• Archives of Pharmacal Research
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• v.21 no.4
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• pp.411-417
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• 1998

In order to investigate the effect of the pretreatment with various doses of diltiazem (DTZ) on the pharmacokinetics of indocyanine green (ICG) at steady state, especially the hepatic blood clearance due to the change of hepatic blood flow, the following experiments were carried out with ICG, a hepatic function test marker, not metabolized in liver and only excreted in bile. The intravenous bolus injection ($3,780\mu\textrm{g}$/kg) and the constant-rate infusion ($10,100\mu\textrm{g}$/kg/hr) of ICG into the left femoral vein were made in order to check the steady-state plasma concentration ($C_{ss} of $10\mu\textrm{g}$/ml) of ICG at 20, 25 and 30 min. Following a 90-min washout period, the intravenous bolus injection (108, 430, 860 and $1,720\mu\textrm{g}$/kg) and the constant-rate infusion (108, 433, 866 and $1,730\mu\textrm{g}$/kg/hr) of DTZ into the right femoral vein were made and the achievement of the steady-state plasma levels ($C_{ss} of 50, 200, 400 and 800 ng/ml) of DTZ were conformed at 60, 70 and 80 min. During the steady state of DTZ, the intravenous bolus injection ($3,780\mu\textrm{g}$/kg) and the constant-rate infusion ($10,200\mu\textrm{g}$/kg/hr) of ICG into the left femoral vein were made and also the steady-state plasma concentration of ICG was checked at 20, 25 and 30 min. The plasma concentrations of DTZ and ICG were determined using a high performance liquid chromatographic technique. At the steady state, the hepatic blood clearance of ICG was obtained from the plasma concentration and blood-to-plasma concentration ratio ($R_B$) of ICG. The pretreatment with various doses of DTZ did not influence the plasma concentrations, $R_B$ and plasma free fraction ($f_p$) of ICG. So the hepatic blood clearance of ICG was independent of concentration of DTZ. The hepatic blood clearance of ICG could be affected by both hepatic bood flow and hepatic intrinsic clearance. But there was no change of the hepatic blood clearance of ICG between the control and the DTZ-pretreated rats in this study. So it may be suggested that DTZ does not influence hepatic blood flow.

• Proceedings of the Korea Society of Environmental Biology Conference
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• 2005.12a
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• pp.87-87
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• 2005

• Proceedings of the Korean Society of Applied Pharmacology
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• 1997.11a
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• pp.47-50
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• 1997

Drug development began with the finding of biologically active compounds which are obtained by chemical synthesis or from natural sources. The advent of Combinatorial Chemistry is recognized as a strategy which has a potential to change the methodology of research and development(R&D) of new drugs. Drug development has been carried out with diverse strategies. In the past several decades a variety of new methodology have been introduced in R&D. Random screening of accumulated synthetic samples which had been synthesized for development of other drugs led to the discovery of new drugs. The typical examples are anti-asthma drug trimethoquinol and calcium antagonist diltiazem. (herbesser). In particular the latter drug has been used as a calcium antagonist worldwide, however it was first synthesized to find new tranquilizer and this is the reason why diltiazem has benzodiazepam skeleton. The random screening contributed in the finding of new drugs were carried out with whole animal test and it is a standard methodology in R&D of new drugs. Aspirin is the first synthetic non-steroidal antiinflammatory drug(NSAID) and has been used for more than one hundred years. It is the first example of drug developed from natural product. Salicin is the main constituent of willow bark which had been used in Europe for a long time to treat arthritis and aspirin was developed from salicin. Most of NSAID used clinically were developed from the structure of aspirin, however it took 70 years to clarify why aspirin exhibits its antiinflammatory, analgesic and antipyretic activities. The target of aspirin is cyclooxygenase(COX)which is the first enzyme involved in arachidonate cascade leading to the production of prostaglandins(PG) and thromboxan(TX). Side effect of aspirin causing ulcer in stomach is rather serious problem, since aspirin is so popular drug easily obtained in drug store(OTP). This problem is now going to be solved by a new finding on COX, which have two different types, one is constitutionally expressed COX 1 in almost all organs and the other is inducible COX 2. COX 2 is the responsible enzyme in inflammation etc and now the search of COX 2 specific inhibitors is the target of R&D of next generation NSAID.

