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lsuhsc.edu

The cytotoxicity of bacterial cell wall components, muramyl dipeptide (synthetic N-acetylmuramyl-L-alanyl-D-isoglutamine; L,D-MDP) and lipopolysaccharide (LPS), was investigated in several kidney cell lines. MDP and LPS were toxic to rabbit and monkey kidney cells, MDP was toxic to canine kidney cells, but not to human or porcine kidney cells. Notably, L,D-MDP was >100-fold more cytotoxic/microg than the D,D-MDP and L,L-MDP, as well as LPS. L,D-MDP and analogs containing L,D-MDP were the most widely cytotoxic of the MDP tested. The MDP-induced cytotoxicity was characterized as apoptosis by DAPI staining and DNA laddering. The acute rabbit kidney (RK13) cell apoptosis (cell death in < 5 h) induced by apical or basal application of MDP was associated with glutamate (Glu) release, decreased gamma-glutamyltranspeptidase (GGT) and acidosis and was suppressed by Indomethacin, Naproxen and Curcumin. The cytotoxic activity of L,D-MDP was decreased significantly by 24 h incubation in human sera. Aged (> 2 year-old) rabbits that apparently failed to quickly clear and excrete a uveitogenic dose of MDP within 24 h died in I week. The results indicate that minute amounts (5 ng/ml) of MDP containing L-alanyl-D-isoglutamine can induce renal cell apoptosis in vitro and support MDP-induced kidney cytotoxicity in rabbits. Also, the results indicate that MDP in sera can be detected utilizing the RK13 cell bioassay and that failure to rapidly clear and excrete L,D-MDP is associated with uveitis and death in aged rabbits.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12190122&dopt=Abstract

cc.kmu.edu.tw

A water-soluble polymeric prodrug containing a naproxen moiety was synthesized. The carboxylic groups of naproxen were condensed with the hydroxyl groups of 2-hydroxyethyl methacrylate (HEMA) to produce a drug-linked monomer, denoted HN. The polymeric prodrug was prepared by copolymerization of HN with methacrylic acid. The molar percentage of HN in the polymeric prodrug was 26 mol%, as determined by 1H NMR. To investigate the pertinence of this polymeric prodrug, the hydrolysis was studied in-vitro with or without esterase or lipase. The kinetics of enzymatic catalysis was calculated from a Lineweaver-Burk plot. The anti-inflammatory activity was evaluated using the carrageenan-induced oedema test. The polymeric prodrug released a major fraction of the free naproxen and a significant fraction of the hydroxyethyl ester derived-naproxen. The maximum hydrolysis rate Vmax, and the Michaelis constant Km were calculated to be 2.16 x 10(-5) equiv. mol L-1 min-1 and 5.11 x 10(-2) equiv. mol L-1. The maximum anti-inflammatory inhibition of free naproxen appeared at 2 h and quickly decreased thereafter. In contrast, the polymeric prodrug showed a maximum at around 2-3 h and then slowly decreased. This indicates that the polymeric prodrug displays greater potency than free naproxen in the inhibition of acute inflammatory processes over long periods.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12195829&dopt=Abstract

Res Commun Chem Pathol Pharmacol. 1982 Feb;35(2):189-207.
The effects of anti-inflammatory and other agents on the rat dermal arthus reaction.

Carter GW, Martin MK, Krause RA, Young PR.

The inhibitory effects of selected drugs on the Arthus reaction, a model of immune-complex-induced tissue injury, were studied. The reverse passive Arthus reaction (RPAR) was elicited in the dorsal skin of rats, using bovine serum albumin and the gamma-globulin fraction of rabbit anti-BSA. The optimal amounts of antigen and antibody required to elicit the reaction, as well as the reaction kinetics, were examined. Chlorpheniramine, cyproheptadine, d-penicillamine, chloroquine, indomethacin, phenylbutazone, naproxen, and mefenamic acid were found to be inactive despite high doses; aspirin and ibuprofen were only weakly active. Hydrocortisone and colchicine were strong inhibitors of the RPAR: the calculated ED50 values were 13 mg/kg p.o. and 0.3 mg/kg i.v., respectively. The RPAR exhibits a different sensitivity to drug inhibition than conventional models of inflammation (e.g., carrageenin paw edema) end may be useful to detect new types of anti-inflammatory agents.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6122238&dopt=Abstract

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