• Archives of Pharmacal Research
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• v.23 no.3
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• pp.230-236
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• 2000

(1'R, 2R)-, (1'R, 2S)-, (1'S, 2R)- and (1'S, 2S)-$\alpha$-hydroxymetoprolol; (2R)- and (2S)-O-des-methylmetoprolol; and (2R)- and (2S)-metoprolol acid are major metabolites of (2R)-and (2S)-metoprolol, $\beta$-adrenergic antagonist. The focus of most chiral separation methods until now has been on determination of the enantiomeric parent drug. However, it is just as important to be able to follow the metabolism of the enantiomers and their possible chiral metabolites. Therefore, for the study of stereoselective metabolism and pharmacokinetics of metoprolol, the chiral separation of the enantiomers of metoprolol and its metabolites has been investigated using four chiral stationary phases, i.e., Chiralcel OD, Chiral-AGP, Cyclobond I and Sumichiral OA-4900 columns. Metoprolol acid was resolved only by Sumichiral OA-4900. Chiralcel OD provided the highest separation factor and resolution value for metoprolol and O-desmethylmetoprolol and partially resolved the four stereoisomers of $\alpha$-hydroxymetoprolol. Diastereomeric $\alpha$-hydroxymetoprolols were resolved using the coupled column chromatographic system of two chiral stationary phases, Sumichiral OA-4900 column and Chiralcel OD column.

• Korean Journal of Biological Psychiatry
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• v.6 no.2
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• pp.259-263
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• 1999

Nefazodone, a newer antidepressant is a phenylpiperazine derivative that inhibits the reuptake of both norepinephrine and serotonin, and antagonizes $5-HT_{2A}$ and ${\alpha}_1$ adrenergic receptors. Compared with SSRIs, nefazodone caused the fewer activating symptoms, adverse gastrointestinal effects(nausea, diarrhea, anorexia) and adverse effects of sexual function, but is associated with the more dizziness, dry mouth, constipation, visual disturbances and confusion. We report on 4 cases of visual disturbances and hallucinations in patients taking nefazodone. It is not certain what mechanisms mediated these side effects, but three mechanisms are possible. 1) Nefazodone, as a 5-HT2 antagonist, might induce visual disturbances. 2) mCPP, metabolite of nefazodone might contribute to the hallucination through action on 5-HT receptor. 3) Dopaminergic enhancing activity of nefazodone might cause hallucination. These case report raises the possibility that dose-related perceptual disturbances may exist with nefazodone. The fact emphasizes the need to pay close attention to all possible drug interactions, particularly in patients treated with multiple psychoactive agents, older patients, and patients with decreased hepatic function.

• Biomolecules & Therapeutics
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• v.5 no.3
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• pp.239-245
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• 1997

Trimetoquinol (TMQ) and its analogs are known to have thromboxane $A_2$ antagonistic action. We also reported that GS389, chemically similar to TMQ, has competitive antagonistic action in rat aorta and human platelets. In the present study, we investigated the pharmacological characteristics of GS283 and GS 386, analogs of GS389, using vascular smooth muscle, human platelets and rat brain homogenates. In isolated pig coronary artery (PCA), both of GS283 and GS386 relaxed U46619-contracted rings in concentration dependent manner. Pretreatment with several concentrations of GS283 and GS386 shifted the dose-response curves to the right, and reduced of maximum contration dose-dependently. Furthermore, GS283 and GS386 strongly inhibited $Ca^{2+}$ -induced contraction in the PCA. In human platelets, U46619- and A23187-induced platelet aggregation was inhibited by GS283 and GS386, concentration-dependently. Anti-platelet aggregation was related to the compound\`s ability to inhibit ATP release at each stimulation. In rat brain homogenates, receptor-binding assay resulted that both GS283 and GS386 have a relative affinity to $\alpha$-adrenergic receptor. Taken together. we concluded that the mechamism of action of GS283 and GS86 is not related with in TXA$_2$ receptor but concerned with calcium antagonistic action and a-blocking action.n.

