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REFERENCE LINKING PLATFORM OF KOREA S&T JOURNALS
> Journal Vol & Issue
Biomolecules and Therapeutics
Journal Basic Information
Journal DOI :
The Korean Society of Applied Pharmacology
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Volume & Issues
Volume 5, Issue 4 - Dec 1997
Volume 5, Issue 3 - Sep 1997
Volume 5, Issue 2 - Jun 1997
Volume 5, Issue 1 - Mar 1997
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The Effect of Vitamin C on Hypoxia/reoxygenation Induced Hepatic Injury in Isolated Perfused Rat Liver
Biomolecules and Therapeutics, volume 5, issue 1, 1997, Pages 1~7
This study was done to investigate the effect of vitamin C on hypoxia/reoxygenation-induced hepatic injury ul isolated perfused rat liver. Isolated livers from rats fasted 18 hours were subjected to 45 min of hypoxia followed by reoxygenation for 45 min. The perfusion medium used was Krebs-Henseleit bicarbonate buffer (pH 7.4) and 0.5 mmol/L of vitamin C was added to the perfusate. Alanine aminotransferase (ALI) and lactate dehydrogenase (LDH) levels were significantly increased by hypoxia/reoxygenation. These increases were augmented by vitamin C. Glucose output and bile flow were markedly decreased by hypoxia/reoxygenation. Vitamin C aggavated the decrease of glucose output but had little effect on bile flow. Our findings suggest that hypoxia/reoxygenation diminishes hepatic metabolic and secretory functions, and vitamin C significantly aggravates these changes.
A Modern Aapproach to The Natures of Drugs(I) -Relation to The Rectal Temperature-
Biomolecules and Therapeutics, volume 5, issue 1, 1997, Pages 8~11
The odor theory (기미론) has been defined as the Nature (기) and the Taste(미) of traditional herbal medicine to find the logic in treatment of various diseases by them. There is a strong possibility these Na1ures of the drug can be categorized according to yin (음) and yang (음). There is a neutral Nature which does not fit into one of these four categories. To understand the Natures of traditional herbal drugs in modern scientific approaches, changes in rectal temperature of rats have been measured at 0,30, 60, 90 min after a 10 g/Kg oral administration each of 34 different drugs. Following the classification of the four Natures of drugs, only the temperatures of warm group at 30, 60, and 90 min were elevated significantly from the control and the rest groups. Following a modified classification of 3 groups such as cold and cool, warm and hot, and neutral Nature, changes in temperatures after administration of Hot and Warm drugs were also increased significantly from the control (P<0.01). Thus, the measurement of rectal temperature can be a tool to define the Nature (기) of traditional herbal drugs, but the modified classification is another way to do.
Acute Toxicity Study of DA-5018, A Non-narcotic Analgesic Agent
Biomolecules and Therapeutics, volume 5, issue 1, 1997, Pages 12~22
Intravenous and oral acute toxicity tests in ICR mice and SD rats and percutaneous acute toxicity tests in SD rats and NZW rabbits were conducted to evaluate the toxicity of DA-5018 and DA-5018 cream, respectively Clinical signs observed in mice and rats after the administration of DA-5018 were similar regardless of administration route. The observed clinical signs were jumping, wild running, lacrimation, ataxia, reddening of extremities and ears, ventral or lateral recumbency, respiratory distress, cyanosis, convulsion and death. Pulmonary enlargement and hemorrhage were observed in the animals died immediately after the dosing of DA-5018. At terminal necropsy, pulmonary enlargement and hemorrhage, corneal opacity and focal scabbing and depilation around nose were seen. LD
Values of DA-5018 are 11.5 mg/kg (mice, male), 12.6 mg/kg (mice, female), 88.3 mg/kg (rat, male) and 73.2 mg/kg (rat, female) in oral toxicity tests and 11.0 mg/kg (mice, male), 18.7 mg/kg (mice, female), 0.12 mg/kg (rat, male) and 0.32 mg/kg (rat, female) in i.v. toxicity tests. In the percutaneous acute toxicity tests of DA-5018 cream, no deaths occured in all the tested groups during 14-day observation period. There were also no abnormalities in the general conditions, body weight changes and on necropsy findings in all groups. LD
values of 0.1 ~0.9% DA-5018 creams in male and female rats and rabbits are >2000 mg/kg./kg.
