Volume 40,
Issue 11,
2012
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扉・目次
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薬理と治療 40巻11号, 927-930 (2012);
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SERIES 臨床の現場から②
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薬理と治療 40巻11号, 933-939 (2012);
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ORIGINAL ARTICLES
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薬理と治療 40巻11号, 941-952 (2012);
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Maltosyl Cyclodextrin Mixture(ISOELEAT)is a hydrolyzed derivative of starch that is used as a food additive to make flavours stable. To evaluate the subchronic toxicity, ISOELEAT was administered dietary to male and female Crl:CD(SD)rats for 13 weeks at dose levels of 0(control), 2.5 and 5.0% in the diet. No deaths occurred and no toxic changes were noted in the clinical signs, body weight, food consumption, ophthalmology, urinalysis, hematology, blood biochemistry, organ weight or gross and histopathology. Thus, the no observed adverse effect level(NOAEL)of ISOELEAT was concluded to be more than 5.0% in the diet (2851.7 mg/kg/day for males and 3280.7 mg/kg/day for females)under conditions in the present study.
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薬理と治療 40巻11号, 955-964 (2012);
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The cilostazol orally disintegrating tablet currently on the market(current ODT)was developed as a tablet for easier use in patients with difficulty of swallowing water. Cilostazol improved modified formulation orally disintegrating tablet(improved ODT)is a newly-developed formulation that dissolves in the oral cavity more quickly than the current ODT. The bioequivalence of one cilostazol 100 mg improved ODT and one cilostazol 100 mg current ODT, each taken with or without water, was evaluated in healthy adult male subjects in an open-label, randomized, 2-formulation, 2-treatment, 2-period crossover study. A total of 44 subjects were enrolled and 38 subjects completed the study. When administered without water, the differences in the mean log-transformed AUC60h and Cmax values between the improved ODT and the current ODT(improved ODT-current ODT, point estimates)were respectively log(0.91)and log(1.03), with respective 90% confidence intervals of log(0.84)to log(0.98)and log(0.93)to log(1.15). When administered with water, the differences in the mean log-transformed AUC60h and Cmax values between the improved ODT and the current ODT were both log(0.95), with respective 90% confidence intervals of log(0.89)to log(1.02)and log(0.83)to log(1.08). All values were within the range of the equivalence judgment criteria of log(0.8)to log(1.25)specified in the guideline for bioequivalence studies. Based on these results, one cilostazol 100 mg improved ODT was judged to be bioequivalent to one cilostazol 100 mg current ODT when administered either with or without water. All adverse events observed in either group were mild or moderate in severity, and other than one case of influenza, all adverse events were resolved without treatment. There were no deaths or other serious adverse events.
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薬理と治療 40巻11号, 965-971 (2012);
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Background KRN321 is a hyperglycosylated analog of recombinant human erythropoietin that stimulates red cell production. Its production was approved in April 2010, under the indication of“renal anemia”. To unify the liquid volume to 0.5 mL for all standards, we performed a bioequivalence study of two formulations with high and low concentrations(360 and 120 μg/mL). Objectives The objective of this study was to assess the bioequivalence of two formulations (360 and 120 μg/mL)of KRN321 in healthy volunteers. Methods The study was performed to assess the pharmacokinetics of two KRN321 formulations(360 and 120 μg/mL)at a dose of 60 μg each. The study was a single-centre, openlabel, randomized, two-drug, two-period, crossover study in healthy subjects. Bioequivalence was assessed using the 90% confidence interval of the ratios of Cmax and AUC0-t after subcutaneous injection. Results The 90% confidence intervals for pharmacokinetic parameters(Cmax and AUC0-t) obtained for two KRN321 formulations(360 and 120 μg/mL)were within the bioequivalence criteria(0.8-1.25). Conclusion Bioequivalence of the two KRN321 formulations(360 and 120 μg/mL)was confirmed.
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薬理と治療 40巻11号, 973-984 (2012);
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Aim We performed a dose-ranging study of anagliptin, a novel dipeptidyl peptidase-4 inhibitor, with multi-centre, randomized, placebo-controlled, double-blind, parallel-group design, to investigate its efficacy and safety in Japanese patients with type 2 diabetes mellitus. Methods A total of 358 subjects with type 2 diabetes treated with 25 to 200 mg of anagliptin twice a day(BID)or a placebo for 12 weeks. The markers for glycemic control were measured and investigated, and the change in HbA1c levels from baseline to week 12 was assessed as the primary endpoint. Results At week 12, HbA1c significantly decreased in anagliptin-treated groups, but not in the placebo group, in a dose-dependent manner. The difference of HbA1c reduction between the groups treated with 100 and 200 mg BID was only 0.07%. In the subgroup with baseline HbA1c level at 8.4% or more, HbA1c reduction was much greater in the group with 200 mg BID than the group with 100 mg BID. Any clinically important adverse events were not observed. Conclusions The results showed that anagliptin was efficacious for the treatment of the patients with type 2 diabetes, and that its optimum dose was 100 mg twice a day. The results from subgroup analysis suggested that the dose escalation of anagliptin to 200 mg twice a day is useful for the treatment of the patients with a high level of HbA1c.
