• Journal of Pharmaceutical Investigation
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• v.40 no.1
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• pp.15-21
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• 2010

Sibutramine is an orally administered centrally-acting antiobesity agent and inhibits both noradrenaline(norephinephirine) and serotonin(5-HT) reuptake. These effects are contributed by its active metabolites, M1 and M2. However, as the free base form of sibutramine is an oil form in room temperature, it had the problem of handling and stability. Thus, this drug should be used in the form of acid salt form in the pharmaceutical application. Unfortunately, anhydrous sibutramine hydrochloride is highly hygroscopic and unstable. In order to solve the hygroscopicity of the anhydrous salt form, another sibutramine acid salt form must be developed as a hydrate form. In this study. to overcome these problems, various of sibutramine acid salt forms were prepared with the pharmaceutically available salts such as maleate, esylate, mandelate, camsylate, besylate, salicylate, tartrate, isethionate and malate forms, and their physicochemical properties were investigated. Sibutramine malate was selected for excellent solubility and stability among the listed salt forms above. Its pharmacokinetic parameters were evaluated in rats comparing with sibutramine HCl, resulting in similar parameters. In vitro dissolution study of sibutramine malate-loaded capsule was performed comparison with commercial product ($Reductil^{(R)}$) in pH 1.2, pH 4.0, pH 6.8 and water medium. Our results indicated that there were no significant differences in their dissolution profiles were similar in all tested medium. Thus, sibutramine malate-loaded capsule should be a potential candiate due to its excellent solubility, good stability and biosimilar absorption.

• The Korean Journal of Physiology and Pharmacology
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• v.18 no.6
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• pp.489-495
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• 2014

Protease-activated receptor (PAR)-2 is expressed in endothelial cells and vascular smooth muscle cells. It plays a crucial role in regulating blood pressure via the modulation of peripheral vascular tone. Although some reports have suggested involvement of a neurogenic mechanism in PAR-2-induced hypotension, the accurate mechanism remains to be elucidated. To examine this possibility, we investigated the effect of PAR-2 activation on smooth muscle contraction evoked by electrical field stimulation (EFS) in the superior mesenteric artery. In the present study, PAR-2 agonists suppressed neurogenic contractions evoked by EFS in endothelium-denuded superior mesenteric arterial strips but did not affect contraction elicited by the external application of noradrenaline (NA). However, thrombin, a potent PAR-1 agonist, had no effect on EFS-evoked contraction. Additionally, ${\omega}$-conotoxin GVIA (CgTx), a selective N-type $Ca^{2+}$ channel ($I_{Ca-N}$) blocker, significantly inhibited EFS-evoked contraction, and this blockade almost completely occluded the suppression of EFS-evoked contraction by PAR-2 agonists. Finally, PAR-2 agonists suppressed the EFS-evoked overflow of NA in endothelium-denuded rat superior mesenteric arterial strips and this suppression was nearly completely occluded by ${\omega}$-CgTx. These results suggest that activation of PAR-2 may suppress peripheral sympathetic outflow by modulating activity of $I_{Ca-N}$ which are located in peripheral sympathetic nerve terminals, which results in PAR-2-induced hypotension.

• Advances in Traditional Medicine
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• v.7 no.4
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• pp.409-417
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• 2007