Changes in Physiological Responses of Senescence Accelerated Mice(SAM) P6 and SAM R1 by Administration of Herbal Merbal Medicine Extracts
Biomolecules and Therapeutics, volume 5, issue 1, 1997, Pages 23~35
Physiological effects in SAM P6 and Rl by administration of Cervus cornu, Astragali Radix, Rehmanniae Radix, and Angelicae Radix extracts were screened to know in vivo activities of each extracts. We measured complete blood cells (CBC) such as aBC, HGB, and HCT using coulter's method. Plasma concentrations of albumin, glucose, alkaline phosphatase, calcium, creatinine, inorganic phosphate, urea and total iron ere also analyzed using biochemical clinical autoanalyzer. Plasma concentrations of cortisol, total T
, and total T
were measured by chemiluminescent immunoassay methods. At 12 weeks after birth, Cervus conu or Astragali Radix or Rehmanniae Radix extracts were given 5 g/Kg.day p.o. for 0,7,14,21, and 30 days each in both SAM Rl and SAM P6. Angelicae Radix study was done the same as the others except the mice were 16 weeks after birth. The RBC, HGB, and HCT levels after administration of Astragali and Rehmanniae were elevated in SAM Rl, but those in Cervi study were increased in SAM P6 the most. Decreases in alkaline phosphatase concentration of SAM Rl and P6 after Cervi administration were detected. Total plasma iron concentration was decreased by Angelicae administration in SAM P6. In general, Angelicae and Rehmanniae stimulate increases in cortisol, but total T
levels were also elevated by all these extracts. In conclusion, these herval medicine extracts help hematopoiesis in SAMs through probably different mechanisms.
Effects of Ginseng Total Saponin on The Altered Glutamatergic Nervous Systems by AF64A in Brain of Rats
Ma, Young ; Yi, Eun Young ; Choi, Woo Jung ; Lim, Dong-Koo ;
Biomolecules and Therapeutics, volume 5, issue 1, 1997, Pages 36~42
To investigate effects of ginseng total saponin (GTS) on the ethylcholine aziridnium ion (AF64A) -induced glutamatergic nervous system, rats were pretreated with the infusion of AF64A (3 nmole) into lateral ventricle and were posttreated with 50 mg/kg of GTS, i.p., for 1 week. Twenty four hours after the last administration, rats were sacrificed and the levels of glutamate and taurine, [
H]MK801) binding sites and glutamine synthetase activity were assessed in striatum, hippocampus and frontal cortex. The levels of striatal glutamate after GTS treatment in rats were decreased. And the levels of glutamate were decreased in striatum and frontal cortex and increased in hippocampus by the infusion of AF64A. However, the AF64A-induced changes of glutamate were returned to the control level by the administration of GTS in striatum, frontal cortex and hippocampus. After the infusion of AF64A, the level of taurine was decreased in striatum and increased in hippocampus. GTS administrations in the AF64A-treated rats restored to the control level of taurine in the decreased striatal level of taurine, but not in the elevated level of hippocampal taurine. The specific [
H]MK801 binding sites in hippocampus was significantly decreased but not in striatum and frontal cortex after the administration of AF64A. Although GTS itself did not affect the specific [
H]MK801 binding sites, GTS administrations in the AF64A-treated rats did decrease the binding sites of (\`H)Mk801 in all examined regions. The activities of striatal glutamine synthetase were decreased after GTS treatment. The activities of striatal glutamine synthetase (GS) were decreased in AF64A-treated groups. However, the decreased striatal GS activities by AF64A were returned to the control level by GTS treatment. Furthermore, GTS administrations in the AF64A-treated rats increased the hippocampal GS activities. The results indicatethat GTS may adjust the levels of glutamate and taurine constantly and may induce increase in AF64A-induced decrease of GS activity. Thus, it suggests that GTS may antagonize changes in central glutamatergic nervous system induced by AF64A. Also it suggests that the actions of GTS may differently affect in the disease state.
