日本薬理学雑誌
Online ISSN : 1347-8397
Print ISSN : 0015-5691
ISSN-L : 0015-5691
113 巻 , 1 号
選択された号の論文の7件中1~7を表示しています
  • 水島 裕
    1999 年 113 巻 1 号 p. 7-14
    発行日: 1999年
    公開日: 2007/01/30
    ジャーナル フリー
    The trends of new drug development in the 21st century were described. First, the history of drug development including that of the drug delivery system (DDS) was shown. Then, the recent drugs and therapeutic technology were discussed in detail. These topics are biomedicine, gene related technology, vaccine, hybrid artificial organ, chemical and phage library, fetal growth hormone, cell therapy, humanized anti-body and Viagra. In addition, some natural products were introduced, emphasizing the relationship between food and human health. Finally, I stated my opinion about the new drug development in the 21st century in Japan.
  • 長尾 拓
    1999 年 113 巻 1 号 p. 15-18
    発行日: 1999年
    公開日: 2007/01/30
    ジャーナル フリー
    In recent years, drugs developed in Japan are used internationally in other countries. The pharmaceutical pre-clinical phase is critical in the drug developing cycle. Pharmacologists contribute to finding the leading compounds and evaluate the right compound for clinical trial. The selection of the right compound for development will save both time and money. In the pharmacological evaluation of a development candidate, in vivo animal studies that can assure the clinician that the drug is both effective and safe are usually required. Studies on the mechanism of action of the drug and how the drug works in the diseased state becomes important since a known target molecule usually serves as the basis for the development of a new drug.
  • 林 裕造, 松本 一彦
    1999 年 113 巻 1 号 p. 19-30
    発行日: 1999年
    公開日: 2007/01/30
    ジャーナル フリー
    Preclinical studies are defined as experiments other than clinical trials that are conducted in test systems under laboratory conditions for determining the safety of test materials for anticipated human use. It is known that preclinical studies are an indispensable requisite for but constitute time resource-consuming processes in research and development of new pharmaceuticals. Therefore, they must be designed and conducted in a manner to satisfy the criteria that the obtained data are mutually acceptable among various countries to avoid unnecessary duplication of testing. The purpose of the International Conference on Harmonisation (ICH) has been directed towards the resolution of this issue. Major scientific issues in preclinical studies comprise the interpretation of test data with respect to prediction of potential adverse effects of a test material in humans. Mechanistic consideration of the toxic effects occurring in animals given a test material can usually provide a scientific basis for evaluating the potential hazard of the material in humans. For example, when a test material was found to exhibit a carcinogenic effect in a long-term animal test, one will attempt to determine, on the basis of data from genotoxicity studies, repeated dose toxicity tests, toxicokinetic studies or pharmacology studies on the substance, whether the carcinogenic effect is due to its genotoxicity (genotoxic carcinogen) or a sequela of some secondary mechanisms (non-genotoxic carcinogen). In the cases where a test meterial was shown to exert toxic effects with either functional manifestation or non-neoplastic morphological manifestation, elucidation of the mechanism will also be useful for extrapolation of animal data to the human situation. It is known that pharmaceuticals induce their toxic effects through various mechanisms such as covalent binding of active intermediates with macrolecules of target cells, oxidative stress-mediated effects, hormone-mediated effects or cytokinemediated effects. As shown in hepatocarcinogenesis or elevation of plasma transaminase activities in rodents attributable to activation of PPAR-α, nuclear receptors or ligand-dependent transcription factors are, now, regarded as important targets for toxicity evaluation of pharmaceuticals.
  • 藤森 観之助
    1999 年 113 巻 1 号 p. 31-40
    発行日: 1999年
    公開日: 2007/01/30
    ジャーナル フリー
    The working group for reevaluation of the Guideline for General Pharmacology Studies has completed a draft guideline for Safety Pharmacology studies and plan to recommend replacing the existing guideline with the revised one. This proposed guideline is now subject to domestic and international consultation. The basic principle of the revision is to harmonize the guideline with the international concepts. The working group decided to change the title of “General pharmacology” to “Safety pharmacology”, because the objective of this guideline is to assess the safety of a test substance in humans by examining the pharmacodynamic properties of the substance. The proposed guideline includes studies on vital functions as essential studies that should be performed prior to human exposure. Studies are also required to be conducted when predictable or unexpected observed effects are concerned. The working group recommends a case-by-case approach to select the necessary test items in consideration of the variable information available.
