biphenylylacetic-acid and Pain

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

We have evaluated the percutaneous penetration of felbinac following application of topical patches using a microdialysis technique, and have examined correlations with pharmacological effects. A linear microdialysis probe with a 20-mm dialysis fibre was inserted into the skin of anaesthetized rats. Probe perfusion was started at 2.0 microL min(-1) with physiological saline and after a 60-min baseline sampling of dialysate, 0.1 mL croton oil was applied to the skin surface at a concentration of 8%, v/v. A felbinac patch was then applied to the same point 60 min thereafter and dialysate was sampled at 60-min intervals up to 300 min after patch application, for determination of concentrations of felbinac and prostaglandin (PG) E2. Analgesic effects of felbinac patches in an iodoacetateinduced osteoarthritis model and an incisional pain model were evaluated using the weight bearing method. After application of patches, felbinac penetration into the skin was rapid, maximum concentrations in the dialysates with 0.07, 0.5 and 3.5% w/w felbinac patches being 0.046+/-0.02, 0.104+/-0.06 and 0.244+/-0.2 microg mL(-1), respectively. Dermal administration of croton oil caused an increment in PGE2 levels, which was significantly decreased by 0.5 and 3.5% felbinac patches 2-5 h after application. In pharmacological studies, 3.5% felbinac patches suppressed pain-associated behaviour induced by iodoacetate injection and plantar incision. These results suggested that the transdermal patch containing 3.5% felbinac may become a useful formulation.

Topics: Administration, Cutaneous; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dinoprostone; Dose-Response Relationship, Drug; Drug Delivery Systems; Knee Joint; Male; Microdialysis; Models, Animal; Pain; Phenylacetates; Rats; Rats, Wistar; Skin; Skin Absorption; Wounds, Penetrating

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