• Journal of Pharmaceutical Investigation
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• v.31 no.4
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• pp.209-216
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• 2001

The purpose of the present study was to investigate the hepatic uptake and biliary excretion of l-anilino-8-naphthalene sulfonate (ANS) in vivo. The plasma concentration and liver concentration of ANS were determined after its i.v. bolus administration at a dose of $30\;{\mu}mol/kg$ in rats. The hepatic uptake clearance $(CL_{uptake})$ of ANS was 0.1 ml/min/g liver. On the basis of the unbound concentration of ANS, the permeability-surface area product $(PS_{influx})$ was calculated to be l0.4 ml/min/g liver, being comparable of in vitro data. On the other hand, we determined the plasma concentration, liver concentration and biliary excretion rate of ANS at steady-state after its i. v. infusion $(0.2-1.6\;{\mu}mol/min/kg)$ in rats. The excretion clearance $(CL_{excretion})$ of ANS showed Michaelis-Menten kinetics with increasing the infusion rate. The permeability-surface area product $(PS_{excretion})$ based on the unbound concentration in the liver was calculated to be 0.0165 ml/min/g liver, which is negligible compared with the intrinsic clearance $(CL_{int}=3.3\;ml/min/g\;liver)$ by rat liver microsomes. The sequestration process of ANS, therefore, was considered to be mainly due to the metabolic process in the liver $(PS_{seq}{\risingdotseq}CL_{int})$. Furthermore, $PS_{efflux}$ value calculated from $PS_{influx}$ and $PS_{seq}$ was 4.4 ml/min/g liver, which was comparable of in vitro data. In conclusion, in vivo parameters such as $PS_{influx}$, $PS_{efflux}$ and $PS_{seq}$ in the present study showed good in vivo-in vitro relationship. Thus, the kinetic analysis method proposed in the present study would be useful to analyze the hepatic transport of drugs in vivo.

• Journal of Pharmacopuncture
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• v.20 no.1
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• pp.10-17
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• 2017

Objectives: Boswellic acid (BA), a compound isolated from the gum-resin of Boswellia carterii, is a pentacyclic terpenoid that is active against many inflammatory diseases, including cancer, arthritis, chronic colitis, ulcerative colitis, Crohn's disease, and memory impairment, but the mechanism is poorly understood. This study investigated the effects of boswellic acid on spatial learning and memory impairment induced by trimethyltin (TMT) in Wistar rats. Methods: Forty male Wistar rats were randomly divided into 5 groups: Normal group, TMT-administrated rats (8.0 mg/kg, Intraperitoneally, i.p.) and TMT + BA (40, 80 and 160 mg/kg, i.p.)-administrated rats. BA was used daily for 21 days. To evaluate the cognitive improving of BA, we performed the Morris water maze test. Moreover, to investigate the neuroprotective effect of BA, we determined the acetylcholinesterase (AchE) activity, the malondialdehyde (MDA) level as a marker of lipid peroxidation, and the glutathione (GSH) content in the cerebral cortex. Results: Treatment with TMT impaired learning and memory, and treatment with BA at a dose of 160 mg/kg produced a significant improvement in learning and memory abilities in the water maze tasks. Consistent with behavioral data, the activity of AChE was significantly increased in the TMT-injected rats compared to the control group (P < 0.01) whereas all groups treated with BA presented a more significant inhibitory effect against AChE than the TMT-injected animals. In addition, TMT reduced the GSH content and increased the MDA level in the cerebral cortex as compared to the control group) P < 0.01). On the other hand, treatment with BA at 160 mg/kg slightly increased the GSH content and reduced the MDA level in comparison to the TMT-administered group (P < 0.01). Conclusion: The above results suggest that the effect of BA in improving the cognitive function may be mediated through its antioxidant activity.

