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18 results on '"Antiepileptic drug"'

2. Clinical Pharmacometrics for Rational Drug Treatment

Author

Yano, Ikuko

Subjects
warfarin, antiepileptic drug, population analysis, tacrolimus, physiologically based pharmacokinetics, pharmacometrics
Abstract

Pharmacometrics is the mathematical study of pharmacokinetics, disease progression, and clinical outcomes. One objective of pharmacometrics is to facilitate rational drug treatment in patients, also termed clinical pharmacometrics. In this review, our clinical pharmacometric studies conducted over the last 10 years are discussed. Population pharmacokinetic analysis using therapeutic monitoring data for levetiracetam revealed that oral clearance allometrically scaled to both body weight and estimated glomerular filtration rate can accurately predict clinical data from patients of various ages (pediatric to elderly) with varying renal function. Dosage adjustments based on renal function in the package information are effective in controlling the trough and peak concentrations in similar ranges. In addition, a retrospective pharmacokinetic and pharmacodynamic study revealed that the efficacy of low-dose clobazam therapy was significantly influenced by CYP2C19 polymorphisms. Pharmacokinetic and pharmacodynamic models were successfully built using electronic medical information to explain retrospective international normalized ratio values of prothrombin time before and after catheter ablation in warfarin-treated patients. Simulation studies suggest that more than 20 mg of vitamin K2 is unnecessary in the preoperative period of catheter ablation. A physiologically based pharmacokinetic model adapted to tacrolimus pharmacokinetic data in patients who underwent living-donor liver transplantation was constructed, and clarified that oral clearance of this drug was affected by CYP3A5 genotypes in both the liver and intestine to the same extent. In conclusion, pharmacometrics is a useful methodology for individualized and optimized drug therapy.

Published
2019

3. Clinical Pharmacometrics for Rational Drug Treatment

Subjects
warfarin, antiepileptic drug, population analysis, tacrolimus, physiologically based pharmacokinetics, pharmacometrics
Abstract

Pharmacometrics is the mathematical study of pharmacokinetics, disease progression, and clinical outcomes. One objective of pharmacometrics is to facilitate rational drug treatment in patients, also termed clinical pharmacometrics. In this review, our clinical pharmacometric studies conducted over the last 10 years are discussed. Population pharmacokinetic analysis using therapeutic monitoring data for levetiracetam revealed that oral clearance allometrically scaled to both body weight and estimated glomerular filtration rate can accurately predict clinical data from patients of various ages (pediatric to elderly) with varying renal function. Dosage adjustments based on renal function in the package information are effective in controlling the trough and peak concentrations in similar ranges. In addition, a retrospective pharmacokinetic and pharmacodynamic study revealed that the efficacy of low-dose clobazam therapy was significantly influenced by CYP2C19 polymorphisms. Pharmacokinetic and pharmacodynamic models were successfully built using electronic medical information to explain retrospective international normalized ratio values of prothrombin time before and after catheter ablation in warfarin-treated patients. Simulation studies suggest that more than 20 mg of vitamin K2 is unnecessary in the preoperative period of catheter ablation. A physiologically based pharmacokinetic model adapted to tacrolimus pharmacokinetic data in patients who underwent living-donor liver transplantation was constructed, and clarified that oral clearance of this drug was affected by CYP3A5 genotypes in both the liver and intestine to the same extent. In conclusion, pharmacometrics is a useful methodology for individualized and optimized drug therapy.

Published
2019

6. [Paradoxical effect of levetiracetam on seizure suppression: three cases showing U curve association between dose and effect].

Author

Inoue T, Kobayashi K, Usami K, Shimotake A, Inouchi M, Sakai T, Ikeda A, and Takahashi R

Subjects
Adult, Anticonvulsants adverse effects, Dose-Response Relationship, Drug, Drug Therapy, Combination, Electroencephalography, Female, Humans, Levetiracetam adverse effects, Magnetic Resonance Imaging, Male, Seizures diagnosis, Treatment Outcome, Anticonvulsants administration & dosage, Levetiracetam administration & dosage, Seizures prevention & control
Abstract

We experienced 3 adult patients with intractable focal epilepsy treated by levetiracetam (LEV) as polytherapy, who showed paradoxical effect (PE). Starting dose of LEV was small (62.5, 250 mg/day) and we gradually increased by less than 250 mg/day, every more than 2 weeks. Within 6 months after LEV was added, LEV of 750 to 1,000 mg/day brought reduction of seizure frequency. Serum concentration of LEV was 13.3 and 14.0 μg/ml. In order to obtain better seizure control, LEV was increased up to 1,000-2,500 mg/day (19.3-35.0 μg/ml) within one year, and they developed PE. They all showed increased habitual seizures, occurring in cluster. Once dose of LEV deceased down to what produced the maximum seizure suppression, all of the patients regained the better seizure control. It is most likely that at least in some patients like present 3 cases, PE of LEV may express U curve association between dose and effect and that it was only delineated by slow titration.

