• The Korean Journal of Physiology and Pharmacology
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• v.18 no.5
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• pp.425-430
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• 2014

This study was designed to examine the effects of histamine on gastric motility and its specific receptor in the circular smooth muscle of the human gastric corpus. Histamine mainly produced tonic relaxation in a concentration-dependent and reversible manner, although histamine enhanced contractility in a minor portion of tissues tested. Histamine-induced tonic relaxation was nerve-insensitive because pretreatment with nerve blockers cocktail (NBC) did not inhibit relaxation. Additionally, $K^+$ channel blockers, such as tetraethylammonium (TEA), apamin (APA), and glibenclamide (Glib), had no effect. However, $N^G$-nitro-L-arginine methyl ester (L-NAME) and 1H-(1,2,4)oxadiazolo (4,3-A) quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase (sGC), did inhibit histamine-induced tonic relaxation. In particular, histamine-induced tonic relaxation was converted to tonic contraction by pretreatment with L-NAME. Ranitidine, the $H_2$ receptor blocker, inhibited histamine-induced tonic relaxation. These findings suggest that histamine produced relaxation in circular smooth muscle of human gastric smooth muscle through $H_2$ receptor and NO/sGC pathways.

• Journal of Ginseng Research
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• v.39 no.3
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• pp.257-264
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• 2015

Background: Korean Red Ginseng-a steamed root of Panax ginseng Meyer-has long been used as a traditional medicine in Asian countries. Its antipruritic effect was recently found, but no molecular mechanisms were revealed. Thus, the current study focused on determining the underlying molecular mechanism of Korean Red Ginseng extract (RGE) against histamine-induced itch at the peripheral sensory neuronal level. Methods: To examine the antipruritic effect of RGE, we performed in vivo scratching behavior test in mice, as well as in vitro calcium imaging and whole-cell patch clamp experiments to elucidate underlying molecular mechanisms. Results: The results of our in vivo study confirmed that RGE indeed has an antipruritic effect on histamine-induced scratching in mice. In addition, RGE showed a significant inhibitory effect on histamine-induced responses in primary cultures of mouse dorsal root ganglia, suggesting that RGE has a direct inhibitory effect on sensory neuronal level. Results of further experiments showed that RGE inhibits histamine-induced responses on cells expressing both histamine receptor subtype 1 and TRPV1 ion channel, indicating that RGE blocks the histamine receptor type 1/TRPV1 pathway in sensory neurons, which is responsible for histamine-dependent itch sensation. Conclusion: The current study found for the first time that RGE effectively blocks histamine-induced itch in peripheral sensory neurons. We believe that the current results will provide an insight on itch transmission and will be helpful in understanding how RGE exerts its antipruritic effects.

• Tuberculosis and Respiratory Diseases
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• v.54 no.1
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• pp.91-103
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• 2003

Background : Histamine is widely distributed in the lung. It increases capillary permeability and the P-selectin expression on vascular endothelial cell surfaces. We studied the role of endogenous histamine on the pathogenesis of endotoxin-induced acute lung injury (ALI) in rats. Methods: We instilled either normal saline (control group) or lipopolysaccharide (3 mg/Kg, LPS group) to tracheas of Sprague-Dawley rats. H1-receptor blocker (mepyramine, 10 mg/Kg, H1RB group), H2-receptor blocker (ranitidine, 10 mg/Kg, H2RB group), and H3-receptor blocker (thioperamide, 2 mg/Kg, H3RB group) were administered through vein or peritoneum along with intratracheal LPS administration. Statistical significance was accepted at p<0.05. Results : LPS increases the histamine level in BAL fluid significantly at 2 h after the treatment compared with control group. LPS significantly increases protein concentration, PMN cell count in bronchoalveolar lavage (BAL) fluid, and myeloperoxidase (MPO) activity in the lung tissue at 6 h compared to control group. PMN cell count in BAL fluid and MPO activity in lung tissue were significantly lower in H2RB-group compared to LPS-group. However, protein concentration in BAL fluid showed no significant differences between the LPS alone and LPS with histamine receptor blockade. Conclusions : Endogenous histamine might be involved in the recruitment of PMNs in LPS-induced ALI via H2 receptor. However, its role in ALI would not be significant in this model.

