We have been engaged in the development of asymmetric conjugate addition reactions of lithium thiolates, organolithiums and organocopper reagents under the control of external chiral ligands and we have also developed an efficient asymmetric Horner-Wadsworth-Emmons (HWE) reaction using an external chiral Ligand. We attempted to synthesize axial chiral allenes by combination of these conjugate addition reaction and HWE reaction. In the course of this study, we found that Michael-aldol reaction of alkenylphosphonates 1 using LDA and aldehydes results in the direct formation of α,β-unsaturated hydroxyphosphonate 4, which was efficiently converted to allene by treatment with KH or KH-18-crown-6. Furthermore, allenes were synthesized by sequential double HWE reaction in one-flask manner starting from methylenebisphosphonate 8. The key to success is a metal exchange of intermediate lithium alkoxide 4-Li to potassium alkoxide 4-K by the addition of t-BuOK. As our continuous study of carbon-carbon bond formation based on alkenylphosphonates, a cyclization reaction of bisalkenylphosphonate 6 was developed. Although the treatment of 6 with organolithium reagents afforded a mixture of addition-cyclization product 9 and deprotonation-cyclization product 10, the treatment of 6 with LDA gave 10 selectively. These cyclization methods were applied to the synthesis of efficient chiral phosphine ligands.
The authors have discovered a highly selective CXCR4 antagonist, T22 ([Tyr5,12,Lys7]-polyphemusin II), and its shortened potent analogs, T140 and TC14012, which strongly inhibit the T-cell line-tropic HIV-1 (X4-HIV-1) infection through their specific binding to a chemokine receptor, CXCR4. CXCR4 is a major coreceptor (second receptor) for the entry of X4-HIV-1 into T-cells. These peptides have been found through the structure-activity relationship (SAR) study on tachyplesins and polyphemusins, which function as self-defense peptides of horseshoe crabs with immature immune systems. T140 and TC14012 showed the highest level of anti-HIV activity and antagonism of target cell entry by X4-HIV-1 among all the CXCR4 antagonists that have been reported to date. Additionally, bifunctional anti-HIV agents based on the specific CXCR4 antagonists (T140 analogs)-3'-azido-3'-deoxythymidine (AZT) conjugation have been synthesized and evaluated, since T140 analogs can possibly work as a carrier of AZT targeting T-cells due to their specific affinity for CXCR4 on T-cells. T22 have two disulfide bonds and a Trp residue in the molecule. In connection with this study, novel facile and side-reaction-free methodologies for disulfide bond formation have been established for the increase of the efficiency of SAR studies. Furthermore, the completely stereocontrolled synthetic process for a couple of (E)-alkene dipeptide isosteres starting from L-amino acid has been established in order to facilitate nonpeptidylation studies on peptide-lead candidates. In this review, the authors wish to summarize our recent research on the development of specific antagonists against the HIV second receptor CXCR4, involving studies on the establishment of efficient methodologies for the facile synthesis of peptides and peptide mimetics.
Severe nausea and vomiting induced by antineoplastics diminish the patient’s quality of life and the ability to tolerate further chemotherapy. Ramosetron hydrochloride is a 5-HT3 receptor antagonist, which has an active metabolite (M-1), expected to be useful in the inhibition of chemotherapy-induced nausea and vomiting. In the present study, in order to analyze the pharmacological effect of ramosetron hydrochloride in a comprehensive manner, we estimated the 5-HT3 receptor occupancy after intravenous administration of ramosetron hydrochloride using pharmacokinetic parameters and the dissociation constants for the 5-HT3 receptor. The average total receptor occupancy after intravenous administration of 0.3 mg of ramosetron hydrochloride to human was calculated to be 82.9% (ramosetron, 77.8%; M-1, 5.1%), thus exhibiting a significant antiemetic activity. Furthermore, the estimated time course of 5-HT3 receptor occupancies after intravenous administration of 0.3 mg of ramosetron hydrochloride suggested a substantial impact of the active metabolite (M-1). It suggested that M-1 contributed to the long duration of binding on the 5-HT3 receptor. The present analysis method should be useful for designing the rational dosage regimen of ramosetron hydrochloride and predicting the duration of its antiemetic activity in a quantitative manner.
In this study, factors influencing patients adherence to ophthalmic solutions were investigated. Seventy-one subjects (aged 62.3±15.5 years) were randomly selected from patients admitted to the Ophthalmology Department at Hiroshima University Hospital. The patients (n=71) completed questionnaires, which were evaluated by clinical pharmacists. The patient group to which the ophthalmic solutions were applied once or twice daily was more compliant than other patient groups (p=0.00057). A multivariate statistical analysis revealed that the factors influencing patients adherence were the number of ophthalmic solutions used, patient age, taste, administration intervals, the number of drops used, and hand washing before the application of ophthalmic solutions. Patients who understood the significance of the medication made fewer mistakes than those who understood only the route of administration but not the significance. In conclusion, our study shows that patient counseling should emphasis the significance of the administered medicine as well as the route of administration.
