장기간 항경련제를 복용한 간질환자의 골대사 변화에 대한 연구 : DR-XRA(Quantitative Dual-Energy Radiography ; X-Ray Absorptiometry)법에 의한 측정 Measurement by DR-XRA(Quantitative Dual-Energy Radiography ; X-Ray Absorptiometry)

이호택,장호균,이상연,정인과 大韓神經精神醫學會 1997 신경정신의학 Vol.36 No.1

This study examined, among others, the relationship between the use of anticonvulsant and the bone mineral metabolism(measured via DR-XRA and biochemical study) in 46 adult epileptic outpatients who had been on anticonvulsant for more than one year at Seoul Red Cross Hospital. The study findings wel as follows. 1) There was statistically significant difference between index group(i.e. 46 adult epileptic outpatients) and control group(i.e. 46 healthy adults without previous exposure to anticonvulsant) in terms of bone mineral density. Specifically, the bone mineral density in the epileptic outpatients was significantly lower than that in the healthy adults. Although there was no statistically significant difference between male and female outpatients, their bone mineral density tended to decrease with the increase of age. 2) The bone mineral density in the epileptic outpatients was negatively correlated to both ⅰ) the age when the outpatients started anticonvulsant treatment and ⅱ) the period for which the outpatients were on anticonvulsant. 3) Index group was further classified into three subgroups(i.e. low, normal and high subgroup) based on the mean and standard deviation of the bone mineral density in healthy adults control group. 24 outpatients(5.2%) out of 46 fell into low subgroup, of which 10 were male. Overall, there was no statistically significant difference between male and female outpatients in terms of their bone mineral density. 4) Low subgroup's average age(38.6 with SD of 12.5) was significantly higher than those of the other two subgroups. Low subgroup started anticonvulsant treated when their average age was 24.8(SD 15.0) years, which was higher than those of the other two subgroups. Low subgroup was on anticonvulsant, on average, for 13.3(SD 7.6) years, which was also higher than those of the other two subgroups although there was no significant difference among the subgroups. 5) A series of comparison regarding the possible impact of various types of anticonvulsant(e.g. PHT, CBZ PB, SV) in terms of ⅰ) overall dosage and ⅱ) daily average dosage on bone mineral density showed no significant difference across the three subgroups. 6) There was no significant difference in terms of bone mineral density between the epileptic outpatients on only one type of anticonvulsant and those on two or more types of anticonvulsant. 7) A biochemical study showed that ⅰ) each subgroup fell into normal range in terms of blood serum Ca, P, and ALP with no significant difference among the subgroups, and ⅱ) in low subgroup, there were 6 outpatients(25%) with Ca decrease, 2(9.5%) with P decrease, and 5(20.8%) with ALP increase.

Synthesis and Anticonvulsant Activities of N-Cbz-${\alpha}$-aminoglutarimidooxy Carboxylate Derivatives

Byun, Ae-Sun,Choi, Jong-Won,Moon, Kyung-Ho,Lee, Chung-Gyu,Park, Min-Soo The Pharmaceutical Society of Korea 2006 Archives of Pharmacal Research Vol.29 No.6

Previous studies on the anticonvulsant activity of $N-Cbz-{\alpha}-aminoglutarmides$ have shown that the derivatives of $N-Cbz-{\alpha}-amino-N-alkoxy$ glutarimide have significant anticonvulsant activity. In addition, their anticonvulsant activities are dependent on the presence of N-alkoxy groups. Based on these results, a series of $N-Cbz-{\alpha}-amino-glutarimidooxy$ carboxylates derivatives (3a-e) were synthesized in moderate yield using a known synthetic procedure. Their anticonvulsant activities were evaluated using the maximal electroshock seizure (MES) test, the pentylene tetrazole induced seizure (PTZ) test, and the strychinine (Str) threshold test with the ultimate aim of developing more active anticonvulsants. None of the compounds (3a-e) tested showed anticonvulsant activity in the MES and PTZ test. However, all the compounds tested exhibited significant anticonvulsant activity in the Str. test. The most active compound in the Str. test was the methyl ester of $N-Cbz-{\alpha}-amino-glutarimidooxy$ acetic acid 3a $(ED_{50}\;=\;42.9\;mg/kg)$.

