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The effect of ornithine alpha-ketoglutarate (OKG) on cytochrome P-450 enzyme activities was studied in a well-defined model of injury (burn followed by fasting then subsequent hypocaloric diet) administered to young rats for 3 d. Hepatic microsomes were prepared by ultracentrifugation and levels of cytochromes P-450 were determined spectrophotometrically. The activities of ethoxy-resorufin-O-deethylase (EROD), benzyloxy-resorufin-O-dealkylase (BROD), and erythromycin demethylase were measured as markers of P-450 1A, 2A, and 3A isotypes respectively. The level of total hepatic microsomal proteins (8 mg/mL) remained constant. The level of cytochrome P-450 (1.14+/-0.08 nmol/mg microsomal proteins) was decreased by a hypocaloric diet (23%, P = 0.003) and burn further enhanced this phenomenon (15%, P = 0.03). Both healthy and burned rats receiving OKG showed the same level of cytochrome P-450 as the rats fed ad libitum. OKG supplementation counteracted the enhancement (40%) of EROD activity induced by hypocaloric diet but did not influence BROD and erythromycin demethylase activities. OKG sustained cytochrome P-450 levels in rats fed a hypocaloric diet, even after burning. These findings indicate that OKG may favor drug metabolism in this injured population.

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Various inflammatory reactions can be induced by different crystals responsible for various arthropathies. The aim of this work was to study modifications induced in the rat, locally and at distance, by intrapleural injection of 3 forms of pyrophosphate crystals (CaPP dihydrated monoclinic (M), CaPP dihydrated triclinic (T) and CaPP anhydrous (beta]. The data presented here show that the structure of irritants plays a decisive role in the kinetics of inflammatory reactions from a local and systemic point of view.

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Drug influences on polymorphonuclear leucocytes (PMN) and particularly on PMN migration was investigated. PMN chemotaxis and random migration were assessed in vitro, after drug incubation in vitro and/or administration in vivo. An inhibiting effect on directed migration induced both by fMLP and C5a was demonstrated with some anti-inflammatory drugs whereas random migration was unaffected. The effect was dose-related and linked to drug chemical structure and to physiopathological state of the cells. Similar results may be obtained after administration in vivo. However some examples show that metabolism can inactivate the pharmacological effect of chemical substances and that the route of administration is of prime importance. The activity of new pathological compounds on PMN migration might need to be studied both in vitro and in vivo. In vitro experiments might be performed as a first step of the study. However only in vivo experiments are really representative of potential therapeutical use. Thus we conclude that both experimental series may be performed to appreciate drug interaction with PMN functions during clinical assays.

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Using a modified Boyden chamber, random migration and chemotaxis of rat polymorphonuclear leucocytes (PMN) were assessed after incubation in vitro in a solution of colchicine (1.5 X 10(-5) M). The results obtained were compared to random migration or chemotaxis of the same cellular pool treated in vitro or in vivo by N-isopropyl-amino-2-pyrimidine phosphate (isaxonine 4.10(-5) M or 75 and 150 mg/kg respectively). Isaxonine partially inhibited the effect of colchicine on PMN chemotaxis while random migration remained unaffected. Isaxonine might partially inhibit the noxious effect of colchicine on microtubule disruption by a direct effect (polymerization of free tubulin) and/or indirect effect (impairment of disorganizing activity) on PMN microtubules.

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The effect of piroxicam on rat polymorphonuclear leucocytes (PMN) has been studied in vitro and in vivo after the induction of two acute, non specific inflammatory reactions (pleurisies induced by calcium pyrophosphate crystals (CaPP) or isologous serum). An inhibition of chemotaxis by piroxicam has been demonstrated by two techniques, the filter and agarose assays in vivo and in vitro. An inhibition of random cell migration has been observed only at the higher drug concentration using agarose assay with CaPP-elicited cells. Piroxicam also inhibited superoxide anion generation and O2 consumption of CaPP- and serum-elicited cells. These findings suggest that piroxicam may have a direct effect on PMN responses and that this activity could, at least in part, contribute to its anti-inflammatory properties.

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Chemotactic and chemoluminescent activities of substance P, substance K, kassinin and the substance P fragments SP 4-11, SP 7-11, SP 1-4 have been investigated in order to identify the minimum active molecular structure responsible for rat polymorphonuclear activation. Substance P, SP 4-11 and SP 7-11 stimulated directed locomotion (chemotaxis) and were found to be active also in the chemoluminescence assay while SP 1-4 had no effect. Moreover, all peptides, except substance K and SP 1-4, inhibited the chemotactic response of polymorphonuclears to the peptide formyl-methionyl-leucyl-phenylalanine and, to a minor extent, also to leukotriene B4. A maximum of activity was observed with the C-terminal sequence SP 4-11. Substance K was found to be inactive. Kassinin exhibited a weak chemotactic effect and exerted a slight inhibition of attracting activity of peptide-formyl-methionyl-leucyl-phenylalanine. Considering that substance P and related peptides are active only at very high concentrations, it cannot be affirmed that these agents activate specific receptors. If receptors are involved, they would be of the SP-P type, since substance K is inactive.