Published
2021
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7. [Transfer Mechanisms of Compounds between Mother and Fetus/Infant Aimed for Optimized Medication during Pregnancy and Breastfeeding].

Author

Furugen A

Subjects
Anticonvulsants adverse effects, Benzodiazepines adverse effects, Benzodiazepines therapeutic use, Cell Line, Epilepsy drug therapy, Female, Folate Receptor 1 genetics, Folate Receptor 1 metabolism, Gabapentin adverse effects, Gene Expression drug effects, Humans, Lamotrigine adverse effects, Pregnancy, Pregnancy Complications drug therapy, Proton-Coupled Folate Transporter genetics, Proton-Coupled Folate Transporter metabolism, Valproic Acid adverse effects, Anticonvulsants metabolism, Benzodiazepines metabolism, Biological Transport genetics, Breast Feeding, Gabapentin metabolism, Lactation metabolism, Lamotrigine metabolism, Large Neutral Amino Acid-Transporter 1 physiology, Maternal-Fetal Exchange, Milk, Human metabolism, Placenta metabolism, Valproic Acid metabolism
Abstract

Potential risks to the fetus or infant should be considered prior to medication during pregnancy and lactation. It is essential to evaluate the exposure levels of drugs and their related factors in addition to toxicological effects. Epilepsy is one of the most common neurological complications in pregnancy; some women continue to use antiepileptic drugs (AEDs) to control seizures. Benzodiazepines (BZDs) are widely prescribed for several women who experience symptoms such as anxiety and insomnia during the postpartum period. In this review, we describe the 1) transport mechanisms of AEDs across the placenta and the effects of these drugs on placental transporters, and 2) the transfer of BZDs into breast milk. Our findings indicated that carrier systems were involved in the uptake of gabapentin (GBP) and lamotrigine (LTG) in placental trophoblast cell lines. SLC7A5 was the main contributor to GBP transport in placental cells. LTG was transported by a carrier that was sensitive to chloroquine, imipramine, quinidine, and verapamil. Short-term exposure to 16 AEDs had no effect on folic acid uptake in placental cells. However, long-term exposure to valproic acid (VPA) affected the expression of folate carriers (FOLR1, SLC46A1). Furthermore, VPA administration changed the expression levels of various transporters in rat placenta, suggesting that sensitivity to VPA differed across gestational stages. Lastly, we developed a method for quantifying eight BZDs in human breast milk and plasma using LC/MS/MS, and successfully applied it to quantify alprazolam in breast milk and plasma donated by a lactating woman.

Published
2020
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8. [Clinical Pharmacometrics for Rational Drug Treatment].

Author

Yano I

Subjects
Anticoagulants administration & dosage, Anticoagulants pharmacokinetics, Anticonvulsants administration & dosage, Anticonvulsants pharmacokinetics, Clobazam administration & dosage, Clobazam pharmacokinetics, Cytochrome P-450 CYP2C19 genetics, Cytochrome P-450 CYP3A genetics, Drug Dosage Calculations, Genotype, Humans, Immunosuppressive Agents administration & dosage, Immunosuppressive Agents pharmacokinetics, Polymorphism, Genetic, Precision Medicine, Tacrolimus administration & dosage, Tacrolimus pharmacokinetics, Vitamin K 2 administration & dosage, Vitamin K 2 pharmacokinetics, Warfarin administration & dosage, Warfarin pharmacokinetics, Drug Monitoring, Drug Therapy, Health Care Rationing, Pharmacokinetics
Abstract

Pharmacometrics is the mathematical study of pharmacokinetics, disease progression, and clinical outcomes. One objective of pharmacometrics is to facilitate rational drug treatment in patients, also termed clinical pharmacometrics. In this review, our clinical pharmacometric studies conducted over the last 10 years are discussed. Population pharmacokinetic analysis using therapeutic monitoring data for levetiracetam revealed that oral clearance allometrically scaled to both body weight and estimated glomerular filtration rate can accurately predict clinical data from patients of various ages (pediatric to elderly) with varying renal function. Dosage adjustments based on renal function in the package information are effective in controlling the trough and peak concentrations in similar ranges. In addition, a retrospective pharmacokinetic and pharmacodynamic study revealed that the efficacy of low-dose clobazam therapy was significantly influenced by CYP2C19 polymorphisms. Pharmacokinetic and pharmacodynamic models were successfully built using electronic medical information to explain retrospective international normalized ratio values of prothrombin time before and after catheter ablation in warfarin-treated patients. Simulation studies suggest that more than 20 mg of vitamin K 2 is unnecessary in the preoperative period of catheter ablation. A physiologically based pharmacokinetic model adapted to tacrolimus pharmacokinetic data in patients who underwent living-donor liver transplantation was constructed, and clarified that oral clearance of this drug was affected by CYP3A5 genotypes in both the liver and intestine to the same extent. In conclusion, pharmacometrics is a useful methodology for individualized and optimized drug therapy.

