Nakamura M.,Gifu Pharmaceutical University
Biomedical Chromatography | Year: 2011
Benzodiazepines are among the most frequently prescribed drugs due to their sedative, hypnotic, anxiolytic, muscle relaxant and antiepileptic properties. Because of the high consumption of benzodiazepines worldwide, this class of drugs and their metabolites are frequently present in both clinical and forensic cases. For these reasons, the analysis of benzodiazepines and their metabolites in biological fluids is of great interest to clinicians and forensic toxicologists. This paper reviews procedures for multi-analyte single-stage (LC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) using different mass analyzers for the screening, identification and/or quantification of drugs, poisons and/or their metabolites in blood, plasma, serum or urine published since 2001. Basic information about the biosamples assayed, work-up, LC column, mobile phase, ionization type, mass spectral detection mode, matrix effects and validation data for each procedure is summarized. The feasibility of using LC-MS(/MS) techniques to identify and quantify benzodiazepines and their metabolites is also discussed. © 2011 John Wiley & Sons, Ltd.
Sajiki H.,Gifu Pharmaceutical University
Yakugaku Zasshi | Year: 2013
Deuterium (D) labeled compounds are utilized in various scientific fields such as mechanistic elucidation of reactions, preparation of new functional materials, tracers for microanalysis, deuterium labeled heavy drugs and so on. Although the H-D exchange reaction is a straightforward method to produce deuterated organic compounds, many precedent methods require expensive deuterium gas and/or harsh reaction conditions. A part of our leading research agendas is intended to the development of novel and functional heterogeneous platinum-group catalysts and the reclamation of unknown functionalities of existing heterogeneous platinum-group catalysts. During the course of the study, benzylic positions of substrates were site-selectively deuterated under mild and palladium-on-carbon (Pd/C)-catalyzed hydrogenation conditions in heavy water (D2O). Heat conditions promoted the H-D exchange reactivity and facilitated the H-D exchange reaction at not only the benzylic sites but also inactive C-H bonds and heterocyclic nuclei. It is noteworthy that platinum-on-carbon (Pt/C) indicated a quite high afinity toward aromatic nuclei, and the H-D exchange reaction was strongly enhanced by the use of Pt/C as a catalyst under milder conditions. The mixed use of Pd/C and Pt/C was found to be more eficient in the H-D exchange reaction compared to the independent use of Pd/C or Pt/ C. Furthermore, simple alkanes could also be eficiently deuterated under rhodium-on-carbon (Rh/C)-catalyzed conditions. The use of ruthenium-on-carbon (Ru/C) enabled the regiospecific and eficient deuterium incorporation at α-positions of alcohols and results were applied as a regio- and stereoselective multi-deuteration method of sugar derivatives. © 2013 The Pharmaceutical Society of Japan.
Tsukamoto K.,Gifu Pharmaceutical University
Clinical Therapeutics | Year: 2015
Purpose The incidence of Alzheimer's disease (AD) has been steadily increasing worldwide. AD is a serious disease that has both societal and economic impacts. The greatest risk factor for AD is aging. Thus, because of the rapidly aging population in Japan, the development of new, effective drugs for AD is urgently needed. The goal of the present article was to analyze the status, clarify the problems, and discuss the scientific and political challenges of disease-modifying drug development for AD. Methods Public data, official documents, literature, and news releases were surveyed and discussed. Findings Compared with diabetes mellitus drugs, there is a lack of quantitative surrogate end points among AD drugs. Much AD drug development has focused on amyloid-β and its associated pathways; however, these drugs have not shown efficacy in Phase III clinical trials. Thus, the US Food and Drug Administration has appealed for a new draft industrial guidance for the development of AD drugs, including those for early-stage AD. In Japan, the Minister of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency have also taken action, including the publication of potential new guidelines for clinical evaluation and development of new AD therapeutics, including drugs. Moreover, scientific initiatives to develop novel AD drugs are ongoing. Implications The development of quantitative surrogate end points remains necessary to improve the development of AD drugs. Therefore, collaboration among industry, government, and academia should be encouraged. Following the principles of regulatory science, strategies to develop drugs for illnesses with unmet needs can be framed by investigating the effects of past, current, and future AD drug development initiatives. © 2015 Elsevier HS Journals, Inc. All rights reserved.
Hozumi I.,Gifu Pharmaceutical University
Current Pharmaceutical Biotechnology | Year: 2013
Metallothionein (MT) is a small molecular and multi-functional protein containing four atoms of copper (Cu) and three atoms of zinc (Zn) per molecule. It was isolated from the horse kidney in 1957 and half a century has passed since then. Although MT was found to work as a modulator of Zn and induce anti-oxidant reaction, the precise functions and its functional mechanisms remain to be elucidated. Over the years, a new isoform of MT, MT-III (also called growth inhibitory factor (GIF)), has been found in the brain, which was markedly diminished in the brain of Alzheimer's disease (AD). Many new findings on MT have been discovered in neurodegenerative diseases other than AD such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), prion disease, brain trauma, brain ischemia, and psychiatric diseases. In ALS in particular, MTs were markedly diminished in the spinal cord of patients with ALS. Initially, MT, which easily binds to cadmium (Cd) and copper (Cu), was considered to be toxic to our bodies. Molecular biological technologies enabled the production of recombinant MT saturated with zinc (Zn). MT has a high potential for the treatment of neurodegenerative diseases such as ALS, AD, and PD owing to its various functions including anti-oxidant properties and modulators not only for Zn but for Cu in the extra- and intracellular spaces. On the other hand, there are still various problems on MT to be elucidated in detail, including their binding proteins and functional mechanisms. © 2013 Bentham Science Publishers.
Sajiki H.,Gifu Pharmaceutical University
Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry | Year: 2014
The functional group manipulation is fundamental in synthetic organic chemistry. Hence, the development of chemoselective hydrogenation methods using a heterogeneous catalyst has been a topic of sustained interest in a synthetic organic chemistry. While many applications to achieve a chemoselective catalyst system have been evaluated, only a few studies such as Lindlar catalyst and Rosenmund's reaction have been accepted as general chemoselective methodologies. We have successfully developed useful heterogeneous catalysts such as a combination of Pd/C and a nitrogen-containing base, Pd/C-ethylenediamine complex [Pd/C(en)], Pd/C-diphenyl sulfide complex [Pd/C(Ph2S)], Pd-fibroin complex [Pd/Fib], Pd-molecular sieves complex (Pd/MS), Pd-boron nitride complex (Pd/BN), Pd-polyethyleneimine complex (Pd/PEI), and a combination of Pd/BN and a nitrogen-containing base, possessing specific characteristics and suppressed catalyst activities to enable the reliable and chemoselective hydrogenation among various reducible functionalities. This review provides a brief overview of each of the catalyst systems with a focus on specific features and catalyst activities in a comprehensive manner.