[Clinical results of resection arthroplasty for infected shoulder arthroplasty]. / Résultats de la résection arthroplastique dans les arthroplasties d'épaule infectée.

PURPOSE OF THE STUDY: Infection is a rare complication of shoulder arthroplasty. Various therapeutic solutions have been proposed: antibiotics alone, one-stage or two-stage reimplantation, surgical or arthroscopic cleaning without prosthesis removal, scapulohumeral arthrodesis or simple arthroscopic resection. We evaluated the mid-term clinical outcome after resection arthroplasty for the treatment of infected shoulder arthroplasty. MATERIAL AND METHODS: The series included ten infected arthroplasties in ten patients. Mean duration of implantation was two years seven months (range nine months to five years). Bacteriological diagnosis was established from intraoperative articular samples or systematic samples taken during surgical revision procedures: meti-S Staphylococcus aureus strains (n=4), coagulase-negative Staphylococcus (n=5 including three S. epidermidis) Streptococcus mitis (n=1) and Citrobacter koseri (n=1). The mean Constant score before revision was 58 (range 23-77). Subjective patient satisfaction before surgical revision was rated good in six cases, fair in one and poor in three. Surgery associated removal of the implant, complete resection of the cement, resection of the fistular tracts, wide debridement of infected tissues and total synovectomy. RESULTS: Patients were seen at an average follow-up of three years eight months. The objective functional outcome measured with the Constant score was only fair, 28 points (range 20.6-36), and corresponded to a loss of 29 points compared with the preoperative score. This was explained mainly by lower scores for joint motion, function and muscle force but with persistently satisfactory scores for pain. All patients remained pain-free (daytime and nighttime). Patient satisfaction was rated good for two, fair for five and mediocre for three. Clinical and biological proof of eradicated infection was obtained in all patients. DISCUSSION: Infection remains a serious devastating problem for shoulder arthroplasty with an important functional impact. Resection only has a modest clinical effect. Precise identification of the causal germ with institution of adapted antibiotic therapy is required for eradication of the infection. Early diagnosis is probably the most important parameter affecting clinical outcome and surgical options. Functional results after resection arthroplasty are modest. This procedure should be reserved for patients with reduced functional demands. Improved management of the infectious load and reduction of diagnostic delay should help improve functional outcome and favor use of stow-stage procedures for reinsertion.

[Porphyrin catalysts: a tool for preparation of metabolite models]. / Les catalyseurs porphyriniques: un outil pour la préparation de modèles de métabolites.

The porphyrin complexes of manganese catalysts are biomimetic catalysts whose structural analogy with the active site of cytochrome P-450 enzymes can be used to obtain synthetic models of therapeutic agent metabolites. Mn(TDCOO)Cl, a second generation porphyrin, has proven robust enout to be used for scaled-up production in the presence of hydrogen peroxide and imidazole. For this purpose, an improvement in substrate oxidation was obtained by adjunction of formic acid to the reaction medium which preserved the cocatalyst and the catalyst. It was shown that addition of acid played an active role in the oxidation process. After this optimization, the system was used to oxidate the two enantiomers of methyloctalone, an essential chiral intermediate in the synthesis of terpenoids and steroids. The efficacy of this biomimetic method for the preparation of large amounts of oxidized chiral synthons was better than obtained with biological ex vivo pathways.

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.

Competition between the beta-hydroxylation of a primary and a tertiary carbon atom in rats.

In order to study the effect of steric hindrance on competition between two kinds of beta-hydroxylation, a compound bearing on a pyrimidinetrione nucleus both a branched side chain with a tertiary carbon atom in position beta (isobutyl group) and a linear side chain (ethyl group), was selected and administered to rats. Urine and faeces were collected and extracted. Hydroxymetabolites and their derivatives were isolated and then identified. The beta-hydroxylation of the linear chain was more important than the beta-hydroxylation of the branched chain. Steric hindrance plays a decisive role in this regioselectivity.

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.

Phenobarbital metabolism by hepatocytes isolated from rat.

In order to test the validity of the use of hepatocytes as an alternative to studies of metabolism in live animals, phenobarbital (PB) was applied at 37 degrees C to isolated rat hepatocytes, which had been previously induced by PB. The metabolites were extracted by ethyl acetate, at various pH, and identified and evaluated by GC-MS. PB was not metabolized to p-hydroxyphenobarbital as is usually the case in living animals, but it was transformed into sulphoconjugated 2-phenyl-gamma-butyrolactone. This pathway, beta-hydroxylation of the ethyl side chain followed by lactonization, previously described as a secondary metabolic pathway occurring during intoxications, was here the only observed biodegradation. These results show that it is not possible to use hepatocytes as an alternative to live animals.

[Iminodimethylation, a method for pharmacomodulation in pyrimido-[3,4-a]-s-triazine series]. / L'iminodiméthylation, une méthode de pharmacomodulation en série pyrimido [3,4-a]-s-triazinique.

Primary amines react with two formaldehydes and compounds presenting two mobile hydrogen atoms, this reaction can be called iminodimethylation. This reaction can be used in order to perform a pharmacomodulation in the pyrimido [3,4-a]-s-triazine series. Against Epidermophyton floccosum, the activity is better when nitrogen 7 is not substituted, when the heroatom in position 2 is 0 instead of S and when an aromatic nucleus is directly linked to the nitrogen atom in position 3.

Gas chromatographic-mass spectrometric method for analysis of a pyrimido-s-triazine and some of its metabolites in dog urine.

