薬理と治療
Volume 37, Issue 8, 2009
Volumes & issues:
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REVIEW
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迅速承認へ向けての代替エンドポイントの利用法および妥当性検証について
37巻8号(2009);View Description Hide DescriptionSurrogate endpoint is an endpoint that is intended to relate to a clinically important outcomebut does not in itself measure a clinical benefit. Surrogate endpoint was closed up inthe era of accelerated approval initiated by the Food and Drug Administration in 1992. It isreasonably likely to predict the clinical benefit. Bevacizumab is an example of acceleratedapproval in the U. S. The E15 guideline of pharmacogennomics(PGx)in 2008 classified a surrogateendpoint into three categories:known valid, probable valid, and exploratory. Thus,the use of surrogate endpoint has been rapidly increased in many disease categories. A formaldefinition of valid surrogate endpoint was first shown by Ross Prentice in 1989. Two conditionswere presented, namely 1)it must be correlated with the clinical endpoint;and 2)itmust fully capture the net effect of the intervention on the clinical efficacy. Surrogate endpointis usually understood to satisfy the first condition alone. The second condition cannotbe verified in many situations. Furthermore, Journal of American Medical Association(JAMA)showed three principles to define a surrogate from a viewpoint of consistency between surrogateand true endpoints. In any events, surrogate endpoints are useful and efficient in newdrug development. However, we must be careful about the use of surrogate endpoint sincethere have been many examples that led to an inconsistent finding regarding a clinical endpointalthough there was a clear efficacy in a surrogate endpoint. Despite a recent attitudetoward a new drug development using a surrogate endpoint, we must confirm its effectivenesson the clinically meaningful endpoint after approval.(Jpn Pharmacol Ther 2009;37:633−9)KEY WORDS Biomarker, Regulation, Validity, Statistics
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ORIGINAL ARTICLES
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睡眠覚醒リズムに対するオピオイド鎮痛薬の効果
37巻8号(2009);View Description Hide DescriptionThere is little information about the effects of narcotics on the sleep−wake rhythm inrodents, though it is well known that the drugs have several central side effects. The presentstudy was undertaken to investigate the characteristics of narcotics in rat sleep patterns.Electrodes were chronically implanted into the cortex and dorsal neck muscle of rats for electroencephalogram(EEG)and electromyogram(EMG)recordings, respectively. EEG and EMGwere recorded with an electroencephalograph. SleepSigh ver. 2.0 was used to analyse thesleep−wake state. Total times of wakefulness, non−rapid eye movement(NREM)sleep andrapid eye movement(REM)sleep were measured from 10:00 to 16:00. Morphine at doseof 10 mg/kg caused a significant decrease in sleep latency and total REM sleep time, thoughno significant effects were observed in total awake and NREM sleep times. On the otherhand, fentanyl caused no significant effect on sleep latency and total times of wakefulness,NREM sleep and REM sleep. Oxycodone at a dose of 3 mg/kg caused a significant decreasein sleep latency, although the drug showed no influence on total wake, NREM sleep andREM sleep times. From these findings, it can be concluded that morphine and oxycodonecaused somnolence, while fentanyl showed no influence on the sleep−wake rhythm in rats.(Jpn Pharmacol Ther 2009;37:643−7)KEY WORDS Morphine,Fentanyl,Oxycodone,Sleep−wake rhythm -
Effect of an H1−receptor Antagonist, Fexofenadine Hydrochloride, on Substance P Secretion from Sensory Neurons in vitro
