• Journal of Physiology & Pathology in Korean Medicine
• /
• v.21 no.5
• /
• pp.1118-1126
• /
• 2007

The purpose of this study was to examine the anti allergic effect in vivo and in vitro, and to observe single and four weeks repeated toxicity in mice of Bangpung-galgeun-tang (BGT). We investigated anti DNP IgE-mediated passive cutaneous anaphylaxis in rodents and compound 48/80-induced active systemic anaphylatic shock in mice after oral administration with BGT of 0.4 g/kg and 0.8 g/kg for 8 days, and also examined MTT assay, ${\beta}-hexosaminidase$ activity, IL-4 and $TNF-{\alpha}$ from RBL-2H3 and $TNF-{\alpha}$ from Raw264.7 after pre-treatment with BGT of 0.25 mg/ml, 0.5 mg/ml, 1 mg/ml and 2 mg/ml. To ascertain safety and toxicity of BGT, we divided into single and four weeks repeated administration test. In single test, three groups were administrated different dosages and routes (2 g/kg/i.p., 4 g/kg/i.p. and 15 g/kg /p.o.) of BGT, and in four weeks repeated test, 0.8 g/kg BGT was administrated. Control groups were administrated with only saline according to on Korean Food and Drug Administration, respectively. We observed attentively motality, abnormal clinical sign, body weight change, organ weight, AST and ALT of mice after BGT administration. BGT inhibited passive cutaneous anaphylaxis and active systemic anaphylatic shock by oral administration. All the concentrations of BGT from 0.25 to 2 mg/ml didn't have an effect on cell viability and cytotoxicity. In RBL-2H3, ${\beta}-hexosaminidase$ release, IL-4 and $TNF-{\alpha}$, and in Raw264.7, $TNF-{\alpha}$ were significantly reduced by treated all concentrations of BGT. During toxicity experiment period, there was no difference in body weight change, organ weight, AST and ALT among different dose groups. Death were found 3 mice from day 2 to day 3 in single test i.p. group. (2 g/kg, 4 g/kg). Several individuals of single test i.p. group were observed that decreased locomotor activity, exophthalmos, bloodshot eyes, loss of eyesight and so on in early period after administration. But there was no difference in clinical signs among p.o. group. These results indicate that BGT have inhibition effects on allergy and suggest that no observable effect level of the test orally administration was considered to be more than 2 g/kg in mice under the conditions employed in this study.

• Journal of Society of Preventive Korean Medicine
• /
• v.17 no.2
• /
• pp.139-155
• /
• 2013

Purpose : This study was aim to evaluate effects of pharmacodynamics and toxicity in combination therapy of donepezil with Gongjindan. The effects of Gongjindan co-administration on the pharmacokinetics (PK) of donepezil were observed after single and 7-day repeated oral co-administration with 1.5hr-intervals, to evaluate synergic pharmacodynamics and reduce toxicity of combination therapy of donepezil with Gongjindan. Materials and Methods : After 10mg/kg of donepezil treatment, Gongjindan100mg/kg was administered with 1.5hr-intervals. The plasma were collected at 30min before administration, 30min, 1, 2, 3, 4, 6, 8 and 24hrs after end of first and last 7th donepezil treatment, and plasma concentrations of donepezil were analyzed using LC-MS/MS methods. Results : Gongjindan markedly inhibited the absorption of donepezilregardless of sample time, from 30min to 8hrs after end of first 1.5hr-interval co-administration as compared with donepezil single treated rats. Especially the absorption of donepezil was significantly decreased at 2, 4, 6 and 8hrs after co-administration as compared with donepezilsingle treated rats. Accordingly, the Cmax (-26.236%), $AUC_{0-t}$(-26.02%) and $AUC_{0-inf}$(-25.90%) of donepezil in 1.5hr-interval co-administered rats were dramatically decreased as compared with donepezilsingle treated rats, respectively. However, no meaningful changes on the plasma donepezil concentrations and pharmacokinetic parameters were detected after end of last 7th 1.5hr-interval co-administration as compared with donerezil single treated rats, except for non-significant slight increases of Tmax(16.67%) detected in co-administered rats as compared with donepezil single treated rats. Conclusion : These findings are considered as direct evidences that Gongjindan also decreased oral bioavailability of donerezil as inhibited the absorptions, when they were co-administered with 1.5hr-intervals, but they may be adapted after 7 days continuous repeated l.5hr-interval co-administration.

