Tumor cells show a higher glycolytic rate than normal cells. Of glycolytic enzymes, the activity of hexokinase, known as a rate limiting enzyme in glycolysis, is amazingly high in malignant tumor cells. In mammals, four isozymes of hexokinase are expressed but the question which isozyme is responsible for the high hexokinase activity observed in tumor cells was not yet clearly answered. By Northern blot analysis, we found that the type II isozyme, which is only slightly expressed in normal heart, muscle and adipose tissue, was remarkably expressed in malignant tumor cells. We next tried to understand how the expression of type II hexokinase gene is regulated in tumor cells. For this purpose, we first isolated the type II hexokinase gene and characterized its structural features. We further investigated the regulatory machanisms of the expression of type II hexokinase in tumor cells. Results indicate the potential involvement of a serum responsive factor in the regulation of the expression of type II hexokinase in tumor cells. In addition to the remarkable expression, binding of the type II hexokinase to mitochondria is another characteristic of tumor cells, however, the physiological meaning of hexokinase binding to mitochondria was not yet fully understood. Our results clearly showed that the mitochondria-bound hexokinase utilize mitochondrially generated ATP more preferentially under normal conditions. However, when the rate of extramitochondrial ATP generating system (glycolysis) exceed that of mitochondrial ATP generating system (oxidative phosphorylation), the mitochondria-bound hexokinase utilize extramitochondrial ATP. This result indicates that the hexokinase binding enables a cross talk between oxidative phosphorylation and glycolysis.
Triehylborane has the potential to induce radical reactions on solid support and the solid-phase radical reactions were achieved by using triethylborane as a radical initiator. The intermolecular carbon radical addition to glyoxylic oxime ether anchored to Wang resin proceeded under very mild conditions to give α-amino acid derivatives in good yield without interference of the polystyrene skeleton of the resin. Diethylzinc also worked well as a radical initiator at low reaction temperature. Thus, the employment of triethylborane of diethylzinc at low reaction temperature facilitated the control of stereochemistry in solid-phase reactions. Alkyl radical addition to Oppolzer's camphorsultam derivatives of oxime ether anchored to a polymer support proceeded smoothly even at -78°C to give the α-amino acid derivatives with excellent diastereoselectivities. The radical cyclization of oxime the ethers anchored to a polymer support also proceeded effectively to provide functionalized pyrrolidines via a carbon-carbon bond-forming process.
To develop an animal model for negative symptoms, in particular avolition, of schizophrenia, the effect of phencyclidine (PCP) on immobility (regarded as avolition) in the forced swimming test was investigated in mice, since PCP produces negative symptoms in humans. Unlike single, repeated treatment with PCP prolonged the immobility time in the forced swimming test 24 h after the final injection compared with saline treatment. The enhancing effect of PCP on the immobility persisted for 21 d after the withdrawal of the drug. Atypical antipsychotics attenuated the enhancing effect of PCP on the immobility. Since these attenuating effects were antagonized by a serotonin-S2 receptor agonist, (±)-2, 5-dimethoxy-4-iodamphetamine (DOI), the effects may be mediated via serotonin-S2 receptors. In contrast with atypical antipsychotics, typical antipsychotics, antidepressants and anxiolytics had no effect. No functional changes in post-synaptic serotonin-S2 reseptors were observed in PCP-treated mice following the forced swimming test. Serotonin utilization in the prefrontal cortex was increased, but dopamine utilization was decreased in PCP-treated mice showing the enhancement of immobility. The enhancing effect of PCP was significantly attenuated by D-cycloserine, an agonist for glycine binding site of N-methyl-D-aspartate (NMDA) receptor ionophore complex. Decreases of NMDA receptor function or of the cortical glutamate and glycine levels were observed in PCP-treated mice showing the enhancement of immobility. These results suggest that the enhancing effect of PCP on immobility is mediated by the imbalance of the cortical serotonergic, dopaminergic and glutamatergic systems and could be used as an animal model for negative symptoms of schizophrenia.
The AIDS clinical group protocol of zidovudine (AZT) prophylaxis regimen for HIV-1-infected pregnant women and their babies has been associated with a decrease in vertical HIV-1 transmission in non-breastfeeding women in developmental countries. However, scientists furthermore compared the safety and efficacy of short-course nevirapine or AZT during labour and the first week of life. In an advancement that promises to significantly reduce the incidence of AIDS in children in developing countries, scientists have found a simple new way with nevirapine to prevent mother-to-child transmission of the AIDS virus that also is less costly and markedly more effective than the standard therapy with AZT in the third world. The more practical therapy comes from substituting one marketed drug, nevirapine, for the standard drug, AZT. The cost for the two doses of nevirapine was 4, compared with 268 for AZT regimen now used in developing countries and $815 for the much longer and more complicated course used in the U.S. and other developing countries. It is proposed that wide-scale use of nevirapine in developing countries could potentially prevent 300000 to 400000 newborns each year from beginning life infected with HIV.