37巻8号(2009);View Description Hide DescriptionBackground and Objective Fexofenadine hydrochloride(FEX)is a second−generation histamineH1−receptor antagonist that is frequently used as an anti−allergic agent for the treatmentof allergic diseases, including allergic rhinitis(AR). Although it is generally acceptedthat the peripheral sensory neurons that innervate nasal mucosa contribute to the developmentof the clinical condition of AR, the effect of FEX on the function of sensory neurons isnot well defined. The present study was undertaken to determine the effect of FEX on sensoryneurons by investigating its effects on the dorsal root ganglion(DRG)cells from rats invitro.Methods DRG cells obtained from F344 rats on postnatal day 1 were stimulated with nervegrowth factor(NGF)in the presence of various concentrations of FEX. The effect of FEX onthe total number of neurites per DRG cell and on the percentage of DRG cells with outgrowingneurites was examined 24 h or 72 h after the start of culture, respectively. We also examinedsubstance P(SP)levels in 6 h−culture supernatants by ELISA.Results Addition of FEX to DRG cell cultures to a final concentration of 1000 ng/mL, twicethe therapeutic tissue levels, had hardly any effect on neurite growth from DRG cells,because the total number of neurites and the percentage of DRG cells with outgrowing neuritesobserved in the experimental cultures were nearly identical(not significant;p>0.05)tothe value in the control cultures stimulated with NGF alone. FEX inhibited SP productionfrom DRG cells in response to capsaicin stimulation. The minimum concentration of FEXthat caused significant inhibition was 500 ng/mL. The present results demonstrated that FEXinhibits the functions of sensory neurons, especially SP production without lethal effect onneurons.Conclusion These pharmacological actions in turn may contribute, in part, to the potentclinical efficacy of FEX against the neurogenic inflammation observed in AR.(Jpn Pharmacol Ther 2009;37:649−56)KEY WORDS Fexofenadine hydrochloride, Dorsal root ganglion cells, Substance P, Inhibition,in vitro -
ラットの体重,血圧および電解質(Na+,K+,Cl−)に及ぼす芍薬甘草湯の長期投与による影響
37巻8号(2009);View Description Hide DescriptionWe investigated the effects of Shakuyaku−kanzo−toh a long term orally taking on bodyweight, blood pressure and electrolytes(Na+, K+, Cl−)in rats. Shakuyaku−kanzo−toh did notaffects on body weights, blood pressure in rats at normal and 30 times higher doses. Serumelectrolytes K+ significantly decreased both normal dose and 30 times higher dose of Shakuyaku−kanzo−toh. Treatment of Aspara K did not recover the decrease of serum electrolytesK+. Our results suggested that Shakuyaku−kanzo−toh is safety medicine. However, itis important when administration of Shakuyaku−kanzo−toh should be carefully to check constitutionsof each patients.(Jpn Pharmacol Ther 2009;37:657−61)KEY WORDS Shakuyaku−kanzo−toh, Pseudoaldosteronism, Hypertension -
サルメテロールキシナホ酸塩およびフルチカゾンプロピオン酸エステルの併用投与におけるマウスおよびモルモットのタバコ煙曝露誘発性の生理的変化(気道抵抗上昇および気管支肺胞への炎症細胞浸潤)に対する薬理学的効果
37巻8号(2009);View Description Hide DescriptionObjectives Adoair_(Combination of fluticasone propionate and salmeterol) has beenrecently authorized to be used for COPD patients. As a part of studies to be done to get theauthorisation, effectiveness of the compounds were evaluated in tobacco smoke−exposedanimals.Method Guinea pigs were exposed with tobacco smoke for 60 minutes a day and fluticasonepropionate and/or salmeterol were administered with inhalation for 10 min for 4 weeks.Mice were exposed with tobacco smoke for 40 minutes a day and fluticasone propionate and/or salmeterol were administered intranasally for 11 days. Airway resistance was measuredonce a week(guinea pigs only). Inflammatory cells were collected by bronchoalveolar lavageat the experimental end and each kind of cell number was counted.Results In the guinea pigs, fluticasone propionate and/or salmeterol significantly decreasedboth airway resistance increasing during tobacco exposure, and AUC0−26day of time−airwayresistance curve. The combination tended to enhance the decreasing effects of the each drug.Fluticasone propionate and the combination significantly decreased inflammatory cell numberswith similar degrees. In the mice, whereas fluticasone propionate or salmeterol significantlydecreased cell number of only lymphocytes or neutrophils, respectively, the combina-tion showed remarkably enhancement of each effect:cell numbers of the 5 cell species wereall significantly decreased.Conclusions In guinea pigs and mice exposed to tobacco smoke, combination treatment offluticasone propionate and salmeterol showed decreasing effect of guinea pig airway resistanceand inflammatory cell numbers in their bronchi and alveoli superior to the effects ofeach drug. Those effects support clinical effectiveness of Adoair_ in POCD patients.(Jpn Pharmacol Ther 2009;37:665−75)KEY WORDS COPD, Tobacco smoke, Fluticasone propionate, Salmeterol -