We investigated the effect of Arogh, a polyherbal formulation (PHF) on animal models of anxiety based on exploratory behavior. The anxiolytic activity of polyherbal formulation (30, 100, 300 and 500 mg/kg) was studied using various behavioural paradigms such as elevated plus maze (EPM), light/dark apparatus (LDA), open field apparatus (OFA), hole board apparatus (HBA). Diazepam (1 mg/kg) was used as a standard anxiolytic drug. The effect of PHF (100 and 300 mg/kg) on serotonin, dopamine and noradrenaline mediated behaviour was studied by lithium induced head twitches in rats, haloperidol induced catalepsy in mice and clonidine induced hypothermia in rats respectively. In EPM, PHF (100, 300 and 500 mg/kg) significantly (P < 0.05) increased the time spent in open arms and the number of entries in open arms. In LDA, PHF (100, 300 and 500 mg/kg) significantly (P < 0.05) increased the time spent in lit zone. In OFA, PHF (100, 300 and 500 mg/kg) significantly (P < 0.05) increased the number of assisted rearing and the number of squares traversed. In HBA, PHF (100, 300 and 500 mg/kg) significantly (P < 0.05) increased the number of head poking. In lithium induced head twitches, PHF (100 and 300 mg/kg) significantly (P < 0.05) decreased the number of head twitches. In haloperidol induced catalepsy, PHF (300 mg/kg) decreased the duration of catalepsy significantly (P < 0.05) at 60 min. In clonidine-induced hypothermia, PHF (300 mg/kg) did not modify the effect. Drugs must be carefully assessed on EPM test and therefore in the present study EPM is supported by other tests. Present study indicates that Arogh, a polyherbal formulation possess anxiolytic activity. It diminished serotonergic transmission and decreased the duration of catalepsy indicating potentiation of dopaminergic transmission. Thus, Arogh a polyherbal formulation contains bioactive principles which possess anxiolytic activity and modified 5-HT and DA mediated behaviour.

• Advances in Traditional Medicine
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• v.7 no.3
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• pp.261-273
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• 2007

We investigated the antihypertensive effect of Pet ether extract (PE) of ginger rhizome; its toluene fraction (TF) and Korean ginseng extract (KGE) in deoxycorticosterone acetate (DOCA) - salt induced and fructose induced hypertensive rats. In DOCA model, DOCA (25 mg/kg, once a week; s.c) was administered in uninephrectomised animals for 4 w. PE (50 mg/kg/day; p.o), TF (10 mg/kg/day; p.o) and KGE (30 mg/kg/day; p.o) were evaluated for their antihypertensive effect. In the fructose model, drinking water was replaced with fructose (10%) for five weeks to induce hypertension. PE (50 mg/kg/day; p.o) and KGE (30 mg/kg/day; p.o) were assessed for its antihypertensive effect in fructose model. After completion of the treatment schedule, vascular reactivity to various agonists like 5-HT, noradrenaline, adrenaline, phenylbiguanide and acetylcholine were recorded in rats of both the models. A cumulative dose response curve (CDRC) of 5-HT was carried out in isolated rat fundus strip of the fructose induced hypertensive rats. Chronic administration of PE (50 mg/kg/day; p.o), TF (10 mg/kg/day; p.o), and KGE (30 mg/kg/day; p.o) significantly reduced the blood pressure in DOCA salt whereas PE (50 mg/kg/day; p.o) and KGE (30 mg/kg/day; p.o) reduced the blood pressure in fructose induced hypertensive rats. Treatment with PE (50 mg/kg/day; p.o) and KGE (30 mg/kg/day; p.o) in fructose model for five weeks shifted the CDRC towards the right on rat fundus. The mechanism of action may partly involve the serotonergic antagonistic property.

• Korean Journal of Veterinary Research
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• v.47 no.4
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• pp.371-378
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• 2007

To understand the role of $PM_{2X}/P_{2Y}$ receptor in cortex region of kidney and renal artery, molecular and functional analysis of $PM_{2X}/P_{2Y}$ receptor by pharmacophysiological skill in conventional swine tissues were performed. In functional analysis of $P_{2Y}$ receptor for vascular relaxation, 2-methylthio adenosine triphosphate, a strong agonist of $P_{2Y}$ receptor, induced relaxation of noradrenaline (NA)-precontracted renal artery in a dose-dependent manner. Strikingly, relaxative effect of ATP, 2-msATP, agonists of $P_{2Y}$ receptor, abolished by treatment of reactive blue 2, a putative $P_{2Y}$ receptor antagonist. In contrast, no significant differences of gene encoding $PM_{2X}/P_{2Y}$ and protein expression in immortalized suprachiasmatic nucleus from brain, primary isolated vascular smooth muscle cells from renal artery of pigs and HEK293 from human embryonic kidney under with/without adenosine triphosphate were observed. Taken together, the relationship between molecular and functional characteristic of $PM_{2X}/P_{2Y}$ receptors in conventional pig should be considered that they are another important factor which regulate the kidney function in swine. Based on this study, we propose the purinergic receptor as well as adrenergic and cholinergic receptors is an essential component of the renal homeostasis.