• YAKHAK HOEJI
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• v.37 no.4
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• pp.397-407
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• 1993

The muscarinic antagonist l-[benzilic-4,4'-$^3H$]quinuclidinyl benzilate([$^3H$]QNB) bound to a single class of muscarinic receptor with high affinity in guinea pig ileal membranes. The $K_{D}$ and B$_{max}$ values for [$^3H$]QNB calculated from analysis of saturation isotherms were 54 pM and 156fmol/mg, respectively. H$_{1}$-blockers inhibited [$^3H$]QNB binding to ileal membranes with $K_{i}$ values ranged from 0.008 $\mu{M}$ to 1.6 $\mu{M}$. The pseudo-Hill coefficients of H$_{1}$-blockers for inhibition of [$^3H$]QNB binding to the ileal membranes were close to unit. The $K_{i}$ values for H$_{1}$-blockers were similar to the $K_{M}$ values calculated by Schild plot of functional data obtained from inhibition of the carbachol-induced contraction in guinea-pig ileum, suggesting that binding of H$_{1}$-blockers vs [$^3H$]QNB in ileal membranes represents an interaction with a receptor of physiological relevance. The $K_{H}$ values of H$_{1}$-blockers for H$_{1}$-receptor estimated from inhibition of the histamine-induced contraction were the range of 0.15 nM to 56.5 nM. The $K_{M}$/K$_{H}$ ratio of H$_{1}$-blockers varied over a wide range of 3 to 2300. Thus, the antihistaminic potencies of H$_{1}$-blockers do not correlate with their antimuscarinic potencies, which suggest that antihistamines have different antimuscarinic potencies in therapeutic blood levels causing similar antiallergic effect. Among 13 traditional antihistaminics examined in this study, drug having the highest and the lowest $K_{M}$/K$_{H}$ ratio is triprolidine and diphenidol, respectively. The present results demonstrate that the antimuscarinic property of antihistamines is not necessary for their antiallergic effect, and data on the affinity of antihistamines for muscarinic and H$_{1}$-receptors can be an important parameter in the selection and evaluation of these drugs.

• YAKHAK HOEJI
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• v.34 no.4
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• pp.224-237
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• 1990

A single uniform population of specific, saturable, high affinity binding site of $[^3H]QNB$ guinuclidinyl benzilate(QNB) was identified in the rat cerebral microsomes. The Kd value(37.2 pM) for $[^3H]QNB$ calculated from the kinetically derived rate constants was in agreement with the Kd value(48.9 pM) determined by analysis of saturation isotherms at various receptor concentrations. Dimenhydrinate(DMH), histamine $H_1-blocker$, increased Kd value for $[^3H]QNB$ QNB without affecting the binding site concentrations and this effect resulted from the ability of DMH to slow $[^3H]QNB-receptor$ association. Pirenzepine inhibition curve of $[^3H]QNB$ binding was shallow(nH = 0.52) indicating the presence of two receptor subtypes with high ($M_1-site$) and low($M_2-site$) affinity for pirenzepine. Analysis of these inhibition curves yielded that 68% of the total receptor populations were of the $M_1-subtype$ and the remaining 32% of the $M_2-subtype$. Ki values for the $M_1-$ and $M_2-subtypes$ were 2.42 nM and 629.3 nM, respectively. Ki values for $H_1-blockers$ that inhibited $[^3H]QNB$ binding varied with a wide range ($0.02-2.5\;{\mu}M$). The Pseudo-Hill coefficients for inhibition of $[^3H]QNB$ binding by most of $H_1-blockers$ examined except for oxomemazine inhibition of $[^3H]QNB$ binding were close to one. The inhibition curve for oxomemazine in competition with $[^3H]QNB$ was shallow(nH = 0.74) indicating the presence of two receptor populations with different affinities for this drug. The proportion of high and low affinity was 33:67. The Ki values for oxomemazine were $0.045{\pm}0.016\;{\mu}M$ for high affinity and $1.145{\pm}0.232\;{\mu}M$ for low affinity sites. These data indicate that muscarinic receptor blocking potency of $H_1-blockers$ varies widely between different drugs and that most of $H_1-blockers$ examined are nonselective antagonist for the muscarinic receptor subtypes, whereas oxomemazine might be capable of distinguishing between subclasses of muscarinic receptor.

