The author’s work in the past 10 years have been reviewed, focusing on their endeavor to find more effective and versatile reagents applicable to the Mitsunobu-type reactions. The project was originally planned to provide various N-alkyl-N-allylacylamides, the substrates for the aza-claisen rearrangement the authors have developed. The effort was rewarded by more colorful results than expected originally, introducing to the chemical community two new series of reagents, that is, azodicarboxamides, such as TMAD and DHTD, and phosphoranes, such as CMBP and CMMP. The former series mediates the Mitsunobu reaction between primary alcohols and various protonic acids (N- and C-nucleophiles) of pKa up to 12, while the later, though needed a higher temperature, mediates the reactions of both primary and secondary alcohols with protonic acids of pKa of up to 23.5. Utilizing both the aza-Claisen rearrangement and new Mitsunobu reaction, a variety of natural products including isoirridomyrmecin, α-skytanthine, antimycin A3b as well as various alkaloids and pheromones were synthesized in reasonable ease.
I investigated the differences in brain pharmacokinetics of [11C]methamphetamine ([11C]MAP) in normal and MAP sensitized animals using positron emission tomography (PET). [11C]MAP was synthesized by an automated on-line [11C] methylation system. I newly produced MAP sensitized dog and monkey by repeated MAP treatment. The maximal level of accumulation of [11C]MAP in the sensitized dog brain was 1.4 times higher than that in the control. This result suggests the changes in the pharmacokinetic profile of MAP in the brain affect the development or expression of MAP-induced behavioral sensitization. However, the overaccumulation of [11C]MAP in the sensitized monkey brain was not observed due to the influence of anesthesia.
Dendritic cells (DC) are professional antigen-presenting cells with a key function in the immune system as initiators of T-cell responses against microbial pathogens and tumors. Therefore, the immunization using DC loaded with tumor-associated antigens is potential to represent a powerful method of inducing anti-tumor immunity. Recent studies have demonstrated the usefulness of DC genetically modified by adenovirus vectors (Ad) to immunotherapy, while sufficient gene transduction into DC is required for high does of Ad. Entry of Ad into target cells occurs by serial two steps: the binding of Ad-fiber knob to Coxsackie-adenovirus receptor (CAR) on the cell surface, and the subsequent interaction between Arg-Gly-Asp (RGD) motif located in Ad-penton base and αv-integrins. The reverse transcription-polymerase chain reaction analysis revealed that the relative resistance of DC to Ad-mediated gene transfer was due to the absence of CAR expression, and that DC expressed adequate αv-integrins. Therefore, we investigated whether fiber-mutant Ad (FM-Ad) containing the RGD sequence in the fiber knob can efficiently transduce and express high levels of the foreign gene into DC. The gene delivery by FM-Ad was more efficient than that by conventional Ad in both murine DC lines and normal human DC. Furthermore, both antigen presentations via major histocompatibility complex class I molecules and in vivo antigen-specific cytotoxic T lymphocyte induction by DC transduced with antigen gene by FM-Ad were superior to those by DC applied with conventional Ad. We propose that αv-integrin-targeted FM-Ad is a very powerful tool to implement DC-based vaccination strategies.
Several kinds of compounds available as model systems to investigation on metal-metal interaction in metalloproteins and on interaction of aromatics with nucleobases in arene intercalation to DNA were synthesized and characterized by spectrometry. Double and triple layered porphyrinophanes linked with 1,1'- or 1,3-disubstituted ferrocene moieties and their iron and cobalt complexes were prepared. Stabilities of their oxygenation complexes depended on bridging mode, lengths of alkyl linkers, distance between metals, and feature of hydrophobic cavity. Ferrocenophane derivatives in which nucleobase and aromatic hydrocarbon (naphthalene or anthracene) moieties substituted to their cyclopentadienyl rings in a stacking mode between the two chromophores were synthesized, as a model system of intercalation of aromatic condensed-ring hydrocarbons to DNA. Characterization of the ferrocenophanes by spectrometriy and molecular modeling suggested that these chromophores interacted due to NH-π hydrogen bonding and π-π charge transfer. A number of porphyrin derivatives covalently connected with a nucleobase or a nucleobase pair in a face-to-face mode between the porphyrin and nucleobase moiety were synthesized. The spectroscopic behavior of the derivatives indicate a greater affinity of the guanine-cytosine pair for porphyrin in comparison with the adenine-thymine pair. These results are compatible with the already reported spectroscopic and kinetic properties of mixing system of DNA and porphyrin derivatives. Moreover, the fluorescence spectra of the nucleobase-porphyrin derivatives gave a piece of evidence to cause DNA cleavage by photosensitizer via “type I” mechanism, in which direct action of singlet or triplet state of photosensitizer excited by laser irradiation brings about damage of cell or DNA.
