薬理と治療

Recently, pain control therapy is actively started with chemotherapy. Fentanyl has been demonstrated to have high analgesic efficacy and cause less gastrointestinal disturbance. Fentanyl patches require only replacement every 72 hours so they are expected to improve QOL of patients suffering from cancer pain. However, there are several clinical reports that the analgesic effect of the patches can not be sustained or maintain a steady state of pain control. In this study, we focused on the relation between skin condition, especially dry skin and drug absorption. By measuring Transepidermal Water Loss（TEWL）, we established a dry skin rat model treatment with silica−gel. Applying fentanyl a patch on this model, serum fentanyl concentration of dry skin rat was significantly inhibited compared with that of control. In this study, by optimizing the narcotics patches used, we conclude the importance of prevention of skin drying. Thus, it is significant for pharmacists not only to purchase, administer and prepare them but also to apply them to patients in light of their skin condition using aids like TEWL. As a result, patients may be relieved of pain.（Jpn Pharmacol Ther 2008；36：589−92）KEY WORDS Fentanyl patch, Dry skin, TEWL, Pain control

Objectives To evaluate the clinical usefulness of BR−99S, a bicarbonated Ringer’s solution with magnesium. BR−99S is a kit product packaged in a plastic bag（direct container）using a gas−barrier film that keeps the stability of the solution by preventing carbon dioxide gas emission and pH elevation. Methods To assess preparation efficiency, 6 pharmacists compared formulation time between BR−99S and Ringer’s solution＋Maylon 84＋corrective use magnesium sulfate solution（RMM）. Also, to evaluate the usability of BR−99S, 10 pharmacists and 10 nurses filled out 13 questionnaires related to preparation efficiency, bacterial infection, medical malpractice, storage space, medical waste, and total usefulness. Results The average time needed to prepare one dose for a single patient was 76.0 sec for BR−99S and 226.2 sec for RMM. The average time needed to prepare one dose each for five patients was 241.0 sec for BR−99S and 662.2 sec for RMM. Both times were significantly shorter for BR−99S（p＜0.01）. In the usability questionnaire survey, all responses were significantly superior for BR−99S compared to RMM（p＜0.01）.Conclusion BR−99S is a bicarbonated Ringer’s solution with magnesium packaged in a plastic bag using a gas−barrier film that keeps the stability of the solution by preventing carbon dioxide gas emission and pH elevation. The time needed to prepare BR−99S was significantly shorter than that needed to prepare RMM. In the results of questionnaire survey, BR−99S was shown to prevent bacterial and foreign particle contamination, reduce medical malpractice, meet the speedy preparation for emergency use, and increase the quality of treatments. Based on the results of this study, BR−99S is thought to be useful as a kit product. （Jpn Pharmacol Ther 2008；36：593−602）KEY WORDS Bicarbonated Ringer’s solution, Magnesium, Kit product, Clinical usefulness

Oxidative responses are well recognized to play essential roles in the development and maintenance of osteoporosis. Although bisphosphonate is well accepted to be effective in the treatment of osteoporosis, the influence of bisphosphonate on oxidative responses is not well understood. Therefore, the present study was designed to examine the influence of bisphosphonate on oxidative responses using risedoronate（RS）, the third generation bisphosphonate, and adjuvant arthritis in vivo. Adjuvant arthritis was induced in male Lewis rats by a single subcutaneous injection of 0.1 mL complete Freund’s adjuvant into the hind paw. Oxidative responses were evaluated by measuring hydroperoxide contents in plasma with a newly developed free radical analysis system, FREE. Daily administration of RS at more than 0.028 mg／kg could suppress the production of hydroperoxide in plasma, which was increased by adjuvant injection. It is also observed that daily administration of RS also suppress the levels of plasma cartilage oligometric matrix protein（COMP）that is the marker of cartilage destruction. The minimum dose of the agent, which causes significant suppression of COMP production, was 0.028 mg／kg, which is a human recommended therapeutic dose. These results may suggest that RS could suppress the production of reactive oxygen species and results in favorable modification of clinical conditions of osteoporosis.（Jpn Pharmacol Ther 2008；36：605−11）KEY WORDS Bisphosphonate, Free radical, Adjuvant arthritis, COMP