• Journal of Chest Surgery
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• v.21 no.6
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• pp.970-978
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• 1988

There is tendency of increasing number and decreasing age of patients who are indicated for Rastelli operation for their cyanotic congenital heart disease. So there is the need to find the criterion which saves the patients from early postoperative hemodynamic disturbances. We reviewed the 26 patients who had been performed Rastelli operation at Seoul national University Hospital from January 1981 to June 1988. mean age of the patients was 7.8*3.4 years[range 2.5-15years], mean body surface area[BSA] 0.79*0.25m2[range 0.49-1.51m2] and mean hematocrit 57.95*12%[range 48-80%]. We divided these patients into survived group and died group before postoperative 72 hours, and analyzed preoperative arterial oxygen saturation[SaO2], the ratio of diameter of right pulmonary artery to ascending aorta[RPA/AA], the ratio of both right and left pulmonary artery diameter to descending thoracic aorta[RPA+LPA/DTA], pulmonary artery index[PA index], cardiopulmonary bypass time, aorta cross-clamping time, postoperative perfusion state and total amount of dopamine infused postoperatively. The results showed that RPA+LPA/DTA and PA index were statistically significant factors to influence early postoperative cardiac death rate[P< 0.05]. Especially there were good linear correlations between PA index[X] and peripheral perfusion index[Y][Y= - 1.15+0.02 X, r=0.86, P<0.01]and between PA index[X] and total amount of dopamine infused before postoperative 72 hours[mg/kg, Y][Y=61.94 - 0.15 X, r=-0.80, P < 0.01]. Also there were tendencies that the higher RPA+LPA/DTA[Y], the better peripheral perfusion [X] and the lower need of dopamine[X], but no statistical significance.[Y=0.78+1.60 X, r =0. 49, P >0.05] And the discriminate analysis showed that patients with PA index over 221 mm2/BSA could undergo correction with 25 per cent of error rate. In conclusion, early postoperative hemodynamic states could be predicted by preoperatively measured PA index, and which can be used as a criterion for Rastelli operation performed on cyanotic congenital heart disease.

• The Korean Journal of Pharmacology
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• v.23 no.1
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• pp.33-44
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• 1987

NADPH oxidase dependent superoxide generation and phagocytosis in neutrophils stimulated with opsonized zymosan or heat aggregated IgG were coincided with the process of calcium uptake. The responses in activated neutrophils were enhanced with increasing concentrations of extracellular calcium and these effects were significantly inhibited by calcium chelators, EGTA and EDTA. The superoxide generation in activated neutrophils was reduced by dantrolene and chlorpromazine. Calcium antagonists, bepredil, diltiazem, verapamil, nifedipine and nimodipine effectively inhibited the calcium uptake, superoxide generation and phagocytosis in activated neutrophils, and NADPH oxidase activity was also inhibited. The results suggest that calcium antagonists may inhibit the superoxide generation and phagocytosis in activted neurtophils by the inhibition of calcium influx and by the action on intracellular redistribution of calcium and NADPH oxidase system.

• The Korean Journal of Physiology and Pharmacology
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• v.6 no.2
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• pp.87-91
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• 2002

The aim of this study was to investigate the role of $Ca^{2+}-channel$ blockers in norepinephrine (NE) release from rat hippocampus. Slices and synaptosomes were incubated with $[^3H]-NE$ and the releases of the labelled products were evoked by 25 mM KCl stimulation. Nifedipine, diltiazem, nicardipine, flunarizine and pimozide did not affect the evoked and basal release of NE in the slice. But, diltiazem, nicardipine and flunarizine decreased the evoked NE release with a dose-related manner without any change of the basal release from synaptosomes. Also, a large dose of pimozide produced modest decrement of NE release. ${\omega}-conotoxin$ (CTx) GVIA decreased the evoked NE release in a dose-dependent manner without changing the basal release. And ${\omega}-CTxMVIIC$ decreased the evoked NE release in the synaoptosomes without any effect in the slice, but the effect of decrement was far less than that of ${\omega}-CTxGVIA.$ In interaction experiments with ${\omega}-CTxGVIA,\;{\omega}-CTxMVIIC$ slightly potentiated the effect of ${\omega}-CTxGVIA$ on NE release in the slice and synaptosomal preparations. These results suggest that the NE release in the rat hippocampus is mediated mainly by N-type $Ca^{2+}-channels,$ and that other types such as L-, T- and/or P/Q-type $Ca^{2+}-channels$ could also be participate in this process.