Vancomycin hydrochloride (VCM) is widely used for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. However, this drug can cause sever adverse reactions, such as red neck syndrome, nephrotoxicity and ototoxicity. Thus, therapeutic drug monitoring (TDM) was bringing into effect for well effectiveness and to prevent side effects. In Kanto Medical Center NTT EC, TDM of VCM has been brought into effect since 1994. The date were accumulated from 200 patients. In this study, the retrospective research was carried out based on 117 cases selected from the above accumulated data, and then several factors such as VCM inducing side effect, a therapeutic effect, and the forecast of pharmacokinetic parameter using laboratory data were examined. Consequently, the high blood concentration trough level, the high value after 1 to 2 hours infusion, and the extension of t1/2 were brought forward as a nephrotoxicity causing factor, and more over each laboratory data (BUN, Cr, GOT, GPT, γ-GTP, T-BiL, ALP, LDH) was high before infusion of VCM in patients with renal dysfunction. High value T-Bil and lower value TP were brought forward in patients with hepatic dyfunction, and high eosinophils and high blood concentration were brought forward after 1 or 2 hours infusion. In relation to side effects, it was found that the outbreak rate of side effects is high in patients with a complication of hypertension or diabetes. The administration term was considered as a factor which influences the therapeutic effects. The unchanged effect was 10.9±7.9 days, the improved effect was 14.6±9.3 days, the remarkably improved effect was 17.7±14.1 days. As the administration term gets longer, the improvement rate was recognized to be an upward tendency. The difference in significant effects was recognized between unchanged and remarkably unchanged (p<0.05) effects. As the forecast of pharmacokinetic parameter using the laboratory data, VCMt1/2 showed a significant correlation between Cr and T-BiL, and it was VCMt1/2=8.56Cr+2.169T-Bil+7.1. This result shows that VCMt1/2 can be estimated.
For the appropriate use of drugs for injection, injection dispensing by pharmacists has been initiated at various institutions. With this movement, automatic injection dispensers have actively been developed. In our hospital, an injection order system was connected with an automatic injection dispenser in November, 1997, and this integrated system has been operating in all wards. However, the efficiency of dispensing work was not satisfactory because there were limitations in the types and volume of drugs placed in the automatic injection dispenser. Therefore, we constructed an automatic injection dispenser system that allows us to use more than 100 ml infusion fluids and also to use drugs stored in a cool place, which could not be used in the conventional system. In the new system, two trays coming from an ampoule-vial line and an infusion fluid line are automatically coordinated using a discharge lifter for each patient and transported into an injection cart. After the introduction of this system, the automatic dispenser utilization rate in terms of the number of used injections increased from 52.6% to 73.3%. In addition, since the dispensing time for infusion fluids and drugs stored in a cool place, which had been collected by man power, was reduced, it became possible to pay more attention to checking for prescription.
Objective: To establish a new method for preoperative bowel preparation that facilitates nursing care and minimizes the patient’s discomfort during the clinical pathway of laparoscopic surgery. Method: A randomized controlled trial was conducted for the following two preparation methods. Twenty cases were assessed with Method 1 and 18 cases with Method 2. Method 1 (the conventional procedure) : oral magnesium citracte is given in the afternoon of the day before surgery, followed by a glycerin enema in the night of the day before surgery and in the morning of the day of surgery. Method 2 (a new procedure) : oral magnesium citrate is given in the afternoon of the day before surgery, followed by oral picosulfate in the night before the day of surgery and a bisacodyl suppository in the morning of the day of surgery. To evaluate the two methods we sent questionnaires to the surgeons (blinded to the method used), nurses, and patients. Results : No statistical difference existed between the two methods in their effectiveness as a preoperative treatment. Facilitation of nursing care was significantly better in Method 2, and patients had considerably reduced discomfort with Method 2. Discussion: Patients who received oral picosulfate and a bisacodyl suppository experienced much less discomfort and nursing care was easier when compared with the conventional method of administering a glycerin enema. Since an enema is disliked by young women and an effect comes out with discomfort very shortly after the administration, the degree of discomfort of patients would have become high. Picosulfate is an oral medicine and thereby the effect comes out mildly. That would be the reason why the degree of discomfort of patients was low. In the nursing care, an enema requires time for preparation and administration, while picosulfate is easy to administer, making the nursing care easier. Therefore, Method 2 was chosen as a preperative bowel treatment for the clinical pathway. Thus, we could establish a new evidence-based method useful for the preperative bowel preparation in the clinical pathway of laparoscopic surgery.
To understaqnd the meaning of blending crude drugs in Chinese medicinal prescriptions, the influence of Saussurea root on the pharmacological action of Corydalis tuber was examined. Saussurea root increased the depression of acetylcholine-induced contraction caused by the hot water extract solution of Corydalis tuber in mouse ileum at low dosage, which showed no direct influence on acetylcholine. Dehydrocostuslactone in Saussurea root was characterized as the component having increasing activity and the relationship between the concentration of acetylcholine and the variation in the contraction depressed by Corydalis tuber alone or a mixture of the Corydalis tuber and dehydrocostuslactone was investigated for clarification of the mode of action.