Objectives We developed a black tea beverage supplemented with indigestible dextrin. In this study, we investigated whether the beverage would suppress the postprandial elevation of blood glucose level of volunteers. We also evaluated the safety of the beverage. Methods Human trial 1. We conducted a double−blinded crossover trial. 24 volunteers （48.0±13.3 years old）ingested a test meal and a 350 mL of black tea beverage supplemented with 5 g of indigestible dextrin or a placebo. The blood glucose level and insulin level were measured after meal. Human trial 2. We conducted two open−label trials to evaluate safety of the beverage. For each trial, 16 volunteers, including four volunteers with impaired glucose regulation（110≦FGP＜126 and／or 5.8≦HbA1C＜6.5）, were enrolled（45.4±15.7 and 44.6±15.5 years old, respectively）. In the first trial, volunteers consumed the test beverage three times a day for 12 weeks. In the second trial, volunteers consumed another test beverage supplemented with an excess amount of indigestible dextrin three times a day for four weeks. They had health interviews, blood tests and urine tests during the test period. Results Human trial 1. Concurrent ingestion of the test beverage with the test meal significantly lowered the blood glucose level and insulin level at 30 minutes after meal compared to concurrent ingestion of the placebo. Human trial 2. No harmful effect caused by the test beverages was observed throughout the study periods. Conclusions The data obtained through these trials suggested that the black tea beverage supplemented with indigestible dextrin suppresses the elevation of the postprandial blood glucose level and that the beverage is safe when it is consumed continuously at the recommended dose.（Jpn Pharmacol Ther 2008；36：613−22）KEY WORDS Indigestible dextrin, Black tea, Blood glucose level, Safety

We found recently that α−lactalbumin, major component of whey proteins, had antinociceptive and anti−inflammatory activity provided by inhibiting cyclooxygenase−2. This study aimed thus to investigate the effects of α−lactalbumin on menstrual pain and on their quality of life in healthy women volunteer. Thirty subjects with menstrual pain were enrolled and randomized into two groups. One group ingested two tablets containing α−lactalbumin （150 mg／tablet）3 times a day. Another group ingested placebo tablet containing lactose instead of α−lactalbumin. Each tablet was ingested during one menstrual cycle and following one menstrual cycle was withdrawal. After non−ingested period, another tablet was ingested following one menstrual period. Menstrual pain, degree of taking analgesic drugs and quality of life were conducted in the form of questionnaire according to the verbal rating scales during three periods；non−ingested period, placebo−ingesting period and α−lactalbumin−ingesting period. α−Lactalbumin−ingestion significantly decreased the score of menstrual pain as compared with non−ingested period but placebo−ingestion did not. α−Lactalbumin−ingestion and placebo ingestion significantly decreased the score of the degree of analgesic drugs as compared with non−ingested period. α−Lactalbumin−ingestion showed a tendency to improve the degree of quality of life as compared with non−ingested period and placeboingestion period. In this study, adverse effects were not observed during the experimental period. These results suggest that α−lactalbumin is a safe and useful material for the relief of the menstrual pain.（Jpn Pharmacol Ther 2008；36：623−8） KEY WORDS α−Lactalbumin, Menstrual pain, Quality of life, Cyclooxygenase−2

Background Zinc has been reported to stimulate bone metabolism and prevent progression of hepatic fibrosis. We administered polaprezinc, a preparation containing zinc, to patients with liver cirrhosis, for the purpose of evaluating the effects of zinc on hepatic fibrosis and bone loss. Method Seventeen patients were randomly assigned to receive polaprezinc（P−group）, and 18 were assigned to receive rebamipide（R−group）. Patients were evaluated at entry, 1 year and 2 years after the initiation of the treatment. Results The mean percent change in bone mineral density（BMD）was＋1.05％ in the Pgroup and＋0.09％ in the R−group after 1 year of treatment, and＋0.11％ in the P−group and−0.87％ in the R−group after 2 years of treatment, but the difference between the groups was not significant. The mean percent of serum zinc in the P−group was significantly higher than that in the R−group at 6 months, 1 year and 2 years after treatment. The mean percent of serum bone specific alkaline phosphatase in the P−group was significantly higher than that in R−group at 1 year after treatment. The mean percent of serum osteocalcin in the P−group was significantly higher than that in the R−group at 1 year and 2 years after treatment. The mean percent of serum markers for hepatic fibrosis in the P−group and those in R−group did not show significant differences during treatment. Conclusions These results suggest that zinc replenishment in patients with liver cirrhosis can prevent progression of hepatic bone mineral loss. （Jpn Pharmacol Ther 2008；36：633−40）KEY WORDS Zinc, Liver cirrhosis, Hepatic fibrosis, Osteocalcin, Bone mineral density