• Archives of Pharmacal Research
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• v.17 no.2
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• pp.124-130
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• 1994

Plasma phamacokinetics and renal excretion of theophylline (TP) and its metabolities were ivnestigated in rats. Plasma concentrations of TP declined in a monoexponential manner, while those of 1-methyluric (MU) and 1,3-dimethyluric(DMU) declined in a biexponential manner upon respective iv bolus injection of each compound at 6mg/kg dose. The total body clearances $(CL_r)$ of the metabolites were 4-6 fold larger than that of TP, while the distribution volumes of them at steady-state $(Vd_{ss})$ were 40-50% smaller than that of TP. The metabolites showed their plasma peaks in 30 min after iv injection of TP indicating than that to MU. Renal excretion of TP and its metabolites was studied in urine flow rate (UFR)-controlled rats. The renal clearance $(CL_r)$ of TP was inversely related to pasma TP concentrations, and much smaller than the glomerular filtration rate (GFR) suggesting tubular secretion and profound reabsorption in the renal tubule. The $(CL_r)$ of each metabolite also showed that inverse relationship, but far exceeded GFR suggesting that tubular secretion than GFR by ip injection of probenecid (142.7 mg/kg). It supports that the metabolies are secreted in the renal tubule, and suggests that they share a common transport system in their sectrtion processes with probenecid. On the other hand, the $(CL_r)$ of TP was not affected significantly by the probenecid treatment. Considering the inverse relationship of TP between the $(CL_r)$ and its ploasma concentrations,no effect of probenecid on $(CL_r)$ of TP is most likely due to negligible contribution of the secretion to the overall $(CL_r)$ of TP.

• Archives of Pharmacal Research
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• v.28 no.5
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• pp.582-586
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• 2005

The present study was designed to characterize the possible roles of spinally located cholera toxin (CTX)- and pertussis toxin (PTX)-sensitive G-proteins in pro- inflammatory cy tokine induced pain behaviors. Intrathecal injection of tumor necrosis factor-a (TNF-${\alpha}$; 100 pg), interleukin-1${\beta}$ (IL-1${\beta}$ 100 pg) and interferon-${\gamma}$ (INF-${\gamma}$; 100 pg) showed pain behavior. Intrathecal pretreatment with CTX (0.05, 0.1 and 0.5 mg) attenuated pain behavior induced by TNF-${\alpha}$ and INF-${\gamma}$ administered intrathecally. But intrathecal pretreatment with CTX (0.05, 0.1 and 0.5${\mu}g$) did not attenuate pain behavior induced by IL-1${\beta}$. On the other hand, intrathecal pretreatment with PTX further increased the pain behavior induced by TNF-${\alpha}$ and IL-1${\beta}$ administered intrathecally, especially at the dose of 0.5 ${\mu}g$. But intrathecal pretreatment with PTX did not affect pain behavior induced by INF-${\gamma}$. Our results suggest that, at the spinal cord level, CTX- and PTX-sensitive G-proteins appear to play important roles in modulating pain behavior induced by pro-inflammatory cytokines administered spinally. Furthermore, TNF-${\alpha}$, IL-1${\beta}$ arid INF-${\gamma}$ administered spinally appear to produce pain behavior by different mechanisms.

• YAKHAK HOEJI
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• v.60 no.3
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• pp.101-106
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• 2016

Allylthiopyridazine derivatives were synthesized and evaluated for anti-proliferative activities in the previous study. In this study, selected two allylthiopyridazine derivatives (compound I, 3-heptylamino-6-allylthiopyridazine and compound II, 3-dipentylamino-6-allylthiopyridazine) were assessed for cytotoxicity and chronic proliferation in human colon carcinoma RKO cells. Two derivatives dose-dependently inhibited cell viability and proliferation. To elucidate the anticancer mechanism of two derivatives, we investigated the expression level of apoptosis-related proteins in RKO cells. Compound I induced the activation of JNK and expression of p53 and p21. On the other hand, compound II showed no change of p53 level. Interestingly, compound II inhibited the nuclear translocation of NF-${\kappa}B$. This result suggested that compound II suppressed cell proliferation. These different mechanisms of these compounds might have occurred through different steric conformation.

