In vivo studies of KR-31125 (2-butyl-5-dimethoxymethyl-6-phenyl-7-methyl-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine) were performed in pithed rats, conscious angiotensin II (AII) challenged normotensive rats, renal hypertensive rats (RHRs) and furosemide-treated beagle dogs. KR-31125 induced a non-parallel right shift in the dose-pressor response curve to AII ($ID_{50}$: 0.095 mg/kg) with a dose-dependent reduction in the maximum responses in pithed rats. Compared to losartan, this antagonistic effect was about 18 times more potent, presenting competitive antagonism. Other agonists such as norepinephrine and vasopressin did not alter the responses induced by KR-31125. Orally administered KR-31125 had no agonistic effect and dose-dependently inhibited the pressor response to AII with a slightly weaker potency ($ID_{50}$: 0.25 and 0.47 mg/kg, respectively) in the AII-challenged normotensive rat model, but with a more rapid onset of action than losartan (time to $E_{max}$: 30 min for KR-31125 and 6 hr for losartan). KR-31125 produced a dose-dependent antihypertensive effect with a higher potency than losartan in RHRs, and these effects were confirmed in furosemide-treated dogs where they presented a dose-dependent and long-lasting (>8 hr) antihypertensive effect with a rapid onset of action (time to $E_{max}$: 2-4 hr), as well as a 20-fold greater potency than losartan. These results suggest that KR-31125 is a potent, orally active $AT_1$ receptor antagonist that can be applied to the development of new diagnostic and research tools as an added exploratory potential of $AT_1$ receptor antagonist.
Park, Yeong-Chul;Kim, Jong-Bong;Kook, Yoon-Boom;Lee, Sun-Dong
Herbal Formula Science
/
v.20
no.1
/
pp.13-24
/
2012
Objectives : Yukmijihwang-tang(Wan), a well-known formula for invigorating yin-particular kidney yin, was first recorded in "Xiao er Yao Zheng Zhi Jue", consisting of Radix Rehmanniae Preparata, Fructus Macrocarpii, Rhizoma Dioscoreae Oppositae, Poria, Rhizoma Alismatis and Cortex Moutan Radicis with dose proportion of 8:4:4:3:3:3. Although clinical trials have been lacking, various pharmacological actions for Yukmijihwang-tang has been identified newly using animal models. In addition, it was reported that Yukmijihwang-tang increases structural chromosome aberrations significantly in Chinese hamster lung cells. In this article, it is purposed that new studies for pharmacology and toxicology of Yukmijihwang-tang are reviewed. Insight into new studies of Yukmijihwang-tang at the cellular and animal levels will enhance our understanding of Yukmijihwang-tang against various diseases will provide new tools to diagnose and treat patients. Methods : Recent researches for Yukmijihwang-tang were reviewed and summarized in terms of pharmacological action and toxicity. All sources for review were based on recent studies loaded on data base of web sites such as Science Direct and National Center for Biotechnology Information. Results and Conclusions : Recently, reports showed that YMJ had antiaging effects, antioxidant and free radical scavenging activities, anti-renal hypertension and prevented tumors, and diabetes mellitus. However, there is little information on its safety except general toxicity, acute and sub-chronic oral toxicity, or genotoxicity. In addition, clinical trial for Yukmijihwang-tang was limited even though Yukmijihwang-tang has been used extensively in Korean traditional medicine. Thus, further studies are necessary to focus on safety evaluation and clinical trial for Yukmijihwang-tang.
Kang, Ju-Seop;Lee, Joo-Won;Jhee, Ok-Hwa;Om, Ae-Son;Lee, Min-Ho;Shaw, Leslie M.
