애엽추출물 , DA-9601 의 실험적 위궤양 모델에 대한 항궤양 효과 및 기전 연구

양중익(Junn Ick Yang),이상득(Sang Deuk Lee),이은방(Eun Bang Lee),오태영(Tae Young Oh),류병권(Byung Kweon Ryu),박정배(Jeong Bae Park) 한국응용약물학회 1996 Biomolecules & Therapeutics(구 응용약물학회지) Vol.4 No.2

Antiulcer effects of Artemisia herbs extract (DA-9601) were evaluated in various types of experimental gastric ulcer induced in rats. And the effects of DA-9601 on mucus, basal and stimulated gastric acid secretion were also investigated in rats. DA-9601 (12.5∼400 ㎎/㎏, p.o.) prevented the formation of gastric ulcers induced by 60% EtOH in 150 mM HCl, restraint water immersion stress, platelet activating factor (PAF), aspirin in 150 mM HCl with Pylorus-ligation and indomethacin. DA-9601 (4∼400 ㎎/㎏, p.o.) significantly accelerated the healing rate of acetic acid-induced gastric ulcer and significantly stimulated mucus secretion in a dose-dependent manner. DA-9601 (20∼200 ㎎/㎏, i.d.), however, did not inhibit basal gastric acid secretion in pylorus ligated rats and DA-9601 (200 ㎎/㎏, i.d.) failed to influence histamine-, pentagastrin- and carbachol- stimulated gastric acid secretion. These results suggest that DA-9601 has inhibitory action on gastric lesion and ulceration through increasing mucus secretion in the stomach of rats without influencing basal and stimulated gastric acid secretion.

피하주사 및 국소도포시 [14C]DA-5018 의 약동력학

김원배(Won Bae Kim),양중익(Junn Ick Yang),이상득(Sang Deuk Lee),이응두(Eung Doo Lee),심현주(Hyun Joo Shim),이종진(Jong Jin Lee),이명걸(Myung Gull Lee) 한국응용약물학회 1997 Biomolecules & Therapeutics(구 응용약물학회지) Vol.5 No.1

Pharmacokinetics of a new capsaicin analog, DA-5018 were evaluated after a subcutaneous injection or topical application of ^(14)C-labelled or unlabelled DA-5018 to rats and rabbits. After subcutaneous injection of ^(14)C-labelled or unlabelled DA-5018, 0.5 mg/kg (equivalent to DA-5018) to rats, the plasma total activity peaked at 2 hr with the terminal half life of 5.34 hr, however, unlabelled-DA-5018 peaked at 1 hr with the terminal half life of 1.26 hr. Moreover, the AUC (0.726 versus 0.233 ㎍ hr/ml) and MRT (7.82 versus 3.55 hr) increased significantly based on total radioactivity compared with intact DA-5018. Above data indicated that DA-5018 is extensively metabolized in rats and the terminal half- life of the metabolites) had a longer half-life than that of DA-5018. The cumulative percentages of biliary excretion of dose after subcutaneous injection of [^(14)C]DA-5018 was 40.2%, however, the value was only 2.14% when unlabelled DA-5018 was injected. After topical application of 0.1% or 0.3% ^(14)C-labelled or unlabelled DA-5018 cream, 500 mg/kg to rats, the plasma and tissue concentrations except applied skin were under the detection limit. After consecutive 7 days topical application of unlabelled DA-5018, 0.1% and 0.3% cream to rats, the plasma concentrations were also under the detection limit. But the urinary excretion of DA-5018 was significantly increased by repeated topical administration. After topical application of unlabelled DA-5018, 0.1% and 0.3% cream to rabbits, the plasma and urine concentrations were under the detection limit. Above data indicated that the skin permeation of DA5018 was lower and the metabolism of DA-5018 was higher in rabbits than that in rats.