• Journal of the Korean Society of Food Science and Nutrition
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• v.21 no.4
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• pp.460-470
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• 1992

Thermogenesis in brown adipose tissue (BAT) can serve the animal in the regulation of its body temperature and of its body weight. Thermogenesis can be switched on by exposure of the animal to cold (non-shivering thermogenesis) or by overeating (diet-induced thermogenesis). BAT mitochondria are uniquely specialized for thermogenesis, possessing a specific proton conductance pathway that is regulated by the concentration of fatty acids in the cells of BAT. The level of fatty acids is in turn controlled by the lipolytic action of noradrenaline on the tissue. When the proton conductance pathway operates, the mitochondria are effectively uncoupled and exhibit extremely high rates of substrate oxidation with a great increase in heat production. Thus it is suggested that BAT is of importance in energy balance and human obesity treatment if thermogenesis can be stimulated specifically.

• The Korean Journal of Pharmacology
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• v.31 no.2
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• pp.145-152
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• 1995

The effects and interactions of $4{\beta}-phorbol$ 12,13-dibutyrate(PDB) and polymyxin B(PMB) with adenosine on the electrically-evoked norepinephrine (NE) release were studied in the rat hippocampus. Slices from the rat hippocampus were equilibrated with $^3H-noradrenaline$ and the release of the labelled product, $^3H-NE$, which evoked by electrical stimulation$(3\;Hz,\;2\;ms,\;5\;VCm^{-1},\;rectangular\;pulses)$ was measured. PDB$(0.3{\sim}10\;{\mu}M)$, a selective protein kinase C(PKC) activator, increased the evoked NE release in a dose related fashion while increasing the basal rate of release. And the effects of $1\;{\mu}M$ PDB were significantly inhibited by $0.3\;{\mu}M$ tetrodotoxin(TTX) pretreatment or $Ca^{++}-free$ medium. $PMB(0.03{\sim}1\;mg)$, a specific PKC inhibitor, decreased the NE release in a dose dependent manner while increasing the basal rate of release. Adenosine $(1{\sim}10\;{\mu}M)$ decreased the NE release without changing the basal rate of release, and this effect was significantly inhibited by 8-cyclopentyl-1,3-dipropylxanthine$(2\;{\mu}M)$, a selective $A_1-receptor$ antagonist, treatment. Also, adenosine effects were significantly inhibited by PDB-and PMB-pretreatment. These results suggest that the PKC plays a role in the NE release in the rat hippocampus and might be participated in a post-receptor mechanism of the $A_1-adenosine$ receptor.

• YAKHAK HOEJI
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• v.24 no.2
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• pp.79-86
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• 1980

CO-intoxication is a serious problem in public health since the coal briquette has been used as one of fuels from 1950's. It has been discussed that the treatment with acetic acid vapor may be effective for CO-intoxication. This study was undertaken to investigate the action of acetic acid therapy, comparing with the spontaneous air treatment The acetic acid vapor was introduced to the blood combined with CO (in vivo and in vitro). The dissociation of COHb, the production of COHb, the levels of Hb and adrenaline and nor-adrenaline were measured. The effect of acetic acid vapor on dissociation of COHb was about 7-9% more effective than the spontaneous air treatment. The acetic acid vapor treatment for the dissociation of COHb was similar effect to the spontaneous air treatment. In an experiment of the combining CO gas with blood, the acetic acid vapor treatment was less effective in the production of COHb than that of spontaneous air treatment. Treatment with the acetic acid vapor to rabbit intoxicated with CO gas induced a little amount of Hb in blood comparing with the spontaneous air treatment. But, it is not a significant increment statistically. By the acetic acid vapor treatment after CO gas intoxication the adrenaline was increased and noradrenaline was decreased. With these results, it is assumed that the effect of acetic acid therapy on CO-gas intoxication would be caused by inductions of Hb and adrenaline and to be reduction of nor-adrenaline.

