• Title, Summary, Keyword: Calcium channel blockers

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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.
    • Journal of the Korean Chemical Society
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    • v.57 no.1
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    • pp.99-103
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    • 2013
  • 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.

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
    • Biomolecules & Therapeutics
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    • v.15 no.3
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    • pp.156-161
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    • 2007
  • 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.

Effects of ${\alpha}-,\;{\beta}-Adrenergic$, and Calcium Channel Blockers on Renin- Angiotensin System in Perfused Rat Heart

  • Park, Chang-Gyo
    • The Korean Journal of Physiology and Pharmacology
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    • v.2 no.1
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    • pp.55-62
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    • 1998
  • ${\alpha},\;{\beta}-Adrenergics$, and calcium channels were known to be related to inducing cardiac hypertrophy. Recently, it was reported that the cardiac renin-angiotensin system (RAS) was an important factor in ventricular hypertrophy. The present study was aimed to investigate the effects of ${\alpha},\;{\beta}-adrenergic$, and calcium channel blockers that might be involved in the regulation of cardiac RAS. The reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the expression of renin gene in the perfused rat heart. Changes in angiotensin converting enzyme (ACE) activity and cyclic AMP (cAMP) content which were thought to play a role in inducing cardiac hypertrophy were measured in the perfused rat heart. The expression of renin gene was not only increased by isoproterenol with metoprolol-pretreatment but also increased by vasopressin treatment in the presence of calcium channel blocker, nifedipine or verapamil. Either prazosin alone or norepinephrine with prazosin-pretreatment significantly increased the ACE activity. However, isoproterenol with metoprolol-pretreatment significantly decreased the ACE activity. On the other hand, the ACE activity was not changed by vasopressin, nifedipine, or verapamil treatments. The content of cAMP was significantly increased by either isoproterenol or vasopressin treatment. According to these results, renin gene expression was associated with ${\beta}2$ - adrenoceptor and calcium channel. ACE activity was associated with ${\alpha}-\;and{\beta}2$ - adrenoceptor. In conclusion, ${\beta}2$ - adrenoceptor was important in cardiac renin gene expression and ACE activity and ${\alpha},\;{\beta}$ -adrenergic, and calcium channel blockers might be involved in the regulation of cardiac RAS in a complicated way.

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No association Between Calcium Channel Blockers and Survival in Patients with Cancer: A systematic Review and Meta-analysis

  • Sun, Hong;Zhuang, Rong-Yuan;Li, Tao;Zheng, Yuan-Ting;Cai, Wei-Min
    • Asian Pacific Journal of Cancer Prevention
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    • v.17 no.8
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    • pp.3917-3921
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    • 2016
  • Background: The association between calcium channel blockers (CCBs) and survival in cancer patients remains unclear and the results of related studies are conflicting. The objective of the study was to investigate the association between calcium channel blockers (CCBs) use and survival in cancer patients. Materials and Methods: We searched PubMed, EMBASE, Web of Science and Cochrane Library for studies published before January 2016 with the terms related to CCBs and survival in cancer patients. The information was reviewed and extracted by two evaluators independently. Data of publications was extracted and calculated into hazard ratios (HRs) for overall survival (OS). Statistical analysis was performed by using Review Manager 5.3. Results: There were 11 studies included in our meta-analysis. Analysis of all studies showed that CCBs use was not associated with survival in cancer patients (HR=1.07; 95% CI: 0.91-1.25; P=0.42). No association between CCBs use and overall survival in cancer patients was existed whether in Asian (HR=1.18, 95% CI: 0.72-1.93; P=0.52) or Caucasian population (HR=1.03, 95% CI: 0.89-1.20; P=0.66). Conclusions: There is no evidence that CCBs use is associated with a better or worse outcome of survival in cancer patients.