ヤーコン葉・茎エキスの安全性試験
37巻8号(2009);View Description Hide DescriptionYacon(Smallanthus sonchifolius, Compositae)is a novel food resource for inhibitingaction on the postprandial elevation of blood glucose levels. To assess the safety of theextract from the leaf and stem of yacon, single, 28−day and 12−week oral repeated dosesafety studies were carried out in mice. Hypoglycemia induced by yacon in combination withoral antidiabetic drugs was investigated in rats. Moreover, to assess the allergenic potentialof yacon, the delayed type hypersensitivity studies were performed in mice. In the singledose study, the yacon extract was administered orally to mice at 5000 mg/kg after overnightfasting. There were no death and no test article−related abnormalities in clinical sign and terminalautopsy. The approximate lethal dose was considered to be greater than 5000 mg/kg.In the repeated dose study, the yacon extract was administered orally to ICR mice at 0.1, 0.3and 0.6% in drinking water for 28 days or 0.15 and 0.3% for 12 weeks. There were no testarticle−related changes in any group during the experimental period. In 12−week repeateddose study of the obese diabetic mice, the yacon extract was administered orally to KK−Aymice at 0.5% in drinking water for 12 weeks. There were no adverse events in the yaconextract−administered group. The yacon extract did not cause hypoglycemia in rats given inadministration of yacon alone and combined administration with oral antidiabetic drugs andyacon. In the delayed type hypersensitivity study, the picryl chloride−induced contact skinreaction tests were performed in mice. The yacon extracts did not initiate inflammation andhad no allergenicity potential. Moreover, the yacon extracts did not affect the picryl chlorideinducedcontact skin reaction. In conclusion, the extract from leaf and stem of yacon has noadverse events in the safety studies of mice and rats. These results suggest that the yaconmay be a novel food resource with high safety.(Jpn Pharmacol Ther 2009;37:677−90)KEY WORDS Yacon, Safety study, Antigenicity study, Mouse, Rat -
健康成人における血清培養または無血清培養にて製造された KRN5702(エポエチンアルファ)製剤間の薬物動態の比較
37巻8号(2009);View Description Hide DescriptionBackground The previous formulation of epoetin alfa(KRN5702)in Japan was manufacturedby CHO cells cultured with bovine serum. The protein was confirmed safety because ofusing fetal bovine serum derived from countries of non−BSE and highly purification. Toimprove the manufacturing method, we have developed a new formulation of epoetin alfa producedby serum−free culture(KRN5702SF).Objectives Our aim is to compare the pharmacokinetics of two formulations of epoetin alfain healthy volunteers after single intravenous(IV)or subcutaneous(SC)administration.Methods Two studies were performed to assess the pharmacokinetics of two epoetin alfaformulations administered by IV(3000 IU)or SC(12000 IU)route. Each study was a singlecentre,open−label, randomized, two−treatment, two−period, crossover study where healthysubjects were enrolled. Pharmacokinetic parameters were compared between two formulationsin both dosing routes.Results There are no significant differences in pharmacokinetic parameters between twoformulations in both IV and SC administration.Conclusion The pharmacokinetic profile of KRN5702SF after IV and SC administrationwas similar to that of KRN5702.(Jpn Pharmacol Ther 2009;37:691−8)KEY WORDS KRN5702,Epoetin alfa,Serum−free,Pharmacokinetics
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