In the 21 century, the management of infectious diseases has become increasingly important. Especially, the establishment of the infection prevention and control system is very important in the healthcare-settings for patient safety. And from this background, infection control teams (ICT) which perform the infectious diseases management have been organized in many institutions. These ICT members are medical doctors, nurses, medical technologists and pharmacists and the role of the pharmacist in the ICT is very important. The pharmacist should play a role as a specialist for antimicrobial agents, antiseptics and disinfectants. The roles and responsibilities of the pharmacist for infection control are leading the antimicrobial stewardship, promoting the appropriate and rational use of antimicrobial agents, advising the health system on the selection and use of appropriate antiseptics, disinfectants and sterilants, developing guidelines for risk assessment, treatment, and monitoring of patients and health care workers. Establishing internal pharmacy policies, procedures and quality control programs to prevent contamination, educating health professionals, patients, and the public activity are also included. It is expected that the infection control pharmacist should contribute to the management of infectious diseases and patient safety in the healthcare-settings.
Recently, the pharmacokinetic (PK)-pharmacodynamic (PD) theory draws attention in the therapy of the infectious disease. Although the theory was only introduced into the field of antimicrobial therapy several years ago, the foundation was in the individualization of administering design by therapeutic drug monitoring (TDM) begun 30 years ago. Although, the main purpose of TDM that had been performed so far was assumption of the evasion of the side effects caused with antimicrobials, it is difficult to say that it has been used as a tool to improve the efficacies. Furthermore, although the information described in the package inserts of antimicrobials must be important grounds to use the agents properly, it was recently recognized that there were pitfalls in PK-PD region. In this review, the following three items are described; 1) problem of dosage regimen described in package insert of antimicrobials, such as aminoglycosides and vancomycin in our country, and findings accumulated through their TDM; 2) strategy for proper use of antimicrobials based on PK-PD theory; 3) finally, the role of the pharmacist expected in the area of the infectious disease treatment.
Early appropriate antibiotic treatment is vital since respiratory tract infection (RTI) is a potentially fatal disease. Therefore, the Japanese Respiratory Society (JRS) provided four guidelines for the management of RTI in adults. The basic policy and main purposes of the JRS guidelines include; 1) prevention of bacterial resistance and 2) effective and long-term use of medical resources. The JRS guidelines have recommended the exclusion of potential and broad spectrum antibiotics from the list of first-choice drugs for empirical treatment. In addition, the JRS guidelines have recommended short-term usage of antibiotics of an appropriate dose.
Many antibiotics have been developed and used for the treatment of infectious diseases. Although they have been known to have various adverse effects, most of the mechanisms remain still unknown. New quinolones are well known to induce convulsions and their convulsant activity enhanced by concurrent administration of anti-inflammatory drugs. Each new quinolone has an individual convulsant activity with individual drug-interaction with anti-inflammatory drugs. And enoxacin, lomefloxacin and gatifloxacin have been reported to decrease blood glucose levels in a dose-depend- ent manner, but ciprofloxacin and levofloxacin had no effect on the levels. It should be important to know the safety profile of antimicrobial agents before doctors administer these agents to the patients with infectious diseases.
Searching for the ligand-binding pockets of proteins plays an important role in structure-based drug design (SBDD), which is based on knowledge of the three-dimensional structures of target proteins. In SBDD, small molecules that can interact with the target protein are designed. SBDD methods require the identification of ligand-binding pockets, in which ligand molecules interact with protein atoms. The computer programs for the detection of ligand-binding pockets are categorized into two types: one is programs using only geometric properties; and the other is programs using the physicochemical properties of proteins as well as geometry. This paper describes the development and evaluation of a program for ligand-binding pocket search. The program HBOP (Hydropho Bicity On a Protein) searches for ligand-binding pockets using hydrophobic potentials derived from experimentally determined functions. This is based on the fact that hydrophobicity plays a significant role in protein-ligand binding. The results of evaluation indicate that programs using physicochemical properties can discover actual ligand-binding pockets more efficiently than those using only geometric properties.