• YAKHAK HOEJI
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• v.55 no.3
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• pp.260-266
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• 2011

Two types of water soluble lysine salts of ibuprofen were prepared and evaluated. Physicochemical properties for ibuprofen-l-lysinate (IBL-l), ibuprofen-dl-lysinate (IBL-dl) and ibuprofen (IB) were studied on melting point, specific ratation, UV spectra and $^1H$-NMR spectra. There were not differences between IBL-dl and IBL-l in UV spectra and $^1H$-NMR spectra. The pharmacokinetic parameters of IB were compared to those of its lysine salts (IBL-l and IBL-dl) after i.v. or oral administration at the dose of 50 mg/kg (calculated as IB). Total body clearance ($CL_t$) and area under the plasma concentration-time curve (AUC) were not different between IB group and IBL groups after i.v. administration. On the other hand, IBL-l and IBL-dl produced peak plasma concentrations ($C_{max}$) significantly ealier and higher than IB. Time to reach peak concentration ($T_{max}$) after IBL administration was lower than that after IB administration. There was no difference in AUC across all different groups (IB, IBL-l and IBL-dl) after oral administration. However, absorption rate constant ($k_a$) of IBL-l and IBL-dl were significantly increased than that of IB. These results indicated that the administration of IBL-l and IBL-dl may be advantageous if rapid and reliable onset of pain relief is required.

• Proceedings of the Plant Resources Society of Korea Conference
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• 2001.11a
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• pp.20-33
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• 2001

A major portion of drugs used in Ayurvedic system of medicine which has been practiced since the early human civilization in Indian subcontinent were of plant origin. It should be noted that 70% of the population in this region depends on Ayurveda for their medical treatment and 60% of the drug resources are obtained from the Himalayan region. Therefore, Nepal becomes a potential source of plant drug resource since it occupies a major portion of the Himalaya. In the present paper, in general a current status of medicinal plant resources of Himalayan region especially Nepal will be discussed. In addition to this, a typical example of antidiabetic activity of Shilajit will be taken for the discussion. Shilajit is one of the crucial elements in several formulations including those of Rasayana, a therapy in Ayurveda, which has been practiced in the prevention of ageing and mental disorder. Although, Shilaiit is widely used for the treatment of diabetes, no satisfactory scientific reports are available up to now. The crude Shilajit in the market is a dark brown or black rock-like substance collected from the Himalayan region with a strong smell of cow's stale urine. In our studies, Shilajit (collected in the central Himalayan region) prevented the diabetes in nonobese diabetic (NOD) mice model. Shilajit also prevented the diabetes in the rats against the action of multiple low-dose (10 ㎎/㎏, i.v., 5 times) of streptozotocin. On the other hand, Shilajit did not show antioxidative activity. The preventive action of Shilajit on diabetes is mainly focused on the Th1 and Th2 cell activities, since Th2 cells activity was found to be significantly upregulated. Shilajit, however, showed a mild action in controlling the blood sugar level in young, old, and mild diabetic rats, but not in the severe diabetic rats. It also stimulated the nitric oxide production in macrophages. Based on these evidences, the antidiabetic activities of Shilajit appear to be immunomodulative probably by protecting or strengthening insulin-producing b-cells In the pancreas. further systematic research on constituents of Shilajit and its quality evaluation is necessary to enable the use of natural medicines in the treatment of diabetes.

• Journal of the Korean Society of Tobacco Science
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• v.31 no.2
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• pp.75-84
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• 2009

The objective of this study was to investigate the effect of nitrogen compounds such as protein on the chemical composition and toxicity of cigarette mainstream smoke. BSA protein was treated into the tobacco leaf of original 2R4F cigarette at 1~4 % level. The studies were performed which included a bacterial mutagenicity assay and a mammalian cell cytotoxicity assay for total particulate matter(TPM), and glutathione(GSH) consumption assay for gas/vapor phase(GVP) and determination of smoke chemical constitute. Cigarettes treated with protein were observed dose-dependent increase in yield of volatiles, semi-volatiles and aromatic amines compared with control cigarette. However, carbonyl compounds such as acrolein was lower than that of control cigarette when calculated on an equal TPM basis. The cytotoxicity of TPM obtained from the protein-added cigarettes was not different from that of control cigarette. However, the mutagenicity of the TPM from protein-treated cigarettes(1~4 %) was up to 10-27 % higher than that of control. On the other hand, toxicity of GVP from protein-treated cigarette(4 %) was significantly decreased compared with control cigarette. An overall assessment of our data suggests that nitrogen compounds such as protein should be important for the chemical composition and biological activity of cigarette mainstream smoke.

