薬理と治療
Volume 37, Issue 3, 2009
Volumes & issues:
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ORIGINAL ARTICLES
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Loxoprofen 含有貼付剤の鎮痛効果発現に要する時間経過の電気生理学的解析
37巻3号(2009);View Description Hide DescriptionThe onset of the analgesic effect of plaster containing loxoprofen sodium(LOX)wasexamined electrophysiologically using a rat model of muscle pain. To establish an animalmodel of persistent mechanical hyperalgesia, saline at pH 4.0 was injected twice every 5 daysinto the gastrocnemius muscle. To quantify hyperalgesia, the paw withdrawal threshold tomechanical stimuli was measured. A total of 19 rats were selected on the basis of behavioralresults that showed mechanical hyperalgesia and were divided into the following two groups:LOX group(application of plaster containing LOX)and Base group(application of plaster withoutLOX). Under halothane anesthesia(1 % in air), an electromyogram(EMG)was recordedfrom the tibialis anterior muscle in the side ipsilateral to mechanical pressure(5.89 N), andthe area of integrated EMG for 1s was measured as the magnitude of EMG activity. In theLOX group(n=12), the magnitude of EMG activity significantly decreased at 40 min followingapplication of the plaster, whereas the magnitude of EMG activity in the Base group didnot produce any change. This result suggests that LOX can produce analgesia on muscle painwithin 40 min after application of plaster containing LOX.(Jpn Pharmacol Ther 2009;37:165−70)KEY WORDS Loxoprofen sodium, Electromyogram(EMG), Muscle pain, Analgesia -
Toxicity of PG2K20 for 28 Days Administration in Rats
37巻3号(2009);View Description Hide DescriptionWe examined the toxicity of PG2K20, γ−aminobutyric acid produced by fermentationfor 28 days administration in rats. We found no remarkable difference in growth, daily intakeof feed and water in both group and no abnormal findings in health condition. In the histopathologicaltest, fatty degeneration in the liver cell was simple one and other findings were allat low levels. The numeric value of the liver function and kidney function from histopathologicaltest do not connected to these findings. The testis weight of testing rats was significantlyheavier than that of control, however, this difference is within the limit of normal weight andno abnormal finding was recognized in histopathological test.(Jpn Pharmacol Ther 2009;37:173−9)KEY WORDS γ−aminobutyric acid,GABA,Toxicity -
104−Week Carcinogenicity Study of Monoammonium Glycyrrhizinate by Subcutaneous Administration to CD Rats and CD−1 Mice
37巻3号(2009);View Description Hide DescriptionMonoamminium Glycyrrhizinate (MGL) has been used for the clinical therapies ofchronic hepatitis as well as allergic diseases in Japan. To complement the information of toxicologyunder the ICH Guideline, MGL was tested for the carcinogenic potential in rats andmice. The animals were treated with 15, 45 or 135 mg/kg(rats), 10, 30 or 90 mg/kg(malemice), and 5, 15 or 45 mg/kg(female mice)by subcutaneous administration daily for 104weeks. The dose levels of the high−dose groups were switched in the range between 67.5and 225 mg/kg(rats), 90 and 180 mg/kg(male mice), and 45 and 90 mg/kg(female mice),to result in a sufficient degree of toxicity as required by the ICH guidelines. In rats, a doserelated systemic toxicity was noted above all in the high−dose group. Both male and femalemice experiments were terminated at test week 94 instead of 104 weeks in accordance withthe termination criteria in the guidelines. All other mortality rates of the mice in all dosegroups were within the range of the control group. All neoplastic lesions recorded in thesestudies are commonly encountered in corresponding animals of these strains and ages. Type,incidence, and severity of the lesions recorded were not increased in MGL−treated animalsas compared to the control animals. Toxicokinetic evaluation revealed a dose−dependent linearexposure to glycyrrhizin and glycyrrhetic acid. It is concluded that MGL given subcutaneouslydaily for 104 weeks has no carcinogenic potential in rats and mice.(Jpn Pharmacol Ther 2009;37:181−96)KEY WORDS Glycyrrhizin, Carcinogenicity study, Subcutaneous administration, Rat,Mouse -
