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Volume 124, Issue 1
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Technical Note
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Kumiko ARAKI, Tsuneyuki YAMAMOTO2004 Volume 124 Issue 1 Pages 3-9
Published: 2004
Released on J-STAGE: June 26, 2004
JOURNAL FREE ACCESSMost human behaviors (responses) are volitional, the frequency of which is changed based on stimulus presentations contingent upon the response, that is, operant behavior. It is considered that the findings on cognitive functions based on operant behaviors are more reliable in extrapolating the results to humans. Impairment of memory function, most notably the impairments of working memory and attention, is an important research focus to elucidate the mechanism underlying the core syndrome of Alzheimer's disease. Among various methods to measure working memory and attention, a delayed matching-to-sample paradigm utilizing operant chambers equipped with 3 levers and a choice reaction time paradigm have been proven to be very useful. Aside from these, adaptation to new environment is an important function for survival, and its impairment has been considered to be one of the factors inducing psychiatric disorders. Preclinical methods to measure the adaptation ability include a position reversal learning paradigm utilizing 2-lever operant chambers. Since the findings of studies on cognitive functions utilizing operant behaviors have been in good correlation with clinical findings, it would serve as a good strategy for elucidating the causes of such disorders as well as developing therapeutic agents.
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Masahiro KAWAHARA, Kazuyo MURAMOTO, Midori KATO-NEGISHI, Ritsuko HOSOD ...2004 Volume 124 Issue 1 Pages 11-17
Published: 2004
Released on J-STAGE: June 26, 2004
JOURNAL FREE ACCESSSynapse plasticity, in particular, formation of new synapses, plays crucial roles in learning and memory. We have developed a convenient assay system for measuring the number of newly formed synapses between cultured rat cerebrocortical neurons using the multisite fluorometry system of intracellular calcium. We found that cultured neurons exhibited spontaneous oscillatory changes in intracellular calcium levels and that the frequency of the oscillation was strongly correlated with synaptic density. Combined with immunohistochemical studies, this assay system enables us to study the molecular mechanism of synapse formation, in particular, the involvement of ecto-protein kinase. Other applications of the assay system are discussed here.
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Fuminobu SUGAI, Yoichi YAMAMOTO, Saburo SAKODA2004 Volume 124 Issue 1 Pages 19-23
Published: 2004
Released on J-STAGE: June 26, 2004
JOURNAL FREE ACCESSAmyotrophic lateral scleorsis (ALS) is a progressive neurodegenerative disease, which predominantly affects both upper and lower motor neurons. ALS is usually fatal within a few years after clinical onset. An organotypic slice culture of rat spinal cord, in which glutamate toxicity induces slow loss of spinal motoneurons, has been used for preclinical drug screening for ALS. In this report, we modified the conventional slice culture to put mouse spinal cords to use, as an alternative in vitro model of ALS. L-trans pyrrolidine 2, 4-dicarboxylic acid (PDC), an inhibitor of glutamate uptake, induced slow loss of spinal motoneurons in anterior horns, whereas small neurons in posterior horns were relatively preserved. This technique using mouse allows us to use transgenic and knockout mice. In addition to glutamate toxicity, many other mechanisms including oxidative stress and neurofilamentous disorganization are also considered to be involved in development of this devastating disease. Thus, a better in vitro model of ALS is strongly anticipated. At present, we are making efforts to apply this technique to establish a better in vitro model using spinal cord from transgenic ALS model mice, where spontaneous loss of spinal motoneurons will be observed.
