Isosorbide-based aspirin prodrugs: II. Hydrolysis kinetics of isosorbide diaspirinate

Aspirin prodrugs have been intensively investigated in an effort to produce compounds with lower gastric toxicity, greater stability or enhanced percutaneous absorption, relative to aspirin. This report describes the hydrolysis kinetics and aspirin release characteristics of isosorbide diaspirinate (ISDA), the aspirin diester of isosorbide. ISDA underwent rapid hydrolysis when incubated in phosphate buffered human plasma solutions (pH 7.4) at 37 degrees C, producing appreciable quantities of aspirin. In 30% human plasma solution the half-life was 1.1 min and 61% aspirin was liberated relative to the initial ester concentration. The hydrolysis kinetics of ISDA were monitored in aqueous solution at 37 degrees C over the pH range 1.03-9.4. The aqueous hydrolysis followed pseudo-first-order kinetics over several half-lives at all pH values, resulting in a U-shaped pH rate profile. Salicylate esters and salicylic acid were formed during these processes. The hydrolysis characteristics of ISDA were also investigated in pH 7.4 phosphate buffered solutions containing alpha-chymotrypsin [EC 3.1.1.1] (t(1/2)=200.9 min), carboxyl esterase [EC 3.1.1.1] (t(1/2)=31.5 min), human serum albumin (t(1/2)=603 min), purified human serum butyrylcholinesterase [EC 3.1.1.8] (80 micro g/ml; t(1/2)=9.4 min; 55% aspirin), purified horse serum butyrylcholinesterase (100 micro g/ml; t(1/2)=1.85 min;11% aspirin) and in 10% human plasma solution in the presence of physostigmine (3 micro M). The results indicate that a specific enzyme present in human plasma, probably human butyrylcholinesterase, catalyses aspirin release from isosorbide diaspirinate.     

Membrane osmometry of solubilized systems

The solubilization of decane, ethyl p-hydroxybenzoate, methyl anisate and p-hydroxybenzoic acid by aqueous micellar solutions of cetomacrogol 1000 has been examined by membrane osmometry and viscosity techniques. The effect of the solubilizates on the number-average micellar molecular weight, M_n, has been related to their site of incorporation in the micelle. Decane and methyl anisate are solubilized in the hydrocarbon core of the micelles and both compounds produce an increase in M_n up to a maximum value of 2·0 times 10⁵, at a solubilizate concentration of approximately 80% of the saturation limit for each compound. This increase is shown to result from an increase in the number of molecules of both solubilizate and of surfactant per micelle. Further addition of solubilizate, to produce a saturation level in excess of 80%, results in a decrease in micellar size in both systems. The solubilization of ethyl p-hydroxybenzoate and p-hydroxybenzoic acid is thought to involve the oxyethylene region of the micelle and both solubilizates cause an increase in M_n owing to the inclusion of solubilizate into the micelle, the number of molecules of surfactant per micelle being unaffected by the solubilization process. Viscosity studies on the decane-ceto-macrogol-water system are interpreted as indicating no change in either micellar symmetry or hydration as a result of solubilization. A spherical model for the micelles is shown to be consistent with the experimental data.     

Water-in-oil solubilized vaccine adjuvants

The solubilization of water and toxoid solutions in oils by non-ionic surface-active agents has been examined. Water-in-oil solubilized adjuvant formulations of vaccines containing Clostridium welchii type D toxoid as antigen have been tested in laboratory animals. The antitoxin titres in rabbit serum induced by the most successful formulation were as high 14 weeks after a single dose, as the peak titres after two doses of a simple aluminium hydroxide adsorbed vaccine. The vaccines are clear and of low viscosity which facilitates accurate measurement and handling by syringe.     

The dissolution of aspirin and aspirin tablets

An attempt has been made to standardize the “beaker” method of measuring in vitro dissolution rates of tablets against published data for aspirin. An unexpected problem arose when it was found that samples of commercial aspirin have different intrinsic dissolution rates. The form of aspirin used in tablet manufacture is likely therefore to be of significance from the viewpoint of in vivo dissolution and drug availability.     

Stability of indomethacin solubilized system.

Physical and chemical stability testing was carried out for indomethacin in the form of solution, syrup and elixir solubilized by Tween 80 and Brij 99. It was found that sucrose and alcohol markedly stabilize the indomethacin solution.     

Factors affecting solubilized dopamine-sensitive adenylate cyclase

Bovine striatal adenylate cyclase was solubilized with sodium cholate and assayed for its responsiveness to a variety of agents. Magnesium ions (0–20 mM), guanylyl-imidodiphosphate (10–50 μM), and striatal lipids were effective in increasing enzyme activity. The adenylate cyclase could be stimulated by dopamine, and neuroleptic drugs inhibited the effect of dopamine (50 μM) with potencies that paralleled their clinical potencies. The ic₅₀ values for spiroperidol, haloperidol and chlorpromazine were 0.2, 3 and 500 nM respectively.     

阿司匹林抵抗机制及防治研究进展

阿司匹林是预防心血管事件的常用药物,但并不是所有服用阿司匹林的患者均能获得满意的疗效,这一现象称之为阿司匹林抵抗。对于它的发生机制及防治方法说法众多,该文根据已有文献报道,进行了综述。     

Modified USP assay for simultaneous determination of aspirin and nonaspirin salicylates in aspirin and buffered aspirin tablets.

Modified USP procedures are described for the simultaneous determination of nonaspirin salicylates and aspirin in aspirin and buffered aspirin tablets. The existing USP procedures are not stability indicating for intact aspirin when significant levels of nonaspirin salicylates are present, as is often the case in short-term, high temperature stability programs. The modified procedures yeld considerably shorter analysis times and stability-indicating assays for intact aspirin without the need for sophisticated equipment other than that presently required by USP XIX.     

Nonplatelet-mediated effects of aspirin

Aspirin has nonplatelet-mediated effects that contribute to its efficacy in the primary and secondary prevention of coronary events. These include antiarrhythmic effects, as shown in animal studies, and antiatherosclerotic effects related to increase in nitric oxide synthesis/activity and reduction in inflammatory mediators. Epidemiological studies have also shown primary antiinflammatory properties. Aspirin is known to inhibit vascular smooth muscle cell proliferation and to produce an endothelial stabilizing effect. Other observed outcomes from the administration of this compound include a modest anticoagulant activity, angiogenesis reduction and a decrease in oxidant stress. We believe that these results complement the antiplatelet effect and make this agent unique in the management of ischemic heart disease.     

阿司匹林抵抗的研究进展

患者尽管服用阿司匹林,但缺血性血管事件仍时有发生,故认为可能与阿司匹林抵抗(Aspirin resistance,AR)有关.阿司匹林抵抗有临床定义和实验室检测血小板活性定义2种,可分为3种不同类型.AR不仅存在于健康人,也可发生在不同疾病患者中,发病机制有多种可能.不同类型AR患者,可以通过增加阿司匹林剂量或通过使用其他抗血小板制剂获益.