竹節人参,黄連,黄ごん ,黄柏,当薬を含む生薬製剤「片仔黄(R) 」の薬理学的研究
37巻3号(2009);View Description Hide DescriptionObjectives Henshikou is a crude OTC drug for gastrointestinal complaints. To establish itspharmacological profile, several tests using rats and mice were conducted.Methods Effects on alcohol dehydrogenase activity and heme oxygenase−1 induction werestudied in vitro. Effects on blood ethanol level after oral administration of ethanol, gastriclesion induced by ethanol, restraint and water−immersion stress, experimental reflux esophagitisand dextran sulfate induced colitis were studied in vivo using rats and mice.Results Henshikou showed lowering effect of blood ethanol level after oral administrationof ethanol, and protective effect on the injury model of esophagus, gust and colon in rats ormice by oral administration. The effective doses were not apart from that for humans. Thisdrug also showed anti−inflammatory effect in mice and increased heme oxygenase−1 level incultured Hep G2 cells.Conclusions Above results suggest that Henshikou, as an OTC drug for gastrointestinalcomplaints, is effective for reducing ethanol toxicity and protection of gastrointestinal mucosa.(Jpn Pharmacol Ther 2009;37:197−208)KEY WORDS Ethanol disposition, Peptic ulcer, Colitis, Heme oxygenase−1 -
エピルビシン塩酸塩注射用「サワイ」の局所刺激性試験
37巻3号(2009);View Description Hide DescriptionThe present study reports the local toxicities of Epirubicin hydrochloride for injection「SAWAI」, a generic epirubicin hydrochloride for injection, in comparison with Farmorubicin_for injection. Hepatotoxicities of Epirubicin hydrochloride for injection「SAWAI」and Farmorubicin_for injection were determined by a hepatotoxic test following hepato−arterial injectionfor rats. Male rats were injected with Epirubicin hydrochloride for injection「SAWAI」andFarmorubicin_ for injection into hepato−artery and tested for blood biochemistry sequenciallyand autopsied after last blood collection. There was no difference between the hepatotoxicitiesof Epirubicin hydrochloride for injection「SAWAI」and Farmorubicin_ for injection.These studies demonstrated that the local toxicity of Epirubicin hydrochloride for injection「SAWAI」was equivalent to that of Farmorubicin_ for injection.(Jpn Pharmacol Ther 2009;37:209−13)KEY WORDS Epirubicin hydrochloride, Local toxicity, Intra−arterial injection -
エピルビシン塩酸塩注射用「サワイ」の局所刺激性試験
37巻3号(2009);View Description Hide DescriptionThe present study reports the local toxicities of Epirubicin hydrochloride for injection「SAWAI」, a generic epirubicin hydrochloride for injection, in comparison with Farmorubicin_for injection. Vessel irritancies of Epirubicin hydrochloride for injection 「SAWAI」andFarmorubicin_ for injection were determined macroscopically and histologically by a vesselirritation test following intravenous injection to rabbits. There was no difference between theinflammation and thrombogenesis of Epirubicin hydrochloride for injection 「SAWAI」andFarmorubicin_ for injection. The intravesical irritancy of Epirubicin hydrochloride for injection「SAWAI」and Farmorubicin_ for injection were determined macroscopically and histologicallyby an intravesical irritation test. The female beagles were intravesically injected withEpirubicin hydrochloride for injection「SAWAI」and Farmorubicin_ for injection. There wasno difference between the intravesical irritancies of the two formulations. These studies demonstratedthat the local toxicity of Epirubicin hydrochloride for injection「SAWAI」was equivalentto that of Farmorubicin_ for injection.(Jpn Pharmacol Ther 2009;37:215−22)KEY WORDS Epirubicin hydrochloride, Local toxicity, Intravenous administration,Intravesical administration -
注射用エピルビシン塩酸塩製剤(エピルビシン塩酸塩注射用「サワイ」およびファルモルビシン 注射用)のin vivo および in vitro 抗腫瘍作用の比較
