Inhibition of 3',5'-AMP phosphodiesterase by biflavonoids and xanthones.
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3',5'-Cyclic-AMP Phosphodiesterases↗
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Results for “Xanthones”
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Inhibition of experimental immediate hypersensitivity reactions by a novel xanthone, RU 31156.
RU 31156, the tris-(hydroxymethyl)-aminomethane salt of 7-(S-methylsulphonimidoyl)-5-(n-hexyl)-xanthen-9-one-2-carboxylic acid has been found to be a potent inhibitor of experimental immediate hypersensitivity reactions in vivo. In the IgE-mediated rat PCA test, RU 31156 had an ED50 of 0.0046 (00037--0.0057) mg/kg which compared to a figure of 1.21 (1.04--1.42) mg/kg for disocium cromoglycate (DSCG), both compounds being administered intravenously. RU 31156 was also active when administered orally, having an ED50 of 0.19 (0.07--0.30) mg/kg when given 10 min before antigen. RU 31156 partially inhibited an IgG-mediated PCA reaction in the rat. Both RU 31156 and DSCG inhibited anaphylactic bronchoconstriction in the rat, giving bell-shaped dose-response curves. From the upward part of the curves, approximate ED30 values of 0.02 and 2.0 mg/kg were obtained for RU 31156 AND DSCG respectively. Anaphylactic bronchoconstriction in the guinea-pig was not affected by RU 31156 and pinnal anaphylaxis was inhibited at only relatively high doses of 1--10 mg/kg i.v. The effects of both histamine and 5-hydroxytryptamine in the mouse pinna were not affected by RU 31156. In PCA experiments, RU 31156 showed self-tachyphylaxis following both intravenous and oral administration. It also showed cross-tachyphylaxis with DSCG, indicating that these compounds are likely to share a similar mode of action.
Anaphylaxis↗
Pulmonary absorption studies utilizing in situ rat lung model: designing dosage regimen for bronchial delivery of new drug entities.
The absorption of 7-methylsulfinylxanthone-2-carboxylic acid, 7-(methylthio)xanthone-2-carboxylic acid, and their sodium salts from the respiratory tract of anesthetized rats was studied after intratracheal administration of 0.1 ml of a solution or suspension containing the drug. At various times after administration, the lungs and trachea were removed and assayed radiochemically for unabsorbed drug. Sodium 7-(methylthio)xanthone-2-carboxylate from solution was absorbed approximately 20 times faster than sodium 7-methylsulfinylxanthone-2-carboxylate from a solution. The absorption from solutions was three to four times faster than the absorption from suspensions. For inhalation aerosol dosage forms intended for prophylactic use, the drug entity with slower systemic absorption probably would be more desirable than the drug entity with rapid absorption. Rapid systemic absorption following inhalation of powder or liquid aerosols would lead to more frequent dosing if the biological activity is related to the drug concentration in the tracheobronchial tissues. Therefore, the powder or liquid inhalation aerosols of organic acids rather than the corresponding sodium salts may be preferable for designing a dosage regimen. However, if the dosage form is intended for utilizing the bronchodilator activity of the compound, the drug entity with rapid absorption is more desirable. Therefore, in the treatment of asthmatic attacks, liquid or powder inhalation aerosols of the sodium salt of the rapidly absorbing drug entity are preferable. The absorption rates were directly proportional to concentration when the initial concentration of sodium 7-methylsulfinylxanthone-2-carboxylate was varied over a 333-fold range. The effect of the pH of the drug solution administered intratracheally to the rat lung indicated a sharp increase in the pulmonary absorption at a pH near the pKa. The results suggested that structurally related xanthones are absorbed possibly by passive diffusion across the lipoidal region of the pulmonary membranes and that the absorption of organic acids and organic electrolytes is mainly controlled by the lipid solubility of the unionized species.
Absorption↗
Genetic Incorporation of a Thioxanthone-Containing Amino Acid for the Design of Artificial Photoenzymes.
Genetically encodable photosensitizers allow the design of artificial photoenzymes to expand the scope of abiological reactions. Herein, we report the genetic incorporation of a thioxanthone-containing amino acid into a protein scaffold via an engineered pyrrolysyl-tRNA/pyrrolysyl-tRNA synthetase pair. The designer enzyme was engineered to catalyze a dearomative [2+2] cycloaddition reaction in high yields (up to>99 % yield) with excellent enantioselectivity (up to 98 : 2 e.r.). This work provides a robust and facile method for photoenzyme design and lays the foundation for the development of further photoenzymatic reactions.
Xanthones↗
Determination of 3-(5-tetrazolyl) thioxanthone 10,10-dioxide in human plasma, urine and faeces.
A gas chromatographic method is described for assay of 3-(5-tetrazolyl) thioxanthone 10,10-dioxide (BW 59C) in human plasma, urine and faeces. After extraction into 1,2-dichloroethane from alkaline medium the compound is converted to the heptafluorobutyrate derivative which is injected into a gas chromatograph and measured using a 63Ni electron capture detector. The assay produces a linear calibration curve over the range 0-30 mug/ml when the internal standard method is used. Reproducibility is good and sensitivity down to 1 ng injected on column is possible. The method has been used to investigate the pharmacokinetic properties of BW 59C in man and has been semi-automated by the use of an autosampler and dedicated computer.
Chromatography, Gas↗
Doxantrazole, an antiallergic agent orally effective in man.
In-vivo studies have demonstrated antiallergic properties in doxantrazole when given orally to rats. These properties were confirmed in work with in-vitro preparations. No significant animal toxicity has been detected. 200 mg. given by mouth inhibited the immediate-type asthmatic response in volunteer patients challenged with specific antigen.
Administration, Oral↗
Cold urticaria: inhibition of cold-induced histamine release by doxantrazole.
Thirteen patients with cold urticaria were studied to assess the effect of the systemic drug doxantrazole, which has actions resembling disodium cromoglycate, on cold evoked histamine release. The patients, all of whom developed an immediate local whealing response after cooling of the forearm, demonstrated release of histamine into venous blood draining that forearm. Following doxantrazole treatment, significant suppression of histamine release occurred. In some but not all patients this was accompanied by diminution of urtication in response to cooling. A double-blind study was carried out in 3 subjects, all of whom showed diminished cold-stimulated histamine release after doxantrazole. Two of these showed clinical improvement. Doxantrazole had no effect on erythema due to intradermal histamine, but did suppress the erythematous reaction to intradermal injection of compound 48/80. Our results suggest that doxantrazole or related anti-allergic agents might be useful in the treatment of cold urticaria.
Child↗
Correlation of bioavailability in man with simulated absorption data for three doxantrazole preparations.
The in vitro and in vivo availability of doxantrazole, a potential antiallergic compound has been evaluated. A solution was significantly less bioavailable than either tablet or suspension formulations and it is suggested that this is associated with the large volume of the solution vehicle altering the hydrophilicity of the gastrointestinal fluids. In vitro availability was determined from absorption rate constants and absorption profiles obtained using the Sartorius absorption and solubility simulators. A statistically significant correlation was found between the percentage absorbed in vitro at 1 h and both total urinary recovery and area under plasma curve values in vivo. It is considered that in vitro determination of diffusion through artificial lipid membranes may be a useful predictive method of in vivo availability.
Biological Availability↗
Trial of doxantrazole in asthma.
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Administration, Oral↗