薬理と治療
Volume 36, Issue 2, 2008
Volumes & issues:
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DRUG PROFILE SERIES
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小腸コレステロールトランスポーター阻害薬エゼチミブ(ゼチーア)錠の基礎と臨床
36巻2号(2008);View Description Hide Descriptionエゼチミブは,1994 年,米国シェリング・プラウ社で創製された高コレステロール血症治療薬である。その作用機序は,HMG−CoA 還元酵素阻害薬(スタチン),陰イオン交換樹脂製剤,フィブラート系薬剤,ニコチン酸製剤,プロブコールなどとは異なり,小腸上部刷子縁膜上に存在し,コレステロール吸収に関与する蛋白質,コレステロールトランスポーター(NPC1L1:Niemann−Pick C1 Like 1)に結合してその機能を阻害することにより,小腸壁細胞での食事性コレステロール,胆汁性コレステロールおよびコレステロールと構造が類似した植物性ステロールの吸収を選択的,かつ強力に阻害する,世界初の小腸コレステロールトランスポーター阻害薬である。臨床的には,エゼチミブ 10 mg の単独投与で LDL コレステロールを約 18%低下させ,スタチン製剤単独で十分な効果が得られない症例にエゼチミブ 10 mg を併用することにより,LDL コレステロールをさらに低下させる。また,エゼチミブと作用メカニズムが類似する陰イオン交換樹脂製剤であるコレスチミドを対照薬として行われた二重盲検比較試験では,エゼチミブ 12 週間投与後の LDL コレステロール変化率についてコレスチミドに対する非劣性が検証されている。安全性についても副作用発現率は,エゼチミブ群 18.6%で,コレスチミド群 35.3%に比較して有意に低く,エゼチミブ群に発現した副作用はすべて軽度または中等度であった。剤形は小型の錠剤で服用しやすく,腸肝循環して小腸に長時間作用し 1 日 1 回投与で有効性を持続する。主要代謝経路は,グルクロン酸抱合で,生体内で CYP が関与する代謝を受けないことが明らかにされている。エゼチミブは,従来の高脂血症治療薬と異なる作用機序を有することから高コレステロール血症治療薬に選択肢を増やすという意義があり,より積極的な治療を必要とする高コレステロール血症患者においてスタチンとの併用による効果の増強が期待でき,さらにスタチンに忍容性がない場合などにも適応できる意義があると考えられている。なお,適応症としては,高コレステロール血症に加え,家族性高コレステロール血症,難治性であるホモ接合体性シトステロール血症が承認されている。
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ORIGINAL ARTICLES
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新規過活動膀胱治療薬コハク酸ソリフェナシン(ベシケア 錠)の in vitro および in vivo 膀胱組織選択性
36巻2号(2008);View Description Hide DescriptionSolifenacin succinate is a new muscarinic receptor antagonist developed for the treatment of overactive bladder. The aim of the present study was to evaluate the in vitro and in vivo bladder selectivity profile of solifenacin over salivary gland in the same animal species, and to compare the results with those obtained for tolterodine, imidafenacin, oxybutynin, darifenacin, propiverine and atropine. Solifenacin and the other antimuscarinic drugs inhibited carbachol−induced increases in intracellular Ca2+ levels in bladder smooth muscle cells and salivary gland cells isolated from rats in a concentration−dependent manner. The inhibitory effect of solifenacin for bladder smooth muscle cells(pKi=8.12)was 3.6−fold more potent than that for salivary gland cells(pKi=7.57). The inhibitory effects of tolterodine, oxybutynin and darifenacin for bladder smooth muscle cells were also 1.7− to 2.1−fold more potent than those for salivary gland cells. In contrast, imidafenacin, propiverine and atropine showed the same inhibitory potencies for both cells. In anesthetized rats, solifenacin dose−dependently inhibited carbachol−induced intravesical pressure elevation and salivary secretion, and exhibited functional selectivity(3.7− to 6.5−fold)for urinary bladder over salivary gland. Tolterodine was also 2.2− to 2.4−fold more selective in inhibition of bladder response. In contrast, imidafenacin, oxybutynin, darifenacin, propiverine and atropine did not show functional selectivity for urinary bladder. These results indicate that solifenacin exerts greater selectivity for urinary bladder over salivary gland than tolterodine, imidafenacin, oxybutynin, darifenacin, propiverine and atropine, and may consequently provide a benefit in the treatment of overactive bladder with less dry mouth than currently used antimuscarinic drugs. (Jpn Pharmacol Ther 2008;36:119−28)KEY WORDS Solifenacin, Tolterodine, Imidafenacin, xybutynin, Darifenacin, Propiverine, Atropine, Muscarinic receptor, Overactive bladder, Dry mouth, Intravesical pressure, Salivary secretion, Bladder selectivity -
ジエノゲストの子宮内膜症患者に対する臨床評価
36巻2号(2008);View Description Hide DescriptionObjective To compare the efficacy and safety of dienogest(DNG)over intranasal buserelin acetate(BA)in endometriosis. Design PhaseIII, multicenter, randomized, double−blind, active−controlled trial. Setting Twenty−four clinical trial sites in Japan. Patient(s) Two hundred seventy−one patients with endometriosis. Intervention(s) DNG(2 mg/day, oral)or BA(900μg/day, intranasal)for 24 weeks. Main outcome measure(s) Global improvement based on the change of subjective symptoms during non−menstruation(lower abdominal pain, lumbago, defecation pain, dyspareunia and pain on internal examination)and objective findings(induration of the pouch of Douglas and limited uterine mobility)from baseline to the end of treatment;adverse drug reactions; bone mineral density(BMD)measured by dual−energy X−ray absorptiometry. Result(s) Two hundred fifty−three patients were evaluable for efficacy and 255 for safety. The proportion of patients with marked or moderate global improvement was 78.1%(100/128)with DNG and 80.8%(101/125)with BA. Genital bleeding and hot flushes were the most common adverse drug reactions occurring in 95% versus 67% and 50% versus 67% (DNG versus BA)of patients respectively. The reduction in BMD was−1.0% with DNG and−2.6% with BA. Conclusion(s) DNG was at least as effective as BA in alleviating endometriosis, with less BMD loss than BA.