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PubMed2002

Enthalpy relaxation studies of celecoxib amorphous mixtures.

PURPOSE: The purpose of this study was to compare the structural relaxation and molecular mobility of amorphous celecoxib (CEL) with that of CEL amorphous mixtures consisting of various excipients and to study the effect of different excipients on the relaxation of high-energy amorphous systems. METHODS: The measurement of glass transition temperatures (Tg) and enthalpy relaxation were performed using differential scanning calorimetry. The interactions between drug and excipients and the absence of crystalline forms were further confirmed by conducting Fourier transform infrared spectroscopic and X-ray powder diffraction studies on same samples. RESULTS: All samples exhibited a single Tg value. Polymers had a prominent effect on the lowering of the relaxation rate in amorphous CEL. The lowering of the rate of relaxation was directly dependent on the concentration and type of polymer used. The total enthalpy required for relaxation was same, although additives affected the rate of relaxation. CONCLUSIONS: In absence of any specific interactions during Fourier transform infrared studies, it was concluded that the antiplasticizing activity of polymers is responsible for the stabilization of CEL amorphous systems. Glassy amorphous dispersions of CEL exhibited a complex type of relaxation pattern, which failed to fit in Kohlrausch-Williams-Watts equation with respect to calculation of relaxation time constants.

Calorimetry, Differential Scanning↗

PubMed2006

Bioavailability enhancement of poorly water soluble and weakly acidic new chemical entity with 2-hydroxy propyl-beta-cyclodextrin: selection of meglumine, a polyhydroxy base, as a novel ternary component.

The purpose of the present study was to investigate the influence of a polyhydroxy base, N-acetyl glucamine (also know as Meglumine), as a ternary component on the complexation of DRF-4367, a poorly water-soluble and weakly acidic anti-inflammatory molecule, with 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD). The molecular inclusion of DRF-4367 with HPbetaCD alone and in combination with ternary component was aimed at improvement in solubility and, subsequently, dissolution rate-limited oral bioavailability. The solid complexes of DRF-4367 and HPbetaCD with or without meglumine (binary and ternary systems, respectively) were prepared as coevaporated product in different stoichiometric ratios and compared against physical mixture. The formation of inclusion complexes was confirmed by using classical instrumental techniques. Phase solubility studies suggested that meglumine was responsible for solubility improvement via multiple factors rather than just providing a favorable pH. Mechanisms and factors governing solubility enhancement were investigated by using phase solubility and thermodynamic parameters. The complexation of DRF-4367 with HPbetaCD is thermodynamically favored because the Gibbs free energies of transfer of the drug to the cyclodextrin cavity are negative. The solubilization efficiency and stability were further improved while retaining the favorable Gibbs free energies of transfer with the addition of meglumine. Inclusion ternary complex of DRF-4367 with HPbetaCD and meglumine showed significant improvement in dissolution compared with uncomplexed drug and binary system. Moreover, the phenomena of reprecipitation observed with binary system during dissolution could be avoided with meglumine as an enabling ternary component. This improved physicochemical behavior of ternary complex with the novel inclusion of a polyhydroxy base translated into an enhanced oral bioavailability of DRF-4367 compared with either uncomplexed drug or nanosuspension.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1992

Potentiation of N-methyl-D-aspartate-stimulated dopamine release from rat brain slices by aluminum fluoride and carbachol.