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The effect produced by three gold salts (sodium aurothiomalate, allochrysine, auranofin) on chemotaxis and random migration of rat polymorphonuclear leucocytes (PMN) was investigated under various experimental conditions. The drug activity was examined after incubation in vitro or after administration in vivo. PMNs were recruited after the induction of two acute inflammatory reactions (pleurisies induced by isologous serum or a suspension of calcium pyrophosphate (CaPP) crystals). The three gold salts administered in vivo and in vitro inhibited the chemotactic responses of the two cell types. This action was dose-dependent. Auranofin was the most effective substance while sodium aurothiomalate was the least. The random migration was not always significantly depressed especially for CaPP-elicited cells. Reduction in neutrophil chemotaxis might be an important additional mechanism in the action of gold salts and their activity on inflammatory PMNs recruited at inflammatory foci might be beneficial in the treatment in rheumatic diseases in which PMN migration would be implicated.

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The effect of indomethacin, acetyl salicylic acid and niflumic acid on the chemotaxis and random migration of rat polymorphonuclear leucocytes (PMN) was investigated with a modified Boyden chamber technique under various experimental conditions (two cell sources, administration of drugs in vivo or incubation in vitro, modulation of antichemotactic activity of sera obtained from animals with inflammatory reactions). Indomethacin and niflumic acid inhibited the chemotactic responsiveness of cells collected from the rat pleural cavity after induction of two types of acute inflammatory reactions. This action was dose-dependent and appeared after either in vivo administration of the drug or in vitro incubation of the cells with various concentrations of the drug. However, random migration was not significantly modified and acetyl salicylic acid had no effect under any of the conditions. The same drugs, acetyl salicylic excepted, inhibited the antichemotactic activity exhibited by sera obtained from animals with inflammatory reactions.

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The effect of piroxicam on the chemotaxis and random migration of rat polymorphonuclear leucocytes was investigated with two techniques of assessment (filter and agarose assay) under various experimental conditions. The drug was administered in vivo or tested in vitro on polymorphonuclears collected in the pleural cavity after induction of an immune (reverse passive Arthus reaction) or an acute non-specific inflammation (pleurisy induced by a suspension) (1%) of calcium pyrophosphate crystals (CaPP). In all cases a dose-dependent inhibition of chemotaxis was observed, more striking in the case of CaPP elicited cells which were more reactive than cells collected after the induction of the Arthus reaction. No modification of random migration appeared using the filter assay while a slight inhibition was demonstrated at the higher dose using the agarose assay.

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The effects produced in vivo and in vitro by indometacin, niflumic acid, acetylsalicylic acid and dexamethasone have been studied on rat polymorphonuclear leucocyte migration with the Boyden chamber technique (formyl - methionyl - leucyl - phenylalanine was the chemoattractant). Excepting acetylsalicylic acid, the drugs tested determined an inhibiting effect on leucocyte migration investigated by four experimental approaches. These substances exerted a direct effect and modified the chemotactic reactivity towards the chemotactic peptide after incubation in normal or inflammatory sera. They impeded the action of an antichemotactic factor released in sera during acute inflammatory reaction.

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A method is described for allowing the sampling of a homogeneous population of polymorphonuclear cells (PMN) from the rat pleural cavity a well as a technique involving the use of a phase-contrast microscope and video-recording system to study the necrotaxis of rat PMN towards a single erythrocyte lysed by ruby-laser irradiation. This allows both the speed of the leucocytes and the degree of their chemotactic response to be determined. The advantages and disadvantages of the experimental technique are discussed along with its application to the study of in vitro and in vivo actions of various drugs on rat PMN chemotaxis.

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A method is described for allowing the sampling of a homogeneous population of polymorphonuclear cells (PMN) from the rat pleural cavity a well as a technique involving the use of a phase-contrast microscope and video-recording system to study the necrotaxis of rat PMN towards a single erythrocyte lysed by ruby-laser irradiation. This allows both the speed of the leucocytes and the degree of their chemotactic response to be determined. The advantages and disadvantages of the experimental technique are discussed along with its application to the study of in vitro and in vivo actions of various drugs on rat PMN chemotaxis.

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