Published papers

Digoxin (DX) is mainly excreted unchanged in the urine. In patients undergoing hemodialysis (HD patients), the relative contribution of hepatic elimination is increased. DX is a substrate of OATP1B3 (SLCO1B3), expressed on the sinusoidal membranes of hepatocytes in humans. Therefore, we investigated the relationship between SLCO1B3 gene polymorphisms and the value of trough concentration-to-dose ratio (C/D ratio) of DX in HD patients. We investigated two deletion polymorphisms in complete linkage disequilibrium (-28 to -11 and -7 to -4) and two SNPs in complete linkage disequilibrium (T334G and G699A). Blood was sampled 62-72 hours after the oral administration of DX. The C/D ratio of DX was lower in patients with the deletion allele than in those homozygous for the insertion allele, and was lower in patients with the 334T/669G allele than in those homozygous for the 334G/699A allele, although the differences were not statistically significant. The C/D ratio of DX was significantly higher in patients with homozygous for the insert-variant allele (median: 121.8 (ng/mL)/(mg/week/kg), range: 92.5-259.4 (ng/mL)/(mg/week/kg) than in others (median: 93.4 (ng/mL)/(mg/ week/kg), range: 66.5-154.3 (ng/mL)/(mg/week/kg)). In conclusion, the insert-variant allele of the OATP1B3 gene may increase the C/D ratio of DX in HD patients.

薬物による催不整脈作用をin vitroの実験から定量的に予測するために,動物実験におけるin vivo-in vitro相関の解析と,ヒトカリウムチャンネル発現系におけるカリウム電流阻害作用と臨床的報告に基づく副作用リスクとの解析を試みた.モルモットを用い,in vivo実験系として心電図の薬物動態・動力学的解析を,in vitro実験系としては摘出心臓還流標本における心電図測定を行い,両者の関係を解析した.in vivo実験ではキニジン(30mg/kg/h),ソタロール(5mg/kg/h)のいずれによっても心電図QTc間隔は最大30-40msec程度延長した.in vitro実験でもQTcはいずれの薬剤でも延長し,灌流液濃度とQTc延長との関係は直線関係が認められた.いずれの薬剤でもin vivoではin vitroよりもQTc延長の強度が強いことが明らかとなった.従って,in vitro実験結果をin vivoに外挿する場合には,両者の濃度的乖離を十分に考慮する必要があると考えられた

Not only the renal clearance but also the hepatic clearance of drugs varies with the progression of renal failure. The aim of this study was to investigate the effects of human uremic serum and various uremic toxins on the hepatic uptake of digoxin (DX), a drug mainly excreted into bile in patients with severe renal failure, using isolated rat and human hepatocytes as model systems. Uremic serum inhibited the uptake of DX into rat hepatocytes in a concentration-dependent manner, whereas normal serum did not affect the uptake. In addition, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), hippuric acid, indole-3-acetic acid, indoxyl sulfate, and p-cresol (PC) concentration dependently inhibited the uptake. CMPF and PC at the concentration of 400 μΜ, which is within the plasma concentration range attained in patients with renal failure, inhibited the uptake of DX into rat hepatocytes by 27% and 23%, respectively. In human hepatocytes, 10% uremic serum, 400 μΜ CMPF, and 400 μΜ PC inhibited the uptake of DX by 23.3%, 23.4%, and 28.2%, respectively. In conclusion, our results suggest that hepatic uptake of DX is likely to be inhibited by uremic toxins, such as CMPF and PC, present in the serum of patients with renal failure. Copyright © 2008 by Lippincott Williams & Wilkins.