The cycloaddition and cycloisomerization of the allene with an alkyne, alkene, or an additional allene for construction of various monocyclic and bicyclic ring systems has been developed. The characteristic features of these methods using allene functionality instead of a simple alkene or alkyne include the reaction mode that originated from the double function as well as the high efficiency for the constructions of medium-sized rings. Furthermore, asymmetric formal synthesis of (+)-nakadomarin A and total synthesis of (+)-fawcettimine and (+)-lycoposerramine-B based on highly stereoselective Pauson-Khand reaction of alkene-alkynes were completed.
Opioid analgesics exhibit cationic properties under physiological conditions, and the mechanism underlying permeation of the blood-brain barrier thus cannot be fully explained by simple diffusion alone. Various types of transporters that exhibit substrate specificity are localized on the blood-brain barrier, and play a role in transporting substances from circulating blood and from brain interstitial fluid. Progress is being made in explaining the mechanisms, functions, and physiological roles of polyspecific organic cation transporters, but little evidence has indicated that these previously identified organic cation transporters are involved in the transport of opioid analgesics across the blood-brain barrier. Consequently, clarifying the role of transporters in the distribution of opioid analgesics into the brain and determining their transport molecule will not only provide clues to effective drug delivery to the brain, but will also contribute to optimizing pain relief treatment, and by extension play a role in drug discovery for analgesics. Currently there are enthusiastic discussions in the literature regarding the existence of putative transporters involved in the transport of opioid analgesics across the blood-brain barrier. This review article introduces the results of our research as well as recent findings on the involvement of transporters in the blood-brain barrier transport of opioid analgesics such as morphine, morphine metabolites, oxycodone, fentanyl, codeine, and pentazocine.
This review article describes our recent efforts to develop environmentally benign transformations of allyl and propargyl alcohols via the 1,3-transposition of their hydroxyl groups using combined catalyst systems. This methodology allows for successful transformation under mild conditions, which has never been achieved using each catalyst. Representative examples of this methodology include the following three reactions. First, the combination of oxo-vanadium compounds and lipases resulted in the dynamic kinetic resolution of racemic allyl alcohols to give optically active allyl esters in high yields. Second, Mo-Au-Ag combination catalysis dramatically accelerated the rearrangement of diverse propargyl alcohols into α,β-unsaturated carbonyl compounds. Finally, the choice of suitable heteropoly acids for the rearrangement of propargyl alcohols led to the selective preparation of both (Z)- and (E)-enones.
RecQ5 belongs to the family of RecQ DNA helicases. There are 5 RecQ homologs in mammals, and defects in 3 of them (BLM, WRN, and RECQL4) give rise to cancer predisposition syndromes in humans. Although no human disease has yet been genetically linked to a mutation in RecQ5, this enzyme is thought to have unique functions, based on its ubiquitous expression profile and specific C-terminal amino acid sequence, both of which are very different from those of other RecQ DNA helicase family members. The analysis of MEF and ES cells derived from RecQ5-deficient mice investigated by Hu et al. suggested an important role for RecQ5 in the DNA metabolism of the early embryo. However, it is unknown how RecQ5 deficiency destabilizes DNA. To address the DNA instabilities in RecQ5-deficient animals, we chose Drosophila melanogaster which has simple checkpoint systems in its syncytial embryos. By analyzing Drosophila syncytial embryos, we demonstrated that the loss of RecQ5 increased the frequency of spontaneous mitotic defects such as anaphase bridge formation. A pair of daughter nuclei that had been linked by such DNA bridges was simultaneously eliminated via a Chk2-dependent pathway. These findings suggest that the lack of RecQ5 causes spontaneous double-strand DNA breaks. RecQ5 may thus function in the resolution of anaphase DNA bridges during mitosis in syncytial embryo.