Effects of Calcium Channel Blockers on Human Erythrocyte Ghost Membranes

  • Park, Aeh-Jin;Shin, Young-Hee;Lee, Chi-Ho
    • Archives of Pharmacal Research
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    • v.18 no.6
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    • pp.402-409
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    • 1995
  • The effects of calcium channel blockers (CAB's) verapamil, diltiazem and nicardipine, on erythrocyte ghost membranes have been studied. Using the fluorospectroscopic method, it was observed that the fluidity of the inner layer of ghost membranes was increased with an increase of drug concentrations but did not any changes in the fluidity of the outer layer. These drugs showed protectuve effect against hypotonic hemolysis of erythrocytes. Thus, the expansion of surface area in response to corpuscular volume of erythrocytes in the presence of CAB's is seemed to play an important role in protecting hypotonic hemolysis of erythrocytes.

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Synthesis and Biological Evaluation of 1-Heteroarylmethyl 1,4-Diazepanes Derivatives as Potential T-type Calcium Channel Blockers

  • Ullapu, Punna Reddy;Ku, Su-Jin;Choi, Yeon-Hee;Park, Ji-Yeon;Han, So-Yeop;Baek, Du-Jong;Lee, Jae-Kyun;Pae, Ae-Nim;Min, Sun-Joon;Cho, Yong-Seo
    • Bulletin of the Korean Chemical Society
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    • v.32 no.spc8
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    • pp.3063-3073
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    • 2011
  • The synthesis and biological evaluation of 1-heteroarylmethyl 1,4-diazepane derivatives as potential T-type calcium channel blockers is described. In this study, we have identified the compound 21i exhibiting the most potent T-type calcium channel blocking activity with $IC_{50}$ value of 0.20 ${\mu}M$, which is superior to that of mibefradil.

In silico Analysis on hERG Channel Blocking Effect of a Series of T-type Calcium Channel Blockers

  • Jang, Jae-Wan;Song, Chi-Man;Choi, Kee-Hyun;Cho, Yong-Seo;Baek, Du-Jong;Shin, Kye-Jung;Pae, Ae-Nim
    • Bulletin of the Korean Chemical Society
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    • v.32 no.1
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    • pp.251-262
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    • 2011
  • Human ether-a-go-go related gene (hERG) potassium channel blockade, an undesirable side effect which might cause sudden cardiac death, is one of the major concerns facing the pharmaceutical industry. The purpose of this study is to develop an in silico QSAR model which uncovers the structural parameters of T-type calcium channel blockers to reduce hERG blockade. Comparative molecular similarity indices analysis (CoMSIA) was conducted on a series of piperazine and benzimidazole derivatives bearing methyl 5-(ethyl(methyl)amino)-2-isopropyl-2-phenylpentanoate moieties, which was synthesized by our group. Three different alignment methods were applied to obtain a reliable model: ligand based alignment, pharmacophore based alignment, and receptor guided alignment. The CoMSIA model with receptor guided alignment yielded the best results : $r^2$ = 0.955, $q^2$ = 0.781, $r^2_{pred}$ = 0.758. The generated CoMSIA contour maps using electrostatic, hydrophobic, H-bond donor, and acceptor fields explain well the structural requirements for hERG nonblockers and also correlate with the lipophilic potential map of the hERG channel pore.

Extracorporeal Membrane Oxygenation and Continuous Renal Replacement Therapy for Treatment of Calcium Channel Blockers, Angiotensin II Receptor Blockers, and Metformin Overdose (에크모와 신대체요법을 이용하여 치료한 칼슘채널차단제, 안지오텐신 수용체 차단제, 메트포민 중독 환자 증례)

  • Jeong, Jae Han;Sun, Kyung Hoon;Park, Yong Jin;Kim, Sun Pyo
    • Journal of The Korean Society of Clinical Toxicology
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    • v.16 no.2
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    • pp.165-171
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    • 2018
  • An overdose of antihypertensive agents, such calcium channel blockers (CCBs) and angiotensin II receptor blocker (ARBs), and the antihyperglycemic agent, metformin, leads to hypotension and lactic acidosis, respectively. A 40-year-old hypertensive and diabetic man with hyperlipidemia and a weight of 110 kg presented to the emergency room with vomiting, dizziness, and hypotension following an attempted drug overdose suicide with combined CCBs, ARBs, 3-hydroxy-3-methylglutaryl-coemzyme A reductase inhibitors, and metformins. A conventional medical treatment initially administered proved ineffective. The treatment was then changed to simultaneous extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), which was effective. This shows that simultaneous ECMO and CRRT can be an effective treatment protocol in cases of ineffective conventional medical therapy for hypotension and lactic acidosis due to an overdose of antihypertensive agents and metformin, respectively.