• The Korean Journal of Pharmacology
• /
• v.31 no.2
• /
• pp.153-164
• /
• 1995

Sympathomimetic amines, especially ephedrine, are a major ingredient in proprietary medications for symptomatic treatment of upper respiratory infections. Their frequent uses can lead to occasional instances of abuse and habituation. The clinical symptoms of ephedrine abuse are similar to that of amphetamine psychosis and resemble closely that of schizophrenia. Because both amphetamine psychosis and schizophrenia are thought to be mediated primarily through the action on catecholamines, ephedrine-induced changes of the biogenic amines can be suspected. However, there were few studies about the central effects of ephedrine because of the milder central action than peripheral. Therefore, the present investigation was undertaken to elucidate the relations between the effects of single or repeated administration of ephedrine on the regional levels of biogenic amines in rat brain and ephedrine-induced CNS stimulation. The male Sprague-Dawley rats weighing $100{\sim}200\;g$ were used. After single or repeated administrations of ephedrine, blocks of tissue were obtained from frontal cortex, corpus striatum, hippocampus, thalamus, hypothalamus, substantia nigra and cerebellum. The concentration of biogenic amines(norepinephrine, epinephrine, dopamine, 5-hydroxytryptamine(5-HT)) and their metabolites (3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid(HVA), 5-hydroxyindoleacetic acid(5-HIAA)) were measured by means of high performance liquid chromatography-electrochemical detector(HPLC-ECD). The results obtained were as follows: 1) In the normal rat, the concentration of norepinephrine was the highest in hypothalamus. Dopamine, DOPAC and HVA were highest in corpus striatum, and 5-HT and 5-HIAA were highest in substantia nigra. Epinephrine was not detectable in any part of the brain tissue. 2) In a single administration of ephedrine, the concentration of DOPAC was decreased in corpus striatum. However, the other biogenic amines and their metabolites were not changed. 3) In repeated administration of ephedrine, the concentration of norepinephrine was decreased in all brain region checked. Dopamine was decreased in corpus striatum and substantia nigra and, increased in hypothalamus, and HVA was decreased in corpus striatum. 5-HT was decreased in all brain region except cerebellum and, 5-HIAA was decreased only in frontal cortex. The ratio of 5-HIAA/5-HT was increased in corpus striatum, thalamus, hypothalamus and substantia nigra. These data indicated that, although a single administration of ephedrine did not change the central neurotransmitters, repeated administration of ephedrine caused the decreases of norepinephrine and 5-HT in the most regions of brain, which may be responsible for the emergence of abnormal behavioral effect after ephedrine abuse.

• Biomolecules & Therapeutics
• /
• v.14 no.3
• /
• pp.125-131
• /
• 2006

The inhibitory effects of (-)-epigallocatechin gallate (EGCG), a major compound of green tea, on the development of locomotor sensitization, conditioned place preference (CPP) and dopamine receptor supersensitivity induced by the repeated administration of morphine were investigated in mice. A single administration of morphine produces hyperlocomotion. The repeated administration of morphine develops sensitization, a progressive enhancement of locomotion, which is used as a model for studying the craving and drug-seeking behaviors characterizing addiction, and CPP, which is used as a model for studying drug reinforcement, respectively. EGCG inhibited morphine-induced hyperlocomotion, sensitization and CPP. In addition, EGCG inhibited the development of postsynaptic dopamine receptors supersensitivity, which may be an underlying common mechanism that mediates the morphine-induced dopaminergic behaviors such as sensitization and CPP. Apomorphine (a dopamine agonist)-induced climbing behaviors also were inhibited by a single direct administration of EGCG These results provide evidence that EGCG has anti-dopaminergic activity, as inhibiting the development of dopamine receptor supersensitivity and apomorphine-induced climbing behaviors. Therefore, it is suggested that green tea may be useful for the prevention and therapy of these adverse actions of morphine.

