• Journal of Pharmaceutical Investigation
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• v.31 no.4
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• pp.289-295
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• 2001

Carvedilol is an antihypertensive and antianginal compound that combines nonselective beta-adrenoceptor blocking and vasodilation properties and is devoid of intrinsic sympathomimetic activity. The purpose of the present study was to evaluate the bioequivalence of two carvedilol tablets, $Dilatrend^{TM}$ (Chong Kun Dang Pharmaceutical Co., Ltd.) and $Carvelol^{TM}$ (Dae Won Pharmaceutical Co., Ltd.), according to the prior and revised guidelines of Korea Food and Drug Administration (KFDA). The carvedilol release from the two carvedilol tablets in vitro was tested using KP VII Apparatus II method with various different kinds of dissolution media (pH 1.2, 4.0, 6.8 buffer solution, water and blend of PSB80 into water). Eighteen normal male volunteers, $24.22{\pm}1.86$ years in age and $64.81{\pm}4.56\;kg$ in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After one tablet containing 25 mg of carvedilol was orally administered, blood was taken at predetermined time intervals and the concentrations of carvedilol in serum were determined using HPLC method with fluorescence detector. The dissolution profiles of two carvedilol tablets were very similar at all dissolution media. Besides, the pharmacokinetic parameters such as $AUC_t$, $C_{max}$ and $T_{max}$ were calculated and ANOVA test was utilized for the statistical analysis of the parameters using non-transformed and logarithmically transformed $AUC_t$ and $C_{max}$. The results showed that the differences in $AUC_t$, $C_{max}$ and $T_{max}$ between two tablets based on the $Dilatrend^{TM}$ were 2.23%, -2.00% and 0.00%, respectively. Minimum detectable differences $({\Delta})$ at ${\alpha}=0.05$ and $1-{\beta}=0.8$ were less than 20% (e.g., 13.55% and 17.61% for $AUC_t$ and $C_{max}$, respectively). The powers $(l-{\beta})$ at ${\alpha}=0.05$, ${\Delta}=0.2$ for $AUC_t$ and $C_{max}$ were 98.08% and 88.81%, respectively. The 90% confidence intervals were within ${\pm}20%$ (e.g., $-5.69{\sim}10.16$ and $-12.30{\sim}8.30$ for $AUC_t$ and $C_{max}$, respectively). There were no sequence effect between two tablets in logarithmically transformed $AUC_t$ and $C_{max}$. The 90% confidence intervals using logarithmically transformed were within the acceptance range of log(0.8) to log(1.25) (e.g., $0.95{\sim}1.11$ and $0.89{\sim}1.09$ for $AUC_t$ and $C_{max}$, respectively). Two parameters met the criteria of prior and revised KFDA guideline for bioequivalence, indicating that $Carvelol^{TM}$ tablet is bioequivalent to $Dilatrend^{TM}$ tablet.

• The Korean Journal of Pharmacology
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• v.11 no.1 s.17
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• pp.33-38
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• 1975

The clinical efficacy of Ethaverine, a peripheral vasodilator, was studied according to a double-blind, non-cross over method in 29 diabetic patients with peripheral arterial diseases. The clinical improvement was assessed from the history of patients including the incidence and frequency of intermitten claudication. Ethaverine, after 4 weeks of therapy, was not effective in improving clinical symptoms compared to placebo. Ethaverine, however, was an efective vasodilator than placebo. The quality of vasodilation induced by Ethaverine, was similar to that of alcohol. A new clinical method of studying peripheral vasodilator was presented. The clinical symptoms of peripheral vascular arterial disease in the lower extrimities include reduced intensity of palpable pulses, coldness, and discoloration of the skin. Intermittent claudication may be present. Pathologic changes in vessel architecture precede the symptoms, and recognition of impending vascular insufficiency is a determining factor in selecting vasodilating therapy or surgical management. Also, post-operative patients who have chronic peripheral vascular arterial disease may be candidates for subsequent vasodilating therapy. Peripheral vasodilators, according to the series of reports, may be indicated in vasospastic peripheral vascular condition rather than an occlusive vascular disease and the vessel responds best when a relatively large vascular beds are involved rather than a small, capillary beds. Recently, the clinical efficacy of peripheral vasodilators have been challanged by many clinical investigators and clinicians. In this study, we have re-evaluated the efficacy of Ethaverine HCl as peripheral vasodilator in patients with vasospastic peripheral arterial disease. Ethaverine is claimed to be two to four times as potent a spasmolytic agent as papaverine in a variety of laboratory and clinical work.