AIM: To assess whether or not co-administration of proton pump inhibitors (PPIs) is a risk factor for delayed elimination of plasma methotrexate (MTX) in high-dose MTX (HDMTX) therapy for malignant diseases. METHODS: To assess the effects of PPI co-administration on elimination of plasma MTX, we examined plasma MTX concentration data on 171 cycles of HDMTX therapy performed in 74 patients. We performed multiple logistic regression analysis to evaluate PPI co-administration as a risk factor. Inhibitory potencies of omeprazole, lansoprazole, rabeprazole and pantoprazole on MTX transport via breast cancer resistance protein (BCRP, ABCG2) were also investigated in an in vitro study using membrane vesicles expressing human BCRP. RESULTS: We identified co-administration of PPIs as a risk factor for delayed elimination (odds ratio 2.65, 95% confidence interval 1.03, 6.82) as well as renal and liver dysfunction. All four PPIs inhibited BCRP-mediated transport of MTX, with half-maximal inhibitory concentrations of 5.5-17.6 μM - considerably higher than the unbound plasma concentrations of the PPIs. CONCLUSIONS: Our results support previous findings suggesting that PPI co-administration is associated with delayed elimination of plasma MTX in patients with HDMTX therapy. This drug interaction, however, cannot be explained solely by the inhibitory effects of PPIs on BCRP-mediated MTX transport. © 2008 The Authors.

OBJECTIVE: To report a case of impaired absorption of orally administered phenobarbital associated with the concomitant administration of activated charcoal, and recovery of the absorption after administration of the 2 drugs was separated by a 1.5-hour interval. CASE SUMMARY: A 78-year-old woman, weighing 50 kg, who had undergone brain surgery was prescribed phenobarbital 120 mg/day for postoperative convulsions. Her serum phenobarbital concentration reached 24.8 μg/mL (therapeutically effective level 10-30). Thereafter, her renal function worsened, and activated charcoal 6 g/day was started. Four months after the start of activated charcoal, blood analysis revealed that the serum phenobarbital concentration was as low as 4.3 μg/mL. The phenobarbital dose was increased to 150 mg/day. Further evaluation revealed that activated charcoal and phenobarbital had been administered concomitantly. The dosage regimen was altered to separate the administration of the agents by at least 1. 5 hours. Subsequently, the patient's serum phenobarbital concentration increased to 11.9 μg/mL within 3 weeks. Her serum phenobarbital concentration was measured monthly thereafter and remained stable in the range of 14.8-18.6 μg/mL. DISCUSSION: Our patient's low serum phenobarbital concentration was considered likely to have been due to impaired gastrointestinal absorption of phenobarbital as a result of adsorption of phenobarbital on the activated charcoal. An objective causality assessment showed that the interaction was probable. CONCLUSIONS: Administration of activated charcoal and phenobarbital should be separated by an interval of at least 1.5 hours.

The purpose of this study was to assess the bitterness intensity and pH of the solutions of clarithromycin dry syrup (CAM-DS), carbocisteine preparation (CC), and the concomitant use of both drugs. We conducted 6 types of human gustatory sensation tests with 6 healthy male volunteers. As a result, there was almost no difference in the bitterness intensity of CAM-DS between the branded (the latest and former preparations) and the generic formulations. The bitterness intensity of CAM-DS (the latest and former preparations of the branded as well as the generic formulations) was almost equally enhanced by mixing it with either the branded CC-DS or the branded and the generic carbocisteine granule (CC-Gr). On this occasion, the enhancing the bitterness of the branded CAM-DS (latest and former preparation) was nearly avoided safely by dosage form's changing CC-DS or CC-Gr to the branded CC-Sy. However, unlike the branded CC-Sy, some generic CC-Sy failed to suppress the bitterness. Furthermore, it was proven that some generic CAM-DS were shown to exhibit bitterness when mixed with even branded CC-Sy. In conclusion, it should be noted that the extent of bitterness of the mixture of CAM-DS and CC highly varies among the generic formulations. © 2008 The Pharmaceutical Society of Japan.

薬剤師間情報交換・研修システムに登録していた薬剤師4106名を対象に、電子メールを用いて患者のノンコンプライアンスへの対応に関するアンケート調査を行った。99.0%の薬剤師がノンコンプライアンス症例を経験し、そのうち75.5%が患者にノンコンプライアンス後の対処法を指示した経験があった。どのようにして対処法を決定したかについては、「次回から処方どおり服用するように指示した」が最も多く、「薬物動態シミュレーション等により血中濃度または薬効の経時的変化を計算して指示した」は2.6%のみであった。しかし、薬物動態シミュレーション等による投与設計で対応をしなかった薬剤師の57.5%が「対処法は適切だった」と回答した。対処法を決定する際の問題点については、「薬物動態シミュレーション等により対処すれば良いと考えたが、具体的な方法がわからなかった」が最も多く、問題点を解決するための要望については、「対処法について投与設計できるシステムが欲しい」が最も多かった。