37巻3号(2009);View Description Hide DescriptionWe performed comparative bioequivalence studies of the generic injectable epirubicindeveloped by Sawai and the branded product(Farmorubicin_)in cultured human tumor celllines and experimental tumor−bearing mouse models. Both products inhibited the proliferationof a variety of cultured malignant human cell lines, including THP−1 monocytic leukemia,UM−UC−3 bladder cancer, Hep G2 hepatocellular carcinoma, and the breast cancerMDA−MB−231 and SK−BR−3. Their IC50 values ranged from 9.8 to 639.4 ng/mL. The inhibitoryeffects of the two products on proliferation were biologically equivalent. To assess invivo antitumor activity, Sarcoma−180 or Ehrlich carcinoma was transplanted to mice i. p.(ascites tumor)or s. c.(solid tumor)and each product was administered i. v. on days 1, 5 and9 at 1.25 or 5.0 mg/kg/day. Administration of each product at 5.0 mg/kg was significantly butslightly prolonged survival time in Sarcoma−180 and Ehrlich ascites tumor−bearing mice.The increase of life span was 5.7−13.2%(1.25 mg/kg)and 22.2−34.3%(5.0 mg/kg). In caseof the solid tumor−bearing mice, however, markedly inhibitory effects on tumor growth wereobserved at a dose of 1.25 or 5.0 mg/kg. The tumor inhibition rate was 38.1−44.8%(1.25 mg/kg)and 73.1−76.7%(5.0 mg/kg). In ascites and solid tumor−bearing mice, antitumor activityof the two products was equivalent. These results show that epirubicin hydrochloride forinjection developed by Sawai is biologically equivalent to the innovator’s product.(Jpn Pharmacol Ther 2009;37:223−30)KEY WORDS Epirubicin hydrochloride, Farmorubicin, Antitumor activity, Bioequivalencestudy -
2 型糖尿病に対する二相性インスリンアスパルト−30(BIAsp 30)の安全性および有効性
37巻3号(2009);View Description Hide DescriptionThe safety and efficacy of BIAsp 30, a biphasic insulin analogue, were investigated ininsulin naificantdecrease(p<0.001), and the HbA1c levels at week 26 were less than 6.5% in 19.7%and less than 7.0% in 35.2%. The mean fasting blood glucose levels were 201.7 and 142.3mg/dL, and the mean blood glucose levels after breakfast were 287.8 and 184.8 mg/dL atweeks 0 and 26, respectively, showing significant decreases(p<0.001).In conclusion, 26−week treatment with BIAsp 30 improved HbA1c and blood glucose profileof insulin naive T2D patients with few major hypoglycaemic events. -
Evaluation of the Clinical Efficacy of Continuous Pitavastatin Treatment for 36 months in Patients with Hypercholesterolemia
37巻3号(2009);View Description Hide DescriptionBackground and objectives Pitavastatin, a 3−hydroxy−3−methylglutaryl coenzyme A(HMG−CoA)reductase inhibitor(statin), is known as a potent cholesterol−lowering action.However, the efficacy and safety of long−term use of the drug for more than 2 years hasscarcely been reported. We examined the effectiveness of therapy with pitavastatin, as theonly lipid−lowering agent, administered for 36 months.Methods A total of 35 patients with hyperlipidemia(male:female. 21:14;age, 61.3±12.9 years old;17 patients in the cardiovascular high−risk group and 18 in the intermediateriskgroup)were treated with pitavastatin at 2 mg daily. Serum lipids and liver enzymes, forsafety evaluation, were assessed during and after 36 months’pitavastatin treatment.Results Significant reduction of the serum LDL−C levels was observed after 6 months’therapy in both the high−risk and intermediate−risk groups(high−risk group:162.3±45.8mg/dL to 116.9±34.9, intermediate−risk group:166.7±20.7 to 119.3±38.3;p<0.001 forboth.)The rate of successful achievement of the serum LDL−C goal, defined by the JapanAtherosclerosis Society Guideline for the diagnosis and prevention of atherosclerotic cardiovasculardiseases for Japanese, was 64.7% and 72.2%, in the high−risk and intermediateriskgroup, respectively. The significant reduction of serum lipid levels and high rate of successfulachievement of the serum LDL−C goal were maintained until the end of the followupperiod of 36 months. The LDL/HDL ratio reduced by 33.2% and 31.3% from the baseline,and the serum non−HDL−C levels also decreased by 29.8% and 30.1% from the baseline,in the high−risk group and intermediate−risk group, respectively. Pitavastatin was welltoleratedduring the observation period.Conclusion Long−term therapy with pitavastatin, as the only lipid−lowering agent, is efficaciousand safe for improvement of the lipid profile, suggesting the usefulness of the drug inthe prevention of atherosclerosis and cardiovascular events.(Jpn Pharmacol Ther 2009;37:243−53)KEY WORDS Pitavastatin, Hyperlipidemia, Atherosclerosis -