새로운 캅사이신 유도체 DA-5018 의 국소자극성에 관한 연구

김원배(Won Bae Kim),양중익(Junn Ick Yang),배은주(Eun Ju Bae),신명수(Myeong Soo Shin),김순회(Soon Hoe Kim),손문호(Moon Ho Son),김희기(Hee Kee Kim) 한국응용약물학회 1997 Biomolecules & Therapeutics(구 응용약물학회지) Vol.5 No.2

Capsaicin cream has been used to attenuate the pain associated with diabetic neuropathy, rheumatoid arthritis, osteoarthritis and postherpetic neuralgia. But its common side effect, local irritation, limits the use of it and there is still a need for a new analgesic devoid of this side effect. This study was conducted to compare the local irritant effect of DA-5018, a new capsaicin derivative, with that of capsaicin in various animal models and human beings. Capsaicin, applied topically to the mouse ear, produced dose-dependent increase of ear volume and the frequency of ear scratching behavior in mice. Neither ear volume nor scratching behavior was affected by DA-5018. In eye wiping test of rat, DA-5018 was 10 times less irritant than capsaicin. Capsaicin administered intradermally into the rat paw elicited paw lick/lift response with a potency which was three times that of DA-5018. Zostrix-HP (0.075% capsaicin cream), but not DA-5018 0.3% cream, increased ear volume of rat and induced thermal hyperalgesia in normal and carrageenan inflamed paws. Six day-treatment of Zostrix-HP failed to develop tolerance against this thermal hyperalgesia. In human beings, Zostrix-HP produced burning sensation and itching in more than 90% of volunteers involved and its maximum irritant effect was significantly higher than that of DA-5018 cream. These results suggest that local irritation and burning sensation produced by DA-5018 is much less than capsaicin.

새로운 캅사이신 유도체 DA-5018 의 급성통증 모델에서의 진통작용

김원배(Won Bae Kim),양중익(Junn Ick Yang),배은주(Eun Ju Bae),신명수(Myeong Soo Shin),김순회(Soon Hoe Kim),손문호(Moon Ho Son),김희기(Hee Kee Kim),박노상(No Sang Park) 한국응용약물학회 1997 Biomolecules & Therapeutics(구 응용약물학회지) Vol.5 No.1

Analgesic effect of DA-5018, a new capsaicin derivative, was evaluated in various rat models of experimentally induced acute pain. DA-5018(0.2∼10.0 ㎎/㎏, p.o.) prevented the writhing syndromes induced by acetic acid or phenyl-p-benzoquinone(PBQ). It increased the pain threshold of inflamed paw when tested by the Randall-Selitto method at the dose of 2.0∼20.0 ㎎/㎏ by oral administration. And also it showed antinociceptive activities in tail-pinch(1.0∼20.0 ㎎/㎏, p.o.) and tail-flick test(5.0∼50.0 ㎎/㎏, p.o.). The potency and efficacy of DA-5018 were comparable to morphine·HCl in all the models mentioned above. Acetaminophen exhibited the inhibition of acetic acid-induced writhing syndromes and also analgesic activity in Randall-Selitto test, but it showed the limited efficacy in tail-pinch and tail-flick test. These results mean that DA-5018 has a broader analgesic activity profile than acetaminophen. And we found out that the analgesic activity of DA-5018 was 100 times more potent when administered centrally than administered orally in tail-flick test. These results suggest that DA-5018 has an orally active analgesic activity, and central nervous system may be involved in the action of DA-5018.

새로운 캅사이신 유도체 DA-5018 의 일반약리작용

김원배(Won Bae Kim),양중익(Junn Ick Yang),배은주(Eun Ju Bae),신명수(Myeong Soo Shin),김순회(Soon Hoe Kim),손문호(Moon Ho Son),김희기(Hee Kee Kim),차봉진(Bong Jin Cha) 한국응용약물학회 1997 Biomolecules & Therapeutics(구 응용약물학회지) Vol.5 No.1

DA-5018(N-(3-(3,4-dimethylphenyl)propyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide) is a new capsaicin derivative under development as topical analgesic agent. The general pharmacological properties of DA-5018 on central nervous, cardiovascular, gastrointestinal and other organ systems were studied in experimental animals. DA-5018 cream (0.3%) had no effects on behavior, hexobarbital-induced sleeping time, body temperature, spontaneous activity, blood pressure, heart rate, intestinal charcoal propulsion, urine volume and electrolyte excretion even at a high dose of 2000 mg/kg in rats. In addition, DA-5018 cream had little skin irritation compared to Zostrix-HP (capsaicin, 0.075%) cream in rabbits. In isolated guinea pig tissue studies, DA-5018 increased the contractility of trachea and ileum and also increased sinus rate of atrium in a range of 10^(-8)-10^(-5) M, but its efficacy as a agonist was weak. These results suggest that DA-5018 cream might be used topically without serious side effects.