N-Methyl-D-aspartate (NMDA) stimulated the release of endogenous dopamine from striatal slices prepared from adult Sprague-Dawley rats. A mixture of sodium fluoride and aluminum chloride (AlF4-) added to the slices significantly potentiated the NMDA-stimulated release of dopamine in a concentration- and time-dependent manner. The AlF4- mixture had no effect on the nonstimulated basal efflux of dopamine, and no increases in NMDA-stimulated release were observed when NaF was replaced with NaCl. Similarly, AlCl3 or a mixture of NaCl and AlCl3 had no effect on NMDA-stimulated release. The AlF(4-)-induced increase in NMDA-stimulated dopamine release was totally blocked by magnesium or the selective NMDA glycine antagonist 7-chlorokynurenic acid. Striatal slices depolarized with KCl (15 mM) also released dopamine and this release was similarly potentiated by AlF4-. However, KCl-stimulated dopamine release from striatal synaptosomes was not potentiated by concentrations of AlF4- that greatly increased release from striatal slices. NMDA did not stimulate the release of dopamine from striatal synaptosomes in the absence or presence of aluminum fluoride. Modulators of adenylate cyclase (forskolin) and protein kinase C (phorbol esters) did not enhance NMDA-stimulated dopamine release. The protein kinase C inhibitor H-7 also did not reduce the potentiating effects of AlF4-. The mixed cholinergic agonist carbachol and the calcium ionophore A23187 mimicked the AlF4- effect although the increase in NMDA-stimulated dopamine release produced by these agents was less than that seen with AlF4-.(ABSTRACT TRUNCATED AT 250 WORDS)

Aluminum↗

PubMed1999

Quantitative analysis of povidone (PVP) in drug-PVP matrix using multicomponent analysis.

A method for the quantification of povidone (PVP), in solid dispersions and physical mixtures of the polymer and a very slightly soluble drug substance, has been developed by multicomponent analysis using the concepts of chemometrics. Because the UV-absorbance spectra of PVP is completely overlapped by the UV-absorbance spectra of the drug substance, a direct spectrophotometric method of PVP is impossible. However, UV-spectrophotometric data were analyzed by the Quant + Perkin Elmer software for quantitative multicomponent analysis using chemometrics, and by the optimal method developed using a solvent of pH 7.4, a fast, reliable, and precise detection of PVP was obtained when the content of PVP in the powder sample exceeded 20% (m/m). Two methods were developed by the calibration procedure, using buffers of pH 7.4, respectively pH 8.5. By applying a solvent of pH 8.5, more sample could be taken into use because of the enhanced solubility of the drug substance, and hence it was believed that as more PVP was taken into use, a better prediction of PVP would be obtained. However, as more drug substance was taken into use the UV-absorbance spectrum of PVP was even more overlapped, and an inferior prediction was obtained.

Calibration↗

PubMed2004

Fluorogenic derivatization reagents suitable for isolation and identification of cysteine-containing proteins utilizing high-performance liquid chromatography-tandem mass spectrometry.

The fluorogenic derivatization reagents with a positive charge, 4-(dimethylaminoethylaminosulfonyl)-7-chloro-2,1,3-benzoxadiazole (DAABD-Cl) and 7-chloro-2,1,3-benzoxadiazole-4-sulfonylaminoethyltrimethylammonium chloride (TAABD-Cl), are proposed for use in proteomics studies. Following derivatization of protein mixtures with these reagents, a series of standard processes of isolation, digestion, and identification of the proteins were performed utilizing high-performance liquid chromatography-fluorescence detection and tandem mass spectrometry with the probability-based protein identification algorithm. Both DAABD and TAABD derivatives were detected fluorometrically at the femtomole level and showed more than 100-fold improvement in sensitivity compared to the underivatized original compounds with an electrospray ionization ion trap mass spectrometer analysis. The modification of the MASCOT database search system memorized with the fragment information of a DAABD-attached Cys residue allowed the identification of the proteolytic peptide fragments of the derivatized bovine serum albumin (BSA) with an estimated 38% sequence coverage of BSA. Utilizing DAABD-Cl as a derivatization reagent, identification of several proteins was also possible in a soluble extract of Caenorhabditis elegans (10 microg of protein). Consequently, for identification of proteins in the complex matrixes of proteins, DAABD-Cl could be a more appropriate reagent than ammonium 7-fluoro-2,1,3-benzoxadiazole-4-sulfonate as reported previously.

Animals↗

PubMed2004

Stability study of amorphous valdecoxib.

