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YAKUGAKU ZASSHI, 126(7),439-454, 2006
The plasma-induced surface radicals formed on a variety of organic polymers have been studied in detail using electron-spin resonance (ESR) coupled with systematic computer simulations. On the basis of the findings from such studies on the nature of radical formation and radical reactivity, we were able to open up several novel pharmaceutical and biomedical applications in plasma treatment. In this review, applications using plasma-irradiated organic polymers are described, which include: 1) preparation of double-compressed tablets applicable for reservoir-type drug-delivery systems (DDS) for sustained and delayed release, intragastric floating DDS (FDDS) for oral controlled-release dosage forms with gastric retention capabilities, and fabrication of functionalized composite powders applicable for controlled drug release with the mechanical application of plasma-irradiated polymer powder; 2) an approach to “patient-tailored DDS,” administered by taking into account that the environment (pH, transit time, etc.) in the gastrointestinal tract varies with each patient, based on the combination of the above-mentioned DDS devices; 3) plasma-assisted promotion of seed germination of herbal medicines with hard coats; and 4) fabrication of polymer surfaces with durable hydrophilicity and lubricity using plasma techniques and the immobilization of oligo-nucleotides on hydrophilic polymer surfaces thus prepared applicable to constructing DNA diagnosis systems.
Key words--plasma treatment; polymer surface radicals; electron spin resonance (ESR); drug delivery system (DDS)
YAKUGAKU ZASSHI, 126(7),455-471, 2006
Polyamines (putrescine, spermidine, and spermine) are essential for normal cell growth. The polyamine level in cells is regulated by biosynthesis, degradation, and transport. The role of antizyme on polyamine biosynthesis and transport in mammalian cells and characteristics of polyamine transport in Escherichia coli and yeast are described briefly in this review. In addition, the effects of polyamines on protein synthesis and the NMDA receptor are outlined. Finally, the correlation between acrolein produced from polyamines by polyamine oxidase and chronic renal failure and brain stroke is summarized. Increased levels of polyamine oxidase and acrolein are good markers of chronic renal failure and brain stroke.
Key words--polyamine; transport protein; cell proliferation; protein synthesis; NMDA receptor; acrolein
YAKUGAKU ZASSHI, 126(7),473-479, 2006
To study the structure-activity relationship of mugineic acid (MA), a phytosiderophore isolated from Hordeum velugare L. var. Minorimugi, several 2-deoxymugineic acid (DMA) analogues were synthesized. 1H-NMR spectra of DMA analogues and their Co(III) complexes were first measured and analyzed to elucidate the structures of metal complexes. CD spectra of the Co(III) and Fe(III) complexes of DMA analogues were then measured and compared with those of MA. Furthermore, the interaction between the Fe(III) complexes of DMA analogues and the phytosiderophore-Fe(III) complex transporter found in maize was examined.
Key words--mugineic acid (MA); 2-deoxymugineic acid (DMA); phytosiderophore; phytosiderophore-Fe(III) complex transporter; structure activity relationship
YAKUGAKU ZASSHI, 126(7),481-488, 2006
Protease-activated receptor-2 (PAR-2), a G protein-coupled receptor, is activated by proteolytic unmasking of the N-terminal extracellular tethered ligand that presumably binds to the extracellular loop 2 of the receptor itself. PAR-2 is widely distributed in the mammalian body and plays various roles in biological events in the cardiovascular, respiratory, alimentary, and central neurons systems. PAR-2-activating peptides administered systemically to mice and rats trigger prompt salivation in vivo. In an in vitro study, PAR-2 agonists including the endogenous PAR-2 activator trypsin induce secretion of amylase and mucin from isolated rat parotid glands and sublingual glands, respectively. PAR-2-activating peptides administered systemically also modulate pancreatic exocrine secretion in vivo as well as in vitro. In the gastric mucosa, PAR-2 stimulation enhances secretion of mucus and pepsinogen and suppresses acid secretion. Tear secretion can also be caused by PAR-2-related peptides in PAR-2-dependent and -independent manners. PAR-2 thus plays a general or key role in the regulation of exocrine secretion. This review focuses on the physiologic and/or pathophysiologic roles of PAR-2 in glandular exocrine secretion. The possibility of PAR-2 as a target for drug development is also discussed.
