Our previous experiments in the rat showed that aluminum L-glutamate complex (Al L-Glu) crosses the blood-brain barrier and accumulates in selective brain areas and that Al salts may increase D-aspartic acid forms in living brain proteins, probably by inducing more thermodynamically stable structures than L isomers. As magnesium blocks NMDA receptors, D-aspartic acid was used in the present study in the form of magnesium salt to prevent the excitotoxicity of dicarboxylic amino acids. Effects on brain amino acids and Al cortex levels in mature rats were studied after chronic treatment with Al L-Glu or Na L-Glu alone or in association with magnesium D-aspartate (Mg D-Asp). Results demonstrate that treatment with Mg D-Asp induces a decrease in the Al concentration in brain cortex of Al L-Glu-treated rats. In aluminum-free treated controls, treatment with Mg D-Asp in association with Na L-Glu also induces a decrease in Al concentration in brain cortex. These data indicate that Mg D-Asp administration protects rat brain cortex from Al accumulation and suggest that this treatment may be useful in preventing brain Al intoxication. 相似文献
Stereoisomer interconversion of chiral drug substances is of significant importance if it occurs within pharmacological and pharmaceutical time scales and under physiological and shelf life conditions. Several analytical techniques exist for the determination of first order rate constants and enantiomerization energy barriers by dynamic and stopped flow chromatography, mathematical models and functions, and computer programs. The focus of this work is to utilize a simple supercritical fluid chromatography (SFC) chiral assay to determine the possibility of interconversion of the desired R and less active S isomers of a drug candidate. The rate constants of racemization and enantiomerization, the half life of racemization, and enantiomerization energy barriers were determined for the R → S (or, forward) and S → R (or, reverse) conversions. The method was selective and sensitive enough to detect less than 1% interconversion occuring under the conditions studied. The method also demonstrated that R ? S racemization was possible only under extreme conditions of prolonged heating (80 °C) and highly basic pH (9.5). 相似文献
In order to improve physico-chemical properties and to enhance stability of drugs, amino acid salt has been widely adopted
in pharmaceutical synthesis. Acetylsalicylic acid lysinate is one of the widely used analgesics and it is a good example of
this synthesis. In the case of acetylsalicylic acid lysinate synthesis, racemization of naturally occurred lysine is essential
because the racemic lysine salt of the drug shows better yield, crystallinity and dryness than that of the L-lysine salt.
To establish a simple, practical and economical process for L-lysine racemization, L-lysine treatments with phosphoric acid
and with acetic acid were compared and the optimum conditions for its process and derivatization were investigated by chiral
separation methods using GC-MS spectroscopy. 相似文献
A reversed-phase high-performance liquid chromatographic method was developed to determine the optical purity of metoprolol enantiomers. The enantiomers were converted to diastereomeric derivatives using (-)-menthyl chloroformate reagent. Separation of the enantiomers as diastereomers was achieved by reversed-phase HPLC within 30 min using Inertsil C8 column. This method allowed determination of 0.05% of either enantiomer in the presence of its stereoisomer and method validation showed adequate linearity over the required range. Owing to the reaction condition during the derivatization with (-)-menthyl chloroformate, the possibility of racemization had to be established. Different ratios of (S)-(-)-metoprolol and (R)-(+)-metoprolol were prepared. Enantiomeric separation of these mixtures took place on a chiralcel OD column or, after derivatization with (-)-menthyl chloroformate, on a C8 column. The results from the these two independent separation systems were compared with trace racemization and were in very good agreement. No racemization was found during the experiment. 相似文献
The potent histamine H(1)-receptor antagonist cetirizine (Zyrtec) is a racemic mixture of levocetirizine (now available under the trademark Xyzal and dextrocetirizine. In this Commentary, we examine some biological properties of cetirizine and levocetirizine, namely enantioselectivity in pharmacological activity and pharmacokinetic properties, with emphasis on the possibility of racemization, the compared behavior of the two enantiomers, and the potential for interactions with other drugs. Recent data demonstrate that the antihistaminergic activity of the racemate is primarily due to levocetirizine. Levocetirizine is rapidly and extensively absorbed, poorly metabolized, and not subject to racemization. Its pharmacokinetic characteristics are comparable after administration alone or in the racemate. Its apparent volume of distribution is smaller than that of dextrocetirizine (0.41 L kg(-1) vs. 0.60 L kg(-1)). Moreover, the non-renal (mostly hepatic) clearance of levocetirizine is also significantly lower than that of dextrocetirizine (11.8 mL min(-1) vs. 29.2 mL min(-1)). Our conclusion is that levocetirizine is indeed the eutomer of cetirizine. The evidence reviewed here confirms preclinical findings and offers a rationale for the chiral switch from the racemate to levocetirizine. 相似文献
Introduction: Racemization has long been an ignored risk in drug development, probably because of a lack of convenient access to good tools for its detection and an absence of methods to predict racemization risk. As a result, the potential effects of racemization have been systematically underestimated.
Areas covered: Herein, the potential effects of racemization are discussed through a review of drugs for which activity and side effects for both enantiomers are known. Subsequently, drugs known to racemize are discussed and the authors review methods to predict racemization risk. Application of a method quantitatively predicting racemization risk to databases of compounds from the medicinal chemistry literature shows that success in clinical trials is negatively correlated with racemization risk.
Expert opinion: It is envisioned that a quantitative method of predicting racemization risk will remove a blind spot from the drug development pipeline. Removal of the blind spot will make drug development more efficient and result in less late-stage attrition of the drug pipeline. 相似文献
The racemization of (−)-adrenaline was followed by polarimetric variable-temperature kinetic experiments obtaining activation parameters and kobs(T) profile in one tenth of the time usually spent for traditional kinetic runs. A polarimeter connected to a computer for the acquisition and processing of the analytical data was used. The kinetic profiles were processed by both an integral method and a differential method. The results are in good agreement with each other and with those obtained by constant-temperature kinetics. 相似文献