Synthesis and Anticonvulsant Evaluation of a Series of $N-Cbz-\alpha-aminoglutarimides$

Lee, Jaewon,Choi, Jongwon,Park, Minsoo The Pharmaceutical Society of Korea 1996 Archives of Pharmacal Research Vol.19 No.3

In conclusion, a series of N-Cbz-.alpha.-amono-glutarimides (1a-f), combining common structures such as N-CO-C-N and cyclic imide in a single molecule, were prepared from the (R)- or (S)-N-Cbz-glutamic acid and evaluated for their anticonvulsant activities in MES and PTZ tests in order to develope new and broad spectrum anticonvulsant. In this study, N-Cbz-.alpha.-aminoglutarimides (1) except ac and af, showed significant anticonvulsant activity in both MES and PTZ tests enough to be recommended as promising new anticonvulsant drug candidates. Now we are continuing to investigate further anticonvulsant test (quantification)for these compounds and synthesize their analogues in order to develop more active anticonvulsant and define the structure activity relationship more precisely.

간질환아에서 항경련제 투여가 혈청 갑상선 호르몬값에 미치는 영향

이인구(In-Goo Lee),황경태(Kyung-Tai Whang) 대한소아신경학회 1994 대한소아신경학회지 Vol.2 No.1

저자들은 장기간 항경련제 투약을 받고 있는 간질 환아에서 혈청 갑상선 호르몬값(thyroxine; T, free thyroxine; FT, triiodothyronine; T 및 thyrotrophin;TSH)의 변화를 알아보고저, 항경련제 치료군(valproic acid(VPA) 투여군, carbamazepine(CBZ) 투여군, diphenylh-ydantion(DPH 투여군. phenobarbital(PB) 투여군 및 combination (COM, 병용) 투여군)의 환아 89명과 대조군의 소아 40명에서 혈청 T, FT, T 및 TSH값을 각각 방사면역측정법으로 정량 측정하였으며, 다음과 같은 결과를 얻었다. 1. 혈청 T, FT 및 T평균값은 대조군의 것과 각각 비교하여 CBZ 투여군과 병용투여군에서, 그리고 혈청 T 및 FT값은 DPH 투여군에서 각각 유의한 저하가 있었고, 이중 혈청 FT의 평균값은 항경련제 치료군 모두에서 공통적으로 유의한 저하를 보였다(P<0.01). 2. 혈청 갑상선 호르몬 가운데 한 개 또는 그 이상이 대조군의 평균에서 2배의 표준편차 이하로 저하된 낮은 값을 보인 환아는 총 79명중 43명(54.4%)에서 있었다. 이중, 혈청 FT의 낮은 값은 가장 많아 79명 중 37명(46.8%)에서 있었고, 항경련제별로 보면 CBZ 투여군에서 가장 많아 16명중 13명(81.3%)에서 있었다. 3. 혈청 TSH값이 대조군의 평균에서 2배의 표준편차 이상으로 증가된 높은 값을 보인 환아는 총 79명중 1명(1.3%)에서 있었다. 이 환아는 또한 혈청 FT값의 저하를 동반하고 있었으며 추적 조사해 본 결과 갑상선 기능 저하증의 임상 소견은 인지되지 않았다. 이상의 결과로 보아 간질 환아에서 혈청 호르몬값에 대한 항경련제의 영향은 주로 CBZ 및 DPH의 단독투여와 관련이 깊었으며, 이는 약물을 병용 투여시 더욱 현저하였음을 알 수 있었다. 또한, 갑상선 호르몬 가운데 혈청 FT값의 측정은 항경련제 투여와 관련된 갑상선 기능의 이상을 찾아내는데 가장 예민한 방법임을 제시할 수 있었다. The present study was undertaken in order to investigate the effects of the commonly used anticonvulsant drugs on the thyroid hormones in epileptic children. authors examined 79 patients(male 50, female 29)) of five anticonvulsant-treated groups sho received valproic acid(VPA.n=26).carbamazepine(CBZ.n=16). diphenylhydantoin(DPH.n=13) and phenobarbital(PB. n=9) respectively, or a combination of these(COM.n=15) for the periods varying from 4 months to 6 years, and a control group of 40 children(male 30. female 10). The average age of the patients was 10.75±1.19 years and that of the controls 10.88±2.36 years. None of the controls received drugs with known effect on thyroid or pituitary function, and all subjects were clinically euthyroid. All sera from patients and conrols were obtained immediately from blood samples and stored at -20℃ until they were assayed at the same time. In all 119 children, the serum levels of thyroxine(T), free thyroxine(FT), triiodothyronine(T), and thyrotrophin(TSH) were measured by a radioimmunoassay. The comparison of the control and anticonvulsant-treated groups was conducted by means of analysis of variance. In the case of statistically significant differences, the Dunnet multiple comparison tests were performed to check which group is statistically different from the control group. The results were summarized as follows: 1. The mean serum levels of T. FT and T were significantly decreased in the groups treated with CBZ and COM, as compaired with those of the control, and those of T and FT were also significantly decreased in the group treated with DPH. 2. Forty-three of 79 patients who treated with various anticonvulsant drugs had low serum thyroid hromonal levels below 2 SD from the mean of control group. Of the 79 patients 37(46.8%) had low serum level of Ft. and abnormally low FT was most common in the group treated with CBZ and it was observed in 13 of 16 patients(81.3%). 3. One of the 79 patients had high serum TSH level above 2 SD from the mean of control group, and the patient was clinically euthyroid during the study. Our study revealed that the decreasing effects on serum levels of thyroid hormones by anticonvulsant drugs were mainly related to the treatment of CBZ, DPH and COM. Also, we demonstrated that estimation of the serum level of FT was a suitable test for the initial laboratory work-up to detect thyroid hormonal abnormality in epileptic children taking various anticonvulsant drugs.