• The Journal of Korean Medicine
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• v.26 no.1 s.61
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• pp.26-36
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• 2005

Objective : Many traditional herbal remedies exhibit several beneficial effects including anti-inflammation. Euonymus alatus (Thunb.) Sieb (EA), known as Gui jun woo in Korea, has long been used in folk medicine to regulate Qi (bodily energy) and blood circulation, relieve pain, eliminate stagnant blood, and treat dysmenorrhea in oriental countries. The exact mechanism of the anti-inflammatory action of Euonymus alatus (Thunb.) Sieb (EA), however, has not been determined. Methods: Since there is increasing evidence that nitric oxide (NO) plays a crucial role in the pathogenesis of inflammatory diseases, this study was undertaken to address whether the methanol (MeOH) extract and its fractions of the bark of EA could modulate the expression of inducible NO synthase (iNOS) in thioglycollate-elicited murine peritoneal macrophages and murine macrophage cell line, RA W264.7 cells. Results: Stimulation of the peritoneal macrophages and RAW264.7 cells with $interferon-\gamma\;(IFN-\gamma)$ and lipopolysaccharide (LPS) resulted in increased production of NO in the medium. However, the butanol (BuOH) fraction of the MeOH extract of EA barks showed marked inhibition of NO synthesis in a dose-dependent manner. The inhibition of NO synthesis was reflected in the decreased amount of iNOS protein, as determined by Western blotting. The BuOH fraction did not affect the viability of RA W264.7 cells, as assessed by methylthiazol-2-yl-2, 5-diphenyl tetrazolium bromide (MTT) assay; rather, it reduced endogenous NO-induced apoptotic cell death via inhibition of NO synthesis in RAW264.7 cells. On the other hand, the MeOH and BuOH fraction showed no inhibitory effect on the synthesis of NO by RAW264.7 cells, when iNOS was already expressed by the stimulation with $IFN-\gamma$ and LPS. Conclusion: Collectively, these results demonstrate that the MeOH and BuOH fraction inhibits NO synthesis by inhibition of the induction of iNOS in murine macrophages.

• The Journal of Korean Medicine
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• v.19 no.2
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• pp.36-49
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• 1998

HERBA SAURURI (HS) has been known to use antiinflammatory drug. To investigated the mechanism of HS-induced NO synthesis, I evaluated the ability of protein kinase C (PKC) inhibitors such as staurosporine (STSN) or polyymyxin B to block HS-induced effects. HS alone had only a small effect, whereas in combination with $rIFN-{\gamma}$, markedly increased NO synthesis in a dose dependent manner. STSN and polymyxin B decreased NO synthesis, which had been induced by $rIFN-{\gamma}$, plus HS. Furthermore, prolonged incubation of the cells with phorbol ester, which down-regulates PKC activity abolished synergistic cooperative effect of HS with $rIFN-{\gamma}$ on NO synthesis. STSN and Polymyxin B potently inhibited HS-induced $TNF-{\alpha}$ secretion by $rIFN-{\gamma}$ plus HS. However, $rIFN-{\gamma}$ plus $TNF-{\alpha}-induced$ NO synthesis was not blocked by STSN or polymyxin B. On the other hand, tyrosine kinase inhibitor, genistein, blocked the NO synthesis and $TNF-{\alpha}$ secretion by $rIFN-{\gamma}$ plus HS. In conlusion, the present results strongly suggest that the capacity of HS to increase NO synthesis from $rIFN-{\gamma}-primed$ macrophages is the result of HS-induced $TNF-{\alpha}$ secretion via the signal transduction pathway of PKC and tyrosine kinase.