benzofurans and talniflumate

Talniflumate, an anti-inflammatory molecule that was originally developed by Laboratorios Bago, is currently being developed by Genaera as a mucoregulator for the treatment of cystic fibrosis, chronic obstructive pulmonary disease and asthma. Phase I trials with talniflumate had been completed by August 2001, and phase II trials were underway in Ireland for the treatment of cystic fibrosis.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Benzofurans; Chloride Channels; Clinical Trials as Topic; Cystic Fibrosis; Expectorants; Humans; Pulmonary Disease, Chronic Obstructive; Pyridines; Sinusitis; Structure-Activity Relationship

Talniflumate, a prodrug of niflumic acid, is a potent analgesic and anti-inflammatory drug that has been widely used for the treatment of rheumatoid diseases.. The aim of this study was to compare the pharmacokinetics and to evaluate the bioequivalence of two formulations of talniflumate 370 mg tablets (test formulation: Flumagen. A randomized, open-label, single dose, two-sequence, two-period crossover clinical study was conducted. After oral administration of the study drug in each period, blood samples were collected up to 15 hours post-dose. The plasma concentration of niflumic acid, a metabolite of talniflumate, was determined using HPLC-MS/MS. The pharmacokinetic parameters were estimated by non-compartmental method.. The maximum plasma concentration (Cmax) and area under the concentration-time curve from zero to the time point with the last measurable concentration (AUClast) for the test formulation were 290.7 ± 199 µg/L and 1,154 ± 643 µg×h/L, respectively, and the corresponding values for the reference formulation were 286.8 ± 193 µg/L and 1,151 ± 577 µg×h/L, respectively. The geometric mean ratio and 90% confidence intervals (CI) of the test formulation to the reference formulation for the Cmax and -AUClast were 0.983 (0.829 - 1.166) and 0.979 (0.856 - 1.121), respectively.. The pharmacokinetic profiles of the test and reference formulations were found not to be significantly different, meeting the Korean regulatory criteria for bioequivalence.
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Topics: Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Benzofurans; Cross-Over Studies; Drug Compounding; Healthy Volunteers; Humans; Male; Middle Aged; Prodrugs; Pyridines; Tablets; Therapeutic Equivalency; Young Adult

Systemic exposure to niflumic acid was significantly increased when talniflumate was given orally together with a meal. To clarify the underlying mechanism, an in vitro dissolution study of talniflumateonducted at different pH values, and magnesium hydroxide was co-administered in healthy volunteers.. In vitro dissolution tests of talniflumate tablets were performed in a USP Paddle apparatus at pH 1.2, 4.0, and 6.8, respectively, in the presence and absence of Tween 80 (2%). Serial samples of the talniflumate solution were taken and analyzed on a high-performance liquid chromatography (HPLC)/ultraviolet system. Healthy volunteers were divided randomly into two groups, and each volunteer received a single 740-mg dose of talniflumate, with or without 1 g of magnesium hydroxide, following an overnight fast. The plasma concentrations of niflumic acid were measured using HPLC coupled with tandem mass spectrometry.. Talniflumate was completely insoluble at each of the tested pHs in the absence of Tween 80. The drug was slowly and steadily dissolved (54%) at pH 4 in the presence of the surfactant, but the extent of dissolution was only 15 and 0.5% at pH 1.2 and 6.0, respectively. Magnesium hydroxide co-administered with talniflumate significantly increased systemic exposure to niflumic acid: the mean maximum plasma concentration (C (max)) and area under the concentration-time curve (AUC (inf)) were augmented by 2.0- and 1.9-fold, respectively, compared with those in the absence of the antacid. Magnesium hydroxide significantly accelerated the appearance of niflumic acid in plasma by 2.8-fold.. Magnesium hydroxide increases the rate and extent of systemic exposure to niflumic acid owing to the enhanced solubility of talniflumate and absorption of niflumic acid. The possible combination of talniflumate and an antacid should be considered in the development of pharmaceutical formulations.

