biphenylylacetic-acid and fenbufen

Musculoskeletal disorders such as soft tissue injuries have traditionally been treated with oral NSAIDs, despite the significant side-effects associated with their clinical use. However, four separate multicentre, double-blind, double-dummy clinical trials have shown that the efficacy of the topical NSAID, felbinac, is equivalent to that of the oral NSAID, ibuprofen, in the treatment of soft tissue injuries, and to that of oral ibuprofen or fenbufen in mild to moderate osteoarthritis. In general practice the incidence of side-effects with felbinac is low, while oral NSAIDs have been associated with significant problems, particularly in the gastrointestinal system. Consequently, the cost of treating side-effects is reduced with felbinac treatment compared with oral NSAIDs, making it a logical treatment alternative from an economic view point as well as for reasons of efficacy and safety.

Topics: Administration, Oral; Administration, Topical; Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials as Topic; Cost-Benefit Analysis; Double-Blind Method; Humans; Knee Joint; Neck Injuries; Osteoarthritis; Phenylacetates; Phenylbutyrates; Sprains and Strains; Treatment Outcome

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

gamma-Oxo(1,1'-biphenyl)-4-butanoic acid (fenbufen) and biphenylacetic acid have effects on platelets similar to other non-steroidal antiinflammatory agents. In vitro biphenylacetic acid (BPAA), a metabolite of fenbufen, is more potent than fenbufen and in vivo metabolism of fenbufen to BPAA is probably required for activity. The arachidonate-thromboxane system appears to play a critical role in explaining a major part of the mechanism of action of these agents on platelets and other systems. Fenbufen, however, also inhibits collagen-induced platelet aggregation without requiring metabolic conversion to BPAA. The mechanism for this inhibition appears to be independent of the arachidonate-thromboxane system, as well as unrelated to serotonin release or inhibition of phosphodiesterase activity. The effects of fenbufen and BPAA on platelet biochemistry and function suggest their utility as clinical anti-thrombotic agents. This is further supported by the absence of any thrombocytopenia or bleeding tendency in animals and man.

Topics: Animals; Anti-Inflammatory Agents; Arachidonic Acids; Biphenyl Compounds; Blood Platelets; Fibrinolytic Agents; Humans; In Vitro Techniques; Phenylacetates; Phenylbutyrates; Phosphoric Diester Hydrolases; Platelet Aggregation; Propionates; Prostaglandins; Rats; Serotonin

A procedure based on solid-phase extraction (SPE) followed by high performance liquid chromatography (HPLC) with PDA detection has been developed for the analysis of multiple drugs in rat plasma. The analytes evaluated were ulifloxacin, fenbufen and felbinac. Eight different solid phase extraction cartridges were tested to evaluate their applicability for the isolation of drugs from rat plasma. Comparison were recovery of different drugs and reproducibility. The samples were analyzed by HPLC using a Kinetex C18 EVO column and acetonitrile-10mM ammonium acetate-methanol as the mobile phase under gradient elution conditions. SPE combined with HPLC-PDA allowed the determination of drugs over a linear range of 0.05-15 μg/mL for ulifloxacin while 0.5-50 μg/mL for felbinac and fenbufen, with limit of detection at 0.05 for ulifloxacin and 0.5 for felbinac and fenbufen. Bond Elut Plexa sorbent was found to provide the most effective clean-up, removing the greatest amount of interfering substance and simultaneously ensuring analyte recoveries higher than 93.54% with relative standard deviation (RSD) <10%. The method was applied with good accuracy and precision in the determination of ulifloxacin, fenbufen and felbinac in rat plasma obtained from rats treated with selected drugs. This method permits its application to pharmacokinetic and pharmacodynamic studies of these analytes and will facilitate detailed investigations on the interactions between new fluoroquinolones and fenbufen.

Topics: Animals; Chromatography, High Pressure Liquid; Fluoroquinolones; Limit of Detection; Phenylacetates; Phenylbutyrates; Piperazines; Plasma; Rats; Reproducibility of Results; Solid Phase Extraction

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

A simple, specific and sensitive high-performance liquid chromatographic method has been developed for the simultaneous determination of rufloxacin, fenbufen and felbinac in human plasma. Plasma, spiked with internal standard, was vortex-mixed for 1 min with a mixture of dichloromethane-diethyl ether (80:20, v/v). The evaporated extract was dissolved in 0.02 M NaOH. Drugs were resolved at room temperature on a 5 microns Zorbax SAX column (250 x 4.6 mm I.D.) equipped with a 20 x 4.6 mm anion-exchange Vydac AXGU (10 microns particle size) precolumn. The mobile phase consisted of acetonitrile and phosphate buffer (pH 7.0), delivered at a flow-rate of 1.2 ml/min. Detection was made at 280 nm. 2-[4-(2'-Furoyl)phenyl]propionic acid was used as internal standard. The calibration curve was linear from 0.2 to 10 micrograms/ml for rufloxacin, from 0.5 to 30 micrograms/ml for fenbufen and from 0.2 to 10 micrograms/ml for felbinac, respectively. The detection limit was 0.1 microgram/ml for rufloxacin, 0.3 microgram/ml for fenbufen and 0.1 microgram/ml for felbinac, respectively.

