双極性障害におけるラモトリギンの有効血中濃度とその変動因子に関する研究

金沢大学附属病院LTGは双極性障害において標準治療とされる薬剤の1つであり、治療ガイドラインにおいて大うつ病エピソードの治療および維持療法として、単剤および他剤との併用による使用が推奨されている。しかし、もう一つのLTGの適応疾患であるてんかんにおける治療濃度域は報告されているが、双極性障害におけるLTGの血中濃度と効果や副作用との関係については十分に研究されていない。本研究は, 双極性障害患者におけるラモトリギン(LTG)の血中濃度を測定し、治療濃度域を明らかにするとともに、体格や併存疾患などLTGの血中濃度の変動因子についても調査することを目的とした。特に、UDP-グルクロン酸転移酵素(UGT)1A4、UGT2B7の遺伝子多型がLTGの血中濃度に変動因子として寄与したということもこれまでに報告されている。有効血中濃度とその変動因子を明らかにすることで、LTGの血中濃度の測定意義を明らかにし、患者への薬物療法への寄与を図る。本研究を実施するにあたり、遺伝子情報を取り扱うこととなるため、ヒトゲノム・遺伝子解析研究倫理審査委員会に研究計画書を提出し、現在ヒアリングの後の修正を実施している。臨床サンプルを用いた研究を実施するに当たり、市販血液を用いUGT1A4ならびにUGT2B7の遺伝子多型の解析法(RFLP法)の手技を確立した。また、検体のラモトリギン血中濃度の測定法としてHPLC法を用い適切な条件設定を確立した。今後、ヒトゲノム・遺伝子解析研究倫理審査委員会にて承認の後、患者からサンプルを入手し解析を実施していく予定である。研究課題/領域番号:17H00527, 研究期間(年度):201

非定型抗精神病薬処方時の耐糖能フォローアップに対する薬剤師の介入と影響

金沢大学附属病院本研究は,精神疾患における薬物治療へ薬剤師が介入することで,非定型抗精神病薬服用患者の耐糖能フォローアップ状況がどの程度改善されたのかを検証することを目的とした。昨年度までに,当院精神科神経科を受診し,非定型抗精神病薬を連続して処方されていた患者の約60%で,1年間に1度も血糖値やHbAlc値を測定されていないことを明らかにした。しかし,医師に対して意識調査を行ったところ,70%以上が血糖値やHbAlc値を1年間に1回以上モニタリングしていると回答しており,実態調査との乖離が浮き彫りとなった。精神科神経科病棟に専任の薬剤師を配置した後,血糖値やHbA1c値を測定されていない患者は約40%に減少した。特に入院患者において,血糖値を測定されていない患者は26.6%から2.7%に減少し,HbA1c値を測定されていない患者は435%から8.2%に減少した。また,血糖値を測定されていた患者のうち,随時血糖値が200mg/dl以上を示した患者は10.6%から7.6%に減少した。HbA1c値を測定されていた患者のうち,HbA1c値(NGSP値)が65%以上を示した患者は11.2%から6.0%に減少した。しかし,外来患者に関しては,入院患者に匹敵するほどの大幅な耐糖能フォローアップ状況の改善は認められなかった。これは外来診療における医師の業務が多忙であり一人の患者に割ける診察時間が少ないことや,検査等に対する精神科患者の理解が得られにくいこと,外来患者の耐糖能を,薬剤師を含めたメディカルスタッフが十分に確認できていないことなどが原因として挙げられる。今後は,メディカルスタッフ同士の連携システムの構築や,電子カルテシステムの改善などを検討すべきと考える。これらのことから,精神科神経科病棟への専任薬剤師の配置は,非定型抗精神病薬服用患者の耐糖能フォローアップを行う上で有意義であった。この結果は精神科病棟における薬剤師の病棟薬剤業務の必要性に寄与する重要な知見と考えられる。研究課題/領域番号:24929013, 研究期間(年度):201

Thrombin Activates Ca2+-permeating Nonselective Cation Channels through Protein Kinase C in Human Umbilical Vein Endothelial Cells

