Drugs online research references
Eur J Clin Pharmacol. 1996;49(4):305-8.
Role of human liver microsomal CYP2C9 in the biotransformation of lornoxicam.
Bonnabry P, Leemann T, Dayer P.
Division of Clinical Pharmacology and Pain Clinic, University Hospital, Geneva, Switzerland.
OBJECTIVE: The nature of the enzyme(s) catalysing the biotransformation of lornoxicam to one of its major metabolites, 5'-hydroxy-lornoxicam, has been investigated in human liver microsomes. The reaction kinetics were characterised, the affinity of lornoxicam for three major human drug metabolising cytochrome P-450 isozymes (CYP2C9, CYP2D6 and CYP3A4) was determined, and inhibition of the reaction by known substrates (diclofenac, ibuprofen, mefenamic acid, phenytoin, tolbutamide and warfarin) and the prototype inhibitor (sulphaphenazole) of CYP2C9 was investigated. RESULTS: Lornoxicam 5'-hydroxylation displayed single enzyme Michaelis-Menten kinetics, with a KM of 3.6 mu mol center dot l-1 and a Vmax of 2.6 nmol center dot h-1 center dot mg-1 microsomal protein. The apparent affinity of lornoxicam was high for CYP2C9, but negligible for CYP3A4 and CYP2D6. Inhibition of lornoxicam 5'-hydroxylation by CYP2C9 substrates and sulphaphenazole competitively and completely inhibited lornoxicam 5'-hydroxylation (Ki = 0.31 mu mol center dot l-1 as well as lornoxicam clearance (Ki = 0.33 mu mol center dot l-1), partial metabolic clearance (fm) = 0.95). CONCLUSION: 5'-Hydroxylation appears to be the only cytochrome P-450 catalysed metabolic reaction of lornoxicam by human liver microsomes and this major in vivo biotransformation pathway is catalysed virtually exclusively by CYP2C9.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8857077&dopt=Abstract
Acta Pol Pharm. 2000 Nov-Dec;57(6):431-40.
Evaluation of properties microcrystalline chitosan as a drug carrier. Part 1. In vitro release of diclofenac from mictocrystalline chitosan hydrogel.
Bodek KH.
Department of Physical Chemistry Institute of Chemistry, Medical University of Lodz, Poland.
The influence of microcrystalline chitosan hydrogel, alone (MCCh) as well as in combination with methylcellulose (MC) or Carbopol (CP), on the release of diclofenac free acid (DA) and its salt (DS) was studied in vitro. Commercial Olfen gel (Mepha Ltd., Switzerland) was applied as a reference preparation. The influence of hydrophilizing agents (1,2-propylene glycol and glycerol) and methycellulose hydrogel on the rheological properties of the vehicle and on the release of drug from modified MCCh hydrogel was studied. The quantity of the released substance was determined by UV-spectroscopy. The results confirmed that release was dependent on the chemical character of the drug and on the type of vehicle. The process of diclofenac release from MCCh hydrogels as well as from Carbopol hydrogels runs in two phases. The first phase is characterised by rapid release whereas in the second phase the release is much slower. The most suitable basis for diclofenac is microcrystalline chitosan hydrogel with addition glycerol, 1,2-propylene glycol, and methylcellulose hydrogel.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11243249&dopt=Abstract
Dig Dis Sci. 1995 Jul;40(7):1435-44.
Chronic effects of misoprostol in combination with the NSAID, diclofenac, on gastrointestinal tract of pigs. Relation to diarrheagenic activity, leukocyte infiltration, and mucosal leukotrienes.
Rainsford KD, Perkins WE, Stetsko PI.
Department of Biomedical Sciences, McMaster University Faculty of Health Sciences Hamilton, Ontario, Canada.
To determine the mode of protective effects of misoprostol against the chronic gastrointestinal ulceration from the NSAID, diclofenac, studies were undertaken in domestic pigs, a model of human gastrointestinal ulceration, to determine (1) the effects of repeated daily dosing for 10 days of diclofenac 5 mg/kg/day twice a day (as Voltaren tablets) on the gastrointestinal morphology, 59fe-red blood loss, mucosal myeloperoxidase (MPO) activity (as an indicator of leukocyte infiltration), and mucosal leukotrienes (LTS); and (2) the mucosal protective effects of 10-40 micrograms/kg/day misoprostol twice a day (as Cytotec tablets) given with diclofenac 5 mg/kg/day twice a day compared with diclofenac 5 mg/kg/day alone and aspirin 150 mg/kg/twice a day (USP tablets) as a standard. These effects were compared with the dose range for potential diarrheagenic effects of misoprostol (determined by fecal analysis of NA+, K+, CL-, CA2+, H2O, and phenol red transit) given alone or with diclofenac to determine if this could be discriminated from antiulcer effects of misoprostol. Plasma and gastric mucosal concentrations of the drugs were determined to establish if misoprostol affects diclofenac absorption/elimination, and vice versa. The results showed that: (1) diclofenac produced gastric mucosal damage without any prior or concurrent bleeding from the gastrointestinal tract, although aspirin significantly increased blood loss; (2) misoprostol produced a dose-related reduction in diclofenac-induced mucosal damage of the upper gastrointestinal tract; (3) no significant increase in mucosal MPO occurred with diclofenac despite mucosal damage being evident, (4) mucosal LTS were unaffected by the drug treatments; (5) plasma, gastric and intestinal concentrations of diclofenac were not affected by misoprostol, while conversely plasma misoprostol concentrations were not influenced by the diclofenac treatment; (6) no significant effects on fecal water, electrolyte, or phenol red transit times were observed with an of the drug-treatments; and (7) mild diarrhea observed as "loose bowel motions" was only observed in most pigs receiving the misoprostol treatments during fasting on days 9-10. Thus, misoprostol protects against chronic lesions/ulcers in the upper gastrointestinal tract from diclofenac without: (1) signs of diarrhea becoming evident (the latter occurring when there is reduced food intake), (2) generalized leukocyte infiltration or effects on mucosal LTs, or (3) any reduction in bioavailability of diclofenac.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7628265&dopt=Abstract
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