Biomolecules & Therapeutics
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v.13
no.2
/
pp.65-77
/
2005
Present article reviews about clinical pharmacology of mycophenolic acid (MPA), the active form of mycophenolate mofetil (MMF), as widely used component of immunosuppressive regimens in the organ transplantation field. MMF, used alone or concomitantly with cyclosporine or tacrolimus, has approved in reducing the incidence of acute rejection and has gained widespread use in solid organ such as kidney, heart and liver transplantation. The application of MPA and development of MMF has shown a considerable impact on immunosuppressive therapy for organ transplantation as a new immunosuppressive agent with different mechanism of action from other drugs after early 1990s. In particular aspect, use of MMF, a morpholinoethyl ester of MPA, represented a significant advance in the prevention of organ allograft rejection as well as allograft and patient survival. In considering MMF clinical data, it is important to note that there is a strong correlation between high MPA area under curve(AUC) values and a low probability of acute allograft rejection. Individual trials have shown that MMF is generally well tolerated and revealed that MMF decreased the relative risk of developing chronic allograft rejection compared with azathioprine. Recent clinical investigations suggested that improved effectiveness and tolerability will results from the incorporation of MPA therapeutic drug monitoring into routine clinical practice, providing effective MMF dose individualization in renal and heart transplant patients. Therefore, MMF has a selective immunosuppressive effect with minimal toxicity and has shown to be more effective that other agents as next step of immunosuppressive agents and regimens that deliver effective graft protection and immunosuppression along with a more favorable side effect.
Ginseng is a popular medicinal plant highly valued throughout the world. Asian ginseng is one of the most common species of ginseng. It has long occupied a significant position in oriental medicine and has been justified its name as the 'king herb'. As a nutritional supplement, ginseng is an extremely common and popular herbal medicine in the United States and Canada in recent decades. The multiple constituents of ginseng possess equally multifaceted pharmacological actions as demonstrated by numerous studies. Ginseng root and its constituents influenced the central nervous system, endocrine, cardiovascular, gastrointestinal system, sexual, renal organ and immune system, etc. One important action is its anti-hyperglycemic effect. Previous studies on ginseng demonstrate that only the root of ginseng has been used in the treatment of diabetes, while the other parts of ginseng plant were always neglected. Recently, we analyzed the constituents of ginseng berry, leaf and discovered that ginseng berry, leaf extracts and its total ginsenosides have the ability to reduce hyperglycemia and body weight and increase the peripheral glucose utilization in obese or diabetic ob/ob or db/db mice. Our data suggest that all parts of ginseng plant, including root, berry, leaf and stem exhibit potent anti-hyperglycemic and anti-obese effects and may provide an opportunity to develop a novel class of anti-diabetic agents.
Mizoribine (MZR) has been shown to possess immunosuppressive activity that selectively inhibits the proliferation of lymphocytes by interfering with inosine monophosphate dehydrogenase. The efficacy of MZR is not only in patients who have had renal transplantation, but also in patients with rheumatoid arthritis (RA), lupus nephritis, and primary nephritic syndrome. Because the exact mechanism of its immunosuppressive action is not clear, the object of this study was to examine the ability of MZR to regulate the antigen presenting cells (APCs), dendritic cells (DCs). In this work, we tested whether MZR ($1{\sim}10\;{\mu}g/mL$) could inhibit the cross-presentation of DCs. DC2.4 cells ($H-2K^{b}$) or bone marrow-derived DCs (BM-DCs) generated from BM cells of C57BL/6 mouse ($H-2K^{b}$) were cultured in the presence of MZR with OVA-microspheres, and the amount of OVA peptide-class I MHC complexes was measured by a T cell hybridoma, B3Z, that recognizes OVA (257-264 : SIINFEKL)-$H-2K^{b}$ complex and expresses-galactosidase. MZR profoundly inhibited the expression of SIINFEKL-$H-2K^{b}$ complexes. This inhibitory activity of MZR appeared to affect the phagocytic activity of DCs. MZR also decreased IL-2 production when we examined the effects of MZR on $CD4^{+}$ T cells. These results provide an understanding of the mechanism of immunosuppressive activity of MZR on the inhibition of MHC-restricted antigen presentation and phagocytic activity in relation to their actions on APCs.
Journal of the Korea Academia-Industrial cooperation Society
/
v.10
no.11
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pp.3473-3479
/
2009
The pharmacological profile of KR-31081, a newly synthesized AT1 receptor antagonist, was evaluated in pithed rats, conscious renal hypertensive rats (RHRs) and conscious furosemide-treated beagle dogs. In pithed rats, KR-31081 (i.v.) induced a non-parallel right shift in the dose-pressor response curve to angiotensin II (ID50: 0.05 mg/kg) with a dose-dependent reduction in the maximum responses; this antagonistic effect was about 40 times more potent than losartan (ID50: 1.74 mg/kg) which showed competitive antagonism. KR-31081 did not alter the responses induced by other agonists such as norepinephrine and vasopressin. In RHRs, orally given KR-31081 produced a dose-dependent and long-lasting (>24 h) antihypertensive effect with a higher potency to losartan (ED20: 0.30 and 3.36 mg/kg, respectively). In furosemide-treated dogs, orally given KR-31081 produced a dose-dependent and long-lasting (>8h) antihypertensive effect with a rapid onset of action (time to Emax: 1-1.5 h) and 20-fold greater potency than losartan (ED20: 0.41 and 8.13 mg/kg, respectively). These results suggest that KR-31081 is a potent, orally active AT1 receptor antagonist useful for the research and diagnostic tools as an added exploratory potential.
