The Study on Association of Calcium Channel SNPs with Adverse Drug Reaction of Calcium Channel Blocker in Korean

Chung, Myeon-Woo,Bang, Sy-Rie,Jin, Sun-Kyung,Woo, Sun-Wook,Lee, Yoon-Jung,Kim, Young-Sik,Lee, Jong-Keuk,Lee, Sung-Ho,Roh, Jae-Sook,Chung, Hye-Joo The Korean Society of Applied Pharmacology 2007 Biomolecules & Therapeutics(구 응용약물학회지) Vol. No.

Rapid advances in pharmacogenomic research have provided important information to improve drug selection, to maximize drug efficacy, and to minimize drug adverse reaction. The SNPs that are the most abundant type of genetic variants have been proven as valid biomarkers to give information on the prediction of pharmacokinetic/pharmacodynamic properties of drugs based on genotype. In order to elucidate a correlation between SNPs of calcium channel encoding gene and adverse reactions of calcium channel blockers, we investigated SNPs in CACNA1C gene known as a binding site of calcium channel blocker. 96 patients with hypertension who had taken or are taking an antihypertensive drug, 1,4-dihydropyridine (DHP) were included for analysis. These patients were composed of 47 patients with adverse drug reactions (ADR) such as edema from calcium channel blockers and 49 patients without ADR as a control group. The exons encoding the drug binding sites were amplified by PCR using specific primers, and SNPs were analyzed by direct sequencing. We found that there was no SNP in the exons encoding DHP binding site, but four novel SNPs in the exon-intron junction region. However, four novel SNPs were not associated with the ADR of calcium channel blockers. In conclusion, this study showed that ADR from calcium channel blockers may not be caused by SNPs of the binding sites of calcium channel blockers in CACNA1C gene.

The Study on Association of Calcium Channel SNPs with Adverse Drug Reaction of Calcium Channel Blocker in Korean

( Myeon Woo Chung ),( Syrie Bang ),( Sun Kyung Jin ),( Sun Wook Woo ),( Yoon Jung Lee ),( Young Sik Kim ),( Jong Keuk Lee ),( Sung Ho Lee ),( Hye Joo Chung ),( Jae Sook Roh ) 한국응용약물학회 2007 Biomolecules & Therapeutics(구 응용약물학회지) Vol.15 No.3

Rapid advances in pharmacogenomic research have provided important information to improve drug selection, to maximize drug efficacy, and to minimize drug adverse reaction. The SNPs that are the most abundant type of genetic variants have been proven as valid biomarkers to give information on the prediction of pharmacokinetic/pharmacodynamic properties of drugs based on genotype. In order to elucidate a correlation between SNPs of calcium channel encoding gene and adverse reactions of calcium channel blockers, we investigated SNPs in CACNA1C gene known as a binding site of calcium channel blocker. 96 patients with hypertension who had taken or are taking an antihypertensive drug, 1,4-dihydropyridine (DHP) were included for analysis. These patients were composed of 47 patients with adverse drug reactions (ADR) such as edema from calcium channel blockers and 49 patients without ADR as a control group. The exons encoding the drug binding sites were amplified by PCR using specific primers, and SNPs were analyzed by direct sequencing. We found that there was no SNP in the exons encoding DHP binding site, but four novel SNPs in the exon-intron junction region. However, four novel SNPs were not associated with the ADR of calcium channel blockers. In conclusion, this study showed that ADR from calcium channel blockers may not be caused by SNPs of the binding sites of calcium channel blockers in CACNA1C gene.

고혈압 환자에서 칼슘차단제의 부작용에 관한 시판 후 조사

조홍준,최현림,서홍관,양윤준,신호철,김경수,김영주,조경환,이신휘,정승필,이정권,안윤옥,김영식,Cho, Hong-Jun,Choi, Hyun-Rim,Seo, Hong-Gwan,Yang, Yoon-Joon,Shin, Ho-Cheol,Kim, Kyung-Soo,Kim, Young-Joo,Cho, Kyung-Hwan,Lee, Shin-Whee,Jung, Seung- 대한임상약리학회 1994 臨床藥理學會誌 Vol.2 No.2