• Korean Journal of Veterinary Research
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• v.27 no.1
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• pp.19-25
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• 1987

To validate the comparision of proximal and distal large intestinal motility, the amplitude and frequency of spontaneous motility, the effect of acetylcholine, the effect of atropine on the response of acetylcholine, the effect of histamine and the effect of pyrilamine and cimetidine on the response of histamine were investigated in rabbit. The results were summarized as follows: 1. The amplitude of spontaneous motility was more powerful on the proximal large intestine than that of the distal large intestine, but the frequency of spontaneous motility was similar on the both proximal and distal large intestine in rabbit. 2. Acetylcholine caused the contraction of proximal and distal large intestine, and the contractile response were increased between the concentration of acetylcholne $10^{-9}$ and $5{\times}10^{-6}M$ and $10^{-7}$ and $10^{-4}M$ on the proximal and distal large intestine, respectively, with dose-dependent manner in rabbit. 3. The contractile response induced by acetylcholine was completely blocked by the post-treatment with cholinergic receptor blocker, atropine $10^{-6}M$. 4. Histamine caused the contraction of proximal and distal large intestine and the contractile response were increased between the concentration of histamine $10^{-9}$ and $5{\times}10^{-5}M$ and $10^{-5}$ and $10^{-3}M$ on the proximal and distal large intestine, respectively, with dose-depend ent manner in rabbit. 5. The contractile response induced by histamine was completely blocked by the pretreatment with $H_1$-receptor blocker, pyrilamine $10^{-6}M$, but not blocked by the pretreatment with $H_2$-receptor blocker, cimetidine $10^{-6}M$.

• Korean Journal of Veterinary Research
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• v.34 no.3
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• pp.493-500
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• 1994

The purpose of this study was to investigate the effects of neurotransmitters and the source of $Ca^{2+}$ in the effects of neurotransmitters on the motility of pig oviductal isthmic smooth muscle. The motility of the isolated smooth muscle was recorded by using physiological recording system. The results were summarized as follows; Acetylcholine, norepinephrine, histamine and prostaglandin $F_{2{\alpha}}(PGF_{2{\alpha}})$ caused the contraction and the contractile responses were increased in a dose-dependent manner from the concentration of $10^{-7}$ to $10^{-4}M$. The maximum contractility of acetylcholine, norepinephrine, histamine and $PGF_{2{\alpha}}$ was 65.99, 28.66, 83.99 and 47.33% of 100 mM K contraction, respectively. The contractile response induced by acetylcholine$(10^{-6}M)$ was completely blocked by the pretreatment with cholinergic receptor blocker, atropine$(10^{-6}M)$, the contractile response induced by norepinephrine$(10^{-5}M)$ was blocked by the pretreatment with ${\alpha}$-adrenergic receptor blocker, phentolamine$(10^{-6}M)$ but was not blocked and rather increased by the pretreatment with ${\beta}$-adrenergic receptor blocker. propranolol$(10^{-6}M)$, the contractile response induced by histamine$(10^{-6}M)$ was completely blocked by the pretreatment with $H_1$-histaminergic receptor blocker, pyrilamine$(10^{-6}M)$ but was increased by the pretreatment with $H_2$-histaminergic receptor blocker, cimetidine$(10^{-6}M)$. The contractile response induced by acetylcholine$(10^{-6}M)$, norepinephrine$(10^{-5}M)$ and histamine$(10^{-6}M)$ was weakly contracted response in $Ca^{2+}$-free medium, but the contractile response induced by $PGF_{2{\alpha}}(10^{-6}M)$ was disappeared. The contractile response induced by acetylcholine$(10^{-6}M)$, norepinephrine$(10^{-5}M)$ and histamine$(10^{-6}M)$ was powerfully depressed by the pretreatment with $Ca^{2+}$-channel blocker, verapamil$(10^{-5}M)$ but the contractile response induced by $PGF_{2{\alpha}}(10^{-6}M)$ was completely inhibited.