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Drug Development Now
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Masahiro IMAIZUMI2004 Volume 124 Issue 1 Pages 25-29
Published: 2004
Released on J-STAGE: June 26, 2004
JOURNAL FREE ACCESSRecently, anti-cancer antibodies have been launched in Japan and also immunoconjugates with a cytotoxic compound or a radioisotope have been launched in the USA. Gemtuzumab ozogamicin is a conjugate of anti-CD33 antibody and a cytotoxic calicheamicin derivative. After binding the CD33-positive leukemia cells, gemtuzumab ozogamicin is internalized and releases the calicheamicin derivative. The calichemicin derivative breaks DNA and kills the cells. Gemtuzumab ozogamicin was effective and well tolerated in clinical trials in patients with acute myeloid leukemia (AML) in relapse. It was approved in 2000 by the FDA, and Wyeth K.K. has submitted it as an anti-tumor drug for CD33 positive AML. Two kinds of immunoconjugates, anti-CD20 antibodies with radioisotopes, recently have been launched in the USA for CD20-positive non-Hodgkin's lymphoma. These conjugates showed efficacy in patients who are refractory to the conventional chemotherapies. Targeted therapy with the immunoconjugate that can deliver cytotoxic compounds to specific cells is promising for use in oncology.
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Review on New Drug
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Motohiko CHACHIN, Tsuyoshi OHMURA, Naoyuki HAYASHI, Yoichiro NISHIMURA ...2004 Volume 124 Issue 1 Pages 31-39
Published: 2004
Released on J-STAGE: June 26, 2004
JOURNAL FREE ACCESSTelmisartan (Micardis®) is a potent, long-lasting, nonpeptide angiotensin II type-1 (AT1) receptor blocker (ARB) that is indicated for the treatment of essential hypertension. In receptor binding studies, telmisartan showed a high affinity and selectivity for the human AT1 receptors compared with AT2 receptors and a slower dissociation rate from the human AT1 receptor than those of ARBs. In isolated aorta rings, telmisartan was shown to be an insurmountable antagonist of AII-induced contractions. The inhibitory effects of telmisartan on AII-induced contraction persisted even after wash-out procedures. In animal models such as spontaneous hypertension rats and renovascular hypertensive rats, telmisartan produced the consistent reduction of blood pressure. Furthermore, there were no rebound phenomenon and no tolerance to the drug developed in the repeated oral administration. Telmisartan has a longer terminal elimination half-life (about 24 h) than the other ARBs. In patients with mild-moderate hypertension, trough/peak ratios for telmisartan were above 80%. In Japanese patients with mild-moderate hypertension, telmisartan produced a significant reduction in blood pressure (effective rate: 76.0%) with a good safety profile. Therefore, telmisartan is expected to be effective in the treatment of hypertension, producing sustained 24-h blood pressure control.
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Yutaka KAWAKAMI, Kenji NAGINO, Keisuke SHINKAI, Satoshi SOBUE, Masaaki ...2004 Volume 124 Issue 1 Pages 41-51
Published: 2004
Released on J-STAGE: June 26, 2004
JOURNAL FREE ACCESSFosfluconazole is a phosphate prodrug of fluconazole that has been developed to reduce the volume of fluid required to administer fluconazole by the intravenous route. Fosfluconazole is hydrolyzed by alkaline phosphatase to fluconazole and phosphoric acid. Fosfluconazole had no significant antifungal activity in vitro. However, in rat models of acute systemic candidiasis and intracranial cryptococcosis, fosfluconazole retained the antifungal potency and efficacy of fluconazole. This reflects the effective conversion of the prodrug to the parent during the course of the experiments. The 2-day-loading dose regimen led to earlier achievement of target fluconazole steady state plasma concentrations compared to use of the 1-day- or no-loading dose regimen of fosfluconazole. The efficacy and safety of fosfluconazole were investigated with the 2-day-loading dose regimen in patients with deep-seated mycosis caused by Candida and Cryptococcus species. The efficacy rates were 73.8% in the domestic Phase III study and 91.7% in the foreign Phase III study. Adverse events were observed in 31 cases (19.4%) out of 160 in both studies. These results indicate that fosfluconazole is effective for the treatment of deep-seated mycosis and shows no clinically significant adverse events in the Phase III studies
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