• The korean journal of orthodontics
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• v.27 no.4 s.63
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• pp.607-621
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• 1997

GRP was known as the modulator of Pain transmission in central nervous system and local effector to peripheral tissue causing vasodilation, increased blood flow, modulation of immune sysem, stimulation of endothelial cell proliferation, and stimulation of bone formation. Numerous study, therefore, were done to elucidate involvement of CGRP to tooth movement. To investgate the response of CGRP immunoreactive nerve cells according to cell size in trigeminal ganglion during tooth movement, immunohistochemical study was performed using rat. Experimental rats(9 weeks old, 210 gm) were divided as six groups(normal(n=6), 3 hour group(n=5), 12 hour group(n=4), 1 day group(n=5), 3 day group(n=5), 7 day group(n=5)), and were applied orthodontic force (approximately 30 gm) to upper right maxillary molar. After frozen sections of trigeminal ganglions were immunostained using rabbit antisera, the changes of CGRP immunoreactive cells in regard to cell size distribution(small cell(upto $20{\mu}m$), medium cell($20-35{\mu}m$), large cell(above $35{\mu}m$)) were observed. The results were as follows 1. The percentage of CGRP immunoreactive cells to all nerve cells in trigeminal ganglion was 33.0% in normal control group, was decreased to 24.5% in 1 day group, and was increased to 41.8% in 7 day group. 2. The percentage of small, medium, and large cells expressing CGRP immunoreactivity in normal trigeminal ganglion to all CGRP immunoreactive cells were 51.3%, 44.0%, 4.7%, respectively. 3. The percentage of small cells with CGRP immunoreactivity to all CGRP immunopositive cells was increased in 3 hour and 12 hour groups. 4. The percentage of medium cells with CGRP immunoreactivity was increaed in 3 day and 7 day groups. 5. The percentage of large cells with CGRP immunoreactivity was increaed in 7 day group. Conclusively, the small cells with CGRP immunoreactivity in trigeminal ganglion respond to orthodontic force during initial phase of tooth movement, and later the medium and large cells with CGRP immunoreactivity respond

• Journal of Life Science
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• v.28 no.11
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• pp.1361-1368
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• 2018

Inflammation is the most common condition in the human body. Tissue damage triggers inflammation, together with vasodilation and increased blood flow at the inflamed site, resulting in edema. Inflammatory responses are also triggered by lipopolysaccharide (LPS), a Toll-like receptor Enterococcus faecalis, a gram-positive organism, has been reported to possess immunomodulatory and preventive activities; however, its use may present risks of sepsis and other systemic infections. Heat-killed Enterococcus faecalis (EF-2001) has been reported to induce antitumor activity, but its effects on inflammation are not known. In the present study, we investigated the effect of EF-2001 on LPS-induced macrophage inflammatory responses. EF-2001 treatment reduced nitric oxide (NO) production, indicating suppression of inflammatory reactions. EF-2001 showed no cytotoxicity in macrophages. Further investigation of the anti-inflammatory mechanism of EF-2001 indicated that EF-2001 reduced the LPS-induced expression of inducible nitric oxide synthase and cyclooxygenase-2. EF-2001 also reduced f the LPS induction of several inflammatory molecules involved in the nuclear factor-${\kappa}B$ ($NF-{\kappa}B$) and mitogen-activated protein kinase pathways, including ERK, JNK, and p38 phosphorylation, in a concentration-dependent manner. Additionally, EF-2001 inhibited Akt phosphorylation and increased the expression of the inhibitory ${\kappa}B$ ($I{\kappa}B$) protein, an inhibitor of $NF-{\kappa}B$. EF-2001 also inhibited the nuclear translocation of p65. These results suggest that EF-2001 has anti-inflammatory properties and may be useful for treating inflammatory diseases.

• Journal of Chest Surgery
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• v.37 no.3
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• pp.210-219
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• 2004