• Archives of Pharmacal Research
• /
• v.29 no.10
• /
• pp.904-910
• /
• 2006

The inhibitory effects of paeonol, a major compound of Paeoniae radix, on the development of locomotor sensitization, conditioned place preference (CPP) and dopamine receptor supersensitivity induced by the repeated administration of morphine were investigated through behavioral experiments. A single administration of morphine produces hyperlocomotion. Repeated administration of morphine develops sensitization (reverse tolerance), a progressive enhancement of locomotion, which is used as a model for studying the drug-induced drug-seeking behaviors, and CPP, which is used as a model for studying drug reinforcement. Paeonol inhibited morphine-induced hyperlocomotion, sensitization and CPP. In addition, paeonol inhibited the development of postsynaptic dopamine receptors supersensitivity, which may be an underlying common mechanism that mediates the morphine-induced dopaminergic behaviors such as sensitization and CPP. Apomorphine (a dopamine agonist)-induced climbing behaviors also were inhibited by a single direct administration of paeonol. These results provide evidence that paeonol exerts anti-dopaminergic activity, and it is suggested that paeonol may be useful for the prevention and therapy of these adverse actions of morphine.

• Biomolecules & Therapeutics
• /
• v.6 no.4
• /
• pp.400-405
• /
• 1998

The pharmacokinetics of CJ-50001 (recombinant human granulocyte-colony stimulating factor, developed by R&D center of Cheil Jedang Corp.) were investigated in rats and dogs. The serum concentrations of CJ-50001 were measured by a sandwich enzyme immunoassay. After single intravenous (iv) administration of Cf-50001 to rats at a dose of 5 $\mu$g/kg, the mean terminal half-life and area under the concentration-time curve (AUC) were 0.96 h and 124.497g . h/ml, respectively. After single subcutaneous (sc) administration at the same dose, maximum serum concentration was observed at about 2 hours after administration, and the mean terminal half-life, AUC and the bioavailability were 1.11 h,63.58$\mu$g . h/ml and 51.07%, respectively. In repeated dosing studies, CJ-50001 was administered iv and sc to rats at a daily dose of 5$\mu$g/kg for 7 days. The pharmacokinetic parameters, such as mean AUC and terminal half-life, were no significantly different from those of single administration. Following single iv and sc administration of CJ-50001 to dogs at a dose of 5 $\mu$g/kg, mean AUCs were much higher than those of rats, due to the decreased clearence (CL). After sc administration to dogs, maximum serum concentration was observed at 2~4 hours after administration and the bioavailability was 54.60%.

• Archives of Pharmacal Research
• /
• v.26 no.12
• /
• pp.1074-1078
• /
• 2003

The effects of glycine on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity in mice was examined. A single administration of morphine (10 mg/kg, s.c.) induced hyperactivity as measured in mice. The morphine-induced hyperactivity was inhibited by pretreatment with glycine (100, 200 and 400 mg/kg, i.p.). In addition, it was found repeated administration of morphine (10 mg/kg, s.c.) to mice daily for 6 days caused an increase in motor activity which could be induced by a subsequent morphine dose, an effect known as reverse tolerance or sensitization. Glycine (100, 200 and 400 rng/kg, i.p.) also inhibited morphine-induced reverse tolerance. Mice that had received 7 daily repeated administrations of morphine also developed postsynaptic dopamine receptor supersensitivity, as shown by enhanced ambulatory activity after administration of apomorphine (2 mg/kg, s.c.). Glycine inhibited the development of postsynaptic dopamine receptor supersensitivity induced by repeated administration of morphine. It is suggested that the inhibitory effects of glycine might be mediated by dopaminergic (DAergic) transmission. Accordingly, the inhibition by glycine of the morphine-induced hyperactivity, reverse tolerance and dopamine receptor supersensitivity suggests that glycine might be useful for the treatment of morphine addiction.

• Journal of Oriental Neuropsychiatry
• /
• v.24 no.1
• /
• pp.131-144
• /
• 2013

