biphenylylacetic-acid and Inflammation

Fenbufen (Cinopal) is an orally active nonsteroidal anti-inflammatory drug with analgesic and antipyretic activity. Like clinically used nonsteroidal anti-inflammatory drugs, it shows activity in a wide spectrum of laboratory tests in mice, rats, guinea pigs, and dogs. Fenbufen has a long duration of anti-inflammatory and analgesic activity. Mechanistic studies indicate that fenbufen has no intrinsic effect on cyclooxygenase activity, whereas its major metabolite, biphenylacetic acid, is a potent inhibitor of prostaglandin synthesis. These observations indicate that fenbufen is a pro-drug and account for its low ulcerogenic potential. Anti-inflammatory pro-drugs that are readily metabolized to the biologically active molecule are expected to retain a favorable anti-inflammatory to ulcerogenic ratio because the gastrointestinal tract is not exposed to a large concentration of the active molecule. Comparative studies in the type II collagen arthritis model indicate that the anti-inflammatory properties of fenbufen are more potent than those of a second nonsteroidal anti-inflammatory drug, sulindac.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Biotransformation; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Guinea Pigs; Inflammation; Phenylacetates; Phenylbutyrates; Propionates; Rats; Sulindac; Synovitis

Novel mutual prodrugs of biphenylacetic acid were designed as a promising gastro-protective alternative to fenbufen. Biphenyacetic acid was covalently linked with two non-essential amino acids (D-phenylalanine and glycine) possessing wound healing, analgesic, and anti-inflammatory properties. The prodrugs exhibited good stability in stomach homogenates while hydrolytic release of biphenylacetic acid was observed in phosphate buffer, small intestinal homogenates, and 80% human plasma. In vivo behavior of prodrugs on oral administration to Wistar rats demonstrated 33-45% release of biphenylacetic acid in blood over a period of 24 h indicating passage of intact prodrugs to colon, colonic release of parent drug followed by its absorption through colonic mucosa into systemic circulation. Prodrugs were extensively evaluated for analgesic, anti-inflammatory, anti-arthritic, and ulcerogenic activities. Biochemical, haemetological, histopathological, and radiological studies were also performed. Conversion of bioprecusor fenbufen into mutual carrier-linked prodrugs proved to be promising alternative in terms of reduced ulcerogenic propensity, longer duration of analgesia, enhanced/prolonged anti-inflammatory activity, and superior anti-arthritic effect. These prodrugs could be developed further for chronotherapy of rheumatoid arthritis.

Topics: Administration, Oral; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Arthritis, Rheumatoid; Disease Models, Animal; Drug Liberation; Female; Glycine; Humans; Inflammation; Male; Pain; Phenylacetates; Phenylalanine; Phenylbutyrates; Prodrugs; Rats; Rats, Wistar

External medication that is absorbed percutaneously may be used to reduce inflammation and relieve pain from acute injuries such as ankle sprains and bruises. The plaster method of percutaneous absorption for non-steroidal anti-inflammatory drugs (NSAIDs) was established in Japan in 1988. However, due to the possibility of a placebo effect, the efficacy of this method remains unclear. This experimental study was conducted to control for the placebo effect and to study the efficacy of the plaster method in relieving pain by using a rat model of inflammation.. Male Wistar-Imamichi rats were used. A yeast suspension was injected into the right hind paw to induce inflammation. A sheet (2.0 x 1.75 cm) containing the drug was adhered to the inflamed paw. Five treatment groups were used, and each sheet contained a single drug: loxoprofen sodium (loxoprofen-Na) (2.5 mg); felbinac (1.75 mg); indomethacin (1.75 mg); ketoprofen (0.75 mg); or base only (control, 0 mg). Mechanical pain threshold, expression of c-Fos in the dorsal horn, and amount of prostaglandin (PG) E2 in the inflamed paw were evaluated.. Pain threshold increased after treatment, and was significantly increased in the loxoprofen-Na group compared with the control group (p < 0.05). Amounts of PGE2 were significantly decreased in the loxoprofen-Na and indomethacin groups compared with the control group (p < 0.05). Expression of c-Fos was significantly decreased in the loxoprofen-Na group compared with the control group (p < 0.05).. Percutaneously absorbed NSAIDs have an analgesic effect, inhibit expression of c-Fos in the dorsal horn, and reduce PGE2 in inflamed tissue, indicating the efficacy of this method of administration for acute inflammation and localized pain.

Topics: Acute Disease; Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Contusions; Dinoprostone; Indomethacin; Inflammation; Ketoprofen; Male; Pain; Pain Threshold; Phenylacetates; Phenylpropionates; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Sprains and Strains

Using lipid microspheres (LM), average diameter 0.2 micron, and containing methyl and ethyl esters of biphenylylacetic acid (BPAA) in the carrageenan paw oedema tests in rats, it was found that their anti-inflammatory activities were enhanced 3 to 8 times over that of free BPAA. By electron microscopy, LM were seen to be taken up into the endothelial cells of the blood vessels and macrophages at the inflamed sites. In a study using dogs, after an intravenous injection of BPAA-methyl ester incorporated into LM (lipo-BPAA-Me), lipo-BPAA-Me rapidly disappeared from the blood and the BPAA serum level was gradually elevated. These results, together with previous findings, suggest that part of lipo-BPAA-Me was immediately transferred to the inflamed site and taken up by prostaglandin (PG)-producing cells as macrophages. It is considered that the anti-inflammatory effects of BPAA are enhanced by incorporating it into LM.

Topics: Animals; Anti-Inflammatory Agents; Dogs; Drug Compounding; Inflammation; Injections, Intraperitoneal; Injections, Intravenous; Kinetics; Lipid Metabolism; Macrophages; Male; Mice; Mice, Inbred ICR; Microspheres; Phenylacetates; Rats; Rats, Inbred Strains; Solubility