薬理と治療
Volume 37, Issue 2, 2009
Volumes & issues:
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SERIES
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- 国際的視野からみた先端研究の倫理的諸問題
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[第2回]The Harvard Embryonic Stem Cell Research Oversight Committee
37巻2号(2009);View Description Hide Description
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ORIGINAL ARTICLES
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Comparability Study in Humans of EPOCH Manufactured under Serum−free Conditions
37巻2号(2009);View Description Hide DescriptionBackground Epoetinβ is the recombinant human form of the mass−produced glycoproteinerythropoietin and is produced by Chugai Pharmaceutical Co., Ltd.(Tokyo, Japan)usingrecombinant technology. Recent advances in biotechnology have made it possible to manufacturebiologics without using animal by−products. This approach is assumed to be desirable,since it avoids unknown biorisks. Therefore, we changed to a new manufacturing processusing serum−free culture media without addition of animal by−products, and manufactured anew formulation of serum−free EPOCH(sf−EPOCH).Objectives The aim of this clinical trial was to confirm the comparability of the newEpoetinβ formulation sf−EPOCH, to the established EPOCH formulation and to confirm thesafety of sf−EPOCH.Methods Thirty two healthy adult male volunteers were divided randomly into two groups,and 6000 IU sf−EPOCH or EPOCH was given by subcutaneous administration. This studyincorporated a crossover design, where a 14−21 day washout period was inserted betweenthe first and second treatment periods. In pharmacokinetic analysis, bioequivalence wasassessed using Cmax, AUClast and MRT of serum erythropoietin, while pharmacodynamicanalysis comprised comparability assessment using reticulocyte counts.Results sf−EPOCH was determined to be bioequivalent and comparable to EPOCH. Inaddition, no safety difference was observed between sf−EPOCH and EPOCH.Conclusions As a result of this comparability study, sf−EPOCH, assumed to be desirablefrom the aspect of avoiding biorisks, was confirmed to be comparable to EPOCH used in currentclinical practice. It will be possible to use sf−EPOCH in clinical practice with the samedosage regimen as that currently used for EPOCH.(Jpn Pharmacol Ther 2009;37:95−107)KEY WORDS Comparability study, Bioequivalence study, Serum−free, Epoetinβ, Changein the manufacturing process of biotechnological/biological products -
クリンダマイシン注射剤の安定性に関する研究
37巻2号(2009);View Description Hide DescriptionClindamycin(JP, USP)is an effectual antibiotics for gram−positive coccus, anaerobes ormycoplasma genus. In the case of intractable infection caused by anaerobes such as peptococcusgenus or bacteroides genus, clindamycin injections are useful for the combination treatmentwith β lactam antibiotics, which is recommended by the academy guidelines for infectioncontrol.In Japan, there are the brand−name medicine which is sold by Pfizer and five genericmedicines.In Japan, based on the agreement of listing additives of ethical drugs which was formedby the Japan Pharmaceutical Manufacturers Association, JPMA(No. 712 reports of the 1st ofOct.. 2001), the name of all additives must be written on the package insert except for isotonicagents, water for injection and pH adjustments such as HCl or NaOH solution. Accordingto the package insert, most of Clindamycin injections sold in Japan contain only benzylalcoholas preservative. But there are some preparations of clindamycin injection added otherpreservatives above mentioned. One is citrate in Japanese preparations, the other is EDTA inUS products.Clindamycin injections should be stored at room temperature and they are valid for twoyears. We examined the survival rate of clindamycin to consider whether the additives withthe complex agent mentioned above are necessary or not for the stability of the component.It is confirmed that the clindamycin injections get deteriorated with severe conditionsuch as high temperature during the distribution from a wholesale dealer to a hospital by caron a hot summer day.(Jpn Pharmacol Ther 2009;37:109−13)KEY WORDS Clindamycin, Additives, Preservatives, Cirate EDTA -
ベザフィブラートはレムナントリポ蛋白負荷ヒトメサンギウム細胞の TGF−βとTypeIVコラーゲンの発現を抑制する
37巻2号(2009);View Description Hide DescriptionDiabetic nephropathy is one of the main causes of death in diabetic patients. Hyperglycemiaand hypertension are risk factors for diabetic nephropathy. Recently it has been proposedthat hypertriglyceridemia contributes to diabetic nephropathy. In JDCS(Japan Diabetes ComplicationsStudy)and UKPDS(UK Prospective Diabetes Study)74, hypertriglyceridemia wasdetected as one of the risk factors for diabetic nephropathy. In FIELD(Fenofibrate InterventionEvent Lowering in Diabetes)study, fenofibrate therapy reduced plasma level of triglyceride(TG), and prevented and improved diabetic nephropathy in type 2 diabetic patients.Increased remnant lipoproteins underlie hypertriglyceridemia. We first found that increasedremnant lipoproteins contribute to diabetic nephropathy. It is