• Biomolecules & Therapeutics
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• 제6권1호
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• pp.95-110
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• 1998

A 13-week dermal toxicity test was conducted to assess the toxicity of DA-5018, a capsaicin derivative. Three groups of Sprague-Dawley rats (10-15 males and 10-15 females) were treated with DA-5018 cream daily by dermal application at concentrations of 0.1%, 0.3% or 0.9% as 500 mg/kg for 13 weeks. One further group of rats (15 males and 15 females) received cream base at 500 mg/kg/day and acted as controls. One male receiving 0.3% DA-5018 cream died during the treatment period. But the animal did not show any signs of treatment-related toxicity until death. There were no local skin reaction of application site and systemic reaction to the treatment of DA-5018 creams in all experimental groups throughout treatment and recovery period. Weight gain and food consumption in animals that received DA-5018 creams appeared to be comparable to that of the controls. Laboratory analyses (hematology, urinalysis and opthalmoscopic examination) did not revealed pathological values. In biochemical investigations, an increase of glucose level associated with increased food consumption and some other significant changes were noted in the animals of both sexes received DA-5018 creams. But these changes were not considered to be of toxicological importance. Postmortem examination did not show macroscopic or histological alterations attributable to the DA-5018 treatments. Based on these results, NOAEL(no-observable-adverse-effect level) of DA-5018 cream if estimated to be over 500 mg/tg/day as 0.9% cream.

• Parasites, Hosts and Diseases
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• 제52권6호
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• pp.613-619
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• 2014

Neospora caninum (Apicomplexa; Sarcocystidae) is a protozoan that causes abortion in cattle, horses, sheep, and dogs as well as neurological and dermatological diseases in dogs. In the central nervous system of dogs infected with N. caninum, cysts were detected that exhibited gliosis and meningitis. Flavonoids are polyphenolic compounds that exhibit antibacterial, antiparasitic, antifungal, and antiviral properties. In this study, we investigated the effects of flavonoids in a well-established in vitro model of N. caninum infection in glial cell cultures. Glial cells were treated individually with 10 different flavonoids, and a subset of cultures was also infected with the NC-1 strain of N. caninum. All of the flavonoids tested induced an increase in the metabolism of glial cells and many of them increased nitrite levels in cultures infected with NC-1 compared to controls and uninfected cultures. Among the flavonoids tested, 3',4'-dihydroxyflavone, 3',4',5,7-tetrahydroxyflavone (luteolin), and 3,3',4',5,6-pentahydroxyflavone (quercetin), also inhibited parasitophorous vacuole formation. Taken together, our findings show that flavonoids modulate glial cell responses, increase NO secretion, and interfere with N. caninum infection and proliferation.

• Biomolecules & Therapeutics
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• 제5권1호
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• pp.74-81
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• 1997

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 10^{-8}-10^{-5}$$ M, but its efficacy as a agonist was weak. These results suggest that DA-5018 cream might be used topically without serious side effects.

• Archives of Pharmacal Research
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• 제25권6호
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• pp.873-878
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• 2002

OA-8159, a new Phosphodiesterase (PDE) 5 inhibitor, has exhibited potent erectogenic potential in a penile erection test in rats and anesthetized dogs. In this study, we investigated the mechanism of its erectogenic activity by measuring the activity of OA-8159 against a various PDE isozymes and assessing cGMP and cAMP formation in a rabbit corpus cavernosum in vitro. DA-8159 inhibited the PDE 5 activity in rabbit and human platelets, which the $IC_{50}$ was 5.84$\pm$1.70 nM and 8.25$\pm$2.90 nM, respectively. The $IC_{50}$ of DA-8159 on PDE 1, PDE2, PDE 3 and PDE 6 were 870$\pm$57.4 nM, $101\pm$5 $\mu$M, 52.0$\pm$3.53 $\mu$M and 53.3$\pm$2.47 nM, respectively. This suggests that DA-8159 is a potent, highly selective, competitive inhibitor of PDE 5-catalyzed cGMP hydrolysis. The rates of cGMP hydrolysis catalyzed by human platelets-derived PDE 5 as a function of the cGMP concentration (5~100 nM) and two-fixed DA-8159 concentration (11.3 and 18.8 nM) were investigated in order to characterize the mode of PDE 5 inhibition by DA-8159. DA-8159 increased the apparent 4K_{m}$ value for cGMP hydrolysis but had no effect on the apparent $V_{max}$, indicating a competitive mode of inhibition. DA-8159 increased the cGMP concentrations in the rabbit corpus cavernosum dose dependently. In the presence of sodium nitroprusside (SNP), DA-8159 significantly sti\mulated the accu\mulation of cGMP when compared to the control level. This indicated that the enhancement of a penile erection by DA-8159 involved the relaxation of the cavernosal smooth \muscle by NO-sti\mulated cGMP accu\mulation. In conclusion, DA-8159 is a selective inhibitor of PDE 5-catalyzed cGMP hydrolysis and the enhancement of a penile erection by DA-8159 is mediated by the relaxation of the cavernosal smooth \muscle by the NO-sti\mulated cGMP accu\mulation.