Comparison of electrophysiological effects of calcium channel blockers on cardiac repolarization

  • Lee, Hyang-Ae;Hyun, Sung-Ae;Park, Sung-Gurl;Kim, Ki-Suk;Kim, Sung Joon
    • The Korean Journal of Physiology and Pharmacology
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    • v.20 no.1
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    • pp.119-127
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    • 2016
  • Dihydropyridine (DHP) calcium channel blockers (CCBs) have been widely used to treat of several cardiovascular diseases. An excessive shortening of action potential duration (APD) due to the reduction of $Ca^{2+}$ channel current ($I_{Ca}$) might increase the risk of arrhythmia. In this study we investigated the electrophysiological effects of nicardipine (NIC), isradipine (ISR), and amlodipine (AML) on the cardiac APD in rabbit Purkinje fibers, voltage-gated $K^+$ channel currents ($I_{Kr}$, $I_{Ks}$) and voltage-gated $Na^+$ channel current ($I_{Na}$). The concentration-dependent inhibition of $Ca^{2+}$ channel currents ($I_{Ca}$) was examined in rat cardiomyocytes; these CCBs have similar potency on $I_{Ca}$ channel blocking with $IC_{50}$ (the half-maximum inhibiting concentration) values of 0.142, 0.229, and 0.227 nM on NIC, ISR, and AML, respectively. However, ISR shortened both $APD_{50}$ and $APD_{90}$ already at $1{\mu}M$ whereas NIC and AML shortened $APD_{50}$ but not $APD_{90}$ up to $30{\mu}M$. According to ion channel studies, NIC and AML concentration-dependently inhibited $I_{Kr}$ and $I_{Ks}$ while ISR had only partial inhibitory effects (<50% at $30{\mu}M$). Inhibition of $I_{Na}$ was similarly observed in the three CCBs. Since the $I_{Kr}$ and $I_{Ks}$ mainly contribute to cardiac repolarization, their inhibition by NIC and AML could compensate for the AP shortening effects due to the block of $I_{Ca}$.

The Change of Taurine Transport in Osteocytes by Oxidative Stress, Hypertonicity and Calcium Channel Blockers

  • Kang, Young-Sook;Kim, Soon-Joo
    • Biomolecules & Therapeutics
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    • v.16 no.3
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    • pp.219-225
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    • 2008
  • Taurine is the most abundant amino acid in many tissues and is found to be enhancing the bone tissue formation or inhibits the bone loss. Although it is reported that taurine reduces the alveolar bone loss through inhibiting the bone resorption, its functions of taurine and expression of taurine transporter (TauT) in bone have not been identified yet. The purpose of this study is to clarify the uptake mechanism of taurine in osteoblast using mouse osteoblast cell lines. In this study, mouse stromal ST2 cells and mouse osteoblast-like MC3T3-E1 cells as osteoblast cell lines were used. The activity of taurine uptake was assessed by measuring the uptake of [$^3H$]taurine in the presence or absence of inhibitors. TauT mRNA was detected in ST2 and MC3T3-E1 cells. [$^3H$]Taurine uptake by these cells was dependent on the presence of extracellular calcium ion. The [$^3H$]taurine uptake in ST2 cells treated with 4 mM calcium was increased by 1.7-fold of the control which was a significant change. In contrast, in $Ca^{++}$-free condition and L-type calcium channel blockers (CCBs), taurine transport to osteocyte was significantly inhibited. In oxidative stress conditions, [$^3H$]taurine uptake was decreased by TNF-$\alpha$ and $H_2O_2$. Under the hyperosmotic conditions, taurine uptake was increased, but inhibited by CCBs in hyperosmotic condition. These results suggest that, in mouse osteoblast cell lines, taurine uptake by TauT was increased by the presence of extracellular calcium, whereas decreased by CCBs and oxidative stresses, such as TNF-$\alpha$ and $H_2O_2$.