Formulation of poorly water-soluble drugs in the most stable dosage form for oral delivery perhaps presents the greatest challenge to pharmaceutical industry. Physical transformation of drug substance into its more soluble but metastable amorphous form is one of the approaches for improving dissolution rate of such drugs. The present study utilizes technique of spray drying for preparation of solid dispersions (SDs) and includes stability study of the same. Valdecoxib (VLD), a prototype of poorly water-soluble drugs, has been the drug of choice. The hydrophilic carriers selected were polyvinylpyrrolidone K30 (PVP) and hydroxypropylcellulose (HPC). SDs and pure VLD in the form of spray dried powder (SDVLD) in comparison with pure drug and corresponding physical mixtures (PMs) were initially characterized and then subjected to stability testing at ambient temperature and relative humidity up to 3 months. During initial characterization, increase in saturation solubility and dissolution rate was observed in all samples. DSC and XRPD studies of SDVLD and SDs suggested generation of amorphous form of drug. IR spectroscopy revealed presence of hydrogen bonding in SDs. During stability testing, there was gradual decrease in saturation solubility and dissolution rate of SDs, over the period of 3 months. While, saturation solubility of SDVLD dropped drastically within 15 days and was almost comparable with pure VLD. SD PVP retained the amorphous form of drug throughout stability period, whereas SD HPC and SDVLD presented incidence of crystallinity after 1 month and 15 days, respectively. This was justified by enthalpy relaxation studies in which, amorphous VLD showed considerable relaxation of enthalpy at Tg, while it was totally suppressed in SD PVP and partly in SD HPC. The study thus definitely reveals tremendous potential of solid dispersions of valdecoxib with PVP, from stability point of view.

Algorithms↗

PubMed2004

Pycnogenol as an adjunct in the management of childhood asthma.

A randomized, placebo-controlled, double-blind study involving 60 subjects, aged 6-18 years old, was conducted over a period of 3 months to determine the effect of Pycnogenol (a proprietary mixture of water-soluble bioflavonoids extracted from French maritime pine) on mild-to-moderate asthma. After baseline evaluation, subjects were randomized into two groups to receive either Pycnogenol or placebo. Subjects were instructed to record their peak expiratory flow with an Assess Peak Flow Meter each evening. At the same time, symptoms, daily use of rescue inhalers (albuterol), and any changes in oral medications were also recorded. Urine samples were obtained from the subjects at the end of the run-in period, and at 1-, 2-, and 3-month visits. Urinary leukotriene C4/D4/E4 was measured by an enzyme immunoassay. Compared with subjects taking placebo, the group who took Pycnogenol had significantly more improvement in pulmonary functions and asthma symptoms. The Pycnogenol group was able to reduce or discontinue their use of rescue inhalers more often than the placebo group. There was also a significant reduction of urinary leukotrienes in the Pycnogenol group. The results of this study demonstrate the efficacy of Pycnogenol as an adjunct in the management of mild-to-moderate childhood asthma.

Adolescent↗

PubMed2004

Enantioselective HPLC determination of E-6087, a new COX-2 inhibitor, in human plasma: Validation and pharmacokinetic application.

E-6087 is a nonsteroidal anti-inflammatory compound that selectively inhibits cyclooxygenase-2. Because E-6087 has a chiral center, this compound is a racemic mixture of two stereoisomers, (+)-(R)-E-6087 (E-6231) and (-)-(S)-E-6087 (E-6232). A normal-phase liquid-chromatographic method for the enantioselective determination of E-6087 in human plasma was developed and validated. The samples were extracted using solid-phase extraction cartridges containing C(18) sorbent, and the extracts were redissolved in absolute ethanol and injected into the chromatographic system. The enantiomeric separation was achieved on a chiral stationary-phase column of derivatized amylose, and the enantiomers were quantified by fluorescence detection. The method was validated for drug concentrations ranging from 5 to 400 ng/ml for both enantiomers. No peaks interfering with the quantification of enantiomers were observed. The limit of quantification was 5 ng/ml, with precision expressed as a coefficient of variation lower than 10.6% and accuracy expressed as relative error lower than 12.2%. The utility of this method was demonstrated by analysis of plasma samples from healthy volunteers given an oral dose of rac-E-6087. Peak plasma levels of E-6231 were higher than levels obtained for E-6232. Results were consistent with those obtained with a conventional reversed-phase method used for determination of the racemic compound.