• Korean Journal of Clinical Pharmacy
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• v.26 no.1
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• pp.46-52
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• 2016

Background: The use of acid suppressive agents became a standard therapy in an intensive care unit (ICU) to prevent stress related gastrointestinal mucosal damage. However, the risk of infectious diseases has been concerned. Objective: The study was to determine the differences between histamine 2 receptor antagonists (H2RA) and proton pump inhibitors (PPI) in incidence of nosocomial pneumonia and pseudomembranous colitis (PMC) by Clostridium difficile with patients in ICU. Methods: This is a retrospective comparative study including patients admitted to the ICU who were at least 18 years of age and stayed for more than 48hrs from August 1, 2014 to January 31, 2015. The propensity score analysis and propensity matched multivariable logistic regression were used in analyzing data to control for confounders. Results: A total of 155 patients were assessed. H2RA were prescribed in 110 (53.9%) and PPI were in 45 (22.1%). Nosocomial pneumonia developed in 37 (23.9%); 25 (22.7%) were on H2RA and 12 (26.7%) were on PPI. The unadjusted incidence of nosocomial pneumonia was slightly higher in the patients with PPI (odds ratio (OR) 1.24; 95% confidence interval (CI): 0.54-2.71) compared to them with H2A. After adjusting with propensity score, the adjusted OR with PPI was 1.35 (95% CI: 0.44-4.11). The propensity score matched analyses showed similar results. Conclusion: The uses of PPI and H2RA as a stress ulcer prophylaxis agent showed similarity in the incidence of nosocomial pneumonia and PMC.

• Bulletin of the Korean Chemical Society
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• v.34 no.2
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• pp.549-552
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• 2013

An efficient and alternative synthesis of enantiomerically pure (+)-(S)-4-(4-((4-chlorophenyl)(pyrid-2-yl)methoxy]piperidin-1-yl)butanoic acid, bepotastine (1) is described. The key resolution of (R/S)-bepotastine l-menthyl ester (3) is achived via diastereomeric salt crystallization using N-benzyloxycarbonyl-L-aspartic acid (NCbzLAA) as the resolving agent to provide (S)-bepotastine l-menthyl ester (S)-3. Hydrolysis of (S)-bepotastine l-menthyl ester (S)-3 afforded the desired bepotastine (1) with good yields and enantiopurity (> 99%). Finally, bepotastine besilate (4) and bepotastine calcium (5) are achived by salt formation of bepotastine (1) with benzene sulfonic acid and calcium salt respectively. The reaction conditions were optimized to make suitable for commercial scale production.

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.3
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• pp.215-220
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• 2009

Chlorpheniramine is a potent first-generation histamine $H_1$ receptor antagonist that can increase action potential duration and induce QT prolongation in several animal models. Since block of cardiac human ether-a-go-go-related gene (hERG) channels is one of leading causes of acquired long QT syndrome, we investigated the acute effects of chlorpheniramine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. We examined the effects of chlorpheniramine on the hERG channels expressed in Xenopus oocytes using two-microelectrode voltage-clamp techniques. Chlorpheniramine induced a concentration-dependent decrease of the current amplitude at the end of the voltage steps and hERG tail currents. The $IC_{50}$ of chlorpheniramine-dependent hERG block in Xenopus oocytes decreased progressively relative to the degree of depolarization. Chlorpheniramine affected the channels in the activated and inactivated states but not in the closed states. The S6 domain mutations Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG current block. These results suggest that the $H_1$ antihistamine, chlorpheniramine is a blocker of the hERG channels, providing a molecular mechanism for the drug-induced arrhythmogenic side effects.