• Journal of Preventive Medicine and Public Health
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• v.42 no.3
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• pp.165-170
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• 2009

Objectives : We evaluated the risk of fracture associated with hypotension-related adverse drug reaction caused by taking alpha blockers to treat benign prostatic hyperplasia (BPH). Methods : We used the Health Insurance Review and Assessment Service database from January 1st 2005 to June 30th 2006 for this study. The male patients with BPH and who had a prescription for alpha blockers following any fractures were defined as the cases. We set the 20 day long hazard period prior to the index date and the four control periods whose lengths were same with hazard period. After 1:4 matching of the hazard and control periods, conditional logistic regression was used to calculate the odds ratios for the risk of fractures as related to the alpha blocker exposure. Results : Doxazosin and tamsulosin showed the increased risk of fractures, whereas terazosin did not. After stratification using the defined daily doses, a protective effect was shown for the patients who took terazosin at the doses lower than 0.4 DDD and the hazardous effect at the doses higher than or equal to 0.4 DDD. There was no significant difference for the risk of patients taking tamsulosin at the doses higher than 1.0 DDD but there was a statistically significant increase in the risk at the doses higher than or equal to 1.0 DDD. Conclusions : Alpha blockers for BPH may increase the risk of fracture in elderly patients who have comorbidities and take the concomitant medications. Alpha blockers need to be prescribed with caution, although some have high prostate specificity.

• Toxicological Research
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• v.12 no.2
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• pp.195-201
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• 1996

Endotoxic shock causes death in humans and animals via extreme hypoperfusion of peripheral organs. A massive production of nitric oxide (NO) both from the endothelical cells and smooth muscle cells has been proposed as a possible mechanism in this process. Since NO attenuated the contractility to vasoconstricting agents such as norepinephrine (NE) by directly acting on the smooth muscle cells, this mechanism was considered mainly as a postsynaptic mechanism. In this research it was investigated whether NO, thus released, also participates in the presynaptic events for the regulation of vascular tone in endotoxic shock. The role of NO was studied by adding NO donors or NO synthase inhibitor $N^\omega $methyl-L-arginine (NMA) in stimulated sympathetic nerves of the mesenteric vascular bed and the Langendorff heart of rats. Sodium nitroprusside (SNP), an NO donor, reduced the pressor responses of isolated mesenteric artery either to electrical stimulation or exogenously administered phenylephrine (PE). In this mesentery, although neither agent influenced NE release, in the presence of the adrenergic $\alpha_2$-receptor antagonist yohimbine, elecrical stimulation-evoked NE release was augumented by SNP. In the heart SNP facilitated the NE release induced by electrical stimulation, while NMA had no effect. From these results it is proposed that there exists a local reflex phenomenon in the junction between the sympathetic nerve terminals and the smooth muscle of resistance blood vessels; by which sympathetic responses are reduced by NO at the postjunctional level while NO facilitates NE release contributing to augumentation of sympathetic tone. All these facts suggest that NO produced during endotoxic shock has dual effects: whereas NO blunts the vasoconstrictive activity of NE at the postsynaptic level, NO presynaptically facilitates the release of NE from sympathetic nerve terminals.

• Archives of Pharmacal Research
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• v.22 no.2
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• pp.157-164
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• 1999

LB50016 was characterized as a selective and potent$ 5-HT_{1A}$ receptor agonist and evaluate it anxiolytic and antidepressant activities. It shows high affinity for $ 5-HT_{1A}$receptor, moderate affinity for $\alpha$2 adrenergic and $ 5-HT_{2A}$receptors and no significant affinity for other receptors tested. Hypothermia and increased serum corticosterone level were observed in LB50016-treated rats, which are mediated mostly by post synaptic $ 5-HT_{1A}$ receptor activation. In the mouse forced swim model for depression, LB50016-elicited dose-dependent reductions in immobility time, showing $ED_{50}$ of approximately 3 mg/kg i.p., which was blocked by pretreatment of NAN-190, $ 5-HT_{1A}$antagonist. In face-to-face test for anxiolytic activity in mice, estimated $ED_{50}$ was 2 mg/kg, i.p.. In isolation-induced aggression test with mice, fifty-fold increases in latency to attack were observed at 30 min and last up to 4 h after LB50016 treatment (3 mg/kg, i.p.). Taken together, LB50016-induced pharmacological activities are mediated by activation of $ 5-HT_{1A}$receptors, offering an effective therapeutic candidate in the management of anxiety and depression in humans.