Calibration↗

PubMed1985

Thromboxane A2 and prostacyclin do not modulate the systemic hemodynamic response to cold in humans.

The immersion of a limb in a mixture of water and ice induces in normal humans an initial vasoconstriction mediated mainly by catecholamine release. In some studies the cold pressor test was associated with an increase in vasoconstrictor thromboxane A2 and in vasodilating prostacyclin. Dazoxiben hydrochloride, a thromboxane synthase inhibitor, has been reported to suppress cold-induced vasoconstriction. We compared in a double-blind, crossover, placebo-controlled study the effects of indomethacin (a cyclooxygenase inhibitor), dazoxiben hydrochloride, and BM13.177 (a novel thromboxane receptor antagonist) on the changes in cutaneous vascular resistance and arterial blood pressure induced by cold in 12 healthy volunteers. Cold challenge produced an increase in blood pressure and an initial decrease in finger blood flow, reflecting an increase in cutaneous vascular resistance. Neither effective suppression of thromboxane A2 generation or of the effects of thromboxane A2 on platelets by the three active treatments nor increase in prostacyclin generation after ingestion of dazoxiben hydrochloride modified the hemodynamic response to cold. In conclusion, thromboxane A2 and prostacyclin do not play a significant role in the modulation of the systemic hemodynamic response to cold. In addition, thromboxane receptor antagonism in normal humans does not influence basal blood pressure.

6-Ketoprostaglandin F1 alpha↗

PubMed2004

Simultaneous quantification of the new HIV protease inhibitors atazanavir and tipranavir in human plasma by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry.

We have developed and validated an assay, using liquid chromatography coupled with electrospray tandem mass spectrometry (LC-MS/MS), for the quantification of the novel protease inhibitors (PIs) atazanavir and tipranavir. The sample pre-treatment consisted of protein precipitation with a mixture of methanol and acetronitrile using 100 microl plasma for atazanavir and 50 microl for tipranavir. Chromatographic separation was achieved on an Inertsil ODS3 column (50 mm x 2.0 mm i.d., particle size 5 microm), with a quick stepwise gradient using an acetate buffer (pH 5) and methanol, at a flow rate of 0.5 ml/min. The analytical run time was 5.5 min. The triple quadrupole mass spectrometer operated in the positive ion-mode and multiple reaction monitoring (MRM) was used for drug quantification. The assay was linear over a concentration range of 0.05-10 microg/ml for atazanavir and 0.1-75 microg/ml for tipranavir. Saquinavir-d5 was used as internal standard. The intra- and inter-day coefficients of variation were less than 3.8% for atazanavir and less than 10.4% for tipranavir. Accuracies were within +/-7.3 and +/-7.2% for atazanavir and tipranavir, respectively. Both drugs were stable under various relevant storage conditions. The validated concentration ranges proved to be adequate to measure concentrations of human immunodeficiency virus type-1 (HIV-1)-infected individuals. The developed method could easily be combined with a previously developed LC-MS/MS assay for the quantification of protease inhibitors.

Atazanavir Sulfate↗

PubMedDate not supplied

The modification of platelet-induced coronary vasoconstriction by a thromboxane receptor antagonist.