Key words--protease (proteinase)-activated receptor (PAR)-2; exocrine gland; salivation; tear secretion; gastrointestinal tract; gastric secretion
YAKUGAKU ZASSHI, 126(7),489-494, 2006
In optimizing oral pharmacotherapy for patients with renal failure, information on actual urinary excretion ratio of the unchanged drug, which is obtained by dividing a urinary excretion ratio by a bioavailability after oral dose, is quite helpful. In addition, urinary excretion ratio of the active species is sometimes equally important where metabolites have a pharmacological potency. In the present study, we conducted a survey of Japanese package inserts and interview forms of drugs, which is being prescribed at the University of Tokyo Hospital, on pharmacokinetic data that enables an estimation of actual urinary excretion ratio. The total urinary excretion of a drug was documented in 70.1% of package inserts and 84.5% of interview forms, respectively. The total urinary excretion is often measured by radioactivity and thus includes its metabolites and degradation products. However, inclusion of degradation products/metabolites was described explicitly for 43.7% and 66.2%, and the absolute fraction of the unchanged drug or degradation product/metabolite was given only for 29.0% and 48.9% in package inserts and interview forms, respectively. The pharmacological activity of metabolite(s) was documented for 19.8% and 54.3%, and the oral bioavailability was described only for 5.7% and 30.6% in respective documents. For some drugs, the time period for the urine collection was too short to evaluate the urinary excretion ratio. With regard to 65 drugs (38.7%), more detailed information on urinary excretion was found in published books, but not provided in the package inserts or interview forms. It is hoped that more distinct and sufficient descriptions on the urinary excretion and bioavailability will be associated to the package inserts and the interview forms in future, for safe and efficient use of prescription drugs.
Key words--pharmacokinetic data; package insert; interview form; drug information
YAKUGAKU ZASSHI, 126(7),495-498, 2006
Meloxicam, a non-steroidal anti-inflammatory drug is used in the treatment of rheumatoid arthritis and osteoarthritis. It is practically insoluble in water leading to poor dissolution, variations in bioavailability and gastric irritation on oral administration. In order to modulate its gastric side effect and to increase aqueous solubility, physical mixture and solid dispersion of the drug were prepared with skimmed milk. The analgesic, anti-inflammatory and ulcerogenic effects were assessed for physical mixture and solid dispersion in comparison to pure meloxicam. The results indicate that solid dispersion possess better analgesic and anti-inflammatory properties with less ulcerogenic potential as compared to pure meloxicam.
Key words--meloxicam; solid dispersion; analgesic; anti-inflammatory; ulcerogenic study; skimmed milk
YAKUGAKU ZASSHI, 126(7),499-504, 2006
Critical care nurses and physicians are familiar with the principles of patient controlled analgesia and the opioid analgesics' regimens and observations necessary for pain control in the postoperative cardiac surgical patients. The objective of the study was to compare the effects of morphine, fentanyl, meperidine, remifentanil and tramadol which were administered by patient controlled analgesia and continuous intravenous infusion combination on the various parameters. This study was designed as prospective randomised trial. Fifty patients undergone open heart surgery with sternotomy were entered equally into five randomized groups. Visual analog scale was used by researcher nurse to assess the patient' pain status. Respiratory rate, heart rate and blood gases (pO2, pCO2, SaO2), radial arterial blood pressures were measured in the first 24 hrs postoperatively. Bolus requirements were determined by physicians and side effects of the analgesics were documented. Fentanyl group showed statistically higher levels of mean pO2 (p=0.002). Meperidine had the lowest number of bolus doses (p=0.001). There were no significant differences between the groups for pain management except higher visual analog scales on tramadol. Headache, stomachache and, palpitations were observed in our patients. Remifentanil, meperidine, fentanyl and morphine showed similar effect with each other for pain relief except tramadol.