Published
2019
Full Text
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9. Effects of Antiepileptic Drugs on Epoxide Hydrolase and Glutathione S-transferase Activities

Subjects
antiepileptic drug, 内科系臨床医学, epoxide, teratogenicity, 493.7, epoxide hydrolase, glutathione S-transferase
Abstract

抗てんかん薬(antiepileptic drugs:AED)の催奇性の機序解明の一環として、胎児毒性との関連が指摘されているepoxide体の加水分解酵素epoxide hydrolase(EH)および抱合酵素glutathione S-transferase(GST)の両酵素活性に与えるcarbamazepine(CBZ)、phenobarbital(PB)、phenytoin(PHT)、valproic acid(VPA)、zonisamide(ZNS)の影響を検討した。ラット肝マイクロゾームを用いて両酵素の活性を各AEDの影響下で対照群と比較検討したところ、VPAはEHおよびGST(2-2、4-4、7-7)活性を治療濃度(50～100μg/ml)より濃度依存性に抑制し、CBZ(10μg/ml)およびPB(40μg/ml)は治療濃度よりGST7-7活性を有意に抑制した。一方、PHTおよびZNSはEH、GSTの両酵素活性に対し治療濃度では影響を与えなかった。以上の結果から、VPA、CBZおよびPBを含む多剤併用時の奇形発現の増加の一因として、これらの薬剤によるepoxide解毒機構の低下が関与する可能性が示唆された。, てんかん研究. 15(3), 1997, p.165-171

Published
1997

11. Treatment of Epileptic Women of Childbearlng Age

Subjects
malformation, antiepileptic drug, treatment, 内科系臨床医学, 493.74, epilepsy, pregnancy
Abstract

application/pdf, てんかん治療の進歩により,多くのてんかん者が結婚し,挙児を望むようになった｡ そこで,妊娠可能てんかん女性の治療基準設定のため,抗てんかん薬(AED)の催奇形性, 服薬中に授乳可能か否か,妊娠中におけるてんかん発作頻度変化などの問題を中心に前方視 的に検討し,以下の結果を得た｡AEDの服薬が規則的であれば80%以上の症例で妊娠中にて んかん発作頻度は変化しない｡AEDは胎盤を通過し,母乳中にも排推される｡奇形はAED 多剤併用投与により増加し,催奇形性の強いAED,あるいは危険なAED併用パターンの存 在が明らかになった｡パルビツール剤,ベンゾジアゼピン服用中には出産後1週間は授乳を 避けたほうがよいが,それ以外のAED服薬は授乳を妨げない｡AEDにより,胎児の発達は 遅れるが,生後3年頃までに回復し,服薬てんかん妊婦の子供でも,育児に配慮することに より,身体精神の発達に大きな問題は残らないことが明らかとなった｡, てんかん治療研究振興財団研究年報. 4, 1992, p.24-35

Published
1992

12. A study on the prevention of congenital malformation caused by antiepileptic drug therapy during pregnancy

Subjects
antiepileptic drug, congenital malformation, 内科系臨床医学, dose, polypharmacy, 493.7, prevention of malformation
Abstract

抗てんかん薬(AED)による奇形発現防止のため,その発現に関連すると考えられる各種危険要因の相対的重要性およびAEDによる奇形防止の可能性を検討した.対象は従来からのAED療法を受けたてんかん妊婦とその児192例(A群)と妊娠前にAED投薬量を少なくし,かつ可能な限り多剤併用から単剤投与へとdrug regimenを変更したてんかん妊婦とその児145例(B群)である.A,B両群の奇形発現率はそれぞれ13.5%,6.2%であり,両群間には有意差が認められた(p=0.031).妊婦の出産時年齢,てんかんの病因,てんかん発作型での頻度がA群,B群問で有意に異なっていた(p, 精神薬療基金研究年報. 22, 1991, p.88-94

Published
1991

13. Prospective study on psychomotor development in the offspring of epileptic mother : risk factors for the developmental retardation

Subjects
antiepileptic drug, psychomotor development, 内科系臨床医学, EEG in neonatal period, Enjohji's test, infant born to epileptic mother, 493.7
Abstract