연구배경 : 칼슘차단제 투여 시 나타나는 각종 부작용의 발생률과 이와 관련된 요인을 밝히고자 칼슘차단제를 투여 받은 고혈압 환자를 대상으로 시판 후 조사를 하였다. 방법 : 1993년 2월부터 1993년 10월까지 칼슘차단제를 투여 받은 고혈압 환자 360명을 연구대상으로 하였다. 연구대상자중 남자가 142명, 여자가 218명이었으며, 연령별로는 50세 미만 103명, $50{\sim}59$세 155명, 60세 이상이 102명 이었다. 약물투여 후 2,4,6,8주에 추적 관찰하였으며, 부작용의 발생률은 Kaplan-Meier 방법과 Log-Rank 방법으로 분석하였다. 결과 : 대상자중 혈관확장과 관련된 부작용의 8주간 누적발생률이 전체적으로 38.9%였으며, 안면홍조 23.3%, 두통 13.5%, 심계항진 13.3%, 현기증 7.6%, 하지부종 6.6% 였다. 이와 같은 부작용들은 발생 후 시간경과에 따라 없어지는 경향이었으며, 최초 발생자중 $6{\sim}12%$에서만 증상이 지속되었다. 안면홍조의 누적발생률은 여자가 29.9%로서 남자의 12.9%보다 높았으며, 하지부종의 경우도 여자가 8.6%로 남자의 3.4%보다 높았다(P<0.05). 안면홍조의 발생률이 여자는 50세미만에서 46.4%로서 $50{\sim}59$세의 21.9%, 60세 이상의 25.9%보다 높았으며, 두통의 발생률도 여자는 50세 미만에서 29.9%로서 $50{\sim}59$세의 12.4%, 60세 이상의 9.3%보다 높았다(P<0.01). 여자에서 Nitrendipine 투여 후 안면홍조의 발생률이 46.1%로 Nitrendipine 투여 후 25.8%(P<0.05), Amlodipine 투여 후 14.3%(P<0.01) 보다 높았으며, 여자에서 Nitrendipine 투여 후 하지부종의 발생률이 18.1%로, Nicardipine의 0.0%보다 높았다(P<0.05). 그 외 부작용으로는 변비 13예, 소화장애 8예, 오심 6예, 잇몸비후, 안면부종, 피로감이 각각 2예, 탈모증, 불면증, 허약감, 피부질환, 호흡곤란, 손발저림, 발한, 구강건조 등이각각 1예 있었다. 칼슘차단제 투여 후 부작용으로 인한 투약 중단율은 10.0% 였다. 결론 : 칼슘차단제 투여 시 혈관확장과 관련된 부작용의 발생률은 39%로 높았으나 시간경과에 따라 점차 없어져서 발생자중 10%정도에서만 증상이 지속되었으며, 안면홍조, 두통, 하지부종의 부작용은 성별, 연령 및 약제에 따라 발생률에 차이가 있었다. Purpose : To estimate the incidence and features of adverse events resulting from the use of calcium channel blockers a multicenter postmarketing surveillance study was carried out. Method : To ascertain adverse events associated with calcium channel blockers usage, we followed regularly the hypertensive patients with the use of calcium channel blockers at the interval of 2,4,6,8 weeks. A total of 360 patients, 17,825 person-days, at 11 clinics were observed from February 1993 to September 1993. The incidence patterns of adverse events were analysed using Kaplan-Meier method. Results : Median follow-up days per person were 54 and the proportion of uncensored cases was 56.7%. Vasodilatory adverse events were observed in 38.9% of the patients during 8 weeks, where flushing, headache, palpitation, dizziness and peripheral edema occurred in 23.3%, 13.5%, 13.3% , 7.6% and 6.6% of the patients, respectively. These declined with time during continued therapy. The incidence of flushing and headache in younger patients(<50 years) were higher than those in older patients(>50 years). The incidence of flushing and peripheral edema associated with use of Niterndipine were higher than those associated with the use of Nicardipine and Amlodipine. The incidence of withdrawal due to adverse events was 10%. Apart from flushing headache, palpitation dizziness and peripheral edema, all other adverse events were constipation, indigestion nausea, gingival hyperplasia, facial edema and fatigue. Conclusion : Vasodilatory adverse events were observed in 38.9% of the patients with the use of calcium channel blockers, which declined with time during continued therapy. Incidences of flushing, headache and peripheral edema were associated with sex, age and the type of calcium channel blocker.

Nitrendipine, an antihypertensive alpha calcium channel blocker, is cytotoxic to neuroblastoma cells

Isabel Rivera,David M. Cauvi,Nelson Arispe,Antonio De Maio 대한독성 유전단백체 학회 2019 Molecular & cellular toxicology Vol.15 No.4

Backgrounds: Alpha calcium channel blockers (CCB) are widely prescribed for the treatment of hypertension, including Nitrendipine (NTD). The anti-hypertension effect of NTD is related to binding and blocking the activity of the voltage-gated L-type calcium channels. These channels consist of four subunits (α1, α2/δ, γ and β subunits), localized in the plasma membrane. Methods: Cellular proliferation was determined by the XTT method and apoptosis was measured by flow cytometry. The expression of the α1c subunit (Cacna1c) of the voltage-gated L-type calcium channels was reduced by siRNA and assessed by quantitative RT-PCR. Results: NTD blocked the proliferation of murine neuroblastoma (N2a cells) and induced apoptosis in a concentration- dependent manner. A decrease in Cacna1c expression did not have a significant effect on NTD toxicity of N2a cells. Conclusion: NTD induced apoptosis on neuroblastoma cells, appears to be independent of the expression of the L-type calcium channel.

