Biomedical subjects

M Pairet

Publications and source records attributed to M Pairet.

At least 19 recordsLinked to original sources

PubMed2000

Effects of caffeine and paracetamol alone or in combination with acetylsalicylic acid on prostaglandin E(2) synthesis in rat microglial cells.

Paracetamol has mild analgesic and antipyretic properties and is, along with acetylsalicylic acid, one of the most popular "over the counter" analgesic agents. However, the mechanism underlying its clinical effects is unknown. Another drug whose mechanism of action is unknown is caffeine, which is often used in combination with other analgesics, augmenting their effect. We investigated the inhibitory effect of paracetamol and caffeine on lipopolysaccharide (LPS)-induced cyclooxygenase (COX)- and prostaglandin (PG)E(2)-synthesis in primary rat microglial cells and compared it with the effect of acetylsalicylic acid, salicylic acid, and dipyrone. Furthermore, combinations of these drugs were used to investigate a possible synergistic inhibitory effect on PGE(2)-synthesis. Both paracetamol (IC(50)=7.45 microM) and caffeine (IC(50)=42.5 microM) dose-dependently inhibited microglial PGE(2) synthesis. In combination with acetylsalicylic acid (IC(50)=3.12 microM), both substances augmented the inhibitory effect of acetylsalicylic acid on LPS-induced PGE(2)-synthesis. Whereas paracetamol inhibited only COX enzyme activity, caffeine also inhibited COX-2 protein synthesis. These results are compatible with the view that the clinical activity of paracetamol and caffeine is due to inhibition of COX. Furthermore, these results may help explain the clinical experience of an adjuvant analgesic effect of caffeine and paracetamol when combined with acetylsalicylic acid.

Acetaminophen↗

PubMed2000

COX-2 selectivity and inflammatory processes.

Increasing amounts of experimental and clinical data support the role of selective cyclooxygenase (COX)-2 inhibition in anti-inflammatory processes and the involvement of COX-1 inhibition in the side effects associated with non steroidal anti-inflammatory drug use. This review will focus on the differences in the structure of the COX-1 and COX-2 molecules, particularly the active site and how they are bound by various NSAIDs to achieve COX-2 selectivity. This COX-2 selectivity will then be characterized in pharmacological assays in vitro and in animal models in vivo. Finally, clinical information available for this new class of selective inhibitors will be discussed.

Animals↗

PubMed1999

Clinical experience with cyclooxygenase-2 inhibitors.

Increasing amounts of experimental and clinical data support the role of selective cyclooxygenase (COX)-2 inhibition in anti-inflammatory processes and the role of COX-1 inhibition in increasing the frequency of side effects. This article reviews the regulation of COX-2 in inflammatory processes based on in vitro and in vivo work. In addition, it summarizes the various in vitro assays used to classify the new generation of selective and highly selective inhibitors of COX-2, since prior categorization of NSAIDs does not satisfactorily encompass the COX-2 concept. Finally, the latest published clinical data of new selective and highly selective inhibitors of COX-2 (meloxicam, nimesulide, etodolac, celecoxib and MK966) are discussed.

Cyclooxygenase 1↗

PubMed1998

Cyclooxygenase-2 up-regulation after FLAP transfection in human adenocarcinoma cell line HT29 cl.19A.

Five-lipoxygenase-activating protein (FLAP) is usually described as an essential protein to activate the leukotriene (LTs) synthesis via the 5-lipoxygenase pathway. In the enterocyte model HT29 cl.19A cell line, 5-lipoxygenase metabolism was found despite the lack of FLAP expression. Therefore HT29 cl.19A represents an original mammalian model to study FLAP-dependent leukotriene synthesis. In FLAP cDNA transfected HT29 cl.19A cells, FLAP expression led to an increase in cyclooxygenase pathway products (mainly PGE2) without an increase in 5-lipoxygenase metabolism. This increase in PGE2 synthesis was associated with a cyclooxygenase-2 upregulation in comparison to untransfected HT29 cl.19A cells. These results suggest a possible interaction between the two major pathways of arachidonic acid metabolism.