3-Phenylpyrimido-[3,4-a]-s-triazines exhibit antiparasitic, antibacterial and antifungal activity. In order to study the metabolism of these heterocycles, 9,9-diethyl-3-phenyl-6,8-dioxo-2,3,4,5,6,7,8,9-octahydropyrimido[3 ,4-a]-s- triazine (TZ) was administered to dogs. Three potential metabolites were synthesized, and these models were identified and quantified with gas chromatography-mass spectrometry. The heterobicyclic compounds, TZ and its hydroxy derivative, underwent thermal degradation under chromatographic conditions. Dog urine spiked with the model metabolites was extracted, and the substances were quantified. The urine of dogs treated with TZ was studied, and two of the potential metabolites were recovered, identified and quantified.

[Chromic oxidation and synthesis of barbiturate metabolites]. / Oxydation chromique et synthèse de métabolites de barbituriques.

Chromic oxidation using chromium trioxide in acetic medium is presented as a tool for the synthesis of models of metabolites of various barbiturates. When the pyrimidinetrione is monosubstituted in position 5, a hydroxy group is introduced on the ring. For 5,5-disubstituted barbiturates, branched chains are preferentially converted into tertiary alcohols, while ethylenic chains are, according to their substitution, oxidized into ketones or carboxylic acids. Secondary alcohols lead to ketones but an alcohol function can be protected by esterification. Oxidations followed by other transformations and oxidations of related heterocycles are also described.

[Preparation of monodesethylamodiaquine from human urine]. / Préparation de monodéséthylamodiaquine à partir d'urines humaines.

60 mg of monodesethylamodiaquine, the active metabolite of amodiaquine were prepared by extraction from human urine, at pH 11-12, using ethyl acetate. The purification was carried out by medium pressure liquid chromatography. The identity and the purity of the compound were checked by thin layer chromatography, 1H nuclear magnetic resonance and mass spectrometry.

[Synthesis of potential metabolites of a barbiturate containing two branched side chains]. / Synthèse des métabolites potentiels d'un barbiturique porteur de deux chaînes ramifiées.

The two branched side chains of 5-(3-methylbutyl)-5-(2-methylpropyl)-barbituric acid present a tertiary carbon atom, which can be oxidized in vivo by hepatic enzymes. Potential metabolites of this compound are synthesised: the gamma-hydroxy metabolite can be oxidized directly by CrO3 while the beta-hydroxy metabolite can only be prepared by hydration of a double bond. This beta-hydroxybarbiturate then undergoes an alcoholysis leading to an allophanyl-gamma-lactone, which is hydrolysed into a carboxylic lactone, which can give a lactone by decarboxylation. On the other hand, a beta-gamma-dihydroxymetabolite is synthesised by double hydration of two double bonds using two different methods. A spirobilactone can also be synthesised from this dihydroxy compound.

Passage of allophanoyl-gamma-lactones through the kidney.

In order to establish if allophanoyl-gamma lactones (B compounds) can pass through the kidney or if only the corresponding delta-hydroxybarbiturates (A compounds), formed by intramolecular alcoholysis, are able to do so, nine experiments were performed to study the urinary excretion of four different allophanoyl gamma-lactones B after administration to dogs. Excreted compounds were extracted, identified and quantised. From the amounts of unmodified administered lactones that were recovered, it is concluded that B compounds can pass through the kidney before isomerisation into the corresponding barbiturates A.

[Microdetermination of pyrazinamide and its metabolites (pyrazinoic acid, 5-hydroxypyrazinoic acid, 5-hydroxypyrazinamide and pyrazinuric acid) in plasma and urine with liquid chromatography]. / Microdétermination du pyrazinamide et de ses métabolites (acide pyrazinoïque, acide hydroxy-5-pyrazinoïque, hydroxy-5-pyrazinamide, acide pyrazinurique) plasmatiques et urinaires par chromatographie en phase liquide.

The method reported here for determining pyrazinamide and its metabolites (2-pyrazinoic acid, 5-hydroxypyrazinamide, 5-hydroxypyrazinoic acid and pyrazinuric acid) consists of diluting urine or acid deproteinisation of serum followed by chromatography on a cation-exchange column. The column length and the detection system (ultraviolet or fluorimetry) allow for a very good separation of the different compounds; the sensitivity of the method makes it suitable for pharmacokinetic studies.

[Determination of plasma ethambutol with liquid chromatography and ultraviolet spectrophotometry]. / Détermination de l'éthambutol plasmatique par chromatographie liquide et détection spectrophotométrique ultraviolette.

The method presented here is based on the ability of ethambutol to give chelates with divalent cationic metals. With copper salts, the chelate presents a characteristic ultraviolet absorbance at 270 nm, making it possible to titrate ethambutol extracted from plasma with chloroform in alkaline medium. The column which was used contained silica (LiChrosorb Si 60, 5 microns) and the mobile phase was a mixture of equal parts of water and acetonitrile, containing copper sulphate and ammonia. The internal standard was a lower homologue of ethambutol with the same chelating ability. The detection limit was 0.15 mg/l. No interference with other antitubercular agents was observed.

[Simultaneous microdetermination of pyrazinamide and pyrazinoic acid by liquid chromatography]. / Microdétermination simultanée du pyrazinamide et de l'acide pyrazinoïque sériques par chromatographie liquide.

The technique reported here enables to titrate concomitantly pyrazinamide as well as its main metabolite, the 2-pyrazinoic acid. The serum sample is deproteinized with acetonitrile and the portion floating on the surface is injected on an anionic column of copolymer. The detection occurs at 270 nm and the sensitivity of the method enables its use during pharmacokinetic studies. The other anti-tuberculous drugs, usually associated, produce no interference.