Amlodipine에 의한 잇몸비후 1예

윤인상,이남호,최승혁,고진석,박동양,김대성,남대익 대한내과학회 2003 대한내과학회지 Vol.64 No.6

약물에 의한 잇몸비후는 주로 항경련제, 칼슘통로 차단제, cyclosporin 등에 의해 발생하며, 그 기전은 아직 명확하게 밝혀져 있지 않다. 칼슘통로 차단제 중에서는 nifedipine에 의한 잇몸비후의 발생이 가장 많으나 다른 여러 종류의 칼슘통로차단제들에 의해서도 드물게 유발되는 것으로 알려져 있다. 본 저자들은 amlodipine에 의 한 잇몸비후 1예를 경험하였기에 이를 문헌 고찰과 함께 보고하는 바이다. Calcium channel blockers are used to treat hypertension. Unwanted side effects associated with calcium channel blockers are facial flushing, headache, palpitation, dizziness, peripheral edema, constipation, indigestion, nausea, gingival hyperplasia, facial edema and fatigue. Gingival hyperplasia is a rare adverse effect of calcium channel blockers. Calcium channel blockers are known to contribute to gingival hyperplasia. Among all calcium-channel blockers, the prevalence of gingival hyperplasia is highest with nifedipine. Amlodipine is used extensively for the management of hypertension. Several cases have been published since 1994 indicating that amlodipine may also promote gingival hyperplasia. Amlodpine-induced gingival hyperplasia has not reported yet in Korea. We report a case of gingival hyperplasia caused by amlodipine.

한국적 의학 기준에 근거한 고혈압환자의 Angiotensin II Receptor Blockers와 Calcium Channel Blockers의 약물 평가

이옥상,천영주,예경남,윤희영,김정태,이윤정,임성실 대한약학회 2014 약학회지 Vol.58 No.2

Oriental lifestyle for treating diseases has been developed and well-accepted for a long time among Koreans. Sasang Constitution theory, originated from Korean traditional medicine, suggests that medication treat-ment should be differentiated by each patient’s body classification (So-yang [SY], So-eum [SE], Tae-yang [TY], and Tae-eum [TE]), in contrary to western medicine’s theory that medication should be applied equally by disease indication without such classification. However, the pharmacotherapeutic outcomes of these theories have not been compared to date. In this study, we aimed to compare the two theories by evaluating blood pressure (BP), which is lowered as a therapeutic outcome, among hypertensive patients taking angiotensin II receptor blockers (ARBs) or calcium channel blockers (CCBs), two most com-monly used antihypertensive classes in Korea. Methods: From April 2006 to June 2012, we retrospectively collected data on hypertensive patients with Sasang Constitution classification at Kyunghee University Hospital at Gangdong, one of the East-West collaborative medical centers in Korea. We collected information on age, gender, underlying diseases, anti-hypertensive drugs (ARB, CCB, ARB+CCB), and BP by reviewing the electronic medical records. We excluded patients with missing blood pressure at baseline or follow-up, or those who had a change in their antihypertensive drug class during follow-up. Results: We selected a total of 573 patients (SY: 165, SE: 158, TY: 0, TE: 250). Baseline BPs were on average 139.0/82.0 mmHg for SY, 137.8/78.5 mmHg for SE, and 138.7/79.2 mmHg for TE. In all three groups, CCBs were the most prescribed, followed by combination therapy with ARB+CCB, then ARBs. BP reduction after 1 month of initial medication was significantly different among the drug classes, but not in Sasang constitutional classification (ARB [SY: -12.4/-4.7, SE:-12.3/-2.5, TE: -8.6/-1.8], CCB [SY: -12.3/-5.4, SE: -13.0/-2.3, TE: -10.8/-6.0], ARB+CCB [SY: -15.6/-6.7, SE: -18.4/-8.1, TE:-20.2/-6.7], drug [P≤0.05/P>0.05], constitutional type [P>0.05/P>0.05]). Conclusion: We observed significant differences in reduction of blood pressure by classes of drugs (ARB+CCB>CCB>ARB) but not by Sasang constitutional classification. Therefore, current approach of antihypertensive pharmacotherapy assisted by Western medicine is appropriate for treat-ment of hypertension. However, further larger scale or prospective studies are required in order to confirm these results.

