benzofurans and Granuloma

This study examines the alteration in Staphylococcus aureus gene expression following treatment with the type 2 fatty acid synthesis inhibitor AFN-1252. An Affymetrix array study showed that AFN-1252 rapidly increased the expression of fatty acid synthetic genes and repressed the expression of virulence genes controlled by the SaeRS 2-component regulator in exponentially growing cells. AFN-1252 did not alter virulence mRNA levels in a saeR deletion strain or in strain Newman expressing a constitutively active SaeS kinase. AFN-1252 caused a more pronounced increase in fabH mRNA levels in cells entering stationary phase, whereas the depression of virulence factor transcription was attenuated. The effect of AFN-1252 on gene expression in vivo was determined using a mouse subcutaneous granuloma infection model. AFN-1252 was therapeutically effective, and the exposure (area under the concentration-time curve from 0 to 48 h [AUC(0-48)]) of AFN-1252 in the pouch fluid was comparable to the plasma levels in orally dosed animals. The inhibition of fatty acid biosynthesis by AFN-1252 in the infected pouches was signified by the substantial and sustained increase in fabH mRNA levels in pouch-associated bacteria, whereas depression of virulence factor mRNA levels in the AFN-1252-treated pouch bacteria was not as evident as it was in exponentially growing cells in vitro. The trends in fabH and virulence factor gene expression in the animal were similar to those in slower-growing bacteria in vitro. These data indicate that the effects of AFN-1252 on virulence factor gene expression depend on the physiological state of the bacteria.

Topics: Acetyltransferases; Animals; Anti-Bacterial Agents; Bacterial Proteins; Benzofurans; Enoyl-(Acyl-Carrier Protein) Reductase (NADPH, B-Specific); Enzyme Inhibitors; Fatty Acids; Gene Expression Profiling; Gene Expression Regulation, Bacterial; Granuloma; Lipid Metabolism; Mice; Protein Kinases; Pyrones; Staphylococcal Infections; Staphylococcus aureus; Virulence Factors

Interstitial granulomatous dermatitis is most commonly associated with rheumatoid arthritis (RA) but may be induced by medications as well. Darifenacin is a muscarinic antagonist which was FDA approved for the treatment of overactive bladder in December 2004. The authors describe a case of interstitial granulomatous dermatitis associated with darifenacin.

Topics: Benzofurans; Drug Eruptions; Female; Granuloma; Humans; Middle Aged; Muscarinic Antagonists; Pyrrolidines; Urinary Bladder, Overactive

2-Methyl-5-(3-phenylpropionyl)-1-benzoxolane (CAS 159264-96-7) was synthesized and studied for anti-inflammatory properties. This new aryl ketone was more active than the previously reported 5-acyl substituted 1-benzoxolanes except 5-cinnamoyl-2-methyl-1-benzoxolane (the unsaturated analogue) which exhibited similar anti-inflammatory activity and similar toxicity but was more gastrotoxic. Anti-inflammatory and analgesic effects of 2-methyl-5-(3-phenylpropionyl)-1-benzoxolane were less pronounced than those of indometacin but greater than those of acetylsalicylic acid (ASA). The new ketone was less toxic and less gastrotoxic than both the reference drugs mentioned above. Therapeutic indices of the new compound were significantly greater than those of ASA and indometacin.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bentonite; Benzofurans; Carrageenan; Edema; Gossypium; Granuloma; Lethal Dose 50; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred BALB C; Pain Measurement; Rats; Rats, Wistar; Spectrophotometry, Ultraviolet; Stomach Ulcer

A series of new 7-acyl substituted 1-benzoxepanes and 5-acyl substituted 2-methyl-1-benzoxolanes were synthesized and studied for anti-inflammatory properties. The benzoyl derivatives were more active than the corresponding halogenobenzoyl derivatives and previously reported structural analogues containing less methylene groups in their heterocyclic ring. The introduction of a methyl group at the 2-position of 5-cinnamoyl-1-benzoxolane heterocyclic ring significantly potentiated the activity. Anti-inflammatory and analgesic effects of 7-benzoyl-1-benzoxepane and 5-cinnamoyl-2-methyl-I-benzoxolane were less pronounced than those of indomethacin and diclofenac but greater than those of acetylsalicylic acid (ASA). Both compounds were less toxic and 5-cinnamoyl-2-methyl-1-benzoxolane was also less gastrotoxic than all the reference drugs mentioned above. Therapeutic indices of 5-cinnamoyl-2-methyl-1-benzoxolane were greater than those of diclofenac and significantly greater than those of ASA and indomethacin.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Bentonite; Benzofurans; Benzoxepins; Carrageenan; Chemical Phenomena; Chemistry, Physical; Edema; Gastric Mucosa; Granuloma; Lethal Dose 50; Male; Mice; Mice, Inbred BALB C; Necrosis; Peritonitis; Rats; Rats, Wistar

The antiinflammatory activity of R-803 (alpha-methyl-3-phenyl-7-benzofuranacetic acid), a new nonsteroidal drug, has been demonstrated. The oral administration of R-803 inhibits carrageenan-induced edema of the rat's paw, ultraviolet-induced erythema of guinea-pig skin, adjuvant-induced and 6-sulfonamidoindazole-induced arthritides of the rat at doses in the range of 1.0 to 6.0 mg/kg. It also inhibits the cotton pellet-induced granuloma in the rat at higher doses.

Topics: Animals; Anti-Inflammatory Agents; Arthritis; Benzofurans; Edema; Erythema; Female; Granuloma; Guinea Pigs; Male; Radiation Injuries, Experimental; Rats; Ultraviolet Rays