Objectives To investigate the pharmacodynamic efficacy of lansoprazole（AG−1749）15 mg and 30 mg in controlling intraesophageal pH, as well as reflux−associated symptoms such as heartburn in Japanese patients with grade M non−erosive reflux disease in a multi−center, randomized, double−blind trial, with the primary endpoint being the ％ of time intraesophageal pH below 4.0 and the secondary endpoint being the percentage of days in which they remain free of heartburn, as well as the severity of their heartburn, before and after treatment with lansoprazole. Methods Patients were randomized to AG 15 and AG 30 group after 1−week observation period with antacids to confirm to have heartburn for at least 2 days per week, to have endoscopic findings of grade M, and to be 4％ or more in the ％ of time intraesophageal pH below 4.0. Results A total of 10 patients each judged to be assessable in the AG 15 and AG 30 group were included for analyses, although a total of 39 patients were enrolled in the stxudy. The ％ of time intraesophageal pH below 4.0 was 16±12.9％ nd 10±4.0％ in the AG 15 and AG groups, respectively, before treatment, while those of the treatment periods of 5 to 8 weeks was 2±1.4％ and 1±2.7％ in the AG 15 and AG 30 groups, respectively. This accounted for a statistically ignificant difference of−15±12.5％ in the AG 15 group and −8±4.0％ in the AG 30 group between before and after eatment, while there was no significant difference between the treatment arms. The percentage of days in the treatment period in which patients remained free of heart burn was 59％ and 65％ in the AG 15 and AG 30 group, respectively. The median severity of heartburn symptoms was similar and not significantly different between the AG 15 group and AG 30 roup at 0.5, and 0.5, respectively. Conclusions Lansoprazole was shown to be efficacious in controlling intraesophageal pH, as well as acid reflux−associated symptoms such as heartburn, thus offering a clear clinical benefit to NERD patients.（Jpn Pharmacol Ther 2008；36：641−54）KEY WORDS Lansoprazole, Pharmacodynamic efficacy, Multi−center randomized ouble blind trial, Non−erosive reflux disease, NERD, 24−hour intraesophageal pH monitoring, Heartburn

Objectives To investigate the efficacy and safety of lansoprazole（AG−1749）15 mg and 30mg in Japanese patients with non−erosive reflux disease（NERD）in a phaseIII multi−center, double−blind, placebo−controlled trial, with the primary endpoint being the proportion of the treatment period in which patients remain free of heartburn symptoms, as well as the severity of their heartburn symptoms. Methods Patients were eligible for treatment with antacids（1−week observation period）if they had heartburn symptoms for at least 2 days per week during 3 weeks prior to the start of the study with endoscopic findings of grade M in the modified LA classification system. Patients were randomized to lansoprazole 15 mg（AG 15 group）, lansoprazole 30 mg（AG 30 group）or placebo for an 8−week treatment. Results A total of 248 patients were enrolled in the study and 220 patients were randomized. The median percentage of days without heartburn symptoms during the 8−week treatment period in the AG 15, AG 30 and placebo groups was 77％, 67％, and 54％, respectively, and the median heartburn symptom scores during the 8−week treatment period in these groups were 0.3, 0.4, and 0.6, respectively, with both AG groups found to be more effective than the placebo group. When stratified by response to lansoprazole the cumulative percentage of days without heartburn symptoms in responders in the both AG groups was consistently significantly higher than in the placebo group, while those in non−responders in both AG groups remained low. Conclusions Study results demonstrate that lansoprazole is significantly more effective at 15 mg or 30 mg once daily than placebo in relief of heartburn symptoms in patients with NERD during the 8−week treatment period, especially in responders and that 15 mg oncedaily was considered to be optimal in Japanese patients with NERD. （Jpn Pharmacol Ther 2008；36：655−71）KEY WORDS Lansoprazole, PhaseIII multicenter, Double−blind, Placebo−controlled trial, Heartburn symptoms, NERD, Non−erosive reflux disease