Comparison of calcium-channel blockers for long-term clinical outcomes in patients with vasospastic angina

( Sung Eun Kim ),( Sang-ho Jo ),( Seung Hwan Han ),( Kwan Yong Lee ),( Sung Ho Her ),( Min-ho Lee ),( Won-woo Seo ),( Seong-sik Cho ),( Sang Hong Baek ) 대한내과학회 2021 The Korean Journal of Internal Medicine Vol.36 No.1

Background/Aims: Calcium channel blockers (CCBs) are the most widely prescribed medication for patients with vasospastic angina (VA). However, few studies have compared the prognosis of VA patients who are prescribed different CCBs. Methods: We enrolled 2,960 patients who received provocation test prospectively in 11 university hospitals in Korea. We divided 1,586 patients received four major CCBs into two groups: a first generation CCB (diltiazem and nifedipine) group and a second generation CCB (amlodipine and benidipine) group. Primary outcome was time to events of composite of death from any cause, acute coronary syndrome (ACS) and symptomatic arrhythmia during 3-year follow-up. We also compared the effect of each CCB on the control of angina symptoms. Results: There was no difference of the primary outcome among the two groups with a cumulative incidence rate of 5.4%, 2.9%, and a person-month incidence rate of 2.33 and 1.26, respectively (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.25 to 1.17; p = 0.120, as reference with the 1st generation CCBs). The incidence of ACS was significantly lower in 2nd generation CCBs group with a person-month incidence rate of 1.66 vs. 0.35 (HR, 0.22; 95% CI, 0.05 to 0.89; p = 0.034). Use of benidipine showed a significant better control of angina symptom compared with diltiazem for 3 years (odds ratio, 0.17; 95% CI, 0.09 to 0.32; p < 0.0001 at 3rd year). Conclusions: The first and second generation CCB groups did not differ in terms of composite outcome occurrence. However, the ACS incidence rate was significantly lower in the users of the 2nd generation CCBs.

Pharmacophore Modelling, Quantitative Structure Activity Relationship (QSAR) and Docking Studies of Pyrimidine Analogs as Potential Calcium Channel Blockers

Choudhari, Prafulla B.,Bhatia, Manish S.,Jadhav, Swapnil D. Korean Chemical Society 2013 대한화학회지 Vol.57 No.1

The present communication deals with the Pharmacophore modeling, 3D QSAR and docking analysis on series of Pyrimidine derivatives as potential calcium channel blockers. The computational studies showed hydrogen bond donor, hydrogen bond acceptor, and hydrophobic group are important features for calcium channel blocking activity. These studies showed that Pyrimidine scaffold can be utilized for designing of novel calcium channels blockers for CVS disorders.

Cyclosporine A 신독성에 미치는 칼슘길항제(Verapamil)의 효과에 대한 형태학적 연구

장희경,김혜숙,허만하 고신대학교 의학부 1993 高神大學校 醫學部 論文集 Vol.9 No.1

Effect of calcium channel blocker(CB) on cyclosporin A(C) nephrotoxicity was investigated in the Male Wister rat in a 4-week experiment at the light and electron microscopic level. To accomplish the aim of this study, 25 week old male Wister rats were divided into following 3 experimental groups ; 1CsA(50mg/kg/day) alone daily per os ; 2. CsA(5mg/kg/day) concomitant administration of CB verapamil(20mg/kg/day) daily per os; 3. CsA(50mg/kg/day) concomitant administration of verapamil(10mg/kg/day) daily per os. Morphologically, CsA nephrotoxicity was characterized by the following features ; (1) tubular inclusion bodies corresponding to predominate polymerphous autolysosomes and a small number of markedly enlarged mitochondria ; (2) tubular vacuolization due to dilation of the rough and smooth endoplasmic reticulum ; (3) tubular microcalcification. These morphologic features were limited to the proximal tubules. Simultaneous administration of CB verapamil with CsA reduced CsA induced morphologic damage of the proximal tubules of the kidney ; especially tubular inclusion bodies were significantly reduced, independent of the dosage of the verapamil. These histopathological findings are interpreted as morphological manifestations of the effect of calcium channel blocker, verapamil ameliorating CsA nephrotoxicity

Association Between The Use of Angiotensin Receptor Blockers/ Calcium Channel Blockers and Risk of Interstitial Lung Disease/ Idiopathic Pulmonary Fibrosis: A Nationwide Cohort Study

( Hye Jin Jang ),( Dong Yoon Lee ),( Jin-ho Kim ),( Jihyeon Jeong ),( Won-il Choi ) 대한결핵 및 호흡기학회 2023 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.136 No.0