• Biomolecules & Therapeutics
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• v.1 no.1
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• pp.1-8
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• 1993

It has been known that calcium antagonists also inhibit the radioligand binding to muscarinic and $\alpha$-adrenergic receptors and, in case of verapamil, these inhibitions may play a role in the effects of verapamil on the heart. In this study, the effects of nicardipine, nifedipine, nimodipine, diltiazem and verapamil on the binding of [$^3H$]dihydroalprenolol (DHA) to dog cardiac ${\beta}$-adrenergic receptors were examined. A single uniform [$^3H$]DHA binding site ($K_D/= 5nM\;and\;B_{max}=2600$ fmol/mg protein) was identified in dog cardiac sarcolemma. [$^3H$]DHA binding was not affected by the usual therapeutic concentrations of these calcium antagonists (nanomolar range) but in the "nonspecific"concentration ranges ($28-180{\mu}m$) these drugs inhibited [$^3H$]DHA binding to $\beta$-adrenergic receptors. Nicardipine, nifedipine, nimodipine and diltiazem competed for [$^3H$]DHA binding to ${\beta}$-adrenergic receptors with dissociation constants ($K_i$) of $28{\mu}m,\' 74{\mu}m, 39{\mu}m \;and \;35{\mu}m,$ respectively. Verapamil ($K_i=176.5 {\mu}m$) was less potent inhibitor than other drugs and this inhibition was noncompetitive; the maximal binding capacity ($B_{max}$) $300 {\mu}m$ verapamil without change in the apparent dissociation constant (4K_D$) for DHA. These results indicate that the inhibitory action of calcium antagonists at high concentrations on ${\beta}$-adrenergic receptors is not involved in the therapeutic effects of these drugs by the calcium channel blocking action.

• KSBB Journal
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• v.14 no.3
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• pp.291-296
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• 1999

Chiral epoxides are key intermediates for the production of chiral pharmaceuticals, agrochemicals, and functional food additives. Chiral epoxides can be produced by either chemical or biological method. In biocatalytic production routes, chiral epoxides can be produced via epoxidations of prochiral alkenes by monooxygenase or peroxidase. Kinetic resolution of racemic epoxides using whole cells of bacteria or fungi might be commercially useful, since it is possible to obtain chiral epoxides with high optical purities from relatively cheap and readily avaiable racemic epoxides. Some bioprocesses already are commercially developed: the biocatalytic production of chiral epichlorohydrin via microbial stereospecific dehalogenation, and lipase-catalyzed enantioselective hydrolysis in a hollow fiber membrane bioreactor for the production of chiral methyl trans-3-(4-methoxyphenyl)glycidate. the intermediate for calcium antagonist diltiazem. The importance of biocatalytic production of chiral epoxides with several examples from literature are presented.

• Journal of Veterinary Clinics
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• v.25 no.1
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• pp.23-26
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• 2008

A 2-year-old, female, Turkish Angora cat was presented due to hindlimb paralysis with 2-day history of vomiting and depression. Physical examination revealed weak femoral pulse and cyanotic footpads of hind limbs. Chest auscultation, thoracic radiography, and electrocardiogram were no remarkable. Abdominal ultrasonography showed suspected hyperechoic thrombus in abdominal aorta. Underlying causes of the arterial thromboembolism were not found on multiple diagnostic examinations and the cat was diagnosed as idiopathic saddle thromboembolism. Despite 4-week regimen with heparin sodium, aspirin, and diltiazem, the hind limbs were progressively and irreversibly necrotized. Therefore, coxofemoral amputation was performed. After surgery, the clinical condition of this cat returned to normal without further complications.

• Journal of Veterinary Clinics
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• v.29 no.5
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• pp.404-407
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• 2012

A 3 years-old female mixed dog (weighing 5.3 kg) was referred to veterinary teaching hospital of Kangwon National University with primary complaints of syncope, severe exercise intolerance, depression and lethargy. Diagnostic studies revealed polycythemia, right sided cardiac enlargement on thoracic radiography and right-to left atrial septal defect, severe pulmonary stenosis (~5 m/s of peak velocity) and right ventricular hypertrophy. Based on diagnostic findings, the dog was diagnosed as trilogy of Fallot. To improve clinical condition of this dog, diltiazem and enalapril were prescribed with weekly phlebotomy. To author's best knowledge, this is the first case of trilogy of Fallot in Korea.