Novel strategies for microdose studies using non-radiolabeled compounds

Microdose studies using non-radiolabeled compounds enable assessment of the clinical pharmacokinetics of drug candidates in humans without the need to synthesize radiolabeled compounds. We have demonstrated that the quantification limits of many drugs measured by LC-MS/MS are low enough to allow estimation of their pharmacokinetic parameters following administration of a microdose. Our previous microdose studies with LC-MS/MS demonstrated the linear pharmacokinetics of fexofenadine between microdoses and therapeutic doses. We also obtained time profiles of plasma concentrations of nicardipine and its multiple metabolites following administration of a microdose. A significant advantage of using non-radiolabeled compounds is the ability to perform cassette microdose studies. By administering multiple drug candidates to the same subject, we can select compounds with appropriate pharmacokinetic properties simultaneously. We can also clarify major factors dominating the pharmacokinetics of drug candidates by cocktail microdosing of the test compounds and probe substrates with or without specific inhibitors for enzymes/transporters.     

Novel chemical strategies for thymidylate synthase inhibition

Thymidylate synthase (TS) is a well-validated target for cancer chemotherapy. TS was established as the principal target of the widely used anticancer drug 5-fluorouracil (5FU). The 5FU metabolite FdUMP forms a covalent complex with TS that is stabilized by 5-formyl tetrahydrofolate (leucovorin; LV). Numerous chemical strategies have been employed to develop novel TS inhibitors that are superior to 5FU/LV. 5FU is non-ideal as a TS-inhibitory drug because it is only inefficiently converted to FdUMP, while the remainder of the administered dose is converted to toxic metabolites. My laboratory has explored the utility of FdUMP[N] compounds (oligodeoxynucleotides comprised of FdUMP nucleotides) as FdUMP pro-drugs. FdUMP[N] compounds result in potent TS-inhibition, and display many advantages relative to 5FU/LV. A number of other chemical strategies have also been employed to develop pro-drugs, or metabolic precursors of FdUMP, and several of these strategies will be reviewed. In addition to chemical strategies to develop FdUMP pro-drugs, a number of chemical strategies have been devised to develop molecules that resemble the reduced folate co-factor required for TS catalysis. The synthesis of antifolates that have TS-inhibitory activity, such as Raltitrexed, has resulted in compounds that are effective and specific TS-inhibitors and, in some cases, have clinical potential. Chemical strategies that target TS mRNA for destruction are also being explored as potential chemotherapeutics. These diverse chemical approaches to control TS activity in tumor cells for the treatment of cancer will be reviewed.     

Novel reactions using organoselenium compounds

Organoselenium compounds are important tools in the field of synthetic chemistry because their specific reactivities have been used as the key reactions in the synthesis of various organic compounds. Nucleophilic organoselenium reagents are frequently utilized to introduce a selenium atom into organic molecules. However, there is no method available for the direct transformation of a hydroxy group into a selenayl group, except for the Grieco-Nishizawa reaction. In this review, novel methods for the conversion of alcohols into selenides in one step are described: both selenolate-aluminum chloride and TMSSePh-aluminum bromide are effective reagent systems for this transformation. Although benzylic alcohols could be efficiently converted to the corresponding selenides, these reagent systems were not applicable to non-benzylic alcohols. On the other hand, the reaction of cinnamyl alcohol with TMSSePh-aluminum bromide afforded 4-phenylselenochroman as a main product. The scope and limitations of this selenochroman formation were investigated using several types of allyl alcohols. To clarify the reaction path, the reaction of cinnamyl phenyl selenide with aluminum bromide was carried out. As expected, 4-phenylselenochroman was obtained in high yield. The transformation of various cinnamyl selenides was also successful in generating the corresponding selenochroman derivatives. Consequently, we developed a novel method for selenochroman synthesis.     