5-Lipoxygenase-Activating Proteins↗

PubMed1998

Experimental models used to investigate the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2 by non-steroidal anti-inflammatory drugs.

Numerous in vitro assays have been developed for testing and comparing the relative inhibitory activities of non-steroidal anti-inflammatory drugs against cyclooxygenase (COX)-1 and COX-2. Despite variability among these systems, which precludes direct comparison of data, analysis of the ratio of inhibition of COX-1 to COX-2 by non-steroidal anti-inflammatory drugs, suggests inhibitors can be classified based on their COX selectivity. Standard non-steroidal anti-inflammatory drugs can be considered nonselective; compounds such as meloxicam and nimesulide can be classified as COX-2 preferential; and compounds such as SC 58125 and L-754,337 are selective for COX-2. Although in vitro systems are important for characterizing COX-1 and COX-2 inhibitory activity, the clinical relevance of these data should be considered carefully. The level of inhibition of COX-1 and COX-2, in vivo at a given dose in patients, cannot be predicted from in vitro data alone. The pharmacokinetic properties of each compound, including plasma levels, distribution and binding to plasma proteins, have to be taken into account. Human pharmacology studies concentrating on the inhibition of prostanoid synthesis in target tissues are of paramount importance in determining the clinical relevance of COX-2 selectivity.

Animals↗

PubMed1998

Differential inhibition of cyclooxygenases-1 and -2 by meloxicam and its 4'-isomer.

OBJECTIVE AND DESIGN: Two structurally related compounds, meloxicam (Mel) and its structural 4'-isomer (4'-Mel), were compared to examine the role of a slightly different chemical structure on cyclooxygenase (COX) selectivity in in vitro and in vivo experimental models. MATERIAL OR SUBJECTS: In vitro studies were performed using human whole blood obtained from healthy volunteers, in vivo studies were performed in rats. TREATMENT: A concentration-response curve was obtained in the whole blood assay for Mel, 4'-Mel, indomethacin, piroxicam and diclofenac. These were used to calculate the respective IC50 values of either prostaglandin E2 (PGE2) or thromboxane B2 (TxB2). Similarly, a dose-response curve was obtained for Mel, 4'-Mel and piroxicam when measuring in vivo prostaglandin production, anti-inflammatory activity and gastric tolerance to determine the dose resulting in a 50% reduction of the each parameter. METHODS: COX selectivity was investigated in vitro using a human whole blood assay. PGE2 synthesis in vivo was measured in inflammatory exudate, in the stomach and kidneys of rats. Anti-inflammatory effects were measured in an adjuvant arthritis model and gastric tolerance was tested in an ulcerogenicity model in vivo in rats. RESULTS: In the human whole blood assay, the ratio of IC50 values for COX-1 vs. COX-2 inhibition was 13 for Mel and 1.8 for 4'-Mel. In inflammatory exudate in rats, Mel and 4'-Mel inhibited PGE2 synthesis to a similar extent, ID50 values approximately 0.3 mg/kg. In contrast, Mel was a weaker inhibitor of PG synthesis than 4'-Mel in the rat stomach and in the rat kidney. Paw swelling was reduced by 50% with 0.1 and 0.2 mg/kg for Mel and 4'-Mel, respectively, in the rat adjuvant arthritis model. Gastric tolerance (UD50) was 2.4 mg/kg for Mel and 0.4 mg/kg for 4'-Mel. CONCLUSIONS: These data demonstrate that the in vitro and in vivo pharmacological profile of meloxicam is structurally dependent and that minor structural changes can lead to significant differences in the selectivity for COX-1 and COX-2 in vitro and to different profiles in vivo suggesting different therapeutic potential.

Animals↗

PubMed1998

Meloxicam inhibits the growth of colorectal cancer cells.