We investigated the possible potentiation of the convulsive toxicity of enoxacin (ENX) by the concomitant topical application of a felbinac (FLB) patch in rats. A felbinac patch (Seltouch®; 0.5%, 3 cm x 4 cm) was attached on the back of rats where their hair has been removed. ENX was infused from the left jugular vein at 8 h after the application of FLB patch under an unanesthetized and unstrained condition. Blood, CSF and brain samples were collected at the occurrence of convulsion, and ENX concentrations of each part were determined. As a result, no significant potentiation by FLB patch was found in the onset time of convulsion or in the ENX concentration of each part. Moreover, based on the assumption that there are no inter-species differences in ENX concentration in the brain at the occurrence of a convulsion (C(br)), the predicted plasma ENX concentration required to elicit convulsions in humans, which was estimated from the C(br) and K(p) value of ENX in the brain of rats, was 20 times higher than the therapeutic plasma level.

処方設計支援や処方チェックシステムの構築にあたっては、医薬品情報は、システム上でテキストとして保持されているだけでは不十分であり、利用状況を考慮に入れた適正な規格化が行われている必要がある。本研究においては、医薬品の製剤特性に基づいた処方設計支援機能を提供するために必要な医薬品情報を抽出、整理するとともに、それらを規格化するための基準と、適正に保持できるデータベース(DB)の構造を設計することを目的とした。既存の医薬品102種について、製剤特性や剤形加工後の安定性などのデータを収集し、我々がすでに報告した処方チェックパターンと照合して解析することによって、最適なDBのフォーマットを設計するとともに、剤形加工の可否について、DBに収載するための規格化基準を作成した。設計したDB構造と規格化基準を、それらの設計や構築に用いた薬剤とは異なる既存の88種の医薬品に適用したところ、処方設計支援に必要な製剤特性情報をもらすことなく収載することができた。今回構築したDBは、医薬品の製剤特性情報を適正に保持し、処方薬に対する錠剤の粉砕などの可否をチェックするシステムに利用できると考えられた。今回設計した製剤特性・剤形加工DBは、処方チェックおよび処方設計支援システムの構築に有用な基盤を提供すると考えられる。(著者抄録)

臨床現場の薬剤師が患者の健康食品使用に対してどのように関わっているのか、また、健康食品情報の収集状況、被害情報の収集・アウトプットといった行動の現状を明らかにすることを目的として、著者らが2000年より構築・運営しているインターネットによる全国薬剤師間情報交換・研修システムi-PHISSを介してアンケートを行った。323名から回答が得られ、内訳は薬局薬剤師219名、病診薬剤師104名であった。処方箋受付時に患者の健康食品使用の有無を確認するか?という薬局薬剤師への問いに対して、「必ず確認する」と回答した人が29%、「必要に応じて確認する」が58%、「患者からの申し出がない限り確認しない」が12%であった。入院患者に健康食品使用の有無を確認するか?という病診薬剤師への問いに対して、「必ず確認する」と回答した人が44%、「必要に応じて確認する」が32%、「患者からの申し出がない限り確認しない」が10%であった。

東京23区及び多摩地区の医療機関、保険調剤薬局に後発医薬品に関するアンケート用紙を配布し、臨床において後発医薬品が関係して生じたトラブルの事例を収集し、その要因を分析した。アンケートの総回答数は1148件(回収率64.9%)であった。後発医薬品が関係したインシデント・アクシデント事例として87例を収集した。医薬品の取り違えは49件と最も多く、その多くは薬名が類似しているものであった。次いで、先発医薬品と後発医薬品の適応症の違いが11件、使用感・服用感の違いが9件などであった。後発医薬品への切り替えに伴う効果の増強・減弱や有害事象の発生に関する訴えが5件収集されたが、これらの事象と後発医薬品への切り替えとの因果関係は不明である。