새로운 캅사이신유도체 DA-5018 의 피하주사 및 구소도포시 진통효과

김원배(Won Bae Kim),양중익(Junn Ick Yang),배은주(Eun Ju Bae),신명수(Myeong Soo Shin),손문호(Moon Ho Son),김희기(Hee Kee Kim),공재양(Jae Yang Kong) 한국응용약물학회 1997 Biomolecules & Therapeutics(구 응용약물학회지) Vol.5 No.2

The analgesic effects of DA-5018, a new capsaicin derivative, were evaluated in various experimental pain models. Drugs were administered subcutaneously or topically. When drugs were administered subcutaneously, 1) the ED_(50) values of DA-5018, morphine ·HCl, capsaicin and acetaminophen were 0.091-2.0, 0.3-4.3, 1.4-26.5 and 45.4-643 mg/kg, respectively in various pain or inflammatory models including acetic acid writhing, formalin, tail flick, Randall-Selitto, hot plate and croton oil-induced ear edema test, 2) the AD₂ values (the dose for doubling of pain threshold of vehicle control) of DA-5018, capsaicin and ketoprofen were 1.07±0.18, 23.47±4.46 and 2.97±0.43 mg/kg in Freund`s complete adjuvant (FCA)-induced arthritic pain model. And by topical application, 1) neither DA-5018 0.3% cream nor Zostrio-HP (capsaicin 0.075%) were effective in formalin test, 2) although DA-5018 0.3% cream significantly inhibited the croton oil-induced ear edema being better than Zostrix-HP and Kenofen (ketoprofen 3%). 3) Ln FCA model, DA-5018 0.3% cream reversed the decreased pain threshold of arthritic rat from 136.4 g (day 0) to 289.0 g (day 5) and 250.1 g (day 10), which was similar to Zostrix-HP, These results suggest that DA-5018 administered subcutaneously has a potent and broad analgesic spectrum than nonsteroidal antiinflammatory drugs against acute and chronic pain, and by topical application it exerts comparable analgesic and antiinffammatory effects to capsaicin cream.

당부분에서 4'-플루오린 또는 4'-아자이드로 치환된 3'-히드록시다우노루비신과 3'-히드록시독소루비신 유도체의 합성과 항암활성

옥광대,박정배,김문성,정동윤,양중익,Ok, Kwang-Dae,Park, Jeong-Bae,Kim, Moon-Sung,Jung, Dong-Yoon,Yang, Junn-Ick 대한약학회 1996 약학회지 Vol.40 No.2

3'-Deamino-3-hydroxy-4'-fluoro- or 3'-deamino-3'-hydroxy-4'-azido-daunorubicin(6,8) and -doxorubicin(7,9) have been synthesized, respectively. Compounds 7,8 and 9 were mo re cytotoxic than daunorubicin(1) and doxorubicin(2) against L1210 murine leukemic cell in vitro. When administered intraperitoneally for 9 days starting 1 day after tumor inoculation, compounds 7(T/C 605%) and 9(T/C 488%) showed significant antitumor activity for ip-inoculuated L1210 murine leukemia at wide range of doses.

새로운 Anthracycline계 항암제 DA-125의 일반약리작용

김명석,박종완,김영훈,김순회,신명수,김원배,양중익,Kim, Myung-Suk,Park, Jong-Wan,Kim, Young-Hoon,Kim, Soon-Hoe,Shin, Myeong-Soo,Kim, Won-Bae,Yang, Junn-Ick 대한약리학회 1994 대한약리학잡지 Vol.30 No.2

The general pharmacological effects of a new anthracycline anticancer agent, DA-125 $[7-0-(2,\;6-dideoxy-2-fluoro-{\alpha}-L-talopyranosyl)-adriamycinone-14-{\beta}-alaninate{\cdot}HCI]$ were investigated in mice, rats, guinea pigs, rabbits and dogs. Intravenous administration of DA-125 presented no significant effects on the central and peripheral nervous systems of ICR mice except a decrease in the numbers of acetic acid-induced writhing response at a dose of 10 mg/kg. In anesthetized rats and dogs, DA-125 produced a transient depression of blood pressure and an increase in heart rate, but did not affect the peripheral blood flow in the isolated ear vessels of rabbits and the mechanical functions of the isolated hearts of guinea pigs. No significant effects were observed on the gastrointestinal functions and the contractilities of smooth muscle preparations obtained from guinea pig trachea, rabbit ileum, pregnant and non-pregnant uterus and vas deferens of rats. DA-125 Increased the contractility of the isolated ileum of guinea pigs in a dose range of $10^{-6}{\sim}10^{-9}g/ml$, and also increased, but weaker than adriamycin, the vascular permeability in rat skin. DA-125 had no effect on the kallikrein-induced increase in permeability and the permeability of the visceral organs. DA-125 did not adversely affect the liver function and the blood coagulation system, and did not induce hemolysis in vitro. It is concluded from the results that the general pharmachological effects of DA-125 are similar to or weaker than those of adriamycin, and that little adverse effects are anticipated with a therapeutic dose range.