Antihyperlipidemic Effects of Bupleuri Radix, padix and Uncariae Ramulus et Uncus on Experimental Hyperlipidemia in rats
Biomolecules and Therapeutics, volume 5, issue 1, 1997, Pages 43~47
Effects of Bupleuri Radix, Paeonie Radix or Uncariae Ramulus et rncus on experimental yperlipidemia were studied. Hyperlipidemia was induced on male Wistar rats by feeding them on high holesterol diet for one week, as previously described by the authors. Blood lipid profile was verified on these ats by measuring total cholesterol(TC), triglyceride(TG), high density lipoprotein cholesterol(HDL) and low ensity lipoprotein cholesterol(LDL). Then, the rats were followed by feeding normal diet. At the same time, ethanol extracts of the three individual herb medicines were orally administered to the rats for 4 weeks and the parameters above mentioned were monitored. Methanol extract of 5Bupleuri radix reduced the TC value significantly at 2 week point and Paeoneae Radix reduced the TC value at 4 week point in compare to control group, suggesting the antihyperlipidemic effect of the two herbal medicines in vivo. The extract of Uncariae Ramulus et Uncus however did not show antihyperlipidemic effect in our experiment
Antigenicity Study of CFA-001, cefazolin, a cephalosperin Derivative Produced by an :Enzymatic Semisynthesis
Park, Jong-Il ; Jeong, Tae-Cheon ; Kim, Hyoung-Chin ; Han, Sang-Seop ; Roh, Jung-Koo ; Kim, Jeong-Hwan ; Jeon, Yeong-Joong ; Kim, Dal-Hyun ; Kim, Je-Hak ; Park, Kwan-Ha ;
Biomolecules and Therapeutics, volume 5, issue 1, 1997, Pages 48~52
The antigenic potential of CFA-001, cefazolin, a cephalosporin derivative produced by an enzy-matic semisynthesis, was determined in Hartley guinea pigs. A battery of tests employed consisted of active systemic anaphylaxis (ASA), passive cutaneous anaphylaxis (PCA), and indirect hemagglutination test (IHA). The results were as follows: 1) In ASA, no signs attributable to anaphylaxis was observed in guinea pigs sensitized with CFA-001, whereas OVA-sensitized animals induced severe anaphylactic symptoms; 2) guinea pigs did not produce antibodies against CFA-001 when sensitized with or without Freund's complete adjuvant (FCA) in homologous PCA tests. Meanwhile, antibodies against ovalbumin (OVA) were clearly detected; 3) No CFA-001-specific hemagglutination was observed in the IHA using sera obtained from CFA-001- sensitized guinea pigs. These results suggest that CFA-001 has no antigenicity potential in guinea pigs.
Vector-Mediated Delivers of
-labeled Opioid Peptide,
dermorphin (K7DA), through the Blood-Brain Barrier
Biomolecules and Therapeutics, volume 5, issue 1, 1997, Pages 53~58
dermorphin, abbreviated K7DA, which has structural features similar to a metabolically stable
-opioid peptide agonist
dermorphin analogue (DALDA), but is intrinsically more potent with respect to binding to the
-opioid peptide receptor. The present studies report on attempts to enhance brain uptake of systemically administered K7DA by conjugation to a complex of streptavidin (SA) and the OX26 murine monoclonal antibody to the rat transferrin receptor, which undergoes receptor-mediated transcytosis through the blood-brain barrier (BBB). SA-OX26 conjugate mediates BBB transport of biotinylated therapeutics. The K7DA is monobiotinylated at the
-amino group of the
residue with cleavable linker using NHS-SS-biotin. The brain uptake of
labeled biotinylated K7DA (
-bio-SSa-K7DA) was very small and rapidly metabolized after intravenous injection. The brain uptake, expressed as percent of injected dose delivered per gram of brain, of the
-bio-55-K7DA bound to the SA-OX26 conjugate
-bio-SS-K7DA/SA-OX26) was 0.14
0.01, a level that is 2-fold greater than the brain uptake of morphine. The cleavability of the disulfide linker in vivo in rat plasma and brain was assessed with gel filtration HPLC and intravenous injection of labeled opioid chimeric peptides. The disulfide linker is stable in plasma in vivo but is cleaved in rat brain in vivo. In conclusion, these studies show that delivery of these potential opioid peptides to the brain may be improved by coupling them to vector-mediated BBB drug delivery system.