Objective: To report a significant increase in the serum levels of digoxin associated with the use of clarithromycin in six patients undergoing renal replacement therapy. Case summary: All six patients were males with end-stage renal disease and in need of renal replacement therapy. Four patients were anuric. The mean age was 78.8 ± 5.8 (66-83) years. All patients except one, who was treated by hemofiltration, were treated by hemodialysis. All patients except one, who had been treated with metildigoxin (0.35 mg/week), were also taking digoxin (0.375 mg/week). Clarithromycin was administered at a dose of 200 - 400 mg/day for the treatment of bronchitis in all patients. The concomitant administration of clarithromycin increased serum digoxin levels from 1.8 - 4.0-fold in all cases. In two of six cases, a high probability of digoxin intoxication and suspicion of digoxin intoxication was evident. In three of six cases, serum digoxin levels increased within 12 days after the co-administration of clarithromycin, while in the other three cases, serum digoxin levels were increased 53 - 190 days after the administration of clarithromycin. Conclusion: The simultaneous administration of clarithromycin caused an increase in digoxin levels in six patients undergoing renal replacement therapy. The increase in the serum digoxin can be attributed to the inhibition of P-glycoprotein in the intestine and/or bile capillary rather than the kidney by clarithromycin since renal function was dramatically impaired, and four of the patients were anuric. The issue of why serum digoxin levels were increased so late in three patients undergoing renal replacement is unclear. However, this interaction seemed to be clinically significant even in ESRD patients, whose renal function was highly impaired. The simultaneous use of digoxin and clarithromycin sbould be avoided even in patients undergoing renal replacement therapy whose renal function is impaired, since digoxin levels may increase unexpectedly. ©2005 Dustri-Verlag Dr. K. Feistle.

日本医薬品情報学会(JASDI)は医薬品情報学のあり方を提言することを目的に、ビジョン委員会を発足させた。当該委員会では医薬品情報学の教育が抱える問題点を、KJ法を用いて抽出、明確化することを目的に、2008年7月の第11回JASDI学会においてワークショップを開催した。抽出された大きな問題点は「医薬品情報の範囲が広すぎること」と「医薬品情報の定義とシステムが不明確なこと」であった。関連する問題点は歴史の浅さと独自性の欠如であった。また、研究の方法論が十分に確立していないこと、教育のシステム化ができていないことも指摘された。本ワークショップにより、医薬品情報学の抱える「本学問の定義づけ、体系化ができていない」という問題点が明確化すると共に、参加者に対しても有意な意識変化をもたらしたことが明らかになった。

著者らは、2000年より薬剤師間情報交換・研修システム「Internet-based Pharmacist's Information-Sharing System(i-PHISS)」、2005年より医師間情報交換・研修システム「Internet-based Medical Doctor's Information-Sharing System(i-MEDISS)」を構築・運用してきた。これらシステムは、医療従事者の知識・技能・態度の研鑽、医療ミスの低減を目的として、インターネットを介して医療従事者から臨床現場で起きた医薬品に関するアクシデント・インシデント事例を収集し、それら事例にエビデンスに基づく検討・解説を加えて再度配信する登録制のシステムである。今回、両システムを活用して、医薬品のみならず健康食品に関しても医療従事者のニーズに沿った情報コンテンツを作成し、定期的な提供を行うようにした。このサービスに対するi-PHISS・i-MEDISS登録者の評価をウェブアンケートによって調査した結果、概ね好評であり、健康食品に対する医療従事者の関心を喚起できていたことが確認された。

Long-term practical on-site training, based on the Model Core Curriculum for Pharmaceutical Education, is a core program of the 6-year course of pharmaceutical education, introduced in Japan in 2010. In particular, medication counseling in practical training in 5th-year provides valuable opportunities for communication with real patients rather than simulated patients (SPs). However, it can also cause anxiety in 4th-year students before practical training. To address such concerns, upperclassmen (5th-and 6th-year students), who have already completed practical training, constructed and conducted a new educational program for medication counseling practice in preclinical training based on their experiences. They also developed case scenarios and played the role of patients themselves to create more realistic clinical settings. Advice from professional SPs was also provided. The 5-step program is composed of 1st counseling, 1st small group discussion (SGD) for improving counseling, 2nd revised counseling based on the 1st SGD, 2nd SGD, and development of a counseling plan and presentation. Educational effects of the program were evaluated by questionnaire survey after preclinical training in 4th-year students and after their practical training in 5th-year students. This new program, the Advanced Medication Counseling Practice, was found to be useful to reduce anxiety about communication with patients among 4th-year students (about 90%). Even after their practical training in 5th-year, they still appreciated usefulness of this program (about 80%). This program is still valued 4 years after its development. We developed the Advanced Medication Counseling Practice in preclinical training for junior students by senior students.