Synthesis and Anticonvulsant Activities of N-Cbz-α-aminoglutarimidooxy Carboxylate Derivatives

Aesun Byun,Jong Won Choi,Kyung Ho Moon,Chung Gyu Lee,Min Soo Park 대한약학회 2006 Archives of Pharmacal Research Vol.29 No.6

Previous studies on the anticonvulsant activity of N-Cbz-α-aminoglutarimides have shown that the derivatives of N-Cbz-α-amino-N-alkoxy glutarimide have significant anticonvulsant activity. In addition, their anticonvulsant activities are dependent on the presence of N-alkoxy groups. Based on these results, a series of N-Cbz-α-amino-glutarimidooxy carboxylates derivatives (3a-e) were synthesized in moderate yield using a known synthetic procedure. Their anticonvulsant activities were evaluated using the maximal electroshock seizure (MES) test, the pentylene tetrazole induced seizure (PTZ) test, and the strychinine (Str) threshold test with the ultimate aim of developing more active anticonvulsants. None of the compounds (3a-e) tested showed anticonvulsant activity in the MES and PTZ test. However, all the compounds tested exhibited significant anticonvulsant activity in the Str. test. The most active compound in the Str. test was the methyl ester of N-Cbz-α-amino-glutarimidooxy acetic acid 3a (ED50 = 42.9 mg/kg).

Synthesis and Anticonvulsant Evaluation of 6-Amino-1,4- oxazepane-3,5-dione Derivatives

Gitalee Sharma,박진엽,박민수 대한약학회 2008 Archives of Pharmacal Research Vol.31 No.7

The N-Acyl-α-aminosuccinimides and N-Acyl-α-aminoglutarimides were reported to exhibit moderate anticonvulsant activities. These compounds were 5-membered or 6-membered α- amino cyclic imides and have N-CO-C-N moiety in their structures. Based on these structural characteristics, a series of 6-amino-1,4-oxazepine-3,5-dione derivatives 1, having a heterocyclic 7-memberd α-amino cyclic imide and N-CO-C-N moiety in their structures were designed and synthesized. These syntheses were in view to develop novel anticonvulsant compounds. The 6-amino-1, 4-oxazepine-3,5-dione derivatives were prepared from (S)-N-Cbz-serine by usual synthetic procedures and their anticonvulsant activities were examined by the MES and PTZ tests. The N-H (1a), N-methyl (1b), and N-n-butyl (1e) derivatives showed moderate anticonvulsant activities in the MES test. In the case of PTZ test, all the tested compounds except N-n-propyl compound(1c) also showed moderate anticonvulsant activities. Moreover, N-H (1a), N-methyl (1b), and N-n-butyl (1e) derivatives showed anticonvulsant activities in both the MES and PTZ test. From these studies, it was concluded that the 6-amino-1,4-oxazepane-3,5-dione derivatives were novel compounds enough to be recommended as new anticonvulsants.

Synthesis and Anticonvulsant Evaluation of 6-Amino-1,4-oxazepane-3,5-dione Derivatives

Sharma, Gitalee,Park, Jin-Yup,Park, Min-Soo 대한약학회 2008 Archives of Pharmacal Research Vol.31 No.7

The N-Acyl-$\alpha$-aminosuccinimides and N-Acyl-$\alpha$-aminoglutarimides were reported to exhibit moderate anticonvulsant activities. These compounds were 5-membered or 6-membered $\alpha$- amino cyclic imides and have N-CO-C-N moiety in their structures. Based on these structural characteristics, a series of 6-amino-1,4-oxazepine-3,5-dione derivatives 1, having a heterocyclic 7-memberd $\alpha$-amino cyclic imide and N-CO-C-N moiety in their structures were designed and synthesized. These syntheses were in view to develop novel anticonvulsant compounds. The 6-amino-1, 4-oxazepine-3,5-dione derivatives were prepared from (S)-N-Cbz-serine by usual synthetic procedures and their anticonvulsant activities were examined by the MES and PTZ tests. The N-H (1a), N-methyl (1b), and N-n-butyl (1e) derivatives showed moderate anticonvulsant activities in the MES test. In the case of PTZ test, all the tested compounds except N-n-propyl compound(1c) also showed moderate anticonvulsant activities. Moreover, N-H (1a), N-methyl (1b), and N-n-butyl (1e) derivatives showed anticonvulsant activities in both the MES and PTZ test. From these studies, it was concluded that the 6-amino-1,4-oxazepane-3,5-dione derivatives were novel compounds enough to be recommended as new anticonvulsants.