• Nutrition Research and Practice
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• 제9권3호
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• pp.219-226
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• 2015

BACKGROUND/OBJECTIVES: In this study, potential anti-inflammatory effect of enzymatic hydrolysates from Styela clava flesh tissue was assessed via nitric oxide (NO) production in lipopolysaccahride (LPS) induced RAW 264.7 macrophages and in vivo zebrafish model. MATERIALS/METHODS: We investigated the ability of enzymatic hydrolysates from Styela clava flesh tissue to inhibit LPS-induced expression of pro-inflammatory mediators in RAW 264.7 macrophages, and the molecular mechanism through which this inhibition occurred. In addition, we evaluated anti-inflammatory effect of enzymatic hydrolysates against a LPS-exposed in in vivo zebrafish model. RESULTS: Among the enzymatic hydrolysates, Protamex-proteolytic hydrolysate exhibited the highest NO inhibitory effect and was fractionated into three ranges of molecular weight by using ultrafiltration (UF) membranes (MWCO 5 kDa and 10 kDa). The above 10 kDa fraction down-regulated LPS-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), thereby reducing production of NO and prostaglandin $E_2$ ($PGE_2$) in LPS-activated RAW 264.7 macrophages. The above 10 kDa fraction suppressed LPS-induced production of pro-inflammatory cytokines, including interleukin $(IL)-1{\beta}$, IL-6, and tumor necrosis factor $(TNF)-{\alpha}$. In addition, the above 10 kDa fraction inhibited LPS-induced phosphorylation of extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinase (JNK), and p38. Furthermore, NO production in live zebrafish induced by LPS was reduced by addition of the above 10 kDa fraction from S. clava enzymatic hydrolysate. CONCLUSION: The results of this study suggested that hydrolysates derived from S. clava flesh tissue would be new anti-inflammation materials in functional resources.

• Biomolecules & Therapeutics
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• 제5권2호
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• pp.133-149
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• 1997

4-week repeated dose toxicity of DA-5018, a new capsaicin analogue analgesic agent, was examined in 5D rats at dosage levels of 0,0.4,2, 10 and 50 mg/kg/day. DA-5018 was administered orally to 17 males and 17 females per group at doses of 0, 10 and 50 mg/kg and to 12 males and 12 females per group at doses of 0.4 and 2 mg/kg. After the administration period, 5 males and 5 females at the 0, 10 and 50 mg/kg were placed on withdrawal for 2 weeks. Treatment-related clinical signs were observed at 10 and 50 mg/kg. Clinical signs observed immediately after the administration of DA-5018 were grooming, sedation or depression, lacrimation, atacia, reddening of extremities and ears, ventral or lateral recumvincy, respiratory distress, cyanosis and convulsion. Delayed-type clinical signs including focal scabbing and depilation around nose were also observed 1 or 2 weeks after the start of administration of DA-5018. Only at the 50 mg/kg group, corneal opacities, reduced body weight gain (male) and death (male 6/17, female 3/17) were noted. In blood biochemical analysis, serum levels of glucose and triglyceride decreased at 10 and 50 mg/kg. In hematological examination, there were increases in the number of red blood cell, hemoglobin content and percent of hematocrit at 10 and 50 mg/kg. Pulmonary enlargement and hemorrhagic spot, focal scabbing and depilation around nose and corneal opacities were seen at the necropsy of the animals died during the dosing of DA-5018 50 mg/kg. Focal scabbing and depilation around nose were observed in the animals terminally necropsied at doses of 10 and 50 mg/kg. Histopathological examination revealed pulmonary hemorrhage, focal necrosis in the scabbed area, corneal necrosis, fibrosis and neovasculization in the stroma. At 0.4 and 2 mg/kg, there were no significant toxic changes attributable to the administration of DA-5018. In conclusion, target organs following to 4-week repeated dose of DA-5018 in the rat were determined to be lung, skin and eyes. Definite toxic dose and no-observed-adverse-effect-level (NOAEL) were estimated to be 50 and 2 mg/kg/day, respectively.