Extracellular $K^{+}$ concentration ([ $K^{+}$]$_{0}$ ) can be increased within several mM by the efflux of intracellular $K^{+}$. To investigate the effect of an increase in [ $K^{+}$]$_{0}$ on vascular contractility, we attempted to examine whether extracellular $K^{+}$ might modulate vascular contractility, endothelium-dependent relaxation (EDR) and intracellular $Ca^2$$^{+}$ concentration ([C $a^2$$^{+}$]$_{i}$ ) in endothelial cells (EC). We observed isometric contractions in rabbit carotid, superior mesenteric, basilar arteries and movse aorta. [C $a^2$$^{+}$]$_{i}$ was recorded by microfluorimeter using Fura-2/AM in EC. No change in contractility was recorded by the increase in [ $K^{+}$]$_{0}$ from 6 to 12 mM in conduit artery such as rabbit carotid artery. whereas resistant vessels, such as basilar and branches of superior mesenteric arteries (SMA), were relaxed by the increase. In basilar artery, the relaxation by the increase in [ $K^{+}$]$_{0}$ to from 1 to 3 mM was bigger than that by the increase from 6 to 12 mM. In contrast, in branches of SMA, the relaxation by the increase in [ $K^{+}$]$_{0}$ to from 6 to 12 mM is bigger than that by the increase from 1 to 3 mM. $Ba^2$$^{+}$ (30 $\mu$M) did not inhibit the relaxation by the increase in [ $K^{+}$]$_{0}$ from 1 to 3 mM but did inhibit the relaxation by the increase from 6 to 12 mM. In the mouse aorta without the endothelium or treated with $N^{G}$_nitro-L-arginine (30 $\mu$M), nitric oxide synthesis blocker, the increase in [ $K^{+}$]$_{0}$ from 6 to 12 mM did not change the magnitude of contraction induced either norepinephrine or prostaglandin $F_2$$_{\alpha}$. The increase in [ $K^{+}$]$_{0}$ up to 12 mM did not induce contraction of mouse aorta but the increase more than 12 mM induced contraction. In the mouse aorta, EDR was completely inhibited on increasing [ $K^{+}$]$_{0}$ from 6 to 12 mM. In cultured mouse aorta EC, [C $a^2$$^{+}$]$_{i}$ , was increased by acetylcholine or ATP application and the increased [C $a^2$$^{+}$]$_{i}$ , was reduced by the increase in [ $K^{+}$]$_{0}$ reversibly and concentration-dependently. In human umbilical vein EC, similar effect of extracellular $K^{+}$ was observed. Ouabain, a N $a^{+}$ - $K^{+}$ pump blocker, and N $i^2$$^{+}$, a N $a^{+}$ - $Ca^2$$^{+}$ exchanger blocker, reversed the inhibitory effect of extracellular $K^{+}$. In resistant arteries, the increase in [ $K^{+}$]$_{0}$ relaxes vascular smooth muscle and the underlying mechanisms differ according to the kinds of the arteries; $Ba^2$$^{+}$-insensitive mechanism in basilar artery and $Ba^2$$^{+}$ -sensitive one in branches of SMA. It also inhibits [C $a^2$$^{+}$]$_{i}$ , increase in EC and thereby EDR. The initial mechanism of the inhibition may be due to the activation of N $a^{+}$ - $K^{+}$pump. activation of N $a^{+}$ - $K^{+}$pump.p.p.p.

• Tuberculosis and Respiratory Diseases
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• v.41 no.3
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• pp.231-238
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• 1994

Backgroud: Since the demonstration of the fact that vascular relaxation by acetylcholine(Ach) results from the release of relaxing factor from the endothelium, the identity and physiology of this endothelium-derived relaxing factor(EDRF) has been the target for many researches. EDRF has been identified as nitric oxide(NO). With the recent evidences that EDRF is an important mediator of vascular tone, there have been increasing interests in defining the role of the EDRF as a potential mediator of hypoxic pulmonary vasoconstriction. But the role of EDRF in modulating the pulmonary circulation is not compeletely clarified. To investigate the endothelium-dependent pulmonary vasodilation and the role of EDRF during hypoxic pulmonary vasoconstriction, we studied the effects of $N^G$-monomethyl-L-arginine(L-NMMA) and L-arginine on the precontracted pulmonary arterial rings of the rat in normoxia and hypoxia. Mothods: The pulmonary arteries of male Sprague Dawley(300~350g) were dissected free of surrounding tissue, and cut into rings. Rings were mounted over fine rigid wires, in organ chambers filled with 20ml of Krebs solution bubbled with 95 percent oxygen and 5 percent carbon dioxide and maintained at $37^{\circ}C$. Changes in isometric tension were recorded with a force transducer(FT.03 Grass, Quincy, USA) Results: 1) Precontraction of rat pulmonry artery with intact endothelium by phenylephrine(PE, $10^{-6}M$) was relaxed completely by acetylcholine(Ach, $10^{-9}-10^{-5}M$) and sodium nitroprusside(SN, $10^{-9}-10^{-5}M$), but relaxing response by Ach in rat pulmonary artery with denuded endothelium was significantly decreased. 2) L-NMMA($10^{-4}M$) pretreatment inhibited Ach($10^{-9}-10^{-5}M$)-induced relaxation, but L-NMMA ($10^{-4}M$) had no effect on relaxation induced by SN($10^{-9}-10^{-5}M$). 3) Pretreatment of the L-arginine($10^{-4}M$) significantly reversed the inhibition of the Ach ($10^{-9}-10^{-5}M$)-induced relaxation caused by L-NMMA($10^{-4}M$) 4) Pulmonary arterial contraction by PE($10^{-6}M$) was stronger in hypoxia than normoxia but relaxing response by Ach($10^{-9}-10^{-5}M$) was decreased, 5) With pretreatment of L-arginine($10^{-4}M$), pulmonary arterial relaxation by Ach($10^{-9}-10^{-5}M$) in hypoxia was reversed to the level of relaxation in normoxia. Conclusion: It is concluded that rat pulmonary arterial relaxation by Ach is dependent on the intact endothelium and is largely mediated by NO. Acute hypoxic pulmonary vasoconstriction is related to the suppression on NO formation in the vascular endothelium.