イミダゾールジペプチド配合飲料の日常的な作業のなかで疲労を自覚している健常者に対する継続摂取による有用性
37巻3号(2009);View Description Hide DescriptionObjectives As oxidative stress is known to cause physical fatigue, antioxidants are potentialcandidates for anti−fatigue agents. Imidazole dipeptides, reported to have strong antioxidativeeffects, have been demonstrated to be effective against fatigue−induced decline in physicalperformance. Here, we investigated the effect of imidazole dipeptides−containing drink onfeeling of fatigue from daily activities in healthy people.Methods 207 volunteers participated in a randomized, double−blind, placebo−controlledclinical study. Subjects were randomly divided into three groups;and provided with imidazoledipeptides 200 mg/day(low dose), 400 mg/day(high dose), or placebo for 8 weeks. Weevaluated the subjective sensation of fatigue primarily by the visual analogue scale(VAS).Results The VAS score was significantly lower 2 to 8 weeks after administration in the imidazoledipeptides 400 mg group compared with that in the placebo group.Conclusions Imidazole dipeptides was also effective as well for the attenuation of fatiguefrom daily activities, most likely attributable to its antioxidant action. Imidazole dipeptidescontainingdrink can thus be considered as one promising candidate for anti−fatigue food.(Jpn Pharmacol Ther 2009;37:255−63)KEY WORDS Imidazole dipeptides, Sensation of fatigue, Visual analogue scale, Antifatiguefood -
ヤーコン葉・茎エキス配合食品の長期反復摂取時における安全性および食後血糖上昇抑制効果の減弱性の検討
37巻3号(2009);View Description Hide DescriptionTo evaluate the safety of long−term repeated intake of food containing extract from leafand stem of yacon and the possible attenuation in its inhibitory effect on the postprandial elevationin blood glucose, we conducted a randomized, double−blind, placebo−controlled, parallel−group study on 48 male and female with a fasting blood glucose level of less than 140mg/dL.The subjects in the test food group consumed a test meal containing 900 mg of extractfrom yacon leaf and stem three times a day for 12 weeks, but no adverse events attributableto its repeated ingestion were detected. Furthermore, in the meal challenge test with foodcontaining extract from yacon leaf and stem conducted immediately after 12 weeks of continuousintake, no significant differences in the postprandial rise in blood glucose were notedbetween the test food and control groups, indicating that the inhibitory effect of the test foodon the postprandial elevation in blood glucose was not attenuated.These results demonstrate that food containing extract from yacon leaf and stem ishighly safe for long−term repeated consumption and exhibits enduring medium−and longtermeffectiveness in inhibiting the postprandial elevation of blood glucose.(Jpn Pharmacol Ther 2009;37:265−75)KEY WORDS Yacon, Safety, Attenuation effect, Postprandial blood glucose, Diabetes mellitus -
難消化性デキストリンの食後血糖,インスリン,中性脂肪の上昇に及ぼす影響
37巻3号(2009);View Description Hide DescriptionObjectives We evaluated the influence of resistant maltodextrin on postprandial blood glucose,insulin, and triglyceride levels when it was consumed with meal, by using two mealshaving different nutritional compositions.Methods 4 kinds of meal sets were prepared and loaded to 12 healthy adults in a cross overmanner. The meal preparations were 1)a high carb diet which contains high carbohydratesand 2)a high fat diet with high amount of fat, with a food containing resistant maltodextrin orplacebo. The changes in postprandial blood glucose, insulin and triglyceride levels were monitoredfor comparison.Results resistant maltodextrin suppressed the postprandial rises in blood glucose and insulinlevels when consumed with a high carb diet. When consumed with a high fat diet, resistantmaltodextrin decreased the rise in postprandial triglyceride and insulin levels.Conclusions The affected items by resistant maltodextrin depended on nutritional compositionof diets, however, postprandial insulin secretion was significantly decreased in both highcarb and high fat diets.(Jpn Pharmacol Ther 2009;37:277−83)KEY WORDS Resistant maltodextrin, Meal loading, Blood glucose, Insulin, Triglyceride
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