Topics: Administration, Oral; Adult; Antacids; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Benzofurans; Drug Interactions; Drug Therapy, Combination; Humans; Hydrogen-Ion Concentration; Magnesium Hydroxide; Male; Niflumic Acid; Pyridines; Solubility

Talniflumate was designed as a prodrug of niflumic acid, a potent analgesic and anti-inflammatory drug, which is widely prescribed for treating rheumatoid diseases. The prandial effect on talniflumate absorption remains unclear; therefore, this study investigated the effect of food on the systemic exposure to niflumic acid in healthy volunteers.. Volunteers received a single 740-mg dose of talniflumate 30 min after consuming a high-fat breakfast, a low-fat breakfast, or no food (fasting condition). Plasma concentrations of both talniflumate and niflumic acid were measured using validated high-performance liquid chromatography coupled to tandem mass spectrometry.. The maximum concentration of niflumic acid was 224 +/- 193 ng/ml at approximately 2.7 h in the fasted condition compared with 886 +/- 417 ng/ml (p < 0.05) at 1.8 h and 1,159 +/- 508 ng/ml (p < 0.01) at 2.2 h with the low- and high-fat meals, respectively. The mean area under the curve from zero to infinity (AUC(inf)) values after the low- and high-fat meals were four- and fivefold, respectively, the value while fasting (p < 0.05).. It is strongly recommended that talniflumate be taken after a meal to increase systemic exposure to its active metabolite. Our results suggest a reduction in the daily dosage of talniflumate when taken with food.

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Benzofurans; Biological Availability; Cross-Over Studies; Fasting; Food; Food-Drug Interactions; Half-Life; Humans; Male; Niflumic Acid; Postprandial Period; Prodrugs; Pyridines; Young Adult

Many studies on the efficacy of preemptive analgesia have been processed in different ways. But the value of preemptive analgesia is still controversial. The goal of this study was to compare analgesic effects of a nonsteroidal anti-inflammatory drug (NSAID) for oral surgical pain according to 3 different administration times.. Using a randomized, parallel-group, single-center, and active-controlled test design, this study was conducted with 80 healthy patients undergoing a surgical removal of an impacted mandibular third molar requiring bone removal. The oral NSAID was first administered 1 hour preoperatively, or 1 hour postoperatively, or no scheduled administration pre- or postsurgery. Whenever patients felt at least moderate pain (score > or =5 on a 10-point scale) after surgery, they were instructed to take the same drug. Pain intensities and times to the first and second onsets of postoperative pain from the end of surgery were assessed for 24 hours.. Of the 80 enrolled subjects in this study, 25 patients were assigned to the preemptive group, 26 to the posttreatment group, and 29 to the no-treatment group. The demographic distribution and duration of surgery in the 3 groups were statistically similar. The mean time to first onset of postoperative pain was significantly prolonged in the posttreatment group (277.2 minutes, P < .05) compared to the preemptive group (158.4 minutes) and the no-treatment group (196.5 minutes). The mean time to second onset of postoperative pain was not significantly different among the 3 groups. No significant statistical difference was found among the mean pain intensities at the first and second onsets of postoperative pain in the 3 groups.. In this small selected group of subjects and limited study design, the analgesic effects of NSAID administered preoperatively were no longer effective for postoperative pain. The results in this population imply that scheduled postoperative analgesics before pain development are adequate for postoperative analgesia without preoperative administration.

Topics: Adolescent; Adult; Analysis of Variance; Anti-Inflammatory Agents; Benzofurans; Chi-Square Distribution; Double-Blind Method; Facial Pain; Female; Humans; Male; Mandible; Molar, Third; Pain, Postoperative; Postoperative Care; Preoperative Care; Pyridines; Time Factors; Tooth Extraction; Tooth, Impacted

A simple and rapid quantification method was developed for determining both talniflumate and niflumic acid in human plasma. After simple protein precipitation with acetonitrile, the analytes were chromatographed on a reversed-phase C(18) column and detected by LC/MS/MS with electrospray ionization. The assay accuracy and precision were within the FDA guidance for the analytical method validation. This method was used to measure the plasma concentrations of both compounds from healthy subjects after a single oral dose of talniflumate, 740 mg.

Topics: Benzofurans; Chemical Precipitation; Chromatography, Liquid; Humans; Linear Models; Niflumic Acid; Proteins; Pyridines; Sensitivity and Specificity; Solvents; Tandem Mass Spectrometry; Time Factors

A sensitive LC-MS method was developed and validated for the determination of niflumic acid (NFA), the active metabolite of the talniflumate formulation, in human plasma. The analyses were performed on C(18) column using acetonitrile-ammonium acetate buffer (pH 5.7, 40:60) as a mobile phase with quadrupole MS detection of NFA at m/z 281 in a negative ion-monitoring mode. Calibration curve was linear in the concentration range of 1-1000ng/mL in human plasma. The higher sensitivity of LC-MS allowed low concentrations of NFA to be determined at initial drug absorption and terminal elimination phases following oral administration of talniflumate tablet.

