• The Korean Journal of Pharmacology
• /
• v.22 no.1 s.38
• /
• pp.34-44
• /
• 1986

In our previous studies, we had clarified many pharmacological effects of majarine: the bacteriostatic effect in vitro; the potentiation of hypnotic action of alcohol; hypotensive effect in rats and hypothermic effect in mice. This study was undertaken to search for a new antihypertensive drug. Red crystalline was obtained from majarine (which was extracted from Berberis koreana Palibin) by chemical methods. And this crystalline was identified as $C_{19}H＿{16}NO＿4$ contained one hydroxy group instead of methoxy group of majarine in isoquinoline ring and named 'Majarol' (5,6-Dihydro-9-hydroxy, 10-methoxybenzo-[g]-1,3-benzodioxolo [5,6-a] quinolizinium). We examined the effects of majarol on blood pressure and heart rate in urethane ancsthetized rats and the rate and amplitude of contraction of isolated frog heart. Several drugs: atropine sulfate, diphenhydramine chloride, hexamethonium bromide, phentolamine, epinephrine, propranolol and isoproterenol were used to clarify the mechanism of the hypotensive action of majarol. The results of experimints were as follows; 1. In low dose (0.5-2mg/kg, i.v.), majarol showed a typical transient hypotensive effect and slight decrease in heart rate. In high dose (5-10 mg/kg, i.v.), majarol showed a typical transient and a subsequent prolonged hypotensive effect and a significant prolonged decrease in heart rate was followed. 2. The hypotensive effects of majarol was not abolished by the pretreatments with atropine sulfate, hexamethonium bromide and diphenhydramine. The pretreatment with phentolamine inhibited significantly the hypotensive effects of majarol and the pretreatment wtih majarol blocked markedly the hypertensive effect of epinephrine. The positive chronotropic effect of isoproterenol was not blocked by the pretreatment with majarol. 3. In low dose, majarol increased the amplitude and decreased rate of contraction, but in high dose, majarol inhibited the amplitude and rate of contraction of isolated frog heart.

• The Korean Journal of Pharmacology
• /
• v.24 no.1
• /
• pp.63-70
• /
• 1988

Alterations in splanchnic circulatory hemodynamics along with reactivities to the alpha adrenoceptor agonists were assessed in association with the preventive effects of propranolol 10 days after portal ligation. Decreases in precapillary resistance (Ra) and postcapillary resistance (Rv) along with increases in mesenteric blood flow (MBF) and capillary pressure (CP) were observed in conjunction with an increment of splenic pulp pressure (SPP). Dose-dependent increase in Rv in response to noradrenaline, increases in Ra and RV to adrenaline, and increases in superior mesenteric arterial pressure (SMAP), Ra and Rv to phenylephrine observed in sham group were significantly attenuated by portal vein stenosis. In PPL-3 group (propranolol 3 mg/kg, i.p. three times daily for 10 days), MBF was significantly decreased in association with decrease in mesenteric venous pressure (MVP) when compared with those of protal ligated (PL) group, and decreased Ra and Rv in PL group were recovered toward the values of sham group. Likewise, in PPL-1 group (propranolol 5 mg/kg, i.p. once daily for 10 days), the pressor response of Rv to adrenaline was recovered up to the level of sham group. Thus, it is suggested that decreases in Ra and Rv in association with increases in MBF and CP may have a close relevance to the increased SPP, and the changes in circulatory hemodynamics and vascular reactivities were effectively reversed by longterm propranolol treatment. Based on these results, it is concluded that these changes observed in portal hypertension are closely related with the altered functions of the adrenoceptors in the splanchnic vascular beds.

• Journal of Pharmaceutical Investigation
• /
• v.31 no.4
• /
• pp.289-295
• /
• 2001

Carvedilol is an antihypertensive and antianginal compound that combines nonselective beta-adrenoceptor blocking and vasodilation properties and is devoid of intrinsic sympathomimetic activity. The purpose of the present study was to evaluate the bioequivalence of two carvedilol tablets, $Dilatrend^{TM}$ (Chong Kun Dang Pharmaceutical Co., Ltd.) and $Carvelol^{TM}$ (Dae Won Pharmaceutical Co., Ltd.), according to the prior and revised guidelines of Korea Food and Drug Administration (KFDA). The carvedilol release from the two carvedilol tablets in vitro was tested using KP VII Apparatus II method with various different kinds of dissolution media (pH 1.2, 4.0, 6.8 buffer solution, water and blend of PSB80 into water). Eighteen normal male volunteers, $24.22{\pm}1.86$ years in age and $64.81{\pm}4.56\;kg$ in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After one tablet containing 25 mg of carvedilol was orally administered, blood was taken at predetermined time intervals and the concentrations of carvedilol in serum were determined using HPLC method with fluorescence detector. The dissolution profiles of two carvedilol tablets were very similar at all dissolution media. Besides, the pharmacokinetic parameters such as $AUC_t$, $C_{max}$ and $T_{max}$ were calculated and ANOVA test was utilized for the statistical analysis of the parameters using non-transformed and logarithmically transformed $AUC_t$ and $C_{max}$. The results showed that the differences in $AUC_t$, $C_{max}$ and $T_{max}$ between two tablets based on the $Dilatrend^{TM}$ were 2.23%, -2.00% and 0.00%, respectively. Minimum detectable differences $({\Delta})$ at ${\alpha}=0.05$ and $1-{\beta}=0.8$ were less than 20% (e.g., 13.55% and 17.61% for $AUC_t$ and $C_{max}$, respectively). The powers $(l-{\beta})$ at ${\alpha}=0.05$, ${\Delta}=0.2$ for $AUC_t$ and $C_{max}$ were 98.08% and 88.81%, respectively. The 90% confidence intervals were within ${\pm}20%$ (e.g., $-5.69{\sim}10.16$ and $-12.30{\sim}8.30$ for $AUC_t$ and $C_{max}$, respectively). There were no sequence effect between two tablets in logarithmically transformed $AUC_t$ and $C_{max}$. The 90% confidence intervals using logarithmically transformed were within the acceptance range of log(0.8) to log(1.25) (e.g., $0.95{\sim}1.11$ and $0.89{\sim}1.09$ for $AUC_t$ and $C_{max}$, respectively). Two parameters met the criteria of prior and revised KFDA guideline for bioequivalence, indicating that $Carvelol^{TM}$ tablet is bioequivalent to $Dilatrend^{TM}$ tablet.

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