Journal of Physiology & Pathology in Korean Medicine
/
v.26
no.1
/
pp.19-25
/
2012
This study was designed to investigate the effects of a new herbal medicine named CWS-A on the changes in regional cerebral blood flow (rCBF) and mean arterial blood pressure (MABP) in normal rats, and further to determine the mechanism of action. Also, this study was designed to investigate the effects of CWS-A on the changes in rCBF in cerebral ischemic rats and the safety examination of CWS-A in rats regared to body weight change, renal and liver function test, CBC, $LD_{50}$ and histological observation in rats. The rCBF was significantly and stably increased and MABP was significantly decreased by CWS-A during the period of cerebral reperfusion in normal rats. However, there were no here were no significant changes of rCBF in ischemic rats. In additional, there were no significant changes on the safety examination. In conclusion, these results suggest that medication of CWS-A is effective for the improve the cerebral blood flow and CWS-A can be prescribed as vertigo(眩暈) symptoms treatment.
Kim, Kee-Won;Kwak, Yong-Geun;Chae, Joon-Seak;Cho, Kyu-Park
The Korean Journal of Pharmacology
/
v.23
no.2
/
pp.123-131
/
1987
The possible inolvement of central opiate system in the control of cardiovascular function and in the antihypertensive action of clonidine has been examined in unanesthetized rats with shamoperated or 2-kidney, 1-clip (2K1C) renal hypertension. In both groups of rats, intraventricular clonidine $(3-30\;{\mu}g/kg)$ produced hypotension and bradycardia. Hypotensive action of clonidine was more potent in the hypertensive rats than in the normotensive sham-operated rats. Yohimbine $(30\;{\mu}g/kg,\;i.v.t.)$ inhibited the hypotension and bradycardia produced by clonidine. Naloxone ($50\;{\mu}g/kg$, i.v.t.) inhibited the action of clonidine in 2K1C hypertensive rats but not influenced in the sham-operated rats. Intraventricular morphine $(10-100\;{\mu}g/kg)$ also reduced rats. Intraventricular morphine $(10-100\;{\mu}g/kg)$ also reduced blood pressure and heart rate in both groups of rats. But these effects were not affected by yohimbine, but antagonized by naloxone ($50\;{\mu}g/kg$, i.v.t.). Chronic treatment of 2K1C rats with clonidine ($3{\times}20\;{\mu}g/kg$, p.o.,) for 14 days from 1 day after 2K1C operation) suppressed the development of hypertension and maintained the blood pressure in normal level and this errect of clonidine was abolished by naloxone (2 mg/kg, i. p.). In the 2K1C hypertensive rats, immunoreactive ${\beta}-endorphin$ content was significantly decreased, but maximum binding (Bmax) of $(^3H)-naloxone$ was significantly increased in brain of 2K1C hypertensive rats. However, Kd value was not changed. These results suggest that the opioidergic component might be involved in the antihypertensive action of clonidine only in hypertensive and that central opiate system might play important roles in pathophysiology of development and maintenance of hypertension.
