensitivity.

A double-blind clinical trial was performed on 76 patients with dentine hypersensitivity. For four weeks the patients used either a toothpaste containing nicomethanol hydrofluoride or one containing potassium nitrate and sodium monofluorophosphate. After one, two and four weeks the pain responses of the teeth to three types of stimuli were assessed. In normal conditions of oral hygiene, the nicomethanol hydrofluoride toothpaste was found at least as effective as the potassium nitrate/sodium monofluorophosphate preparation.

[Blood pharmacokinetics of fluorine in man after the oral administration of nicomethanol hydrofluoride]. / Pharmacocinétique sanguine du fluor après administration orale chez l'homme du fluorhydrate de nicométhanol.

The pharmacokinetic parameters of fluoride have been studied, after a single oral administration to human volunteers of two fluoridated compounds: sodium fluoride, and a new organic fluoride salt, nicomethanol hydrofluoride. The results obtained with these two compounds were very similar, suggesting that no abnormal accumulation of fluoride in the body occurs after using nicomethanol hydrofluoride.

Pharmacokinetics, metabolism and elimination of itanoxone in humans.

The pharmacokinetics, metabolism and elimination of Itanoxone was studied after a single oral administration of the carbon-14-labelled drug (500 mg) in four male volunteers. The drug was absorbed fairly rapidly with a mean peak plasma level of 10.3 +/- 1.3 micrograms/ml between 3 and 4 hours after dosing. The pharmacokinetics can be described by a two-compartment open model with the central compartment consisting of the extracellular fluid. The mean elimination half-life was 19.4 +/- 8.5 hours. Two metabolites as well as unchanged Itanoxone were detected in plasma. Approximately 37% of the radioactivity was excreted over a five-day period in the urine and 50% in the faeces. There were only traces of free metabolites in the urine as the rest of the radioactive metabolites were associated with glucuronide conjugates. These conjugates consisted of Itanoxone and up to six metabolites. Five of these metabolites have been tentatively identified by comparison of their chromatographic properties by TLC and HPLC with a number of reference compounds. After repeated administration of Itanoxone (250 mg b.i.d.) the maximum level at steady state was about 7 micrograms/ml and the minimum level, 0.6 micrograms/ml. The mean area under the plasma level time curve was 35% higher than in the single dose study after correction for dose.

[Allergenic properties of a series of N-phenyl N'alcoyl paraphenylenediamines]. / Etude allergologique concernant une série de N-phényl-N'-alcoyl paraphénylène diamines.

The well known high allergenic potential of N-phenyl N'-isopropyl paraphenylenediamine (I.P.P.D.), as well as that of N-phenyl N'-1,3 dimethylbutyl paraphenylenediamine, though allegedly milder, prompted us to investigate the allergenicity of a series of N-phenyl N'-alcoyl paraphenylenediamines. We chose an existing technical grade series with substituents ranging from methyl to dodecyl. The results, on laboratory animals (Kligman and Magnusson's maximalization test), and on I.P.P.D.-sensitized humans (ROC Neodermotest, 48th hour) indicate a group sensitization with nearly systematic cross-reactions.

[Acute toxicity of orthochloroparanitroanisole (OCNA) and orthochloroparaanisidine (OCPA) (author's transl)]. / Etude de toxicité aiguë de l'orthochloroparanitroanisole (OCNA) et de l'orthochloroparaanisidine (OCPA).

The acute effects of two industrial substances were studied in mice, rats, rabbits and guinea pigs: - lethal concentration 50 (L.D. 50) in mice and rats after intraperitoneal and oral administration; - investigation of cell growth inhibition (Hela cells), I.D.50 = inhibitory dose 50%; - neuropharmacological effects Histopathological investigations and biochemical analysis pointed out hepatic and renal damages; besides hematological disturbances were found. Both products had mild irritant effects on rabbits skin and eyes. They produced skin sensitization in guinea pigs.