Cyclooxygenase-2 has been reported to play an important role in colorectal carcinogenesis. The effects of meloxicam (a COX-2 inhibitor) on the growth of two colon cancer cell lines that express COX-2 (HCA-7 and Moser-S) and a COX-2 negative cell line (HCT-116) were evaluated. The growth rate of these cells was measured following treatment with meloxicam. HCA-7 and Moser-S colony size were significantly reduced following treatment with meloxicam; however, there was no significant change in HCT-116 colony size with treatment. In vivo studies were performed to evaluate the effect of meloxicam on the growth of HCA-7 cells when xenografted into nude mice. We observed a 51% reduction in tumor size after 4 weeks of treatment. Analysis of COX-1 and COX-2 protein levels in HCA-7 tumor lysates revealed a slight decrease in COX-2 expression levels in tumors taken from mice treated with meloxicam and no detectable COX-1 expression. Here we report that meloxicam significantly inhibited HCA-7 colony and tumor growth but had no effect on the growth of the COX-2 negative HCT-116 cells.

Animals↗

PubMed1997

Ambroxol improves the broncho-spasmolytic activity of clenbuterol in the guinea-pig.

The effects of ambroxol on the spasmolytic action of clenbuterol were investigated on acetylcholine-induced bronchospasm in guinea-pigs. Ambroxol (50 mg kg-1 day-1) or vehicle was administered orally for 14 days. Approximately 45 min after the final dose on day 14, the animals were anaesthetized and the spasmolytic effects of clenbuterol (3, 6 or 12 micrograms kg-1 injected intravenously) were determined by use of acetylcholine (40 micrograms kg-1, i.v.)-induced bronchoconstriction. For both vehicle- and ambroxol-treated animals, a positive linear relationship was observed between the log-dose of clenbuterol and the percent inhibition of bronchospasm. The calculated ED25 of clenbuterol (i.e., the dose producing 25% inhibition of the acetylcholine-induced bronchospasm) was 3.98 micrograms kg-1 (3.29 to 4.82 micrograms kg-1, 95% confidence interval) in the presence of ambroxol and 5.81 micrograms kg-1 (4.98 to 6.79 micrograms kg-1) in the absence of ambroxol. The linear regressions with or without ambroxol differed from each other (P < 0.001) but ran parallel (covariance analysis), enabling us to calculate a relative potency, the value of which was 1.46 (1.16 to 1.84). These results demonstrate that the spasmolytic activity of clenbuterol is significantly improved in animals pretreated with ambroxol.

Ambroxol↗

PubMed1997

Role of caffeine in combined analgesic drugs from the point of view of experimental pharmacology.

The interactions of caffeine (CAS 58-08-2) with acetylsalicylic acid (CAS 50-78-2, ASA) and paracetamol (CAS 103-90-2) were investigated with regard to the analgesic, antiphlogistic, antipyretic and other properties. The inhibitory effect of paracetamol and ASA on the prostaglandin biosynthesis in a cyclooxygenase preparation from bovine brain in vitro was not affected by the addition of caffeine. Caffeine additively increases the antinociceptive effect of paracetamol with regard to the heat-induced pain in the mouse, as does aminophenazone. The antinociceptive effect of aminophenazone on the mechanically induced pain in the mouse is also additively increased by caffeine. In contrast to the effect of aminophenazone on the inflammatory pain in the rat, the effect of ASA is not increased by caffeine and that of paracetamol only negligibly. The antipyretic effect of paracetamol is additively increased by caffeine in the normothermic rat. The antipyretic effect of ASA and paracetamol on the yeast-induced pyrexia of the rat is not affected by caffeine. Caffeine additively increases the acute antiexudative effect of ASA and aminophenazone on the carageenin-induced oedema of the hind paw of the rat. The increase in locomotor activity caused by caffeine in mouse and rat is neutralised or diminished when the caffeine is given in combination with paracetamol. This effect is maintained even if the rats are pretreated with the combination of active ingredients for 3 weeks. The ulcerogenic effect of ASA in the stomach of the rat is not increased by caffeine. The protective effect of ASA against the hepatotoxic effect of paracetamol in the mouse is not influenced by the addition of caffeine. The plasma levels after the oral administration of 20 mg/caffeine/ kg and 80 mg paracetamol/kg in the rat are not significantly changed when the substances are given in combination. The toxicological advantages resulting from combining ASA and paracetamol with caffeine are discussed.