• Tuberculosis and Respiratory Diseases
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• v.42 no.5
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• pp.744-751
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• 1995

Background: Asthma is an inflammatory disease because there are many inflammatory changes in the asthmatic airways. Axon reflex mechanisms may be involved in the pathogenesis of asthma. Sensory neuropeptides are involved in this inflammation, which is defined as neurogenic inflammation. Substance p, neurokinin A, and neurokinin B may be main neuropeptides of neurogenic inflammation in airways. These tachykinins act on neurokinin receptors. Three types of neurokinin receptors, such as $NK_1$, $NK_2$, and $NK_3$, are currently recognized, at which substance p, neurokinin A, and neurokinin B may be the most relevant natural agonist of neurogenic inflammation in airways. The receptor subtypes present in several tissues have been characterized on the basis of differential sensitivity to substance p, neurokinin A, and neurokinin B. Plasma extravasation and vasodilation are induced by substance p more potently than by neurokinin A, indicating NK1 receptors on endothelial cells mediate the response. But airway contraction is induced by neurokinin A more potently than by substance P, indicating the $NK_2$ receptors in airway smooth muscles. These receptors are used to evaluate the pathogenesis of brochial asthma. FK224 was identified from the fermentation products of Streptomyces violaceoniger. FK224 is a dual antagonist of both $NK_1$ and $NK_2$ receptors. Purpose: For a study of pathogenesis of bronchial asthma, the effect of FK224 on plasma extravasation induced by vagal NANC electrical stimulation was evaluated in rat airway. Method: Male Sprague-Dawley rats weighing 180~450gm were anesthetized by i.p. injection of urethane. Plasma extravasation was induced by electrical stimulation of cervical vagus NANC nerves with 5Hz, 1mA, and 5V for 2 minutes(NANC2 group) and for sham operation without nerve stimulation(control group). To evaluate the effect of FK224 on plasma extravasation in neurogenic inflammation, FK224(1mg/kg, Fujisawa Pharmaceutical Co., dissolved in dimethylsulphoxide; DMSO, Sigma Co.) was injected 1 min before nerve stimulation(FK224 group). To assess plasma exudation, Evans blue dye(20mg/kg, dissolved in saline) was used as a plasma marker and was injected before nerve stimulation. After removal of intravascular dye, the evans blue dye in the tissue was extracted in formamide($37^{\circ}C$, 24h) and quantified spectrophotometrically by measuring dye absorbance at 629nm wavelength. Tissue dye content was expressed as ng of dye per mg of wet weight tissue. The amount of plasma extravasation was measured on the part of airways in each groups. Results: 1) Vagus nerve(NANC) stimulation significantly increased plasma leakage in trachea, main bronchus, and peripheral bronchus compared with control group, $14.1{\pm}1.6$ to $49.7{\pm}2.5$, $17.5{\pm}2.0$ to $38.7{\pm}2.8$, and $12.7{\pm}2.2$ to $19.1{\pm}1.6ng$ of dye per mg of tissue(mean ${\pm}$ SE), respectively(p<0.05). But there was not significantly changed in lung parenchyma(p>0.05) 2) FK224 had significant inhibitory effect upon vagal nerve stimulation-induced airway plasma leakage in any airway tissues of rat,such as trachea, main bronchus, and peripheral bronchus compared with vagus nerve stimulation group, 49%, 58%, and 70%, respectively(p<0.05). Inhibitory effect of FK224 on airway plasma leakage in neurogenic inflammation was revealed the more significant in peripheral bronchus, but no significant in lung parenchyma. Conclusion: These results suggest that FK224 is a selective NK receptor antagonist which effectively inhibits airway plasma leakage induced by the endogenous neurotransmitters relased by neurogenic inflammation in rat airway. Tachykinin receptor antagonists may be useful in the treatment of brochial asthma.