The role of platelet-derived vasoconstrictors in coronary vasospasm was studied using arachidonic acid-stimulated washed human platelets (WPS). Transfer of this system into an organ bath, containing bovine coronary arteries (BCA) and a mixture of blocking agents resulted in a biphasic contraction, consisting of a first phase, mediated by release of thromboxane (TX) A2 and a second phase, mediated by release of 5-hydroxytryptamine (5-HT) from the WPS (1,2). Treatment of the WPS with 4-[2-(benzenesulfonamido)-ethyl]-phenoxyacetic acid (BM 13.177) (0.03-3 mumol/L) prior to stimulation revealed a concentration-dependent inhibition of the 5-HT component of the contractile response with a minor reduction of the TXA2 component of contraction and enhanced amounts of immunoreactive TXB2 in the bath fluid. Treatment of the BCA with BM 13.177 prior to addition of stimulated WPS resulted in a significant reduction of the TXA2 component of contraction, by 56% at 30 mumol/L whereas 3 mumol/L were ineffective. The 5-HT component of contraction was enhanced. For comparison, the IC50 for BM 13.177 to inhibit PGF2 alpha-induced contractions was 6 mumol/L and that to inhibit U-46,619 was 0.5 mumol/L. BM 13.177 was at least 1 order of magnitude more potent as an inhibitor of U-46,619 than of PGF2 alpha- or TXA2-induced contractions. It is concluded that BM 13.177 is a weak inhibitor of TXA2-mediated contractions of coronary vessels, suggesting different thromboxane receptors in coronary vessels and platelets.

Animals↗

PubMed1995

Pharmacological characterization of noradrenaline-induced contractions of the porcine isolated palmar lateral vein and palmar common digital artery.

1. The aim of this study was to examine the pharmacological characteristics of alpha-adrenoceptor-mediated contractions in two porcine isolated blood vessels, the palmar lateral vein (PLV) and the palmar common digital artery (PCDA). This was carried out with noradrenaline used as the agonist throughout, and either phentolamine (non-selective alpha-adrenoceptor antagonist), prazosin and YM-12617 (selective alpha 1-adrenoceptor antagonists) or rauwolscine and CH-38083 (selective alpha 2-adrenoceptor antagonists). 2. Noradrenaline (0.003-10 microM) produced concentration-dependent contractions in both vessels, with the PCDA (pD2 = 6.33 +/- 0.07, n = 10) being approximately 10 fold less sensitive to noradrenaline compared to the PLV (pD2 = 7.39 +/- 0.09, n = 8). Also, the maximal response to noradrenaline was greater in the PCDA compared to the PLV. Phentolamine (0.03-30 microM) produced parallel rightward shifts in the CRC to noradrenaline in both tissue preparations. The pA2 values were similar and slopes of the Schild plots were not significantly different from unity, indicating an interaction between phentolamine and a single receptor in each preparation. 3. In the PCDA the alpha 1-adrenoceptor antagonists, prazosin (0.01-1 microM) and YM-12617 (0.01-1 microM) produced non-parallel rightwards shifts in the CRC to noradrenaline, with the lower 10-15% of the CRC exhibiting greater resistance to the effects of these antagonists compared to the upper part. In contrast, rauwolscine (1-10 microM) and CH-38083 (10 microM) produced parallel displacement of the CRC to noradrenaline. In the PLV, low concentrations of either alpha l- (0.01 microM) or alpha2-adrenoceptor antagonists(0.1-1 microM) produced a large shift in the CRC, but subsequent higher concentrations had only small additional effects. Based upon pKB values estimated from the effects of the lower concentrations of antagonists, the results are consistent with a large population of alpha1-adrenoceptors in the PCDA and a mixture of alpha l- and alpha2-adrenoceptors in the PLV.4. In both tissues, when an ac,- and an a2-adrenoceptor antagonist were used in combination the effect produced was greater than that with either agent alone. In contrast, the combination of the alpha1-adrenoceptor antagonists (prazosin and YM-12617 together) or the alpha2-adrenoceptor antagonists (CH-38083 and rauwolscine together) were no more effective than that produced by the individual antagonists. These findings suggest the presence of functional alpha l- and alpha2-adrenoceptors in the PLV andPCDA.5. Phenoxybenzamine (0.3-3 microM, 60min exposure) produced a concentration-dependent reduction in the maximal response to noradrenaline which was more pronounced in the PCDA than the PLV. After a 60 min exposure to a combination of phenoxybenzamine (1 microM) and rauwolscine (1 microM), the remaining NA-induced contraction after washout was resistant to prazosin (0.1 microM) and sensitive to rauwolscine(1 microM) in both tissue preparations, indicating the existence of functional alpha2-adrenoceptors in both vessels.6. Evidence suggests that post-junctional alpha l- and alpha2-adrenoceptors contribute to noradrenaline-induced contractions in the PCDA and PLV, with the latter possessing a larger population of functional alpha2-adrenoceptors.