The aim of the present study was to synthesize a series of retinamide derivatives using all-trans retinoic acid (ATRA) as raw material and observe their effects on the differentiation and apoptosis of human lung adenocarcinoma A549 cells. Four new synthesized ATRA retinamide derivatives were structurally confirmed by spectral analysis, including 1H-NMR, 13C-NMR, and MS. The results showed that the new ATRA retinamide derivatives significantly decreased the carcinoembryonic antigen secretion of A549 cells, significantly decreased the proliferation of A549 cells in a dose- and time-dependent manner, and promoted the apoptosis of A549 cells compared with ATRA. The Western blot assay indicated that the expression of Bcl-2 was decreased more in A549 cells treated with N-(3-trifluoromethylphenyl) retinamide than that in A549 cells treated with ATRA. The results also showed that the effects of N-(3-trifluoromethyl-phenyl) retinamide on differentiation and apoptosis were the strongest among the newly synthesized ATRA retinamide derivatives. Our results suggested that the effects of novel ATRA retinamide derivatives on increasing the differentiation, decreasing the proliferation, and promoting the apoptosis of A549 cells were greater than those of ATRA. The apoptosis of A549 cells induced by N-(3-trifluoromethylphenyl) retinamide may be related to downregulating the expression of Bcl-2.
The present study was carried out to examine the chemopreventive effects of 5-fluorouracil (5-FU) and lactoferrin (LF) on goldfish intestinal carcinogenesis induced by 1,2-dimethylhydrazine (DMH). DMH was given to fish by intraperitoneal injection in a dosage of 15 mg/kg body weight once a week for 6 weeks. Eight weeks after the initial DMH injection, fish were randomly divided into 2 groups, control and LF-treated groups. Control fish fed a commercial diet. LF- treated fish fed a commercial diet with bovine lactoferrin (oral administration at 200 mg/kg body weight/day). Ten weeks after the initial DMH injection, each was divided into 2 groups, saline- and 5-FU- treated groups. Physiological saline for freshwater fish (0.75% NaCl solution) in the saline-treated fish and 5-FU dissolved in 0.75% NaCl solution in the 5-FU-treated (75 mg/kg body weight) fish were injected intramuscularly three times every other day, respectively. The mean number of precancer cell foci (PCF) per intestine was 2.7 in DMH treated fish. PCF showed broader distribution in the entire intestine derived from DMH-treated fish. LF-only-treatment has no effect on the number of PCF. Mean number of PCF in 5-FU-only-treated fish decreased in comparison with that of the saline-treated control group, though no statistically significant reduction in PCF was found. But if 5-FU treatment was added to LF pretreatment, a statistically significant reduction in the number of PCF was observed. Pretreatment with LF for 2 weeks also reduced the deleterious side effects of 5-FU.
The purpose of this study was to compare the transdermal transfer profiles of brand and generic tulobuterol patch formulations and to evaluate possible changes of in vivo kinetics resulting from increased transdermal transfer by means of pharmacokinetic analysis using reported in vitro drug release rate data and plasma drug concentration profiles. On the assumption that the transdermal transfer rate constant (k2) would be constant (independent of formulation), the drug release rate constant from patch formulation (k1) was predicted to be almost equal to the k2 value (k1≈k2) in the brand formulation, but 2- to 4-fold higher than the k2 value (k1>k2) in the two generic formulations. Under normal conditions, there would be no marked difference in the plasma concentration profiles among the formulations. However, under conditions where transdermal transfer is increased (that is, higher k2), the plasma tulobuterol concentration was predicted to increase more rapidly, with higher Cmax, and then to decrease more rapidly in the elimination phase after applying the generic formulations compared with the brand formulation. These different behaviors would be seen because the transdermal transfer of the generic formulations would be affected by k2, whereas k1 is still rate-determining for the brand formulation. These results suggest that bronchial asthma patients with risk factors for impaired skin barrier function, including atopic dermatitis, long-term treatment with steroids, and advanced age, should be carefully monitored for reduced treatment efficacy or adverse drug reactions after application of rapid-release generic tulobuterol patch formulations.
In the present study, we isolated and determined the pharmacological characteristics of a novel gene encoding the human prostaglandin carrier (hPrC). The isolated cDNA consisted of 1431 base pairs that encoded a 477-amino acid protein, and we found that isolated hPrC does not belong to any drug transporter families. RT-PCR analysis revealed that the hPrC mRNA is expressed in various human tissues ubiquitously. When expressed in Xenopus laevis oocytes, hPrC mediated the transport of [3H]prostaglandin E2 (PGE2) in a sodium-independent manner. The uptake of [3H] PGE2 was not trans-stimulated by PG analogous. Although there are several PG transporters such as multidrug resistance-associated protein 4 (MRP4), organic cation transporter 1 (OCT1) [solute carrier (SLC) 22A1], organic anion transporter 1-3 (OAT1-3) [SLC22A6-8], OAT4 [SLC11], OATP-1 (LST-1) [SLCO1B1], OATP2B1 [SLCO2B1], OATP2A1 (PGT) [SLCO2A1], OATP4A1 (OATP-E) [SLCO4A1] have been isolated and well characterized, our findings suggest that hPrC functions as a novel transport peptide responsible for PG uptake. Our results should provide insight into the novel mechanism of the PG transport in the human body.