(Jpn Pharmacol Ther 2008;36:129−40)KEY WORDS Dienogest, Buserelin acetate, Progestin, Endometriosis, Bone mineral density -
「アクア Q10 P40 配合錠剤」の健常者における疲労軽減作用
36巻2号(2008);View Description Hide DescriptionObjectives Aqua Q10 P40 is water−soluble type coenzyme Q10 powder, which is dispersed in water, developed by Nisshin Pharma Inc. We investigated the effect of Aqua Q10 P40−containing tablet on physical fatigue in healthy volunteers. Method In a present randomized double−blind, placebo−controlled, crossover trial, 15 healthy volunteers under physical load were randomized to oral Aqua Q10 P40 or placebo administration for 15 days so that no statistical differences in age, gender and body mass index(BMI). Subjects took 4 tablets containing Aqua Q10 P40(180 mg as coenzyme Q10) or 4 placebo tablets per day for 15 days. As a fatigue−inducing physical task, subjects performed workload trials on a cycle ergometer at fixed workloads for 4 hours and then rested for 4 hours. We examined fatigue feeling by visual analogue scale, physical performance by physical working capacity test and autonomic nervous activity by accelerated plethysmography before, during and after physical load. Results Oral Aqua Q10 P40 administration attenuated fatigue feeling and inhibited the decrease in physical performance and improved the imbalance of autonomic nervous activity by physical load. Conclusion These results suggest Aqua Q10 P40 has the effect of attenuating fatigue and Aqua Q10 P40−containing tablet is one of the promising candidates for anti−fatigue food. (Jpn Pharmacol Ther 2008;36:141−52)KEY WORDS Coenzyme Q10, Fatigue, Visual analogue scale, Physical performance, Accelerated plethysmography
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REVIEW
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パーキンソン病治療薬としての COMT 阻害剤コムタン の薬理と臨床プロフィール
36巻2号(2008);View Description Hide DescriptionL−dopa remains the most effective drug for Parkinson’s disease(PD). However, its benefits are limited owing to extensive metabolism by catechol O−methyltransferase(COMT), especially if L−dopa is used in combination with peripheral dopa decarboxylase inhibitors. Ldopa is metabolised via O−methylation(3−OMD)by COMT using S−adenosylmethionine (SAM)as the methyl donor, this leading to the subsequent formation of homocysteine. A new orally active, selective, and peripheral COMT inhibitor entacapone has become available recently. Its IC50 value of 10 nmol/L was obtained for rat duodenum. There were no effects on other catecholamine metabolizing enzymes. Entacapone showed 50% inhibition(ED50 value)of rat duodenal, erythrocyte, liver and striatal COMT activity 1 h after oral dosing with 1.1, 5.4, 6.7 and 24.2 mg/kg, respectively. However, penetration of entacapone into the brain was poor. In rat blood serum, AUC of 3−OMD was reduced in a dose−dependent manner, and AUC of L−dopa was increased after the administration of entacapone together with L−dopa and carbidopa. These changes were reflected, in the striatum, by a significant rise in the Ldopa and dopamine content. Oral administration of L−dopa and carbidopa to MPTP−treated common marmosets prolonged an improvement in motor disability. In clinical trials, entacapone reversibly inhibited erythrocyte COMT in dose−related manner in healthy volunteers, prolonged t1/2 of plasma L−dopa and On−time, and increased AUC of plasma L−dopa in PD patients with wearing−off phenomenon. Taken together, these results suggest that entacapone becomes an important means of extending the benefits of L−dopa therapy. Pharmacological characteristics of entacapone is discussed.(Jpn Pharmacol Ther 2008;36:155−63)KEY WORDS Entacapone, COMT, L−dopa, Parkinson’s disease, Wearing−off
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