Key words--morphine; fentanyl; meperidine; remifentanil; tramadol; opioid
YAKUGAKU ZASSHI, 126(7),505-514, 2006
The objective of this study was to develop controlled release matrix embedded formulations of celecoxib (CCX) as candidate drug using hydroxy propyl methyl cellulose (HPMC) and ethyl cellulose (EC), either alone or in combination, using optimization techniques like polynomial method and composite design. This would enable development of controlled release formulations with predictable and better release characteristics in lesser number of trials. Controlled release matrix tablets of CCX were prepared by wet granulation method. The in vitro release rate studies were carried out in USP dissolution apparatus (paddle method) in 900 ml of sodium phosphate buffer (pH 7.4) with 1% v/v tween-80. The in vitro drug release data was suitably transformed and used to develop mathematical models using first order polynomial equation and composite design techniques of optimization. In the formulations prepared using HPMC alone, the release rate decreased as the polymer proportion in the matrix base was increased. Whereas in case of formulations prepared using EC alone, only marginal difference was observed in the release rate upon increasing the polymer proportion. In case of formulations containing combination of HPMC and EC, the release of the drug was found to be dependent on the relative proportions of HPMC and EC used in the tablet matrix. The release of the drug from these formulations was extended up to 21 h indicating they can serve as once daily controlled release formulations for CCX. Mathematical analysis of the release kinetics indicates a near approximate Fickian release character for most of the designed formulations. Mathematical equation developed by transforming the in vitro release data using composite design model showed better correlation between observed and predicted t50% (time required for 50% of the drug release) when compared to first order polynomial equation model. The equation thus developed can be used to predict the release characteristics of the drug from matrix embedded formulations depending upon the proportion of HPMC and EC used in the formulation.
Key words--celecoxib; optimization; controlled release; matrix embedding
YAKUGAKU ZASSHI, 126(7),515-520, 2006
To obtain basic data on the introductory lecture on clinical trials in a School of Pharmacy, we carried out an attitude survey among master course students in the School of Pharmacy of our University. We distributed two types of questionnaire, one before and one after a lecture on the outline of clinical trials and the role of pharmacists in the performance of clinical trials. In the first questionnaire, 67% of respondents were interested in clinical trials, and 89% stated that they had obtained information on clinical trials from lectures at the University. On the other hand, over 92% thought that pharmacists should manage investigational drugs and provide information on those drugs for the rational conduct of clinical trials. Over 80% of respondents hoped that they would receive education on clinical trials in the third or fourth year of study, since that is when basic education ends and clinical education starts. After the first questionnaire and student attendance at an introductory lecture on clinical trials, second questionnaire was distributed. Based on the results of the second questionnaire, almost all of the students hoped to learn more about the actual conduct of clinical trials.
Key words--attitude survey; clinical trial; master course students; education program
YAKUGAKU ZASSHI, 126(7),521-527, 2006
A simple, rapid, and sensitive procedure has been developed using gas chromatography with electron-capture detection to measure diallyl trisulfide levels in rat blood. Blood samples were acidified, and the analyte was extracted with hexane, and then degradation was stopped with acetonitrile before gas chromatographic separation. Two calibration curves were linear over the range of 10−500 ng/ml and 0.2−20 μg/ml, with typical r values of 0.9986 and 0.9993, respectively. The structure of its major metabolite was confirmed using combined gas chromatography-mass spectrometry. The limit of detection was less than 10 ng/ml, and the assay was highly reproducible, giving peaks with excellent chromatographic properties. The method is suitable for pharmacokinetic and therapeutic purposes.
Key words--diallyl trisulfide; diallyl disulfide; electron-capture gas chromatography; gas chromatography-mass spectrometry