Acetaminophen↗

PubMed1996

The antioxidative activity of the mucoregulatory agents: ambroxol, bromhexine and N-acetyl-L-cysteine. A pulse radiolysis study.

Ambroxol and bromhexine are shown to be scavengers of both superoxide and hydroxyl radicals as determined by pulse radiolysis experiments. The dismutation of superoxide was accelerated 3-fold by bromhexine and 2.5-fold by ambroxol over the rate of spontaneous dismutation. The reaction constants of hydroxyl radicals with bromhexine and ambroxol were determined by competition kinetics to be 1.58 +/- 0.15 x 10(10) M-1S-1 and 1.04 +/- 0.1 x 10(10) M-1S-1, respectively. N-acetyl-L-cysteine also reacted with hydroxyl radicals (1.28 +/- 0.14 x 10(10) M-1S-1) but not with superoxide radical. These effects may be clinically relevant in the treatment of oxidant-associated lung damage induced by inflammatory agents and/or environmental pollutants.

Acetylcysteine↗

PubMed1996

Distinct isoforms (COX-1 and COX-2) of cyclooxygenase: possible physiological and therapeutic implications.

The discovery of an inducible isoform of cyclooxygenase (COX-2) requires a refinement of the theory that inhibition of cyclooxygenase activity explains both therapeutic and side effects of non-steroidal anti-inflammatory drugs (NSAIDs). Indeed, new pharmacological results suggest that COX-2 inhibition provides the therapeutic (ie, anti-inflammatory) activity of NSAIDs, whereas inhibition of constitutive COX-1 is responsible for their gastric and renal side effects as well as for their antithrombotic activity. However, a role of COX-1 in inflammation cannot be excluded. Furthermore, the functional relevance of COX-2 expression and induction in various tissues warrants further investigation. These studies should help in predicting potential adverse effects as well as new indications for selective COX-2 inhibitors.

Animals↗

PubMed1993

The novel 5-HT4 receptor antagonist DAU 6285 antagonizes 5-hydroxytryptamine-induced tachycardia in pigs.

The 5-HT4 receptor antagonist action of DAU 6285 was investigated in vivo in anesthetized pigs. DAU 6285 (0.3-3 mg/kg i.v.) dose dependently antagonized 5-hydroxytryptamine (5-HT)-induced tachycardiac responses. In contrast, the 5-HT3 receptor antagonist, ondansetron (0.3-3 mg/kg i.v.) did not influence the tachycardia induced by 5-HT. These results indicate that DAU 6285 is a potent antagonist of 5-HT4 receptor-mediated responses in vivo.

Animals↗

PubMed1993

Hemodynamic parameters of anesthetized pigs: a comparative study of farm piglets and Göttingen and Yucatan miniature swine.

We studied the evolution in time of the main hemodynamic parameters in farm piglets and Göttingen and Yucatan miniature swine anesthetized with droperidol, flunitrazepam, and alpha-chloralose. Measurements included arterial pressure, heart rate, intraventricular pressure, and maximum rate of increase during contraction (dp/dt max). For each parameter and each strain of swine, we determined the mean stability period defined as the longest period of time during which the observed values ranged between their mean value +/- 15% and the mean absolute values during the stability period. In our experimental conditions, the parameters remained constant for 2 to 3.5 hours. Only minor interstrain variations were noticed.

Anesthesia↗

PubMed1989

On the relevance of non-steroidal anti-inflammatory drugs in the prevention of paralytic ileus in rodents.