Anticonvulsant Activity of Ethanol Leaf Extract of Spathodea campanulata P. Beauv (Bignoniaceae)

Emmanuel E. Ilodigwe,Peter. A. Akah,Chukwuemeka S. Nworu 한국식품영양과학회 2010 Journal of medicinal food Vol.13 No.4

The anticonvulsant properties of ethanol leaf extract of Spathodea campanulata, a plant used in traditional medicine to treat convulsion and epilepsy, were studied in mice using pentylenetetrazole-, picrotoxin-, and electroshock-induced models in mice. Other central nervous system effects and anticonvulsant-related activities such as the effects on position sense, righting reflex, Rota-Rod performance, phenobarbital sleep time, and amphetamine-induced stereotypy were also investigated. The acute toxicity potential in mice was determined by the oral route. The results showed that the administration of S. campanulata extract (250–1,000mg/kg, p.o.) 30 minutes prior to intraperitoneal administration of pentylenetetrazole (70mg/kg) or picrotoxin (5mg/kg) protected the treated mice against the respective pentylenetetrazole- and picrotoxin-induced convulsion in a dose-dependent manner, offering 100% protection at the maximum dose of 1,000mg/kg. The extract increased the threshold of maximum electroshock and reduced duration of convulsive episodes, dose-dependently. Oral administration of S. campanulata ethanol extract did not significantly (P>.05) affect other centrally coordinated behaviors and convulsion-related properties such as position sense, righting reflex, Rota-Rod performance, phenobarbital sleep time, and amphetamine-induced stereotypy in treated animals. The oral median lethal dose of the extract was estimated as 4.5g/kg. These results show that the ethanol leaf extracts of S. campanulata possess anticonvulsant activity. The results also show that S. campanulata extract is nonsedating, has no antipsychotic properties, and may not affect motor coordination when used as an anticonvulsant.

신생아 경련성 질환의 항경련제 요법

유재은 대한신생아학회 2009 Neonatal medicine Vol.16 No.1

The immature neonatal brain is susceptible to the development of seizures. Seizures occur in 1% to 5% of infants during the neonatal period. Neonatal seizures are most commonly associated with serious acute illnesses, such as hypoxic-ischemic encephalopathy, birth trauma, metabolic disturbances, or infections. Thus, newborn infants with seizures are at risk for neonatal death and survivors are at risk for neurologic impairment, developmental delay, and subsequent epilepsy. Experimental data have also raised concerns about the potential adverse effects of the currently used anticonvulsants in neonates on brain development. Therefore, in the management of neonatal seizures, confirmatory diagnosis and optimal, but shorter, duration of anticonvulsant therapy is essential. Nevertheless, there has been substantial progress in understanding the developmental mechanisms that influence seizure generation and responsiveness to anticonvulsants. The currently used therapies have limited efficacy and the treatment of neonatal seizures has not significantly changed in the past several decades, This review includes an overview of current approaches to the treatment of neonatal seizures.

Synthesis and anticonvulsant evaluation of a series of (R)-and (S)-N-Cbz-.alpha.-aminosuccinmide and their structure activity relationship

Lee, Jae-Won,Choi, Jong-Won,Park, Min-Soo The Pharmaceutical Society of Korea 1996 Archives of Pharmacal Research Vol.19 No.4

A series of N-Cbz${alpha}$-aminosucinimides (1), combining common moieties of various anticonvulsants such as N-CO-C-N and cyclic imide in a single molecule, were synthesized from the corresponding (R)- and (S)-N-Cbz-aspartic acid (2). And their in vivo anticonvulsant evaluations in MES and PTZ test were investigated. And also the rotorod test for neurotoxicity was investigated. All the tested compounds (1), except 1c and 1f, showed significant anticonvulsant activities in both MES and PTZ test. And the most active compound among them in MES test was (R)-N-Cbz-${alpha}$-amino-N-methylsuccinimide (1b) $(ED_50/=52.5 mg/kg)$ and (S)-N-Cbz-aminosuccinimide((1d) was most active in PTZ test $(ED_50/=78.1 mg/kg)$. And the $TD_50$ values of the tested compounds were above 117.5 mg/kg. These pharmacological data were comparable to those of currently available anticonvulsants. And also we found that the pharmacological effects were dependent on their N-substituted alkyl chains and their stereochemistry.