proposed that remnant lipoproteinsare taken up by mesangial cells, and then cause renal damage. Diabetic nephropathy ischaracterized by the accumulation of extracellular matrix protein(type IV collagen)in theglomerular mesangium and expansion of the mesangial matrix, resulting in glomerulosclerosis.TGF−β stimulates type IV collagen protein synthesis. Fibrate, which is a ligand forPPARα, reduces plasma levels of TG and remnant lipoproteins and possibly may protect andimprove nephropathy thorough PPARα.In the present study we examined the effect of bezafibrate on TGF−β and type IV collagenexpression in human mesangial cells(HMCs)loaded with remnant lipoproteins in themedium.Remnant lipoproteins were isolated from plasma of a patient with type 2 diabetes andtypeIII hyperlipoproteinemia by ultracentrifugal method. HMCs loaded with remnant lipoproteiswere incubated for up to 24 h with bezafibrate at the concentration of 0, 3×10−6, 3×10−5 and 3×10−4 mol/L. To evaluate the expression of TGF−β mRNA and type IV collagenmRNA in mesangial cells, RT−PCR procedure was performed.Remnant lipoproteins significantly(p<0.001)stimulated the expression of TGF−β mRNAand type IV collagen mRNA in HMCs. Bezafibrate significantly(p<0.001 or p<0.01)suppressesthe expression of TGF−β mRNA in HMCs loaded with remnant lipoproteins in adose−dependent manner. Bezafibrate significantly (p<0.001 or p<0.05) suppresses theexpression of type IV collagen mRNA in HMCs loaded with remnant lipoproteins in a dosedependentmanner.Remnant lipoproteins stimulate the expression of TGF−β and type IV collagen inHMCs. It is concluded that remnant lipoproteins play an important role in the developmentand progression of diabetic nephropathy through TGF−β and type IV collagen. In addition,bezafibrate suppresses the expression of TGF−β and type IV collagen in HMCs loaded withremnant lipoproteins. It is suggested that bezafibrate is effective to protect and improve diabeticnephropathy.(Jpn Pharmacol Ther 2009;37:117−22)KEY WORDS Bezafibrate, TGF−β, Type IV collagen, Remnant lipoproteins, Mesangialcells, Diabetic nephropathy -
ケルセチン配糖体のマウス食餌性肥満モデルに及ぼす影響
37巻2号(2009);View Description Hide DescriptionObjectives Obesity is one of the most important worldwide health problems. We investigatedthe effects of quercetin glucosides, which is enzymatically trans−glycosylated isoquercitrinfrom natural resources, on visceral fat weight in diet−induced obese mice and in vitro3T3−L1 adipocytes.Methods Glycerol release and phosphorylation of hormone sensitive lipase(HSL)wereevaluated in differentiated 3T3−L1 adipocytes. In diet−induced obesity model, mice were feddiets containing 0, 0.05 and 0.25%(w/w)quercetin glucosides for 3 months.Results In 3T3−L1 adipocytes, quercetin accelerated the glycerol release and phosphorylationof HSL in dose−dependent manner. Supplementation of quercetin glucosides in dietinducedobese mice resulted in reduced body weight gain, and significant reduction of visceralfat weight and adipocyte hypertrophy.Conclusions These results suggested that the quercetin glucosides activate lipolytic passwayin adipose tissues and this compound is beneficial to prevent and improve obesity.(Jpn Pharmacol Ther 2009;37:123−31)KEY WORDS Polyphenol,Quercetin,quercetin glucoside,Diet−induced obesity,Lipolysis -
「サーモンペプチド配合飲料」の正常高値および軽症高血圧者に対する血圧降下作用の用量相関性確認試験
37巻2号(2009);View Description Hide DescriptionThe salmon peptide digested from salmon muscle showed a strong angiotensinI−convertingenzyme inhibitory activity, and blood pressure reducing effect in spontaneous hypertensiverats. Previously, we reported about the significant blood pressure control effect ofsalmon peptide in subjects with high−normal blood pressure and mild hypertension in thelong−term human clinical trials.In order to evaluate the dose−dependency anti−hypertensive effect of salmon peptide, arandomized, double−blind, placebo−controlled trial was conducted on 76 high−normal bloodpressure or mild hypertensive subjects. The subjects were divided into four groups beforethe study and there were no statistical differences in sex, age, systolic blood pressure and diastolicblood pressure. The test food groups were given a drink containing 1, 2 or 4 g ofsalmon peptide, respectively, for 4 weeks and the placebo group was given a drink containingno salmon peptide during the same period of time.The results showed the dose−dependent anti−hypertensive effect due to salmon peptideintake distinctly from 0 to 4 g, and the significant differences were observed in systolic bloodpressure of the 2 and 4 g intake groups at the 4th week.(Jpn Pharmacol Ther 2009;37:133−43)KEY WORDS Salmon peptide, Blood pressure, AngiotensinI−converting enzyme inhibitor,Dose−dependency -
Ca を含むフィッシュソーセージ過剰量摂取時の安全性
37巻2号(2009);View Description Hide DescriptionThe average Japanese people take less calcium than required, and this may in part beresponsible for the decrease of bone density. Therefore, we recently developed calcium−richfish sausages containing 350 mg of calcium a piece. Here we evaluated the safety
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