• 대한한의학회지
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• 제31권1호
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• pp.1-13
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• 2010

Objective: Functional dyspepsia is a prevalent disease. It impedes subjective quality of life. The purpose of this study was to examine the equivalent effect of herb medicine treatment (DA-9701) for functional dyspepsia. Methods: In this randomized, single-blinded, placebo-controlled study, we compared a herb medicine (DA-9701) with standard treatment (mosapride) and placebo for the treatment of functional dyspepsia. 42 volunteers who satisfied the requirements were enrolled in study. Severity of dyspepsia was measured by Nepean Dyspepsia Index (NDI) and Functional Dyspepsia Quality of Life (FD-QOL) before and after treatments. Results: 1. In the DA-9701 group, total key symptoms score was significantly lower and improve rate of key symptoms was higher than in the mosapride and placebo groups, but there were no statistically significant differences between three groups. 2. In the DA-9701 and mosapride groups, "nausea" and "bad breath" were significantly lower compared with the placebo group. 3. In the DA-9701 group, NDI Quality of Life scores were significantly higher, but there were no [other] statistically significant differences between the three groups. 4. In the DA-9701 and mosapride groups, FD-QOL scores were higher compared with the placebo group, but there were no statistically significant differences between the three groups. Conclusion: Herb medicine treatment (DA-9701) is effective to improve the symptoms and quality of life in patients with functional dyspepsia.

• Biomolecules & Therapeutics
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• 제3권1호
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• pp.63-71
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• 1995

The local irritation studies of DA-3002, an authentic recombinant human growth hormone (rhGH), were carried out in rabbits after the following treatment ; application into the conjunctival sac of the eye (single), single subcutaneous and intramuscular injection, 7-day repeated subcutaneous and intramuscular injection. The results obtained were as follows. In the result of ocular irritation test, 0.16% solution of DA-3002 could be considered as a non-irritating material. In single subcutaneous and intramuscular irritation test, the irritancy of 0.16% DA-3002 solution was not so much different from that of saline. The local irritation of DA-3002 by 7-day repeated injection was negligible and similar to that of saline by both subcutaneous and intramuscular routes. These results suggest that DA-3002 has no irritating activity when injected through subcutaneous or intramuscular route for clinical practice as 0.16% solution.

• Biomolecules & Therapeutics
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• 제7권3호
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• pp.285-291
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• 1999

DA-7101 is a new combined formulation of cefatrizine:clavulanic acid (2:1) under development as oral abtibiotics. The general pharmacological properties of DA-7101 on central nervous, cardiovascular, gas-trointestinal and other organ systems were studied by oral administration, in vivo and in vitro. DA-7101 had no marked effects all tests studied such as general behavior, hexobarbital-induced sleeping, spontaneous activity, anticonvulsion, body temperature, acetic acid-induced writhing, rotarod performance, heart rate and blood pressure in cats, isolated ileum movement, intestinal transition, gastric juice secretion and urine volume and electrolytes in rats. But exceptionally at the highest dose of 900 mg/kg, DA-7101 increased hexobarbital-induced sleeping time, caused a slight hypotension and decreased the secretion of gastric juice. These results suggest that at the estimated clinical dose DA-7101 would not bring about any serious acute adverse effects clinically.

• Biomolecules & Therapeutics
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• 제4권2호
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• pp.174-183
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• 1996

The general pharmacological properties of Artemisia extract powder (DA-9601) produced from Artemisia asiatica leaves were investigated in mice, rats, guinea pigs and rabbits. DA-9601 at the dose of 800 mg/kg po had no influences on general behaviour, barbital sleeping time and motor coordination of mice. The material at the oral dose of 800 mg/kg did exhibit neither analgesic action nor hypothermic effect. Anticonvulsant action, muscle relaxant action and the effect on intestinal propulsion were not identified at 800 mg/kg po. In the isolated ileum and trachea of guinea pig, the material did not show direct erect and inhibitory action of chemically or electrically stimulated contraction at the concentration of $2\times10^{-5}$g/ml. The sinus rates of atria and contractility of papillary muscle of guinea pig were not influenced by DA-9601 at a dose of $2\times10^{-5}$g/ml. No influences on blood pressure and respiration were observed at 40 mg/kg iv, in rabbits. However, transient decreases in blood pressure of rabbits were observed as given 120 mg/kg in iv route with slight respiratory depression, and slight diuretic effect could be found without any changes in $Na^+$ and $K^+$ excretion.