Adrenergic alpha-Antagonists↗

PubMed2003

Solubility enhancement of Cox-2 inhibitors using various solvent systems.

This study examined the solubility enhancement of 4 cox-2 inhibitors, celecoxib, rofecoxib, meloxicam, and nimesulide, using a series of pure solvents and solvent mixtures. Water, alcohols, glycols, glycerol, and polyethylene glycol 400 (PEG 400) were used as solvents and water-ethanol, glycerol-ethanol, and polyethylene glycol-ethanol were used as mixed-solvent systems. A pH-solubility profile of drugs was obtained in the pH range 7.0 to 10.9 using 0.05 M glycine-sodium hydroxide buffer solutions. Lower alcohols, higher glycols, and PEG 400 were found to be good solvents for these drugs. The aqueous solubility of celecoxib, rofecoxib, and nimesulide could be enhanced significantly by using ethanol as the second solvent. Among the mixed-solvent systems, PEG 400- ethanol system had highest solubilization potential. In the case of meloxicam and nimesulide, solubility increased significantly with increase in pH value. Physico-chemical properties of the solvent such as polarity, intermolecular interactions, and the ability of the solvent to form a hydrogen bond with the drug molecules were found to be the major factors involved in the dissolution of drugs by pure solvents. The greater the difference in the polarity of the 2 solvents in a given mixed solvent, the greater was the solubilization power. However, in a given mixed-solvent system, the solubilization power could not be related to the polarity of the drugs. Significance of the solubility data in relation to the development of formulations has also been discussed in this study.

Celecoxib↗

PubMedDate not supplied

Species-dependent stereopharmacokinetics of MK-927, a potent carbonic anhydrase inhibitor.

MK-927 [5,6-dihydro-4H-4(isobutylamino)thieno(2,3-B)thiopyran-2-sul fonamide -7,7 dioxide], a potent carbonic anhydrase inhibitor, contains a chiral center and is a mixture of two forms, R-(-)- and S-(+)-enantiomer. The latter has recently been designated as MK-417. Following iv administration of each enantiomer (0.05 mg/kg), dogs, rabbits, and rats cleared the R-(-)-enantiomer more rapidly than the S-(+)-enantiomer. The elimination clearance of the R-(-)-enantiomer was 2.01 +/- 0.34, 30.0 +/- 2.1, and 53.6 +/- 6.4 ml/hr/kg for dogs, rabbits, and rats, respectively. The corresponding values for the S-(+)-isomer were 0.0380 +/- 0.008, 1.15 +/- 0.20, and 1.29 +/- 0.09 ml/hr/kg. The ratio of the clearance of the R-(-)-enantiomer to that of the S-(+)-isomer was approximately 53 for the dog, 42 for the rat, and 26 for the rabbit, indicating that the degree of stereoselectivity in elimination kinetics of MK-927 enantiomers was species-dependent. Binding of the enantiomers to erythrocytes, presumably carbonic anhydrase, was also stereoselective and species-dependent; the S-(+)-enantiomer was bound more strongly than the R-(-)-isomer in all species. For both enantiomers, binding to carbonic anhydrase was found to be more extensive in dogs than in other species studied. The elimination clearance of the enantiomers in all species was roughly related to their binding affinity, greater Kd1 values being associated with more rapid clearance. However, binding data alone cannot quantitatively explain the degree of the species-dependent stereoselectivity in the elimination kinetics; other factors may also contribute.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed2000

Metabolism and excretion of [(14)C]celecoxib in healthy male volunteers.