Objectives : To provide information on the safety of ACM, we carried out a single oral dose-increasing toxicity and 4-weeks repeated oral dose determining test of ACM in beagle dogs. Methods : In a single oral dose-increasing toxicity test, beagles were treated with ACM orally increasing dose level (1,000, 2,000, 5,000 mg/㎏) at interval of 3 days. After administration, signs of toxicity were observed for two weeks. In 4-weeks repeated oral dose determinating test, beagles were treated with ACM with oral dose 500, 1,000, 2,000 mg/kg for 4 weeks. Mortality, clinical signs, body weight changes, food consumption, urinalysis, hematological and biochemical parameters, organ weights, necropsy findings, and histological findings were monitored during the study period. Results : In a single oral dose-increasing toxicity test, we found no mortality, abnormalities in clinical signs, body weight, and necropsy findings during the study period. In 4-weeks repeated oral dose determinating test, we found no mortality, abnormalities in clinical signs, body weight, food consumption, urinalysis, hematological and biological parameters, gross findings, organ weights, necropsy findings, and histopathological findings in any of the beagles tested. Conclusions : The results obtained in these studies suggest that maximum tolerated dose (MTD) of ACM in male and female beagle dogs was supposed to be over 5,000 mg/kg. For the future studies of toxicity, it is advisable that high dose and low dose are set at 2000 mg/kg and 500 mg/kg, respectively.

• The Journal of Internal Korean Medicine
• /
• v.34 no.4
• /
• pp.349-361
• /
• 2013

Objectives : This study aimed to evaluate the single oral dose toxicity and four weeks repeated dose determination of Gamisasangja-tang (GST) in male and female Sprague-Dawley rats. Methods : In the single oral toxicity study, rats were orally administered a single dose of 0 and 5,000 mg/kg GST. There were 5 rats in each group. After single administration, mortality, clinical signs, body weight changes and gross pathological finding were observed for 14 days. In the 4-weeks repeated oral dose determination study, rats were orally administered a single dose of 0, 1,250, 2,500 or 5,000 mg/kg GST. There were 5 rats in each group. Mortality, clinical signs, body weight changes, food consumption and gross pathological finding were observed for 28 days. Organ weight, clinical chemistry and hematology were tested after 28 days. Results : There was no mortality in either of the two studies. There were also no significant differences in clinical sign, body weight, organ weights, hematological or serum chemical parameters between the GST and control groups. Conclusions : The results obtained in this study suggest that the 50% lethal dose of GST is over 5,000 mg/kg, so this finding would be expected to provide scientific evidence for the safety of GST.

• Journal of Veterinary Clinics
• /
• v.17 no.2
• /
• pp.349-358
• /
• 2000

Effects of repeated administration of diminazene aceturate (Hoechst Veterin r GmbH. Ger- many) that has been introduced as effective compound against Babesiosis and trppanosomiasis were investigated in dogs experimentally infacted with Babesia gibsoni. Adull mongrel dogs of both sexes were inoculated will nonpreserved infected blood and then maintained chronic anemia. A single dose of diminazene aceturate of 7mg/kg b.w. was administrated intramnuscularIy on day 7.1 arid ,7. Clin- ical and hcmatological findings following inoculation and medication were observed and 7enlm bio chemical analysis also was monitored. Parasitemia was detected between 3 and 6 days after inoculation. The rate of parasitized erythrocytes,1 in peripheral blood reached the peak on the 13th day and was maintained the percentage of 0.1 to 1.0 until the medication of diminazene aceturate. RBC was significantly (p<0.01) decreased on the 3rd day and then kept on decreasing. The lowest value was observed on the 16th day. WBC remained generally within normal ranges. PCV revea1ed the sig-nificant (p<0.01) decrease within the range of 24-27% and platelet was significantly (p<0.05) decreased during the period. Senum chemical values (ALT, AST. total bilirubin. LDH BUN, area- tinine, total protein. albumin and glucose) were within normal ranges during the experimental period. Serum CPK values were significantly (p<0.01) increased on the 3rd day. There was no clinically, sig-nificant difference in a single dose of diminazene aceturate of 7 mg/kg b.w. But the administration of diminazene aceturate of 14 mg/kg b.w. revealed vomiting and anorexia and one dog died in 30 hours after administration. The administration of 14mg/kg b.w. resulted in vomiting, salivation, actor- exia, tremor of head and involuntary movement and one dog died in 27 hours after administration. WBC, RBC, PCV and Platelet values were no significant difference and hematological findings revealed persistent anemia and thrombocytopenia during chronic anemia after inoculation. AST activity its was significantly (p<0.01) increased 11\\`from 3 days after medication and AST activity was on the same trend. Serum CPK activity revealed significant (p<0.01) increase within 6 hors)\\`s after every administration and decreased in 48 howl·s after administration.