全球免疫细胞治疗药物开发现状与趋势

细胞治疗作为一种突破性的新型治疗方式,对癌症等重大难治性疾病的治疗具有革命性的意义,目前已成为最具潜力的治疗途径之一。多年来,日本一直在细胞治疗产品的技术研发和监管政策方面保持全球领先地位,得益于其完整的法律体系与特殊的审批政策。系统对比中日两国在细胞治疗产品临床管理方面的相关法规、部门责任以及审批路径,为确立安全、规范、稳定、可追溯的细胞治疗产品管理提供借鉴与参考。

     

Electrospinning of polysaccharides for regenerative medicine

Electrospinning techniques enable the production of continuous fibers with dimensions on the scale of nanometers from a wide range of natural and synthetic polymers. The number of recent studies regarding electrospun polysaccharides and their derivatives, which are potentially useful for regenerative medicine, is increasing dramatically. However, difficulties regarding the processibility of the polysaccharides (e.g., poor solubility and high surface tension) have limited their application. In this review, we summarize the characteristics of various polysaccharides such as alginate, cellulose, chitin, chitosan, hyaluronic acid, starch, dextran, and heparin, which are either currently being used or have potential to be used for electrospinning. The recent progress of nanofiber matrices electrospun from polysaccharides and their biomedical applications in tissue engineering, wound dressings, drug delivery, and enzyme immobilization are discussed.     

中成药非法添加化学成分的现状及对策

目的为中成药及保健食品中非法添加化学药品检验工作的开展提出参考意见。方法针对中成药中非法添加化学药品检验过程中存在的问题,阐述了其对人类健康的危害,归纳了常用的检测方法,提出了相应的对策。结果加大监管力度,完善法律法规与监督管理制度,加快检验标准研究,可有效打击中成药非法添加化学药品的行为。结论应通过多种途径,深入开展中成药中非法添加化学药品的研究工作。     

Small molecules and future regenerative medicine

Recent advances in stem cell biology may make possible new approaches for the treatment of a number of diseases including cardiovascular disease, neurodegenerative disease, musculoskeletal disease, diabetes and cancer. These approaches could involve cell replacement therapy and/or drug treatment to stimulate the body's own regenerative capabilities by promoting survival, migration/homing, proliferation, and differentiation of endogenous stem/progenitor cells. However, such approaches will require identification of renewable cell sources of engraftable functional cells, an improved ability to manipulate their proliferation and differentiation, as well as a better understanding of the signaling pathways that control their fate. Cell-based phenotypic and pathway-specific screens of synthetic small molecules and natural products have historically provided useful chemical ligands to modulate and/or study complex cellular processes, and recently provided a number of small molecules that can be used to selectively regulate stem cell fate and developmental signaling pathways. Such molecules will likely provide new insights into stem cell biology, and may ultimately contribute to effective medicines for tissue repair and regeneration.     

Novel compounds to combat trypanosomatid infections: a medicinal chemical perspective

Introduction: The current therapeutic arsenal against the kinetoplastids Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. is clearly inadequate and underscores the urgent need to develop new effective, safe and cost-effective drugs.

Areas covered: Accordingly, this review of patented products and processes using anti-kinetoplastid agents provides insight into the identification of novel or more refined drugs. In this review, we describe products developed in recent years for the treatment of human African trypanosomiasis, American trypanosomiasis and leishmaniasis from a medicinal chemical perspective.

Expert opinion: Applications so far have looked only superficially for candidate anti-trypanosomatid drugs and are deficient in the final stages of drug development studies, i.e., tolerance/safety, selectivity, drug-resistance, scaling-up, pharmacokinetic and pharmacodynamic assays. The ultimate goal for production of agents with anti-HAT activity has been the development of dicationic agents with parasite DNA-binding activity. Another goal for control of human African trypanosomiasis as well as for Chagas disease and leishmaniasis is the development of protease inhibitors. It should also be noted that several recent studies describing promising targets and compounds have not yet been patented. An effort should be made by foundations, international health organizations and pharmaceutical corporations to support analysis and development of promising new chemotherapeutic agents for controlling the trypanosomiasis and leishmaniasis.     