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薬理と治療 40巻11号, 985-995 (2012);
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Background and Aim Anagliptin, a novel dipeptidyl peptidase-4 inhibitor, has been investigated about its pharmacokinetic profile, efficacy and safety in phaseⅠ and Ⅱ trials. In this study, we investigated the efficacy and safety of anagliptin in a multi-centre, randomized, placebo- and active comparator-controlled, double-blind, parallel-group study in Japanese patients with type 2 diabetes mellitus. Methods A total of 244 subjects with type 2 diabetes were treated with 100 or 200 mg of anagliptin twice a day, 0.2 mg of voglibose three times a day or a placebo for 12 weeks. The markers for glycemic control were measured and investigated, and the change in HbA1c levels from baseline to week 12 was assessed as the primary endpoint of this study. Results HbA1c values in anagliptin-treated groups were decreased much more significantly compared to those in both placebo-treated and voglibose-treated groups. The fasting plasma glucose, 2-h postprandial glucose, area under the curve(AUC)0-2h of glucose, 1,5-AG, glycoalbumin and proinsulin/insulin ratio in anagliptin-treated groups were also more significantly improved compared to those in the placebo-treated group. The ΔAUC0-2h of plasma glucagon in anagliptin-treated groups significantly decreased, but not in the placebotreated group. We did not observe any clinically important adverse events. Conclusions The present results demonstrated the efficacy and safety of anagliptin in the patients with type 2 diabetes mellitus. Additionally, anagliptin decreased the HbA1c level more greatly than voglibose. These results suggest that anagliptin would be a favorable drug for the therapy of type 2 diabetes.
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薬理と治療 40巻11号, 999-1004 (2012);
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Background Epoetin beta pegol(MIRCERA)is a chemically synthesized erythropoiesis stimulating agent with the integration of epoetin beta and linear methoxy polyethylene glycol (mPEG). Serum MIRCERA concentration is determined by sandwich enzyme-linked immunosorbent assay using both anti human epoetin antibody and anti mPEG antibody(MIRCERA determination method). However, this method is not available commercially in Japan. We sought to establish whether RIA2 antibody assay, which is usually used for determining serum epoetin concentration by anti epoetin rabbit antibody, could determine serum MIRCERA concentration appropriately. Methods ①10 kinds of standard solution with various MIRCERA concentrations from 10000 to 0 ng/mL were prepared. Each solution was determined by RIA2 antibody assay as epoetin concentration and the correlation between MIRCERA concentration and epoetin concentration was tested. Then, its conversion formula was estimated. ②100 or 150 μg MIRCERA were administrated intravenously to 8 hemodialysis patients. Serum epoetin concentration was determined by RIA2 antibody assay, then, it was converted to MIRCERA concentration. Area under the serum MIRCERA concentration-time curve(AUClast)and half-lives(t1/2)were estimated. ③These AUClast and t1/2 were compared to those obtained previously by MIRCERA determination method. Results AUClast by RIA2 antibody assay after administration of 100 and 150 μg were respectively equivalent to 42.6 and 40.6% of those obtained by MIRCERA determination method. However, t1/2 were 169 and 129 hours by RIA2 method, these values were similar to those obtained by MIRCERA determination method Conclusions As the concentration determined by RIA2 antibody assay reflected the long t1/2 which is the pharmacokinetic feature of MIRCERA successfully, our novel method is substitutable clinically.
