Effects of encapsulation of primidone on its oxidative metabolism in rats.

The aim of this study was to evaluate the influence of primidone (PRM) nanoencapsulation on its metabolism. Suspensions of PRM powder and PRM-loaded poly-epsilon-caprolactone nanocapsules were administered orally in the same way to rats. Primidone-loaded poly-epsilon-caprolactone nanocapsules were prepared according to the interfacial deposition technique. Free PRM suspensions were obtained by addition of PRM powder to a suspension of 0.212% carboxymethylcellulose CMC 12H in water. The dose was 20 mg/kg, n = 6, for each experiment. Urinary and faecal levels of PRM and of its three major metabolites, phenylethylmalonamide (PEMA), phenobarbital (PB), and p-hydroxyphenobarbital (p-HO-PB), were determined. Concentrations were evaluated by high-performance liquid chromatography (HPLC) according to a validated analytical method. After PRM nanocapsule administration, non-metabolised PRM urinary levels were increased compared to those observed after administration of a suspension of primidone powder (43.7+/-8.8% after PRM-loaded nanocapsule and 37.7+/-8.1% after free PRM administration). For phenylethylmalonamide, no difference was observed in urinary excretion in the two cases. For two of the oxidised metabolites, PB and p-HO-PB, excretion was delayed and shortened. The amount of these oxidised metabolites was lowered from 0.95% after free PRM administration to 0.25% after PRM-loaded nanocapsule administration. No difference was noted in non-metabolised primidone excretion in faeces. These results suggest that primidone-loaded nanocapsules could be used as a vehicle for oral primidone administration in order to minimise the phenobarbital metabolic pathway.

Primidone-loaded poly-epsilon-caprolactone nanocapsules: incorporation efficiency and in vitro release profiles.

This paper describes the preparation of primidone-loaded poly-epsilon-caprolactone nanocapsules according to the interfacial deposition technique. The colloidal suspension obtained showed a monomodal size distribution with a mean diameter ranging from 308 to 352 nm. By adjusting the process parameters, the encapsulation efficiency was about 74% with good reproducibility. Primidone release from the nanocapsules was found to be slower as compared to the oily control solution despite an important burst-effect. The release profile was not influenced by the pH of the release medium.

Preparation of Ulex europaeus lectin-gliadin nanoparticle conjugates and their interaction with gastrointestinal mucus.

One approach to improve the bioavailability and efficiency of drugs consists of the association of a ligand (i.e. lectins), showing affinity for biological structures located on the mucosa surfaces, to nanoparticulate drug delivery systems. In this context, Ulex europaeus lectin-gliadin nanoparticle conjugates (UE-GNP) were prepared with the aim of evaluating their in vitro bioadhesive properties. The lectin was fixed by a covalent procedure to gliadin nanoparticles by a two-stage carbodiimide method. Typically, the amount of bound lectin was calculated to be approximately 15 microg lectin/mg nanoparticle, which represented a coupling efficiency of approximately 16% of the initial lectin concentration. In addition, the activity of these conjugates was tested with bovine submaxillary gland mucin (BSM) and the level of binding to this mucin was always much greater with UE-GNP than with controls (gliadin nanoparticles). However, the presence of 50 micromol fucose, which is the reported specific sugar for U. europaeus lectin, specifically inhibited the activity of these conjugates and, therefore, the UE-GNP binding to BSM was attenuated by 70%. These results clearly showed that the activity and specificity of U. europaeus lectin was preserved after covalent coupling to these biodegradable carriers.

Simultaneous determination of primidone and its three major metabolites in rat urine by high-performance liquid chromatography using solid-phase extraction.

A new high-performance liquid chromatographic method for simultaneous determination of primidone (PRM) and of its three major metabolites, phenobarbital (PB), p-hydroxyphenobarbital (p-HO-PB) and phenylethylmalonamide (PEMA), in rat urine, was developed. After acid hydrolysis, these compounds were extracted from urine by means of a Bond Elut Certify LRC column with good clean-up. The extracts were chromatographed on a C18 reversed-phase column using isocratic elution at 40 degrees C, with UV detection at 227 nm. The limit of detection was 0.5 mg/ml for the four compounds. Good linearity (r2>0.99) was observed within the calibration ranges studied: 37.4-299.3 microg/ml for PRM, 26.4-211.2 microg/ml for PB, 12.5-100.2 microg/ml for p-HO-PB and 12.1-97.0 microg/ml for PEMA. Repeatability was in the range 3.1-6.8%. This method constitutes a useful tool for studies on the influence of various parameters on primidone metabolism.

Determination of pyrazinamide and its main metabolites in rat urine by high-performance liquid chromatography.

A new high-performance liquid chromatograhic procedure for simultaneous determination of pyrazinamide (PZA) and its three metabolites 5-hydroxypyrazinamide (5-OH-PZA), pyrazinoic acid (PA), and 5-hydroxypyrazinoic acid (5-OH-PA), in rat urine was developed. 5-OH-PZA and 5-OH-PA standards were obtained by enzymatic synthesis (xanthine oxidase) and checked by HPLC and GC-MS. Chromatographic separation was achieved in 0.01 M KH2PO4 (pH 5.2), circulating at 0.9 ml/min, on a C18 silica column, at 22 degrees C. The limits of detection were 300 microg/l for PZA, 125 microg/l for PA, 90 microg/l for 5-OH-PZA and 70 microg/l for 5-OH-PA. Good linearity (r2>0.99) was observed within the calibration ranges studied: 0.375-7.50 mg/l for PZA, 0.416-3.33 mg/l for PA, 0.830-6.64 mg/l for 5-OH-PZA and 2.83-22.6 mg/l for 5-OHPA. Accuracy was always lower than +/- 10.8%. Precision was in the range 0.33-5.7%. The method will constitute a useful tool for studies on the influence of drug interactions in tuberculosis treatment.