Topics: Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Chromatography, High Pressure Liquid; Fluoroquinolones; Humans; Phenylacetates; Phenylbutyrates; Quinolones; Reproducibility of Results; Sensitivity and Specificity; Spectrophotometry, Ultraviolet

Fenbufen-induced skin rash was investigated by determining the metabolism of the drug to reactive products. At least five lipophilic products (unidentified), the active metabolite of this drug, biphenyl acetic acid (BPAA), and a gamma-hydroxylated derivative (gamma-hydroxy[1,1'-biphenyl]-4-butanoic acid) were identified in keratinocytes in vitro and in skin of rats and guinea pigs in vivo. The gamma-OH derivatives of BPAA and fenbufen were recovered from papain digests of the prior ether-extracted keratinocyte proteins. Fenbufen and its gamma-OH metabolite stimulated the production of interleukin-1 from keratinocytes exposed to UV radiation but BPAA did not. Inflammatory reactions from fenbufen may therefore, arise from production of its metabolites which yield IL-1 upon exposure to UV radiation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Chromatography, Thin Layer; Erythema; Exanthema; Guinea Pigs; Interleukin-1; Keratinocytes; Phenylacetates; Phenylbutyrates; Rats; Skin; Ultraviolet Rays

Recent animal studies have demonstrated a proconvulsant effect of certain quinolone and non-steroidal anti-inflammatory drug combinations. Radioligand binding experiments have indicated that these actions may be mediated by antagonism of the GABAA receptor. The present study has further investigated this hypothesis in a functional assay by examining the effects of the quinolones ciprofloxacin and ofloxacin alone and in combination with either fenbufen or biphenyl acetic acid (BPAA) upon GABA-evoked currents recorded from voltage-clamped rat dorsal root ganglion neurones (DRG) maintained in cell culture. GABA-evoked whole cell currents were weakly but dose-dependently (30 microM-1 mM) reduced in the presence of ciprofloxacin and ofloxacin. The IC50 for ciprofloxacin was 100 microM but greater than 1 mM for ofloxacin. Application of either fenbufen (100 microM) or BPAA (100 microM) alone produced little effect on the GABA-evoked currents. However, the inhibitory action of ciprofloxacin was enhanced in the presence of 100 microM fenbufen by approximately five-fold whereas the antagonism of GABA responses by ofloxacin was unaffected. In contrast, BPAA (100 microM) had a dramatic effect on the inhibitory actions of both antibiotics such that the IC50 for ciprofloxacin and ofloxacin was reduced to 0.03 and 0.3 microM respectively. The present results support earlier binding studies and extend them by demonstrating electrophysiologically a potent quinolone/NSAID drug interaction at the GABAA receptor. The mechanism(s) of this novel interaction remains to be determined. These results are commensurate with clinical observations of an increased risk of fits in patients prescribed certain quinolones together with certain NSAIDs.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Ciprofloxacin; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; GABA-A Receptor Antagonists; Ganglia, Spinal; Ofloxacin; Phenylacetates; Phenylbutyrates; Rats

The effects of enoxacin, a new quinolone antibacterial agent, and its combination with 4-biphenylacetate (BPA), an active metabolite of the non-steroidal antiinflammatory agent fenbufen, were examined on population spikes induced by electrical stimulation of the stratum radiatum in the CA1 pyramidal cell layer in rat hippocampal slices. Enoxacin (10(-4) M) and bicuculline (10(-6) M) increased the amplitude of the population spikes and anew elicited the second spikes (latency: 10 msec.), while BPA (10(-5) M) decreased the amplitude of the population spikes. However, the combination of enoxacin (10(-6), 10(-5) M) with BPA (10(-5) M) elicited the second spikes or epileptiform bursts with an increase of the population spike amplitude. The dose-response relationships showed that the effect of enoxacin was 100 times potentiated in the presence of BPA (10(-5) M). The second spikes induced by enoxacin (10(-4) M) were suppressed by muscimol (10(-6) M) and baclofen (10(-6) M), but not by clorazepate (5 x 10(-5) M) and pentobarbital (5 x 10(-5) M). The second spikes induced by bicuculline (10(-6) M) were suppressed by these four drugs. The second spikes by the combination of enoxacin (10(-6) M) with BPA (10(-5) M) were suppressed by muscimol (5 x 10(-6) M), but not by clorazepate (5 x 10(-5) M). These results suggest that the combination of enoxacin with BPA exerts a drug interaction to elicit the second spikes or epileptiform bursts with its mode of action different from that of bicuculline.