• The Korean Journal of Physiology and Pharmacology
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• v.27 no.4
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• pp.325-331
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• 2023

α₁-adrenoceptors link via the G-protein Gq/G₁₁ to both Ca²⁺ entry and release from stores, but may also activate Rho kinase, which causes calcium sensitization. This study aimed to identify the subtype(s) of α₁-adrenoceptor involved in Rho kinase-mediated responses in both rat aorta and mouse spleen, tissues in which contractions involve multiple subtypes of α₁-adrenoceptor. Tissues were contracted with cumulative concentrations of noradrenaline (NA) in 0.5 log unit increments, before and in the presence of an antagonist or vehicle. Contractions produced by NA in rat aorta are entirely α₁-adrenoceptor mediated as they are competitively blocked by prazosin. The α_1A-adrenoceptor antagonist RS100329 had low potency in rat aorta. The α_1D-adrenoceptor antagonist BMY7378 antagonized contractions in rat aorta in a biphasic manner: low concentrations blocking α_1D-adrenoceptors and high concentrations blocking α_1B-adrenoceptors. The Rho kinase inhibitor fasudil (10 µM) significantly reduced aortic contractions in terms of maximum response, suggesting inhibition of α_1B-adrenoceptor mediated responses. In the mouse spleen, a tissue in which all 3 subtypes of α₁-adrenoceptor are involved in contractions to NA, fasudil (3 µM) significantly reduced both early and late components to the NA contraction, the early component involving α_1B- and α_1D-adrenoceptors, and the late component involving α_1B- and α_1A-adrenoceptors. This suggests that fasudil inhibits α_1B-adrenoceptor mediated responses. It is concluded that α_1D- and α_1B-adrenoceptors interact in rat aorta and α_1D-, α_1A- and α_1B-adrenoceptors interact in the mouse spleen to produce contractions and these interactions suggest that one of the receptors preferentially activates Rho kinase, most likely the α_1B-adrenoceptor.

• Sleep Medicine and Psychophysiology
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• v.7 no.2
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• pp.96-101
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• 2000

Objectives: Through comparing sleep variables and autonomic activities among three shifts in shift workers, the authors intended to clarify which shift is most tolerable and to identify the characteristics of their psychological and physical problems. This study is also expected to help shift workers to adapt themselves to their work more effectively. Methods: Fifty one shift workers took part in this study. They were working in a rapidly rotating system in which they worked for 3 days in one shift with one day off between each shift. Based on a sleep diary, sleep latency (SL), sleep period time (SPT), and number of wake after sleep onset (NWASO) were estimated and compared among the three shifts. In assessing sleepiness, Epworth sleepiness scale (ESS) and visual analogue scale (VAS) were used. To evaluate mood states among the three shifts, profile of mood states (POMS) was administered. Heart rate variability (HRV), and the level of adrenaline and noradrenaline were measured to assess autonomic activities. HRV included low frequency power (LF), high frequency power (HF), and LF/HF. Results: SPT was significantly lengthened during the evening shift and SL was shortened during the night shift. The workers showed a drop in alertness at wake-up during morning shift and a drop in alertness at work during night shift. During night shift the subjects complained of physical fatigue and cognitive decline. Comparison of HRV showed that parasympathetic activity was most prominent during the evening shift. Secretion of adrenaline and noradrenaline decreased during the evening shift, though statistically not significant. Conclusion: We found that the evening shift was most tolerable among the three shifts. It is recommended that morning light exposure be done during the morning shift and nocturnal light exposure during the night shift.