Vitamins E and C: Are They Synergistic in Protecting Liver Cells against Hepatic Ischimia and Reperfusion Injury\ulcorner
Biomolecules and Therapeutics, volume 5, issue 1, 1997, Pages 59~66
This study was done to determine that vitamins I and C are synergistic in protecting liver cells during hepatic ischemia and repefusion. Rats treated with vitamins I and C were subjected to 60 min of hepatic ischemia and to 1 and 5 hr of reperfusion thereafter. Serum aminotransferase level and microsomal lipid peroxidation were markedly increased by ischemia/reperfusion. These increases were significantly attenuated by vitamins E, C or its combination. Hepatic wet weight-to-dry weight ratio was increased in ischemic group, but this increase was prevented by combination of vitamin I and C. Bile flow and cholate output were markedly decreased by ischemia/reperfusion and vitamin C alone and combination of vitamin I and C restored their secretion. Cytochrome P-450 content and aminopyrine N-demethylase activity were decreased by ischemia/ reperfusion and restored by vitamin C and combination of vitamin I and C to the level of sham-operated rat. Aniline p-hydroxylase activity was increased by ischemia/reperfusion and this increase was prevented by vitamin E. Our findings suggest that ischemia/reperfusion diminishes hepatic secretory and microsomal functions by increasing lipid peroxidation and vitamins I and C synergistically ameliorates these changes.
Analgesic Effect of DA-5018, a New Capsaicin Derivative, against Experimental Acute Pain
Biomolecules and Therapeutics, volume 5, issue 1, 1997, Pages 67~73
Analgesic effect of DA-5018, a new capsaicin derivative, was evaluated in various rat models of experimentally induced acute pain. DA-5018(0.2∼10.0 mg/kg, p.o.) prevented the writhing syndromes induced by acetic acid or phenol-p-benzoquinone(PBQ). It increased the pain threshold of inflamed paw when tested by the Randall-Selitto method at the dose of 2.0∼20.0 mg/kg by oral administration. And also it showed antinociceptive activities in tail-pinch(1.0∼20.0 mg/kg, p.o.) and tail-flick test(5.0∼50.0 mg/kg, p.o.). the potency and efficacy of DA-5018 were comparable to morphine · HCI in all the models mentioned above. Acetaminophen exhibited the inhibition of acetic acid-induced writhing syndromes and also analgesic activity in Randall-Selitto test, but it showed the limited efficacy in tail-pinch and tail-flick test. These results mean that DA-5018 has a broader analgesic activity profile than acetaminophen. And we found out that the analgesic activity of DA-5018 was 100 times more potent when administered centrally than administered orally in tail-flick test. These results suggest that DA-5018 has an orally active analgesic activity, and central nervous system may be involved in the action of DA-5018.