Compressed baby milk powder has proven to be very convenient for parents due to the ease with which it can be handled, and the fact that use of a measuring scoop is not necessary. The purpose of this study was to develop a compressed baby milk powder and analyze the resulting physical properties. The basic production process consisted of the following steps: 1) molding milk powder by low compression pressure, 2) humidification at 25°C·97%RH and 3) drying with use of a desiccant. No chemical additives were used for solidification; therefore the chemical composition of the compressed milk powder is identical to the base milk powder. The important properties of the compressed milk powder are both ready solubility and the strength of the solid. The compressed milk powder obtained at low pressure was too brittle for practical use, but the strength was increased by humidification followed by drying. During the humidification process, the powder particles located close to the surface of the compressed milk powder partially dissolve resulting in bridging structures between the particles, leading to an increase in strength. Both specific surface area and the volume ratio of the compressed milk powder decreased. Testing showed that caking between the particles occurred following humidification, and that the volume of caking affected the ease with which the compressed milk powder dissolves in water.
Community pharmacists can provide effective pharmaceutical care by questioning the physicians about their prescriptions. The regulatory authority (Ministry of Health, Labour and Welfare or the like) has been issuing instructions/advice to health insurance-covered pharmacies about the nature of questions to be asked to physicians under the national health insurance system. However, this practice has been facing similar kind of problems almost every year. To identify the reasons for repetition of the problems and facilitate proper application of drug therapy at hospitals, we recently examined the nature of questions asked to physicians by conducting a survey of 165 health insurance-covered pharmacies belonging to 8 district branches of the Japan Pharmaceutical Association. When the pharmacists were asked to express their view whether each of the 18 sample questions included in the past surveys was actually necessary, the most frequent answer from the respondents (n=1980) was “neutral” (42.9%), followed by “unnecessary” (29.0%) and “necessary” (26.6%). Further, 55.5% respondents answered that it is necessary to refer to publications of the concerned fields (guidelines, etc.) when questioning the prescriptions. However, the responses about the possible reasons for judging the necessity of the questions suggested that sometimes the pharmacists failed to understand the details of such publications. The results from this study suggest that a high percentage of community pharmacists believed that there was little need to ask questions about prescriptions if the suggestions made by the regulatory authority about the relevant questions were taken into account. Further, our study findings suggested that pharmacists working at clinics cannot present a clear-cut rationale for their judgment about the necessity of asking questions about prescriptions under the current circumstances where sufficient information collection and the evaluation of need for asking questions about prescriptions are not possible.
In this study, 162 students in the 6 year Pharmacy Program at the School of Pharmacy, Iwate Medical University were asked to prepare liposomal preparations using chicken egg yolk and to evaluate their properties with the aim of developing novel liposomes. High-purity lecithins are generally used for preparing liposomes but they are expensive. On the other hand, egg yolk has various components, including lecithin and cholesterol, which are important components for the formation of liposomes, so it was hypothesized that liposomes prepared from egg yolk may participate in the formation of cell membrane in chicks. Both liposomes from egg yolk (YL) and from lecithin (LL) exhibited Malthesian crosses using a polarizing microscope and multilamellar vesicles were observed, confirming that liposomal preparations from egg yolk were useful. The particle size of YL was about 100 nm with one peak. Furthermore, the YL are believed to be viable under different conditions because the particle size did not change when they were prepared in buffers having different pH values. The results of these experiments indicate that liposomal preparations from egg yolk can serve as natural materials, although some obstacles remain. This is a unique approach for carrying out practical training in our 6 year pharmaceutical science program.