Topics: Adult; Benzofurans; Chromatography, Liquid; Humans; Male; Mass Spectrometry; Niflumic Acid; Pyridines; Reproducibility of Results; Sensitivity and Specificity; Tablets

Intestinal disease in cystic fibrosis (CF) mice closely mirrors aspects of obstructive syndromes in CF patients. The pathogenesis involves accumulation of mucoid debris in the crypts that fuse with intestinal content to form obstructing mucofeculant impactions. Treatment involves modalities that increase the fluidity of the luminal content, such as osmotic laxatives and liquid diets. We investigated the effects of talniflumate (Lomucin, Genaera Corporation, Plymouth Meeting, PA), a compound that may be beneficial to treatment of CF intestinal disease based on three mechanisms of action: mucus synthesis inhibition by blockade of the murine calcium-activated chloride channel 3 (mCLCA3), nonsteroidal anti-inflammatory effects, and inhibition of Cl(-)/HCO (-)(3) exchanger(s) involved in intestinal NaCl absorption. Cohorts of CF mice were fed control diet or diets containing either talniflumate (0.4 mg/g chow) or ibuprofen (0.4 mg/g chow) for 21 days to assess survival. Talniflumate significantly increased CF mouse survival from 26 to 77%, whereas ibuprofen had no effect (22% survival). Oral talniflumate did not alter crypt goblet cell numbers or change intestinal expression of mCLCA3 but tended to decrease crypt mucoid impaction. Ussing chamber studies indicated that talniflumate slightly increased the basal short-circuit current of CF intestine, but the change was not sensitive to secretagogue stimulation or bumetanide inhibition. In contrast, intracellular pH measurements of intact intestinal villous epithelium indicated that talniflumate significantly inhibited apical membrane Cl(-)/HCO (-)(3) exchange by >50%. We conclude that oral talniflumate increases the survival of CF mice, possibly by the beneficial effects of decreasing small intestinal NaCl absorption through the inhibition of apical membrane Cl(-)/HCO (-)(3) exchanger(s).

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Cell Count; Chloride Channels; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Hydrogen-Ion Concentration; Intestinal Mucosa; Intestinal Obstruction; Intestine, Small; Ion Transport; Mice; Mucins; Mucoproteins; Mutation; Pyridines

A high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of niflumic acid and its prodrug, talniflumate, in human plasma. Niflumic acid and talniflumate were eluted isocratically with methanol-water (73:27, v/v, adjusted to pH 3.5 by acetic acid) at a fl ow rate of 1 mL/min. Indomethacin was used as an internal standard. Signals were monitored by an UV detector at 288 nm. Retention times of indomethacin, niflumic acid and talniflumate were 5.9, 7.2 and 13.5 min, respectively. Calibration plots were linear over the range 50-5000 ng/mL for niflumic acid and 100-5000 ng/mL for talniflumate. The limits of quantitation were 50 ng/mL for niflumic acid and 100 ng/mL for talniflumate. The intra- and inter-day relative standard deviations (RSD) of niflumic acid and talniflumate were less than 10% and the accuracies were higher than 90%. This method is rapid, sensitive and reproducible for the determination of niflumic acid and talniflumate in human plasma.

Topics: Benzofurans; Chromatography, High Pressure Liquid; Humans; Male; Niflumic Acid; Prodrugs; Pyridines

A rapid and simple HPLC method with UV detection (288 nm) was developed and validated for quantitation of niflumic acid in human plasma, the active metabolite of talniflumate. After precipitation with 100% methanol containing the internal standard, indomethacin, the analysis of the niflumic acid level in the plasma samples was carried out using a reverse phase C18 CAPCELL PAK (5 microm, 4.6 mm x 250 mm) column. The chromatographic separation was accomplished with an isocratic mobile phase consisting of a mixture of 0.1M sodium acetate in water and acetonitrile (37:63, v/v), adjusted to pH 6.4. This HPLC method was validated by examining its precision and accuracy for inter- and intra-day runs in a linear concentration range of 0.02-5.00 microg/mL. Stability of niflumic acid in plasma was excellent, with no evidence of degradation during sample processing (autosampler) and 30 days storage in a freezer. This validated method was successfully applied to the bioequivalence study of talniflunate in healthy volunteers.

Topics: Adult; Benzofurans; Chromatography, High Pressure Liquid; Drug Stability; Humans; Male; Niflumic Acid; Pyridines; Reproducibility of Results; Sensitivity and Specificity; Spectrophotometry, Ultraviolet; Therapeutic Equivalency