General Pharmacology of DA-5018, a New Capsaicin Derivative
Biomolecules and Therapeutics, volume 5, issue 1, 1997, Pages 74~81
DA-5018(N-(3-(3, 4-dimethylphenyl)propyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide) is a new capsaicin derivative under development as topical analgesic agent. The general pharmacological properties of DA-5018 on central nervous, cardiovascular, gastrointestinal and other organ systems were studied in experimental animals. DA-5018 cream (0.3%) had no effects on behavior, hexobarbital-induced sleeping time, body temperature, spontaneous activity, blood pressure, heart rate, intestinal charcoal propulsion, urine volume and electrolyte excretion even at a high dose of 2000 mg/kg in rats. In addition, DA-5Ol8 cream had little skin irritation compared to Zostrix-HP (capsaicin, 0.075%) cream in rabbits. In isolated guinea pig tissue studies, DA-5018 increased the contractility of trachea and ileum and also increased sinus rate of atrium in a range of
M, but its efficacy as a agonist was weak. These results suggest that DA-5018 cream might be used topically without serious side effects.
DA-5018 after Subcutaneous Injection and Topical Application
Biomolecules and Therapeutics, volume 5, issue 1, 1997, Pages 82~86
Pharmacokinetics of a new capsaicin analog, DA-5018 were evaluated after a subcutaneous injection or topical application of
--labelled or unlabelled DA-5018 to rats and rabbits. After subcutaneous injection of
c-labelled or unlabelled DA-5018, 0.5 mg/kg (equivalent to DA-5018) to rats, the plasma total activity peaked at 2 hr with the terminal half life of 5.34 hr, however, unlabelled-DA-5018 peaked at 1 hr with the terminal half life of 1.26 hr. Moreover, the AUC (0.726 versus 0.2337g hr/ml) and MRT (7.82 versus 3.55 hr) increased significantly based on total radioactivity compared with intact DA-5018. Above data indicated that DA-5018 is extensively metabolized in rats and the terminal half- life of the metabolite(5) had a longer half-life than that of DA-5018. The cumulative percentages of biliary excretion of dose after subcutaneous injection of
DA-5018 was 40.2%, however, the value was only 2.14% when unlabelled DA-5018 was injected. After topical application of 0.1% or 0.3%
C-labelled or unlabelled DA-5018 cream, 500 mg/kg to rats, the plasma and tissue concentrations except applied skin were under the detection limit. After consecutive 7 days topical application of unlabelled DA-5018, 0.1% and 0.3% cream to rats, the plasma concentrations were also under the detection limit. But the urinary excretion of DA-5018 was significantly increased by repeated topical administration. After topical application of unlabelled DA-5018, 0.1% and 0.3% cream to rabbits, the plasma and urine concentrations were under the detection limit. Above data indicated that the skin permeation of DA-5018 was lower and the metabolism of DA-5018 was higher in rabbits than that in rats.
Analgesic Action Mechanism of DA-5018, a New Capsaicin Derivative : Relationship to Opiate :Receptors and Prostanoids
Biomolecules and Therapeutics, volume 5, issue 1, 1997, Pages 87~93
DA-5018, a new capsaicin derivative, showed potent analgesic effect comparable to that of morphine in various experimental acute pain models. in this study, whether the analgesic mechanism of DA-5018 is related to opiate receptors or prostanoids was investigated. The affinity of DA-5018 for opiate receptor was determined by receptor binding assay. The Ki values of DA-5018 for nonspecific and specific
-opiate receptor was 299
813 nM, respectively and DA-5018 exhibited lower affinity than morphine. DA-5018 (10-"~3
10-′M) inhibited electrically-evoked contractions of the guinea ply ileum and rat vas deferens, and these inhibition was not antagonized by naloxone(10 nM), an opiate receptor antagonist. Antagonism of analgesic effect of 7A-5018 by naloxone was examined by tail pinch test. Analgesic action of DA-5018(0.1 ~2 mg/kg, 5.c.) was not antagonized by naloxone(1 mg/rg, i.p.). These results indicate that pharmacological action of DA-5018 is not related with opiate receptor. Cyclooxygenase and 5-lipoxygenase activities in rat peritoneal neutrophil treated with A23187 and arachidonic acid were measured by radioimmunoassay. DA-5018 stimulated the cyclooxygenase activity and the concentration show-ing the two fold increase of activity was 124
M. DA-5018 slightly inhibited 5-lipoxygenase activity and these results together indicate that analgesic action of 3A-5018 is not mediated through inhibition of cyclooxy genase or lipoxygenase. These results suggest that the analgesic effect of DA-5018 is not due to blocking opiate receptor or to inhibiting the synthesis of prostanoids in the arachidonic acid metabolism pathway.