Topics: Action Potentials; Animals; Anti-Inflammatory Agents, Non-Steroidal; Baclofen; Bicuculline; Clorazepate Dipotassium; Drug Interactions; Electric Stimulation; Enoxacin; Hippocampus; In Vitro Techniques; Male; Muscimol; Pentobarbital; Phenylacetates; Phenylbutyrates; Rats; Rats, Inbred Strains

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chromatography, High Pressure Liquid; Ciprofloxacin; Hydrogen-Ion Concentration; Male; Phenylacetates; Phenylbutyrates; Rats; Rats, Inbred Strains; Regression Analysis

In order to clarify the possibility of pharmacokinetic interaction between quinolone and fenbufen, the plasma concentration-time profiles and serum protein binding of enoxacin, fenbufen and its active metabolite, felbinac, were investigated in rats. The rats were administered an intravenous dose of enoxacin (5 mg/kg) and fenbufen (10 mg/kg) alone or concomitantly. Coadministration with fenbufen tended to prolong the plasma elimination half-life of enoxacin by about 20%, whereas it showed no effect on the area under plasma concentration-time curve, total body clearance or distribution volume of enoxacin. The extent of enoxacin binding to rat serum tended to be slightly reduced by fenbufen in vivo and in vitro. Plasma concentration-time curves, pharmacokinetic parameters and serum protein binding of fenbufen and felbinac were not affected at all by the coadministration with enoxacin. These aspects suggest that there may be only a minor possibility of the pharmacokinetic interaction between enoxacin and fenbufen.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Proteins; Enoxacin; Male; Phenylacetates; Phenylbutyrates; Protein Binding; Rats; Rats, Inbred Strains; Time Factors

The possible pharmacokinetic interaction between a new quinolone and fenbufen was investigated by comparing the plasma concentration-time profiles and serum protein binding of ofloxacin, fenbufen and its active metabolite, felbinac, in rats. The rats were administered intravenous doses of ofloxacin (5 mg kg-1), fenbufen (10 mg kg-1) alone or concomitantly. The plasma elimination half-lives were about 55 min in both groups. A slight elevation of plasma concentration of ofloxacin and a small decrease of its total body clearance were observed after its coadministration with fenbufen. The extent of ofloxacin binding to rat serum tended to be slightly reduced by fenbufen which coexisted at relatively high concentrations. Plasma concentration-time curves, pharmacokinetic parameters and serum protein binding of fenbufen and felbinac were not affected by the coadministration with ofloxacin. These results suggest that any substantive pharmacokinetic interaction may be unlikely after the concomitant administration of ofloxacin and fenbufen.

Topics: Animals; Blood Proteins; Male; Ofloxacin; Phenylacetates; Phenylbutyrates; Protein Binding; Rats; Rats, Inbred Strains

A high-performance liquid chromatographic method for the simultaneous determination of norfloxacin, fenbufen and felbinac extracted from 50 microliters of rat plasma is described. Chromatography was performed on a reversed-phase column with ultraviolet detection. By the present method, quantitative and reproducible determinations were possible for norfloxacin, fenbufen and felbinac over the concentration ranges of 0.2-20, 0.2-120 and 0.4-40 micrograms/ml, respectively. The recoveries of norfloxacin, fenbufen and felbinac added to plasma were nearly 100% with a coefficient of variation of less than 8.0%. This method was found to be applicable to pharmacokinetic studies of each drug after the concomitant administration of norfloxacin and fenbufen.

Topics: Animals; Male; Norfloxacin; Phenylacetates; Phenylbutyrates; Rats; Rats, Inbred Strains

Ofloxacin, fenbufen and its active metabolite, felbinac, were simultaneously extracted from 50 microliters of rat plasma and analysed by high-performance liquid chromatography on a reversed-phase column. Quantitative and reproducible determinations were possible for ofloxacin, fenbufen and felbinac over the concentration ranges 0.15-40, 0.3-80 and 0.45-45 micrograms/ml, respectively. The detection limits for all the drugs were lower than those reported previously. The recovery of ofloxacin, fenbufen and felbinac added to plasma was nearly 100% with a coefficient of variation of less than 3.0%. This method was found to be applicable to pharmacokinetic studies of each drug after the concomitant administration of ofloxacin and fenbufen.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chromatography, High Pressure Liquid; Male; Ofloxacin; Phenylacetates; Phenylbutyrates; Rats; Rats, Inbred Strains

Topics: Animals; Anti-Inflammatory Agents; Drug Interactions; Male; Phenylacetates; Phenylbutyrates; Propionates; Rats; Rats, Inbred Strains; Sulfamethizole; Sulfathiazoles

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Arthritis; Erythema; Guinea Pigs; Phenylacetates; Phenylbutyrates; Propionates; Rats; Sulindac; Ultraviolet Rays

Topics: Animals; Anti-Inflammatory Agents; Digestive System; Gastric Mucosa; Guinea Pigs; Humans; Indomethacin; Phenylacetates; Phenylbutyrates; Platelet Aggregation; Propionates; Prostaglandins

Topics: Animals; Arachidonic Acids; Biphenyl Compounds; Blood Coagulation; Blood Platelets; Humans; Male; Mice; Phenylacetates; Phenylbutyrates; Platelet Aggregation; Propionates; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Respiratory Insufficiency