We analyzed Ca-permeating nonselective cation channels (NSCs)mediating thrombin-induced contraction of human umbilical vein endothelial cells (HUVECs). A Ca chelater, BAPTA-AM (10μM), significantly inhibited the thrombin-induced contraction of HUVECs.Thrombin induced inward currents at -60 mV in the presence of intracellular MgATP. Removal of extracellular Caﾌﾞｸﾞsignificantly decreased the currents. A selective phospholipase C inhibitor, U73122 (1μM) but not its inactive analogue, U73343 (1μM) almost completely inhibited the currents. Neither a selective inhibitor of Caﾌﾞｸﾞ-ATPase of endoplasmic reticulum, thapsigargin (1μM)nor a diacylglycerol analogue, 1-oleoyl-2-acetyl-glycerol (30μM)activated the currents. However, a selective protein kinase C inhibitor, bisindolylmaleimide I (500 nM) significantly inhibited the currents.The thrombin-induced currents were significantly inhibited by SKF96365 (50μM)but not by La(1mM), ruthenium red (10μM) or flufenamic acid (100μM). As assessed with RT-PCR, HUVECs expressed transient receptor potential(TRP)M4,7,TRPV1,2,4,TRPC1,4 and 6 subunits of NSCs.These results indicate that thrombin activates Ca-permeating NSCs containing TRPC4 through protein kinase C in HUVECs. Thus,drugs specifically inhibiting TRPC4-containing channels might be effective to control fatal diseases such as sepsis where thrombin mediates the vicious cycle between inflammation and coagulation.Article信州医学雑誌 59(1): 13-26(2011)departmental bulletin pape

Long-term outcomes of delayed clozapine initiation in treatment-resistant schizophrenia: a multicenter retrospective cohort study

Abstract Background Clozapine is the only antipsychotic medication with proven efficacy against treatment-resistant schizophrenia. This multicenter retrospective cohort study aimed to evaluate the impact of a delay in clozapine initiation on long-term outcomes. Methods Patients who initiated clozapine treatment between July 2009 and December 2018 were included in this study. According to the length of time from the diagnosis of schizophrenia to clozapine initiation, the patients were categorized into one of three groups: early (≤ 9 years), intermediate (10–19 years), and late (≥ 20 years) initiation. The endpoints were psychiatric rehospitalization and all-cause clozapine discontinuation within 3 years. Hazard ratios (HR) and 95% confidence interval (CI) were estimated using the Fine and Gray method or the Cox proportional hazards model. Results The incidence rates of rehospitalization within three years, according to the cumulative incidence function, were 32.3% for early, 29.7% for intermediate, and 62.2% for late initiation, respectively. Late initiation had a significantly higher risk of psychiatric rehospitalization than early initiation (HR, 2.94; 95% CI, 1.01– 8.55; P = 0.016 by the Gray's test). The risk of psychiatric rehospitalization was not significantly different between the early and intermediate initiation groups. The incidence rate of all-cause clozapine discontinuation within three years using the Kaplan–Meier method was 13.0% for early, 10.6% for intermediate, and 20.1% for late initiation. The risk of all-cause clozapine discontinuation was not significantly among the groups. The late initiation group had more patients discontinuing because of death due to physical diseases than the other groups. Conclusions The study suggests that clozapine should be initiated promptly in patients with treatment-resistant schizophrenia to prevent psychiatric rehospitalization during long-term treatment. Further prospective studies with appropriate consideration of confounding factors and large sample sizes are needed to strengthen the evidence

Oxytocin for male subjects with autism spectrum disorder and comorbid intellectual disabilities: A randomized pilot study

Approximately half of autism spectrum disorder (ASD) individual suffer from comorbid intellectual disabilities (ID). Oxytocin (OXT) receptors are highly expressed in temporal lobe structures and are likely to play a modulatory role in excitatory/inhibitory balance, at least based on animal model findings. Thus, it is feasible that in the highly representative group of Kanner type ASD subjects OXT could have a beneficial effect on social communication and social interaction. The aim of this pilot study was to investigate the feasibility and adverse events, such as epilepsy, of the long-term administration of intranasal OXT for adolescent and adult ASD subjects with ID because such patients frequently have seizures. We also addressed the question on how to scale the OXT effects to the core symptoms of social deficits because of the relative difficulty in obtaining objective measurements. Twenty-nine males (aged 15-40 years old) participated in a randomized, double-blind, placebo-controlled crossover study (each for 8 weeks) with OXT (16 international units per day). Except for seizures experienced by one participant, other serious adverse events did not occur. The primary and secondary outcomes measured using the Childhood Autism Rating Scale and several standard scales, respectively, revealed no difference between the OXT and placebo groups. Instead, in an exploratory analysis, the social interactions observed in the play sessions or in daily-life were significantly more frequent in the initial half period in the OXT-first arm of the crossover trial. There were also significant correlations between the plasma OXT concentration and subscale scores for irritability on the Aberrant Behavior Checklist. In conclusion, this pilot study demonstrates that long-term administration of intranasal OXT is tolerable in a representative cohort of ASD individuals with ID and suggests that future multicenter trials of OXT are warranted and should include measurements of reciprocal social interactions based on daily life under closer surveillance for epilepsy. Trial registration: UMIN000007250