投薬ミスを防止するために薬名の類似度を計数化することを試みた.2薬名間の共通文字列部分が長いほど類似度が高いと考え,断片パターン指標を応用した指標を導入した.「共通文字列の連続性」,「先頭・末尾部分の重要性」の係数を配分した指標1,これら2係数に更にカタカナの文字形状の類似性係数を導入した指標2,音韻の類似性係数を導入した指標3を構築した.実際に医薬品名の取り違えが生じた227例を正例とし,負例は無作為に作成した2270組を用いて指標の評価を行った.既に報告されている指標として,薬名の特徴をベクトル化したcos1,先頭・末尾2文字のみに着目したhtcoと比較した.指標1,2,3はいづれもcos1,htcoよりも優れた評価関数値を示し,特に指標2が最良であった.指標2の偽陽性率,偽陰性率はcos1よりも著しく改善された.この指標は薬名に基づく医療ミスを防止する上で重要な情報を提供すると考えられた

e-Learningシステム(アリセプト処方せんチェックe-ラーニング)を構築した。構築・公開したe-Learningシステムの利用実態を把握するとともに、システムに対するユーザーの意見を調査した。会員薬剤師5766例に対して、電子メールで送信した。198件の回答が得られた。薬剤師としての経験年数が10年以上の薬剤師が約62%を占めた。開局薬局が67.7%であった。自己研鑚システムとして有用と評価され、継続したシステムの公開が期待されていると考えた。また、他の医薬品に関しても同様なシステムを望む回答者が多く、要望が多かった医薬品を対象に計画的に作成し、公開してゆくことが望ましいと考えられた。

Plasma potassium concentration plays an important role in the induction of arrhythmia and is closely related to the arrhythmogenicity of various drugs. We quantitatively analyzed the influence of plasma potassium concentration on QT intervals before drug administration and on drug-induced QT prolongation, to estimate the risk of drug-induced arrhythmia under hypokalaemic conditions. The hypokalaemic models were produced by intraperitoneal administration of furosemide and hydrochlorothiazide in male Sprague-Dawley rats. The relationship between the changes in QT intervals and time profiles of plasma quinidine (QND) concentration were analyzed during constant intravenous infusion of QND (10 or 30 mg/kg/h) and post infusion in normal and hypokalaemic rats. The plasma QND concentration reached the therapeutic range (3-7 μg/ml) at the high infusion rate (30 mg/kg/h). No pharmacokinetic differences between normal and hypokalaemic rats were observed. QND induced QT prolongation in parallel with the plasma concentration without hysteresis. Although the potency of QND for QT prolongation was not affected by hypokalaemia, the QT intervals before drug administration were significantly prolonged in hypokalaemic rats (65.90 ± 1.40 vs 56.60 ± 0.748 msec, mean ± SEM, p < 0.0001). Thus, the prolongation of QT intervals before drug administration may act as a risk factor of arrhythmia under hypokalaemic conditions.

We examined and compared the inhibitory effects of three non-sedating antihistamines, terfenadine, ebastine, and epinastine, on delayed rectifier potassium current (I(K)) and transient outward potassium current (I(to)) of rat isolated ventricular myocytes, using a patch clamp technique. Terfenadine, ebastine and epinastine were found to inhibit I(K) with IC50 values of 5.96, 15.3 and 145 μM, respectively. I(to) was suppressed by epinastine with an IC50 value of 69.5 μM. The order of arrhythmogenicity, assessed by the inhibition of I(K), was ranked as terfenadine > ebastine > epinastine, consistent with that of the potencies of each drug for QT prolongation reported in rats.