비 마약성 진통제 DA-5018 의 랫드에 대한 4 주 경구투여 아급성독성

백남기(Nam Gi Baik),안병옥(Byoung Ok Ahn),김원배(Won Bae Kim),양중익(Junn Ick Yang),김옥진(Ok Jin Kim),강경구(Kyung Koo Kang) 한국응용약물학회 1997 Biomolecules & Therapeutics(구 응용약물학회지) Vol.5 No.2

4-week repeated dose toxicity of DA-5O18, a new capsaicin analogue analgesic agent, was examined in SD rats at dosage levels of 0, 0.4, 2, 10 and 50 mg/kg/day. DA-5018 was administered orally to 17 males and 17 females per group at doses of 0, 10 and 50 mg/kg and to 12 males and 12 females per group at doses of 0.4 and 2 mg/kg. After the administration period, 5 males and 5 females at the 0, 10 and 50 mg/kg were placed on withdrawal for 2 weeks. Treatment-related clinical signs were observed at 10 and 50 mg/kg. Clinical signs observed immediately after the administration of DA-5018 were grooming, sedation or depression, lacrimation, ataxia, reddening of extremities and ears, ventral or lateral recumbency, respiratory distress, cyanosis and convulsion. Delayed-type clinical signs including focal scabbing and depilation around nose were also observed 1 or 2 weeks after the start of administrarion of DA-5018. Only at the 50 mg/kg group, corneal opacities, reduced body weight gain (male) and death (male 6/17, female 3/17) were noted. In blood biochemical analysis, serum levels of glucose and triglyceride decreased at 10 and 50 mg/kg. In hematological examination, there were increases in the number of red blood cell, hemoglobin content and percent of hematocrit at 10 and 50 mg/kg. Pulmonary enlargement and hemorrhagic spot, focal scabbing and depilation around nose and corneal opacities were seen at the necropsy of the animals died during the dosing of DA-5018 50 mg/kg. Focal scabbing and depilation arowtd nose were observed in the animals terminally necropsied at doses of 10 and 50 mg/kg. Histopathological examination revealed pulmonary hemorrhage, focal necrosis in the scabbed area, corneal necrosis, fibrosis and neovasculization in the stroma. At 0.4 and 2 mg/kg, there were no significant toxic changes attributable to the administration of DA-5018. In conclusion, target organs following to 4-week repeated dose of DA-5018 in the rat were determined to be lung, skin and eyes. Definite toxic dose and no-observed-adverse-effect-level (NOAEL) were estimated to be 50 and 2 mg/kg/day, respectively.

비 마약성 진통제 DA-5018 의 변이원성 연구

강경구(Kyung Koo Kang),백남기(Nam Gi Baik),김원배(Won Bae Kim),양중익(Junn Ick Yang) 한국응용약물학회 1996 Biomolecules & Therapeutics(구 응용약물학회지) Vol.4 No.3

DA-5018, a non-narcotic analgesic agent, was examined for mutagenicity in the reverse mutation test on bacteria, chromosomal aberration test on cultured mammalian cells and micronucleus test on mice. The reverse mutation test was performed by a plate incorporation method with or without a metabolic activation system(S9 mix) using Salmonella typhimurium strain TA100, TA1535, TA98 and TA1537. DA-5018 did not significantly increase revenant colonies in any of the test strains under any conditions at concentrations ranging from 0.0049 to 1.25 ㎎/plate, compared with the vehicle control. In the chromosomal aberration test using cultured Chinese Hamster Lung(CHL) cells, DA-5018 did not increase the number of aberrant cells in the presence or absence of S9 mix at concentrations of 0.016 mM/plate to 0.25 mM/plate, compared with the vehicle control. In the micronucleus test, male ICR mice were given DA-5018 intraperitoneally at a dose level of 0.55, 1.10 and 2.20 ㎎/kg. The incidence of bone marrow micronucleated polychromatic erythrocytes in the DA-5018 treated mice was not significantly different from that of the vehicle control. These results indicate that DA-5018 does not have mutagenic potential under the present test conditions.