We have implemented an information-provision system for outpatients at the department of pharmacy, University of Tokyo Hospital, in order to comply with the revised Pharmacists' Law by which pharmacists have been obliged to provide patients with information necessary for rational usage of medicine at the time they receive dispensed drugs. This system is linked on-line with the order entry system to print "Drug Usage Sheets" containing important drug information such as therapeutic effects and adverse reactions, as well as photographic color views of drugs. We prepared the sheets by extracting and classifying the original information, and by converting medical terms into lay expressions. Moreover, we developed "Drug Information Cards" to inform each patient of severe side effects and drug interactions, which should affect drug compliance, and implemented an individuals-oriented information system using both the "Drug Usage Sheets" and "Drug Information Cards." In this study, we evaluated the usefulness of this system from the viewpoint of patients' recognition and understanding on necessary drug information. It was indicated from questionnaires to patients that the "Drug Usage Sheets" help most patients understand the names, usage, effects, and general cautions including slight adverse reactions (i.e. grade 1), and that the use of colored letters for important parts and pictograms is a useful method to attract more attention from patients as compared with a conventional method using only letters. Most patients answered that the "Drug Usage Sheets" can be utilized in many ways and valuable in taking drugs with assurance. We formulated the "Drug Information Cards" by information processing : separation of early symptoms of adverse effects into subjective and objective ones and their classification into related organs. Moreover, the brand names of drugs which may cause drug interactions have been listed on the cards so that worsening of adverse reactions and drug interactions can be avoided. Although 14% of the patients answered that they became unsecured when informed on side effects, the percentage of such patients was significantly higher with those who received caution-required drugs for the first time or who have experienced drug side effects before, suggesting the need for combining oral explanation based on each patient's background and understanding on drug adverse effects. In conclusion, an efficient provision of drug information became possible through our integration of necessary drug information in this study, and the individuals-oriented system of drug information was established, which was demonstrated to contribute to the rational usage of medicine.
Objectives : The purpose of this study was to develop, implement, and assess an estimation procedure for preventing adverse drug reaction by subjective symptoms(complaints)of patients. This time, we focused and studied on drug-induced gastrointestinal system disorders. Methods : We have built a database for CARPIS (Case Reports of Adverse Drug Reaction and Poisoning Information System) since 1987. We studied 224 cases of drug-induced Gastrointestinal System Disorders (stomach or colon disorders : 148, esophagus disorders : 31, pancreas disorders : 45) cumulated in the CARPIS database. The evaluation scores were created based on the subjective symptoms and backgrounds of the patients. We estimated 224 cases using these evaluation scores. Results : We could estimate 137 cases (92.6%) in 148 cases to be stomach or colon disorders by the use of these evaluation scores. The validity of this evaluation scores was estimated to be as follows; Sensitivity=92.6%, Specificity=95.0% and Predictive Value of Positive Test (PVP)=96.5%. The positive likelihood ratio (LR) was 18.5 and negative likelihood ratio was 0.08. On the other hand, in the case of esophagus disorders, PVP was 84.8% and LR was 18.1. In the case of pancreas disorders, PVP was 90.7% and LR was 21.7. Conclusions : In this study, PVP and LR values were good. We thought that these evaluation scores could pick up the drug-induced gastrointestinal system disorders efficiently. We reported previously the evaluation scores about drug-induced liver disorders, extra-pyramidal symptoms, leukopenia and eruption before. In order to apply these evaluation scores onto the clinical practice, we prepared an evaluation form for subjective symptoms and backgrounds of the patients with adverse drug reactions. As a result, the adverse reactions symptoms of each one defined more.
The prophylactic effects of a Basidiomycetes preparation, AHCC, against experimental opportunistic infections were investigated in leukopenic mice. In cyclophosphamide-induced leukopenic mice, oral or intraperitoneal administration of the AHCC at doses of 1000 or 50 mg/kg/day, respectively, for 4 consecutive days prior to Candida albicans infection significantly prolonged the survival periods of the infected mice, and decreased the viable counts of C.albicans cells recovered from their kidneys. Similarly, the oral treatment with AHCC protected mice from lethal infection with Pseudomonas aeruginosa and intraperitoneal one also protected mice from infection with methicillin-resistant Staphylococcus aureus (MRSA). These results suggest a potential usefulness of the AHCC as a propylactic agent for the management of patients with opportunistic infections.