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Volume 120 (2002)
- Issue 6 Pages 373-
- Issue 5 Pages 276-
- Issue 4 Pages 215-
- Issue 3 Pages 141-
- Issue 2 Pages 73-
- Issue 1 Pages 7-
Volume 120, Issue 3
Displaying 1-7 of 7 articles from this issue
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Reviews: Pharmacology as Translational Research: Strategies and Problems
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Toshio TANAKA, Gozoh TSUJIMOTO, Yuichi SUGIYAMA, Yasuhiro HASHIMOTOArticle type: Reviews
2002 Volume 120 Issue 3 Pages 141-148
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSThe Human Genome Project provides insights so profound that it has the ability to change everything we know about medicine and how medicines are developed. Pharmacogenomics is defined as studies to identify the genes that are involved in determining the responsiveness to a given drug and to distinguish responders and non-responders to a given drug. Genome sequencing, transcriptome, and proteome analysis are of particular significance in pharmacogenomics. Transcriptome analysis can be done by methods of random cDNA sequencing, mRNA display and, differential hybridization (i.e., cDNA microarray and associated methods). Our results suggest that the pharmacogenomic transcriptome analysis and pharmainformatics have potential as strategies for defining novel drug targets in various diseases. Pharmacogenomics enhances the development, commercialization, and clinical use of conventional pharmaceutical products for common diseases, and it will eventually become a powerful tool for Evidence-Based Medicine. It is also important to predict interindividual pharmacokinetic differences by genetic polymorphisms of transporters or pharmacokinetic changes by transporter-mediated drug interactions during drug development. Pharmacogenomics and pharmainformatics enable us to move quickly and efficiently from targets to appropriate medicines.
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Yoji KAWANO, Takeshi YOSHIMURA, Kozo KAIBUCHIArticle type: Reviews
2002 Volume 120 Issue 3 Pages 149-158
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSAn increment in a cytoplasmic Ca2+ concentration is the key event in smooth muscle contraction. However, smooth muscle contraction is modified upon the stimulation by agonists as well as in some pathophysiological situations through a Ca2+-independent mechanism. The molecular mechanism underlying this modulation has not been elucidated. Small GTPase Rho regulates cytoskeleton, cell adhesion, cell motility, and smooth muscle contraction through its specific effector proteins. Recent studies have shown the important role of Rho and its effector, Rho-associated kinase (Rho-kinase)/ROK/ROCK in Ca2+-independent regulation of smooth muscle contraction. The Rho/Rho-kinase pathway is involved in cardiovascular diseases such as hypertension and vasospasm, and it is a potent target of new therapies for not only cardiovascular diseases, but also for the protection of multiple organs.
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Susumu OKABE, Kazuharu FURUTANI, Kazuhiko MAEDA, Takeshi AIHARA, Terua ...Article type: Reviews
2002 Volume 120 Issue 3 Pages 159-171
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSMechanisms for gastric acid secretion have been elucidated through invention of new methods and new drugs. Current genetic technology have generated knockout (KO) mice lacking receptors such as CCK2, histamine H2, muscarinic M3 and M1, or enzymes such as histidine decarboxylase (HDC) and H+,K+-ATPase. Here, we review the functional and morphological changes in the gastric mucosa of such KO mice. In M3R-KO mice (intragastric pH 5.9), carbachol, histamine and gastrin stimulated acid secretion like they did in wild-type mice. Carbachol-stimulated acid secretion was significantly inhibited by famotidine and pirenzepine. The serum gastrin level in M3R-KO mice was increased, yet the stomach weight and the gastric mucosa remained unchanged. In H2R-KO mice (intragastric pH 3.0), serum gastrin and mucosal histamine levels significantly increased. Carbachol significantly stimulated acid secretion, yet histamine and gastrin had little or no effect on acid secretion. The stomach wet weight increased with time after birth and the serum albumin level was decreased. In the gastric mucosa with hyperplasia, numerous enlarged cysts and a marked expression of TGF-α were observed, indicating the occurrence of Menetrier's disease like mucosal changes. G/D cell ratio was greatly increased, providing evidence of the increased serum gastrin level. In HDC-KO mice (intragastric pH 4.5), the stomach weight was also increased 6 mo after birth, with no enlarged cysts in the gastric mucosa. Conclusion: The above results indicate that KO mice can be used to yield many important findings that selective antagonists cannot reveal.