We determined the disposition of a single 300-mg dose of [(14)C]celecoxib in eight healthy male subjects. The [(14)C]celecoxib was administered as a fine suspension reconstituted in 80 ml of an apple juice/Tween 80/ethanol mixture. Blood and saliva samples were collected at selected time intervals after dosing. All urine and feces were collected on the 10 consecutive days after dose administration. Radioactivity in each sample was determined by liquid scintillation counting or complete oxidation and liquid scintillation counting. Metabolic profiles in plasma, urine, and feces were obtained by HPLC, and metabolites were identified by mass spectrometry and NMR. [(14)C]Celecoxib was well absorbed, reaching peak plasma concentrations within 2 h of dosing. [(14)C]Celecoxib was extensively metabolized, with only 2.56% of the radioactive dose excreted as celecoxib in either urine or feces. The total percentage of administered radioactive dose recovered was 84.8 +/- 4.9%, with 27.1 +/- 2.2% in the urine and 57.6 +/- 7.3% in the feces. The oxidative metabolism of celecoxib involved hydroxylation of celecoxib at the methyl moiety followed by further oxidation of the hydroxyl group to form a carboxylic acid metabolite. The carboxylic acid metabolite of celecoxib was conjugated with glucuronide to form the 1-O-glucuronide. The percentages of the dose excreted in the feces as celecoxib and the carboxylic acid metabolite were 2.56 +/- 1.09 and 54.4 +/- 6.8%, respectively. The majority of the dose excreted in the urine was the carboxylic acid metabolite (18.8 +/- 2.1%); only a small amount was excreted as the acyl glucuronide (1.48 +/- 0.15%).

Administration, Oral↗

PubMed2004

[Effect of various anti-glaucoma eyedrops on human corneal epithelial cells].

PURPOSE: To investigate the effects of antiglaucoma eyedrops and vehicles on the proliferation of human corneal epithelial cells. MATERIAL AND METHODS: Seven eyedrops[prostaglandin F2 alpha analogs(2), beta blockers(40), topical carbonic anhydrase inhibitor(1)], and six of the eyedrop vehicles, excluding that of Xalatan, were used. Anti-glaucoma eyedrops and vehicles were serially diluted 2-fold with culture medium(10-2,560 fold). The mixture was added to human corneal epithelial cells and incubated for 48 hrs. Cell proliferation was measured by commercial assay kit. Dye-reagents were added to the wells and incubated for 1 h at 37 degrees C. Optical density were measured at 490 nm. The dilution rate for 50% inhibition was calculated as the dilution rate of drugs or vehicles necessary to produce 50% inhibition of cell proliferation. RESULT: All drugs completely inhibited cell proliferation when the dilution rate was low. At 40-fold dilution, Trusopt and Timoptol showed a significant decrease in cell growth inhibition. On the other hand, Rescula showed almost 100% inhibition at 160-fold dilution. Above 640-fold dilution, the inhibition rate of all drugs became 50% or less and there was no significant difference between drugs. Vehicles also inhibited cell growth. The dilution rates for growth inhibition by vehicles were different from those of drugs. The dilution rate at 50% inhibition of anti-glaucoma eyedrops decreased in the following order: Rescula > Xalatan > Betoptic > Hypadil > Mikelan > Timoptol > Trusopt. The dilution rate for 50% inhibition of vehicles decreased in the following order: Rescula vehicle > Hypadil vehicle > Betoptic vehicle > Mikelan vehicle > Timoptol vehicle > Trusopt vehicle. CONCLUSION: All anti-glaucoma eyedrops inhibited cell proliferation. These effects were stronger in prostaglandin F2 alpha analogs and weakest in Trusopt. Furthermore, the inhibition of cell proliferation was caused also by the vehicle of eyedrops, and the influence of the vehicle varied in each type of eyedrops.