It has been suggested that ion transport systems are intimately involved in mediating the effects of growth regulatory factors on the growth of a number of different types of animal cells in vivo. The functional importance of the apical membrane $Na^+/H^+$ antiporter in the renal proximal tubule is evidenced by estimates that this transporter mediates the reabsorption of approximately one third of the filtered load of sodium and the bulk of the secretion of hydrogen ions. This study was designed to investigate the pathway utilized by IGF-I in regulating sodium transport in primary cultured renal proximal tubule cells. Results were as follows : 1. $Na^+$ was observed to accumulate in the primary cells as a function of time. Raising the concentration of extracellular NaCl induced an decrease in $Na^+$ uptake compared with control cells in a dose dependent manner. The rate of $Na^+$ uptake into the primary cells was about two times higher in the absence of NaCl($40.11{\pm}1.76pmole\;Na^+/mg\;protein/min$) than in the presence of 140mM NaCl($17.82{\pm}0.94pmole\;Na^+/mg\;protein/min$) at the 30 minute uptake. 2. $Na^+$ uptake was inhibited by IAA($1{\times}10^{-4}M$) or valinomycin($5{\times}10^{-6}M$) treatment($50.51{\pm}4.04$ and $57.65{\pm}2.27$ of that of control, respectively). $Na^+$ uptake by the primary proximal tubule cells was significantly increased by ouabain($5{\times}10^{-5}M$) treatment($140.23{\pm}3.37%$ of that of control). When actinomycin D($1{\times}10^{-7}M$) or cycloheximide($4{\times}10^{-5}M$) was applied, $Na^+$ uptake was decreased to $90.21{\pm}2.39%$ or $89.64{\pm}3.69%$ of control in IGF-I($1{\times}10^{-5}M$) treated cells, respectively. 3. Extracellular cAMP decreased $Na^+$ uptake in a dose-dependent manner($10^{-8}-10^{-4}M$). IBMX($5{\times}10^{-5}M$) also inhibited $Na^+$ uptake. Treatment of cells with pertussis toxin(50pg/ml) or cholera toxin($1{\mu}g/ml$) inhibited $Na^+$ uptake. Extracellular PMA decreased $Na^+$ uptake in a dose-dependent manner(1-100ng/ml). 100 ng/ml PMA concentration significantly inhibited $Na^+$ uptake in IGF-I treated cells. However, staurosporine($1{\times}10^{-7}M$) had no effect on $Na^+$ uptake. When PMA and staurosporine were added together, the inhibition of $Na^+$ uptake was not observed. In conclusion, sodium uptake in primary cultured rabbit renal proximal tubule cells was dependent on membrane potentials and intracellular energy levels. IGF-I stimulates sodium uptake through mechanisms that involve some degree of de novo protein and/or RNA synthesis, and cAMP and/or PKC pathway mediating the action mechanisms of IGF-I.
To investigate the antioxidant activity of extract from the raw walnut, Juglans sinensis Dode, we prepared five fractions (methanol (MeOH), dichloromethane $(CH_2Cl_2)$, ethyl acetate (EtOAc), n-buthanol (n-BuOH) and dehydrogen monooxide $(H_2O)$ fractions) and examined. The effect of walnut extract on the oxidative stress was investigated in vitro. The DPPH (2,2-Di (4-tert-octylphenyl)-1-picrylhydrazyl) free radical scavenging activity of extract from raw walnut was shown in the following order: $EtOAc\;fraction layer. The result showed that the highest activity $(0.56{\mu}g/ml,\;IC_{50}.)$ was observed in EtOAc fraction, whereas n-BuOH fraction, MeOH fraction, $CH_2O_2$ fraction and $H_2O$ layer of $IC_{50}$ were $2.34{\mu}g//ml,\;3.88{\mu}g/ml,\;8.06{\mu}g/ml,\;and\;8.19{\mu}g/ml$, respectively. The radical scavenging activity assay of each fraction showed that the antioxidative activity was observed in the following order: EtOAc fraction $(74.27\pm1.56\%)>MeOH\;fraction\;(60.76\pm3.4\%)>n-BuOH\;fraction\;(59.32\pm0.88\%)>H_2O\;layer\;(41.69\pm2.06\%)$. These results revealed that all fractions, except for $CH_2Cl_2$ fraction, showed high antioxidative activity. Furthermore, the peroxynitrite $(ONOO^-)$ scavenging activity was assayed in each fraction. The result showed that the $ONOO^-$ scavenging activity of EtOAc fraction, MeOH fraction and n-BuOH fraction from raw walnut was $95.14\pm0.36\%,\; 90.02\pm1.19\%\;and\;89.41\pm0.81\%$, respectively. The tert-butylhydroperoxide (t-BHP) treatment in vitro increased lactate dehydrogenase release and lipid peroxidation in renal cortical slices. Such changes were completely prevented by addition of MeOH fraction, EtOAc fraction and n-BuOH fraction of walnut. These results indicate that the walnut extract exerts the benedicial effect against t-BHP-induced cell injury and its effect may be due to antioxidant action. In addition, it is suggested that walnut extract might be developed as the effective scavenger for the prevention of oxidative stress.
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