In the mouse, the gastrointestinal transit of a charcoal marker, halved following the intraperitoneal administration of acetic acid, was no longer inhibited after pretreatment with the non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin, ketoprofen, piroxicam or ximoprofen (0.25-2.5 mg kg-1 orally). In the fasted rat, the migrating myoelectric complex pattern of the small intestine which was disrupted for about one hour by acetic acid was unaltered by pretreatment with indomethacin or ximoprofen (0.5 mg kg-1 i.p.). In the anaesthetized rat, the inhibition by about 50% of the gastrointestinal transit due to laparotomy, did not occur following treatment with NSAIDs. It is concluded that NSAIDs prevent the occurrence of chemically-induced and postoperative ileus in rodents, an effect probably related to the analgesic properties of NSAIDs.

Animals↗

PubMed1988

Effects of intraluminal nutrients on intestinal myoelectric activity in rabbits.

In the unanesthetized rabbit, intraluminal infusions of D- and L-methionine, L-tryptophan, D-glucose, D-xylose, and lactulose had a biphasic effect on small intestinal myoelectric activity. A phase of enhanced activity was followed by a phase of inhibition. The excitatory phase was mimicked by saline solutions equiosmolar to the test solutions. The subsequent inhibition was does dependent and significantly (P less than 0.01) longer for the passively absorbed D-methionine than for the L-stereoisomer. The inhibitory action of 10 mM D-glucose, 10 mM L-methionine, and 5 mM L-tryptophan was blocked by propranolol on the jejunum and by phenoxybenzamine on the ileum. We conclude that the initial excitatory phase induced by luminal amino acids and sugars may be dependent on an action on osmoreceptors, whereas the subsequent inhibitory phase may involve the sympathetic noradrenergic system.

Animals↗

PubMed1987

[Diet type, grinding size and anatomo-functional characteristics of the proximal digestive tract in the rabbit].

Two diets containing either dehydrated lucerne (40%) or dehydrated beet pulp (50%) both being coarsely (4 mm) of finely (1 mm) ground before pelleting, were fed to 120 rabbits after weaning. Feed intake and weight gain were estimated. After 79 days, 11 rabbits in each group were slaughtered between 14.00 and 17.00 h. The parameters measured were stomach and ileal weights, dry matter, fibre and nitrogen contents, volatile fatty acid concentrations. Gastric emptying and intestinal transit time were estimated in each group. Rabbits fed the beet pulp diet had a better feed conversion ratio associated with a higher solid matter gastric retention and also a longer jejuno-ileal transit time. Finely ground diet further increased the transit time, particularly in the ileum, which was also associated with a higher concentration of fermentation by-products.

Animal Feed↗

PubMed1986

Local release of monoamines in the gastrointestinal tract: an in vivo study in rabbits.

Dialysis fibers chronically implanted into the gastric submucosa of rabbits allowed us to collect an interstitial fluid (I.S.F.) dialysate in which biogenic amine concentrations were measured, and compared with those obtained from plasma and tissue samples. The results suggest that I.S.F. concentrations represent a good assessment of the local release of the amines by enteric nerves and/or paracrine cells, under basal conditions. The fact that acetylcholine and neostigmine, when perfused through the dialysis system, increased I.S.F. serotonin (5-HT) concentrations, supports a cholinergic modulation of the release of 5-HT within the gastrointestinal wall, and validates the dialysis method as a powerful tool to monitor, in vivo, dynamic changes in I.S.F. monoamine concentrations.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

Cholinergic modulation of the release of serotonin in the gastric interstitial fluid. An in vivo study in rabbits.

Dialysis fibers chronically implanted into the gastric submucosa of rabbits allowed us to simultaneously (a) collect an interstitial fluid dialysate in which 5-hydroxytryptamine concentrations were measured, and (b) locally perfuse drugs such as acetylcholine, neostigmine, and atropine, which stimulated the release of 5-hydroxytryptamine. The effect of acetylcholine was not blocked by atropine but was blocked by hexamethonium. Furthermore, 5-hydroxytryptamine concentrations in the interstitial fluid were lower when acetylcholine and hexamethonium were injected together than when hexamethonium was injected alone. We conclude that acetylcholine stimulates the release of 5-hydroxytryptamine into the gastric interstitial fluid by acting on nicotinic receptors, and has inhibitory effects by stimulating the muscarinic receptors.

Acetylcholine↗