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

A sensitive (1 ng/mL) and rapid method for the determination of naphazoline in rat plasma is described. Following extraction, the compound is analysed by reversed phase high performance liquid chromatography and ultraviolet detection at 214 nm.

Pharmacokinetic studies of ambenonium chloride in patients with myasthenia gravis.

Serum levels of ambenonium chloride (AC) were monitored in 4 myasthenic patients. This determination revealed important intraindividual variations (up to 10-fold) over a period of 24 h. Levels varied considerably between different patients (maximum serum concentration of ambenonium chloride ranged from 0.129 to 0.812 micrograms/ml) and no correlation between the daily dose and the AUC was found. These characteristic properties of ambenonium chloride could explain the erratic pattern of bioavailability observed as well as the difficulty in controlling the disease in some patients.

Application of an analytical method to calcium acetylhomotaurinate determination in urine.

After urine purification, plasma and urine concentrations of calcium acetylhomotaurinate (Acamprosate, CaAOTA) were determined with a high-performance liquid chromatography method following i.v. administration of the drug in two dogs. Results obtained in serum were in good agreement with those found previously. The CaAOTA urine determination is a promising method to be used in healthy volunteers.

Pharmacokinetics of ambenonium chloride in dogs after intravenous and oral administration.

Plasma concentrations of ambenonium chloride (Mytélase) were studied, using a high pressure liquid chromatographic technique, in 11 dogs, after intravenous or oral administration of the drug. The results found suggest a complex multi-compartment storage with several periodical releases in general circulation.

Physicochemical, pharmacological and pharmacokinetic study of a new GABAergic compound, calcium acetylhomotaurinate.

It has been shown that calcium acetylhomotaurinate (Ca AOTA; Meram Patent, France) decreased voluntary ethanol intake in rats (1); this was antagonized by bicuculline. Homotaurine did not have this effect. We thought this was due to a different blood-brain barrier crossing ability for the two drugs. The present study was, therefore, planned to confirm blood-barrier crossing by Ca AOTA and to study the drug's physicochemical and pharmacokinetic characteristics. Both in vitro and in vivo (i.p.) administration of Ca AOTA increased the accumulation of [3H] GABA in rat striatal synaptosomal preparations. The chemical study confirmed Ca AOTA's great stability in biological and hydrophilic media, excluding a "homotaurine-dispensing" effect. The molecule was totally dissociated in such media, but the absence of any detectable acid form at any pH indicates that ion pairs are formed to cross barriers, and/or that a carrier system is used. The pharmacokinetic study showed short half-lives (5 and 30 min for the distribution and elimination phases) and small distribution volumes. However, the elimination phase distribution volume was dose-dependent, a further argument for a carrier transport system. From the present study it appears that Ca AOTA is an extremely stable drug, totally dissociated in hydrophilic media, which acts centrally as a GABA agonist after crossing the blood-brain barrier. It is not a precursor of homotaurine and presumably crosses barriers with the help of a transporter.

[Diffusion of vancomycin in the cerebrospinal fluid, in the dog, in the absence of meningeal inflammation]. / Diffusion de la vancomycine dans le liquide céphalo-rachidien, chez le chien, en l'absence d'inflammation méningée.

The diffusion of vancomycin into the cerebro-spinal fluid was studied in 5 healthy dogs. Its appears that vancomycin does diffuse across the blood-brain barrier. Though the concentrations reached in the CSF are low, they are of the same order of magnitude as the minimal inhibitory concentrations of this antibiotic towards the germs usually treated. The usual pharmacokinetic parameters were determined.

[Ventricular staphylococcal infections. Treatment with vancomycin by continuous venous infusion]. / Infections ventriculaires à staphylocoque. Traitement par la vancomycine en perfusion veineuse continue.

Thirteen cases of meningeal and/or ventricular infection and 1 case of septicaemia, all caused by staphylococci, were treated with continuous intravenous infusions of vancomycin. Repeated measurements of vancomycin plasma and CSF levels by microbiological assay or by high performance liquid chromatography showed that the antibiotic entered the CSF after 48 hours of treatment and that its concentrations in CSF remained stable at 1 to 4 micrograms/ml (mean: 2 micrograms/ml) throughout the 3 weeks' treatment period. After treatment was discontinued, vancomycin became undetectable in CSF within less than 24 hours. All the children were cured.

[Not Available]. / Formation d'un chelate cuivre-vancomycine: application au dosage de l'antibiotique en flux continu et detection amperometrique.

The formation of a metal-complex of copper(II) with vancomycin, an antibiotic active towards Gram-positive bacteria, has been proved by spectrophotometric, polarographic and potentiometric methods. In particular, the half-wave reduction potentials and voltamperograms indicate the stoichiometry of the addition compound and the equilibrium constant. This complex has been used for determination of vancomycin by a continuous flow method with copper(II) and amperometric detection in a polarographic cell of thin-layer type.