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Tsuneyuki YAMAMOTO, Teruaki UNEArticle type: Reviews
2002 Volume 120 Issue 3 Pages 173-180
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSAnimal models of psychiatric disorders are indispensable tools to gain insights into neural mechanisms underlying these disorders and to assess potential therapeutic actions of novel compounds in preclinical settings. However, it is difficult to establish appropriate animal models for these disorders because there is no proof on whether or not what occurs in the animal brain is comparable to what occurs in the human brain. The initial development of animal models of psychiatric disorders is often based on “face validity” as reflected in the similarity of behavioral signs and symptoms observed in humans and animal and subsequently based on “construct validity” as measured by strong correlation in behaviors and neural events between the animal model and patients of the disorder. The practical value of such animal models is reflected ultimately in their “predictive validity” in predicting the therapeutic efficacy of new treatments for psychiatric disorders. The present review will focus on animal models of schizophrenia and depression by the use of mainly environmental stress and pharmacological treatments, which are expected to induce signs and symptoms analogous to those of patients with such disorders.
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Noritaka ARIYOSHIArticle type: Reviews
2002 Volume 120 Issue 3 Pages 181-186
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSThe human genome project has a large impact on various drug-related fields including drug discovery and clinical medication. Although clinical pharmacogenetics introduced the importance of studying genetic factors determining inter-individual variation on drug response for establishing a personalized medicine, which will be achieved in this century, recent strategies for exploring the genetic factors drastically differ from those of classical pharmacogenetics. The usefulness of an application of findings obtained from basic researches to a medication is uncertain at present because of limited in vivo evidence on the significance of genetic polymorphism to ensure an efficacy or to avoid adverse reactions of the drugs. In this review, a brief history of pharmacogenetics and the current status of the research are summarized. A number of problems that make it difficult to do clinical trials to clarify the significance of genetic polymorphism are discussed. Finally, it is expected in the near future that information on genetic variation with in silico technologies may predict the response toward drugs in each patient with various physiological and therapeutic conditions.
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Tamiko SUZUKI-NISHIMURA, Satoshi TOYOSHIMA, Yoshiaki UYAMA, Hiroaki YA ...Article type: Reviews
2002 Volume 120 Issue 3 Pages 187-194
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSThe Organization for Pharmaceutical Safety and Research (OPSR), Pharmaceuticals and Medical Devices Evaluation Center (PMDEC), National Institute of Health Sciences and Ministry of Health, Labour, and Welfare (MHLW) are working together on the new pharmaceutical approval process in Japan for appropriate scientific approaches. The Consultation Division of OPSR helps the pharmaceutical companies to answer find solutions to their concerns about non-clinical and clinical trials in the new pharmaceutical development process. After a new pharmaceutical application, PMDEC evaluates the quality, efficacy, and safety of each pharmaceutical compound in the review process. Final judgment for approval is made by MHLW. Pharmacological mechanisms examined in non-clinical trials would be useful for selection of the appropriate end-point in the clinical trials. For safety assessment, International Conference of Harmonization (ICH) Guideline on Safety Pharmacology Studies was officially notified. According to pharmacological data on safety, clinical investigators can better design clinical trials to prevent patients from suffering serious adverse events. To development new epoch pharmaceuticals, continuous progress on pharmacological research will be indispensable. Further discussion among all interested parties such as pharmacological researchers, medical doctors, companies, and regulatory sites will be necessary and useful to develop more appropriate approaches in the pharmaceutical development process.
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Original Article
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Masatoshi KOBAYASHI, Kuniko HARA, Yasuhiro AKIYAMAArticle type: Original Article
2002 Volume 120 Issue 3 Pages 195-204
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSTwo experiments were carried out using 7-week-old male Wistar rats. Exp. 1: Rats in the intact group were fed with normal diet (0.5% Ca, 0.09% Mg). Ca/Mg deficient rats were fed low Ca (0.01%) diets containing 0.003, 0.015 or 0.09% Mg for 4 weeks. After 4 weeks, the bone mineral density (BMD) and maximum load in the femur were decreased in Ca/Mg deficient rats, but this was not dependent on dietary Mg concentration. The elasticity, stiffness, and Mg concentration in the femur of these rats were also decreased and Ca deposition in the kidney were increased, compared to those of normal rats, which were related to Mg concentration in the diet. From these results, Mg may play an important role in qualitative changes in bone (i.e., reduced stiffness). Exp. 2: We investigated the effects of V.K2 on the changes in BMD and bone strength in femur induced by low Ca/Mg (0.01%/0.003%) diet for 8 weeks. Compared to the intact group, Ca and Mg levels in serum and femur and cortical thickness, cortical area, and maximum load of the femoral midshaft were decreased in the Ca/Mg-deficient group. In these rats, PTH in the serum and renal Ca concentration were increased. In V.K2-treated rats, these changes in the serum Ca, Mg and PTH levels and the renal Ca concentration were improved. V.K2 also improved the decrease in maximum load in spite of no influence on the cortical thickness, cortical area and Mg concentration in the femur. These findings suggest that V.K2 may affect the qualitative change in bone.
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