てんかん婦人より出生した児,45例(E群)の精神運動発達遅滞の要因を遠城寺式・乳幼児分析的発達検査を用いて検討した.対照群として非てんかん婦人より出生した児,55例(C群)を選んだ.全発達領野で,E群はC群より発達指数(DQ値)が低値であった.E群の年少群では,母親の服薬量と言語理解のDQ値との間に負の相関傾向が,生下時頭囲と発語のDQ値との間に正の相関が,それぞれに見られた.E群の年長郡では母親の学歴と児の発達に相関が見られた.15例の新生児脳波の検討結果では,抗てんかん薬による異常は認められなかった.てんかん男性を父親に持つ児のDQ値は,C群と比較して有意差はなかった.以上より,胎生期の抗てんかん薬曝露が児の精神身体発達に影響するのは,主に年少期(2才以下)と考えられた., 精神薬療基金研究年報. 15, 1984, p.282-291

Published
1984

14. A Study on Diurnal Variation of Serum Level of Antiepileptic Drugs: Clinical Significance of Measurement of Diurnal Variation

Subjects
serum level, antiepileptic drug, 内科系臨床医学, diurnal variation
Abstract

application/pdf, 入院治療中のてんかん患者19名を対象に,血清抗てんかん剤濃度の日内変動を調べた.血清抗てんか ん剤(Phenytoin(PHT),Carbamazepine(CBZ),Phenobarbital(PB))の日内変動のパターンと最低 及び最高血清濃度(Cmin,Cmax)を生じる時間と日内変動の大きさを検討した.ついで診療時間における 外来患者の血清濃度を入院患者の血清濃度の日内変動と比較検討した. 血清濃度の測定には酵素免疫法を用 いた.① 日内変動のパターンはPHT,PBでは変動の小さな平坦なパターンを示す.一方CBZでは変動が 大きく,個々の症例で異なったパターンを示す.②PHT,CBZでは血清濃度は早朝第1回目服薬前にCmin を示し,6時間から8時間後にCmaxを示す.PBではCmin,Cmaxの出現時間はかなり変動する.③ 外来患者では,診療時間における血清濃度はCmin,Cmaxの間にあり,PHT の場合は変動が小さいため にCminに近い値を示す., 弘前医学. 35(3), 1983, p.465‐471

Published
1983

15. Mechanism of teratogenicity of antiepileptic drugs. Third report : Serum folic acid levels during pregnancy

Subjects
antiepileptic drug, serum folic acid level, congenital malformation, 内科系臨床医学, epilepsy, pregnancy, 493.7
Abstract

抗てんかん薬(抗て薬)の奇形発現の機序を解明する目的で，正常妊婦73例(C群),服薬てんかん妊婦48例(E群)を対象に血清中葉酸濃度を測定した.妊娠全期間を通してE群の葉酸濃度はC群より低値であった.E群を奇形児出産の有無により奇形群(n=7)と正常群(n=41)に分け葉酸値を比較すると妊娠前期でのみ奇形群は正常群より有意に低い葉酸濃度を示したが，妊娠期間中は両群間に有意差はなかった.抗て薬総投与量(DS)は奇形群で正常群より高値であった.妊娠時期別に両群のDSを比較すると，妊娠一期では奇形群で高い傾向を有し，二期，三期では有意に奇形群で高値であった. DSは奇形群の妊娠一期および三期では葉酸濃度と負の相関を示した.これらの結果から，抗て薬により誘発された低葉酸濃度が抗て薬による奇形発現に何等かの関連を有することは否定出来ないものの，決定的要因ではないと考えられた., 精神薬療基金研究年報. 19, 1988, p.306-311

Published
1988

16. Mechanism of teratogenicity of antiepileptic drugs. 1st report : Analysis of possible risk factors

Subjects
malformation, antiepileptic drug, 内科系臨床医学, epilepsy, pregnancy, polypharmacy, 493.7
Abstract

服薬てんかん婦人の児に高頻度に認められる奇形発現の機序を解明すべく,1975年から1983年までprospectiveに十分な観察が可能であった児117例を対象に,奇形発現に関連が推定される各種要因を2重指数判別分析,カテゴリカル主成分分析などを用い解析した. 妊娠第1期に服薬していた群の15.7%に,非服薬群の13.3%に奇形が認められ,対象例全体としての奇形発現率は15.4%であった.いわゆる大奇形は服薬群にのみ認められ,服薬群中の単剤治療例には奇形児出産はなく,多剤治療例の奇形発現率は18.0%であった. 要因間における関連性の解釈および各種解析結果から,奇形発現に重要な関連が考えられた要因は多剤併用,特にcarbamazepineとvalproic acidの併用,妊娠第1期における発作発来であったが,その他,部分発作(単純,複雑),抗てんかん薬1日当りの投与の量の関連も推定された., 精神薬療基金研究年報. 16, 1985, p.325-334

Published
1985

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