Novel compounds to combat trypanosomatid infections: a medicinal chemical perspective

INTRODUCTION: The current therapeutic arsenal against the kinetoplastids Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. is clearly inadequate and underscores the urgent need to develop new effective, safe and cost-effective drugs. AREAS COVERED: Accordingly, this review of patented products and processes using anti-kinetoplastid agents provides insight into the identification of novel or more refined drugs. In this review, we describe products developed in recent years for the treatment of human African trypanosomiasis, American trypanosomiasis and leishmaniasis from a medicinal chemical perspective. EXPERT OPINION: Applications so far have looked only superficially for candidate anti-trypanosomatid drugs and are deficient in the final stages of drug development studies, i.e., tolerance/safety, selectivity, drug-resistance, scaling-up, pharmacokinetic and pharmacodynamic assays. The ultimate goal for production of agents with anti-HAT activity has been the development of dicationic agents with parasite DNA-binding activity. Another goal for control of human African trypanosomiasis as well as for Chagas disease and leishmaniasis is the development of protease inhibitors. It should also be noted that several recent studies describing promising targets and compounds have not yet been patented. An effort should be made by foundations, international health organizations and pharmaceutical corporations to support analysis and development of promising new chemotherapeutic agents for controlling the trypanosomiasis and leishmaniasis.     

Electrospun silk biomaterial scaffolds for regenerative medicine

Electrospinning is a versatile technique that enables the development of nanofiber-based biomaterial scaffolds. Scaffolds can be generated that are useful for tissue engineering and regenerative medicine since they mimic the nanoscale properties of certain fibrous components of the native extracellular matrix in tissues. Silk is a natural protein with excellent biocompatibility, remarkable mechanical properties as well as tailorable degradability. Integrating these protein polymer advantages with electrospinning results in scaffolds with combined biochemical, topographical and mechanical cues with versatility for a range of biomaterial, cell and tissue studies and applications. This review covers research related to electrospinning of silk, including process parameters, post treatment of the spun fibers, functionalization of nanofibers, and the potential applications for these material systems in regenerative medicine. Research challenges and future trends are also discussed.     

Chemically-modified HA for therapy and regenerative medicine

Hyaluronan (HA) is a very useful polymer, but its properties sometimes need to be altered or enhanced by chemical modification for biomedical applications. A wide variety of HA derivatives are currently used for eye surgery, joint viscoelastic supplementation, and anti-adhesion films. The future promises to deliver new classes of HA-based reagents as well as new polymers that can be used in situ with living cells or within the body.     

Development of low endotoxin gelatin for regenerative medicine

The basic concept of tissue engineering, an actively applied technology in regenerative medicine, is the coordination between cells, scaffolds, and proliferation factors. Collagen and gelatin are materials that have mostly been used as scaffolds because of their excellent affinity for cells, they are biodegradable, and their ability to form gel. However, very few of the collagen or gelatin preparations used as tissue engineering material have been prepared with low levels of endotoxin, which may trigger fever, shock and a fall in blood pressure even in very minute quantities. Therefore we decided to decrease the content of endotoxin in gelatin so that this biomaterial is not harmful to the body but still maintains its properties, namely, bioaffinity and biodegradation for use in the fields of cell culture and regenerative medicine. In this paper, we describe a method whereby endotoxin could be removed from gelatin solution by using an ultrafiltration membrane with a molecular weight cut-off of 100 kDa and low endotoxin gelatin, endotoxin activity in 0.1% gelatin solution was below 0.03 EU/ml, was obtained as the resulting filtrate solution.     

Novel therapeutic strategies

Of the many sessions during the first day of the EPHAR meeting, several interesting topics emerged. Among these were a number of presentations investigating novel anti-inflammatory targets, including the search for a selective COX-2 inhibitor and the potential of cytokines/cytokine receptor targets (eg TNFalpha) as treatments for rheumatoid arthritis (RA) and other chronic inflammatory conditions. Recent advances in the understanding of the pathogenesis of diabetes and obesity have highlighted the need for a multi-therapeutic approach to treatment; several drugs in preclinical investigations were highlighted. Attention was drawn to the potential of AMPA/kainate receptors, historically investigated for the treatment of neurodegenerative disease, which are now showing promise as anti-ischemic therapeutics. Many novel therapeutics strategies were discussed in detail, including the CCK-B antagonists with considerable anxiolytic potential, mitochondrial mechanisms as targets for the treatment of brain injury and the use of stress-activated proteins in anti-ischemic research.