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薬理と治療 40巻11号, 1005-1010 (2012);
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Objective If a patch preparation(e. g., lidocaine tape or transdermal fentanyl patch)is to be applied on a dry area of a patient’s skin, drug permeability will be low and the expected drug effect may not be obtained. Hence, when a patch preparation is to be applied on a dry skin area, it is necessary to improve skin dryness by hydration. The purpose of this study is to clarify the optimal conditions for use of the hydration patch, Win Back, on human skin. Methods To examine the hydration effect of this hydration patch on the stratum corneum (SC), we measured the conductance on time-dependent changes of six healthy Japanese volunteers whose lower arm was applied with a hydration patch in comparison with ADOFEED Pap, a general poultice, and NIVEA Body Skin Milk, a skin cream. A tape stripping test was performed to investigate disruption of the SC by the test patches(hydration patch and poultice).Results The conductance level of the hydration patch after 30 min exposure was 4.3 times larger than that of the skin cream and 1.6 times larger than that of the poultice. Tape stripping caused few exfoliated SC cells following 30 min immersion with the patch. The hydration patch effectively hydrated the SC, requiring only 30 min for hydration, with few disruptions of the SC by tape stripping. Conclusion Clinical application of the hydration patch is easy and hygienic, making it appropriate for use with patch preparations on dry skin.
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薬理と治療 40巻11号, 1011-1018 (2012);
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Objective It is recognized that chronic cold constitution shall develop various unidentified complaints. Capsinoids, capsaicin analogues in non-pungent chili pepper‘CH-19 Sweet’seem to increase thermogenesis in humans. The aim of this study was to evaluate the effects of capsinoids-containing dietary supplements on sensation of cold constitution and physical and psychological complaints in female students. Methods Following a 2-week non-intake period, 28 young women were instructed to take a daily dose of 2 capsules containing 3.0 mg of capsinoids for 2 weeks. The scores for cold constitution and psychological stress were determined using specific questionnaires at Day 0, 14, and 28, respectively. Defecation frequency and amount and shape of feces were also monitored using a diary throughout the experimental period. Results Two-week capsinoids supplementation significantly improved the scores for subjective symptoms of cold constitution and psychological stress responses(p<0.01, p<0.05). There was a positive correlation between amounts of changes of these scores only in subjects who met a diagnostic criterion for cold constitution. Tendencies of increment of feces and increased frequency of softer feces were observed during the supplementation period. Conclusions Consecutive consumption of capsinoids-containing dietary supplements improved subjective symptoms of cold constitution and its related physical and psychological complaints in female students.
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薬理と治療 40巻11号, 1019-1024 (2012);
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Objectives We examined the effects of administration of unicellular green algae Chlorella on human serum lipid levels. Methods Thirty subjects(22 males and 8 females, 49.8±11.9 years)received one 9-g Chlorella tablet daily for 3 months. Serum total cholesterol(TC), high-density lipoprotein cholesterol(HDL-C), low-density lipoprotein cholesterol(LDL-C)and triglycerides(TG)were evaluated before and after the administration period. These data were evaluated in all subjects. Moreover, TC, LDL-C and TG data were respectively evaluated after dividing subjects into two groups with regard to each measure;namely, normal groups consisting of the subjects whose baseline serum lipid levels had been less than the cutoff for dyslipidemia(TC 220 mg/dL, LDL-C 140 mg/dL and TG 150 mg/dL, JAS guidelines for prevention of atherosclerotic cardiovascular diseases)and high-value groups consisting of the others. Results TC and LDL-C levels in all subjects significantly decreased after the administration of Chlorella(p<0.05). HDL-C and TG levels did not significantly change. The change in TC levels between pre- and post-administration in the TC-high-value group(n=7)was significantly larger than that in the TC-normal group(n=23, p=0.036). The change in LDL-C levels in the LDL-C-high-value group(n=6)was also larger than that in the LDL-C-normal group(n=24). TG levels in the TG-high-value group(n=5)tended to decrease after the administration. The change in TG levels between pre- and post-administration in the TG-high-value group was significantly larger than that in the TG-normal group(n=25, p=0.035). Conclusion These results suggested that the administration of Chlorella was useful for management of serum lipid levels in humans.
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薬理と治療 40巻11号, 1025-1033 (2012);
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Background/Objectives Diacylglycerol(DAG)oil was reported to have an anti-obesity effect and safety by long-term intake in healthy subjects. The objective of this study was to investigate the safety on high dose intake of dietary DAG oil with reduced glycidol fatty acid esters in healthy subjects. Methods A randomized, double-blind controlled, parallel study was coducted in 39 healthy subjects. The subjects ingested mayonnaise containing 30 g of DAG oil or TAG oil with same fatty acid composition at meal per day for 4 weeks. The subjects were instructed to consume either the mayonnaise containing of DAG oil or TAG oil all at once as often as possible. All subjects were received the clinical examination, physical examination, and medical examination/history taking at intervals of two weeks. Results No adverse effects originating in DAG oil or TAG oil were observed in the clinical examination, physical examination, and medical examination/history taking. Conclusions These results suggest that the safety on high dose intake of dietary DAG oil with reduced glycidol fatty acid esters in healthy subjects.