It is important to administer appropriate agents to inpatients and outpatients with various conditions. In addition to the preparation and guidance for taking drugs, we should always consider the patient’s basic information including age, history of allergy, name of disease, and history of examination. In particular, information on contraindications may have serious effects on patients, and must be checked most strictly. However, it is impossible to do routine work after obtaining all information such as the patient’s basic information that are serially changing, drug history frequently revised, and a large volume of information on medication. In this study, we developed a prescription surveillance system. This system facilitates real-time checking of the names of diseases that correspond to contraindications as a rule, drug interactions, and administration to elderly patients and pregnant women on attached documents for medicines, utilizing prescription orders, injection orders, and disease name orders. This system facilitates efficient and accurate checking even in the following cases: when a prescription involves another department; when several prescriptions on different prescription dates occur; when a combination of an oral agent and an injection is contraindicated; or when an agent that can not be administered due to the patient’s disease is prescribed. Therefore, all pharmacists can detect prescriptions involving agents that are contraindicated regardless of job skill. Pharmacists may contribute to higher quality medical practice.
Heat-treated leaves of Cassia alata were studied for any change in chemical constituents using sun dried leaves as the reference standard. A high concentration of a constituent was observed in the heat-treated leaves. Spectroscopic studies revealed the structure of the constituent as kaempferol 3-gentiobioside, which has not yet been detected in the Cassia species. In a stability study disappearance of kaempferol 3-gentiobioside was noted in the sun dried leaves while there was little or no change in the kaempferol 3-gentiobioside concentration in the heat-treated leaves when incubated in an aqueous solution, suggesting a possible presence of enzymatic activities in the sun dried leaves. Therefore, heat-treatment may be a good method to stabilize kaempferol 3-gentiobioside in Cassia alata leaves.
When inspecting unit-dose packaged drugs, there would be some possibility of inspection errors and ultimately dispensing errors due to pharmacist’s incorrect memory of drug identification. Therefore, this study was aimed to establish a computer-aided system for inspecting drugs of unit dose packages more accurately and efficiently. First, we analyzed the identifiability of 5846 tablets and capsules using drug codes, in order to define an identification problem for unit dose-packaged drugs. It was shown that as much as 36% of the drugs do not have any codes, 4.0% of the code-marked drugs have identical codes with others, and that 9.7% of the drugs with codes on both sides of the surface share the same code with other drugs. Thus, it was clearly shown that in many cases it is impossible to identify pharmaceuticals exactly using drug codes only. On the other hand, it was indicated that approximately 80% of the drugs which were not identified with drugs codes only, could be identified when additional information on drugs’ color, size, form, and splitting line was provided. Therefore, in this study, we designed an inspection-supporting system to present promptly all the information necessary for the drug identification by displaying real drug images as linked with prescribing information on the monitor. Retrieval of prescription data from the order entry host was automatically performed by entering patient’s ID number or by selecting a patient from the name list of patients at the inspection terminal computer. Moreover, the system was equipped with abilities to automatically check drug interactions and duplicate prescriptions, to provide various information of prescribed drugs and to monitor patients’ drug history. We used the developed system and evaluated that it is a useful tool for accurate and efficient inspection of unit dose-packaged drugs. In addition, the quality of drug inspection increased by utilizing system functions such as checking drug interactions and providing drug information.
We previously reported the development and clinical efficacy of a 2% aspirin oral ointment and 2% ethenzamide oral ointment as hospital preparations for painful lesions of the oral mucosa. This study investigated methods of preparing a more stable oral ointment with a more effective analgesic action, using diflunisal, another salicylic acid derivative, with an analgesic effect stronger than that of aspirin. A two-percent diflunisal oral ointment was prepared similarly to the aspirin ointment using plastibase and CMC-Na as the ointment base. From the results of spreadability measurement, a CMC-Na content of 20% was considered appropriate. The stability of diflunisal in 2% diflunisal oral ointment stored at 5°C, 20°C and 30°C, was determined using HPLC, and a high stability of diflunisal at room temperature for more than 100 days was confirmed. We also investigated its antinociceptive effect using the Randall-Selitto paw pressure test in rats, which showed that 2% diflunisal oral ointment was as effective as 2% aspirin oral ointment. On clinical application of 2% diflunisal oral ointment to 8 patients with painful oral mucous diseases, it was found to be significantly (p=0.014) more effective that 2% aspirin oral ointment. The results of this study demonstrated that 2% diflunisal oral ointment is a clinically useful analgesic for painful oral lesions.
The Ministry of Health, Labour and Welfare explains the objectives of promotion of separation of the pharmacy and clinics as the elimination of duplicated prescription of similar drugs and drug interactions caused by treatment at several departments or hospitals, and sufficient guidance in the use of drugs by pharmacists. The Pharmacy of Gifu Pharmaceutical University has dispensed prescriptions by outside medical organizations as its routine ativity. In this study, the contents of question inquiries handled in routine activities were compiled and analyzed, and their meaning was evaluated. The contents of question inquiries were accumulated using data cards. The data obtained during 2 and a half years(562 cases) were analyzed. The percentage of the number of inquiries relative to the number of prescriptions was highest at 1.86% during the first 3 months and was 1.05-1.71% per 3 months thereafter. The inquiries were most frequently about “the dosage/regimen” (153 cases), followed by “discrepancy between the contents of prescription and understanding of the patient” (88 cases) and “problems about insurance coverage” (80 cases). There were also 16 inquiries about “the possibility of contraindications and adverse reactions” and 15 inquiries about “duplicated prescription”, which may have exerted serious effects on the patients. Eighty nine % of the inquiries have led to changes in the prescriptions, and about half of these cases were discovered by consultation with the patients or a review of the drug history. Proper and positive execution of these operations in routine pharmacy work is considered to lead to appropriate inquiries about problems with prescriptions and, thus, contribute to the proper use of drugs and prevention of malpractice.