• The Korean Journal of Pharmacology
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• v.22 no.2
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• pp.79-87
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• 1986

Recently it has been shown that central dopaminergic system regulates the renal function and that intracerebroventricularly (icv) administered dopamine (DA) produces antidiuresis and antinaturiuresis, resembling icv norepinephrine, and evidence has been accumulated which would suggest the involvement of adrenergic system in the DA effects. It was attempted therefore in this study to see whether the DA effect is influenced by pretreatment of yohimbine which is known as a specific ${\alpha}_2-adrenoceptor$ antagonist. Yohimbine produced, when given icv in doses of $100\;{\mu}g/kg$, marked antidiuresis and antinatriuresis along with decreases in renal perfusion and glomerular filtration. DA, in doses of $15\;{\mu}g/kg$, also produced antidiuresis and antinaturiuresis. However, after yohimbine-pretreatment DA $15\;{\mu}g/kg$ improved renal hemodynamics, and electrolyte excretion and urine flow rate transiently increased. With $150\;{\mu}g/kg$ DA, the antidiuresis was more marked in the control group. But the yohimbine-pretreated animals responded with marked diuresis and natriuresis, sodium excretion increasing more than three-fold, which lasted for 20 minutes. $K^+-excretion$, osmolar clearance as well as free-water reabsorption increased. Renal hemodynamics improved partly. Apomorphine, a DA agonist, when given icv in doses of $150\;{\mu}g/kg$, produced diuresis and naturiuresis, concomitant with increased renal hemodynamics. Yohimbine-pretreatment however did not abolish the apomorphine-induced diuresis and naturiuresis. Antidiuresis and antinatriuresis elicited by norepinephrine, $10\;{\mu}g/kg$, was not affected by yohimbine-pretreatment. These results indicate that the renal effects of icv DA is not so simple as those of norepinephrine, and the diuretic natriuretic cffect which had been masked by the hemodynamic effect becomes manifest only when the decreases in hemodynamics were removed by the pretreatment of yohimbine. It was further suggested that those DA receptors which mediate the natriuretic response to icv DA is not affected by yohimbine, whereas those receptors involved in the decrease in renal hemodvnamics are blocked by yohimbine. And the possibility of involvement of adrcnergic system in the DA action is not substantiated.

• The Korean Journal of Pharmacology
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• v.21 no.2
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• pp.119-127
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• 1985

The renal function is under regulatory influence of the central nervous system, mainly through activation of sympathetic nerve to the kidney, and it was recently reported that clonidine, an agonist to ${\alpha}_2$-adrenoceptors, induces diuresis and natriuresis when injected directly into a lateral ventricle of the rabbit brain (i.c.v.). This study was undertaken, therefore, to obtain further information as to the role of the central ${\alpha}_2$-adrenoceptors in regulating renal function, by observing the effects of i.c.v. yohimbine, a specific antagonist of adrenoceptors of ${\alpha}_2$-type, on the rabbit renal function, and to elucidate the mechanism involved in it. With 10 ${\mu}g/kg$ i.c.v. of yohimbine sodium excretion transiently increased along with increasing tendency of urine flow, renal plasma flow and glomerular filtration rate. These responses decreased with increasing doses. With 100 and 300 ${\mu}g/kg$ i.c.v. marked antidiuresis and antinatriuresis as well as profound decreases of renal perfusion and glomerular filtration were noted. Systemic blood pressure transiently increased. In reserpinized rabbits, 100 ${\mu}g/kg$ yohimbine i.c.v. did not produce any significant changes in urine flow, sodium excretion as well as in renal hemodynamics. The pressor response was also abolished. In preparations in which one kidney was denervated and the other left intact as control, i.c.v. yohimbine elicited typical antidiuretic antinatriuretic response in the innervated control kidney, whereas the denervated experimental kidney responded with marked diuresis and increases in excretory rates of sodium and potassium and in osmolar clearance in spite of absence of increased filtration and perfusion . Systemic blood pressure responded as in the normal rabbits. These observations indicate that i.c.v. yohimbine affects renal function in dual ways in opposite directions, the first being the antidiuretic antinatriuretic effects which results from decreased renal perfusion and glomerular filtration due to sympathetic activation and which is predominantly expressed in the normal rabbits, and the second less apparent effect being the diuretic and natriuretic action which is not mediated by nerve pathway but brought about by some humoral mechanism and which is effected by decreased sodium reabsorption in the tubules, possibly of the proximal portion.