  • 大野 泰雄
    1999 年 113 巻 1 号 p. 41-45
    発行日: 1999年
    公開日: 2007/01/30
    ジャーナル フリー
    Pharmacokinetics studies are performed to clarify the absorption, distribution, metabolism, and excretion of drug candidates. The data are not only useful for the planning of animal toxicity studies and pharmacological studies but also required for establishing the efficacy and safety in humans by indicating the pharmacokinetically appropriate drug formulation and drug usage. Identification of the major metabolic enzymes related to the major metabolism of a drug is also essential for predicting pharmacokinetic drug interactions. Use of human tissues in drug metabolism studies becomes more and more important for rational and efficient drug development. It is necessary to establish an organization in Japan for supplying human tissues originating from the Japanese population.
  • 内田 英二
    1999 年 113 巻 1 号 p. 47-53
    発行日: 1999年
    公開日: 2007/01/30
    ジャーナル フリー
    The development of a new chemical entity for human use is a stepwise process based on an assessment of both animal and human data on efficacy and safety of the drug. Clinical pharmacologists always refer to animal data through an Investigator's Brochure (IB) when planning and performing a clinical trial(s). The IB should provide the investigator (s) with useful information to select doses, dosing intervals, and safety monitoring procedures and also to support the clinical management of subjects during the trial(s). Non-clinical animal studies contained in the IB, however, lack a relationship to the pharmacological and toxicological findings of the investigated product(s). Most of the non-clinical animal studies address the methodology and the results obtained, but are lacking in a discussion of the relevance of the findings. The IB shoud include not only a summary of the findings in each field of animal study but also relationships of the findings through some indicator (s) such as blood and tissue concentrations of the parent drug and/or metabolites. I do hope Pharmaceutical Companies will provide much useful information about their product (s) through the improvement of their system of research and development.
  • 山西 充洋, 石橋 祐二, 栗山 和彦, 建入 徳栄, 草嶋 久生, 児島 英介, 百々 研次郎
    1999 年 113 巻 1 号 p. 55-64
    発行日: 1999年
    公開日: 2007/01/30
    ジャーナル フリー
    肝機能が低下した骨粗鬆症患者でのカルシトリオールの有用性を調べる目的で,四塩化炭素(CCl4)により肝障害を併発させた卵巣摘出加齢ラット(OVX+CCI4)を用い,カルシトリオールおよびアルファカルシドールの骨粗鬆症モデルに対する作用を検討した.OVX+CCl4ラットにおいて,血清中GOT,GPT,アルカリホスファターゼおよび総ビリルビン量の上昇並びに肝チトクローム依存性酵素(P-450およびb5)活性の低下が認められた.カルシトリオール0.1および0.2μg/kgは,卵巣摘出3週間後から51日間の経ロ投与により血中力ルシウム濃度の低下を改善し,その効力は同用量のアルファカルシドールよりも強かった.また,両薬物とも大腿骨のカルシウム含量の減少を共に改善する傾向を示した.カルシトリオール0.2μg/kgは,アルファカルシドールと異なり乾燥重量/容積もしくは灰化重量/容積から求めた骨密度の低下を改善した.また,軟X線フィルム画像解析により算出した骨密度の低下に対しても,両薬物とも0.2μg/kgで大腿骨遠位端から0.18(全長を1)位の密度を改善する傾向を示した.OVX+CCI4ラットの骨破断時最大荷重を指標とした大腿骨の強度には,偽手術ラットとの間に変化は認められなかった.カルシトリオール02μg/kg最終投与3時間後の血中カルシトリオール濃度は対照群に比べ上昇したが,アルファカルシドール0.2μg/kgには上昇は認められなかった.また,カルシトリオールによる血中および大腿骨カルシウム含量並びに骨密度に対する改善効果と血中カルシトリオール濃度との間に相関性が認められた.以上のことから,カルシトリオールはアルファカルシドールとは異なり,肝機能が低下した骨粗鬆症患者において治療効果が期待できるものと推察された.
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