A Possible Mechanism of Analgesic Action of DA-5018i A New Capsaicin Derivative : Capsaicin-like Effect on The Release of Substance P
Biomolecules and Therapeutics, volume 5, issue 1, 1997, Pages 94~99
Capsaicin is known to be an analgesic agent, affecting the synthesis, storage, , transport and release of substance p, the principal neurotransmitter of pain from periphery to the central nervous system(CNS). DA-5018, a newly synthesized capsaicin derivative has shown potent analgesic effect comparable to that of morphine in various rat models of experimentally inducted acute pairs. In this study the mechanism of analgesic actlvity of DA-5018 was examined. First, the electrically-evoked contraction of guinea pig trachea was inhibited by DA-5018 and these inhibition was recovered by incubation with capsafepine(3
), capsaicin receptor antagonist and this result suggested that DA-5018 has affinity on capsaicin receptor. The correlation between the norciceptive threshold and the release of substance P was evaluated. In vivo perfusion of slices of the rat spinal cord with DA-5018(10, 100
) produced a significant increase of the release of substance P and this increase was less than that of capsaicin(10
). The norciceptive threshold of rat treated with DA-5018(1 mg/kg, p.o) in tall pinch test increased from 2.9
0.3 to 23.5
6.61. Tail pinch latency increased to a maximun at 15 min after DA-5018 treatment and then declined to control values by 120 min. The capsaicin-evoked release ot substance P from the spinal cord slices of rat treated with DA-5018 reduced from 2.38
0.79 to 0.69
0.26 pg/mg wet weight. This reduction reached to a minium at 15 min after DA-5018 treatment and then recovered to control value by 120 min. These results mean that analgesic activity of DA-5018 is due to release of substance P The effect of DA-5018 cream on electrically-evoked neurogenic inflammation of rat saphenous nerve was compared with capsaicin (zostrix-HP). DA-5018 showed 34% inhibition of the neurogenic extravasation while capsaicin showed significant 67% inhibition. This result indicates that the potency of DA-5018 in the release of substance P is less than that of capsaicin. These results suggest that the release of substance P is partially involved in the mechanism of analgesic action of DA-50l8.
Acute Toxicity of DW-166HC (Hlolmium-165-chitosan) in Mice
Biomolecules and Therapeutics, volume 5, issue 1, 1997, Pages 100~105
Holmium-chitosan) is a complex of
-ray emitter, and chitosan, a polymer of glucosamine, with radiotherapeutic potential. The current study was performed to determine the acute toxicities of
Ho-chitosan in mice by two different routes of administration. The both sex mice were given a single intravenous bolus injection of
Ho-chitosan complex at doses of 12, 10, 6, 5 and 4 mg/kg or subcutaneous administration at doses of 600, 500, 400 and 300 mg/kg. Chitosan was dosed to control animals as 16 and 800 mg/kg, intravenously and subcutaneously, respectively. The doses of
Ho-chitosan complex were expressed as
holmium nitrate pentahydrate and the ratio of
to chitosan was 3/4 Severe convulsion and respiratory failure were followed by death within 10 min after intravenous dosing. Transient unilateral hindlimb hypokinesias were found in two mice of 5 mg/kg dosing group during the study period. No abnormalities were observed during the necropsy of survived animals in intravenous dosing group. Only one male animal was found dead in 500 mg/kg subcutaneously dosed group. Alopecia with or without cutaneous ulcer were found in most mice including control animals. During necropsy, omental adhesion was observed in all dose ranges and enlarged spleen was found in several animals including control group. It is suggested that the acute intravenous >).
for male and female mice were 4.90 and 6.03 mg/kg, respectively. The lowest lethal dose in male was 500 mg/kg by subcutaneous administration.