Adrenergic beta-Antagonists↗

PubMed1989

Adjuvant effects of calmodulin antagonists on antitumor activity of 1-(2-tetrahydrofuryl)-5-fluorouracil (ftorafur) and a mixture of ftorafur and uracil (UFT) in nude mice bearing human ovarian carcinomas.

Effects of N-(6-aminohexyl)-1-naphthalenesulfonamide (W-5) and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) on antitumor activity of 1-(2-tetrahydrofuryl)-5-fluorouracil (ftorafur, FT) and a mixture of FT and uracil (UFT) were determined in nude mice bearing human ovarian carcinoma (KF cells). All nude mice developed palpable tumor 17 days after KF cell inoculation unless treated. A combination of UFT and calmodulin antagonists (W-5 and W-7) resulted in a delay in tumor formation in nude mice. One of 10 nude mice treated with a combination of UFT and W-5 and 3 of 10 nude mice treated with UFT and W-7 did not develop tumors during the experimental period. Tumor volumes in groups treated with the combinations of UFT and calmodulin antagonists were significantly smaller than those in the untreated group after 31 days of tumor inoculation. In addition, tumor volumes in a group treated with UFT plus W-7 were significantly smaller than not only those in the untreated group but also those in groups treated with UFT alone, FT alone, W-5 alone, or W-7 alone. The longest median survival time was also observed in the group treated with UFT plus W-7. 5-Fluorouracil (5-FU) content of the tumors of groups treated with FT plus W-5 or W-7 was similar to that of the group treated with FT alone. On the other hand, 5-FU content of a group treated with UFT plus W-7 was about twofold higher than that of a group treated with UFT alone. These results suggest that a synergistic effect of W-7 and UFT on inhibition of tumor growth and prolongation of survival time may result from accumulation of 5-FU in the tumor.

Animals↗

PubMed2001

Quantification of nimesulide in human plasma by high-performance liquid chromatography/tandem mass spectrometry. Application to bioequivalence studies.

A method based on liquid chromatography with negative ion electrospray ionization and tandem mass spectrometry is described for the determination of nimesulide in human plasma. Liquid-liquid extraction using a mixture of diethyl ether and dichloromethane was employed and celecoxib was used as an internal standard. The chromatographic run time was 4.5 min and the weighted (1/x) calibration curve was linear in the range 10.0-2000 ng x ml(-1). The limit of quantification was 10 ng x ml(-1), the intra-batch precision was 6.3, 2.1 and 2.1% and the intra-batch accuracy was 3.2, 0.3 and 0.1% for 30, 300 and 1200 ng x ml(-1) respectively. The inter-batch precision was 2.3, 2.8 and 2.7% and the accuracy was 3.3, 0.3 and 0.1% for 30, 300 and 1200 ng x ml(-1) respectively. This method was employed in a bioequivalence study of one nimesulide drop formulation (nimesulide 50 mg x ml(-1) drop, Medley S/A Indústria Farmacêutica, Brazil) against one standard nimesulide drop formulation (Nisulid, 50 mg x ml(-1) drop, Astra Médica, Brazil). Twenty-four healthy volunteers (both sexes) took part in the study and received a single oral dose of nimesulide (100 mg, equivalent to 2 ml of either formulation) in an open, randomized, two-period crossover way, with a 2-week washout interval between periods. The 90% confidence interval (CI) for geometric mean ratios between nimesulide and Nisulid were 93.1-109.6% for C(max), 87.7-99.8% for AUC(last) and 88.1-99.7% for AUC(0-infinity). Since the 90% CI for the above-mentioned parameters were included in the 80-125% interval proposed by the US Food and Drug Administration, the two formulations were considered bioequivalent in terms of both rate and extent of absorption.

Adolescent↗