• Biomolecules & Therapeutics
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• v.4 no.2
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• pp.122-126
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• 1996

In vitro inhibitory effect of aspalatone ((3-(2-methyl-4-pyronyl)]-2-acetyloxybenzoate) on collagen-, ADP-, and epinephrine-induced platelet aggregation in human platelet rich plasma (PRP) was compared with the effects of reference drugs (acetylsalicylic acid, cilostazol and ticlopidine). Aspalatone inhibited time and dose dependently human platelet aggregation induced by collagen; relative potency was in the order of cilostazol>acetylsalicylic acid>aspalatone>ticlopidine. Aspalatone, like acetylsalicylic acid, potently inhibited only the secondary phase of ADP-and epinephrine-induced aggregation. Thromboxane $B^2$ production evoked by collagen in human PRP was inhibited significantly and concentration-dependently by aspalatone and acetylsalicylic acid. These results were in agreement with the earlier studies in which the antiplatelet action of aspalatone was indicated to be due to the inhibition of platelet cyclooxygenase activity (Han et al., Arzneim. Forsch./Drug Res. 44(II), 1122, 1994; Suh and Han, Yakhak Hoeji 39, 565, 1995). In addition, the inhibitory activity of aspalatone on the platelet aggregation appears to be inversely related to the rate of nonspecific deacetylation of the drug in plasma.

• Biomolecules & Therapeutics
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• v.8 no.1
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• pp.99-106
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• 2000

Aspalatone [3-(2-methyl-4proponyl)]-2-acetyloxybenzoate, CAS 147249-33-0) is a compound having an antithrombotic action. General pharmacological properties of aspalatone were studied. Aspalatone had no effect on central nervous system and no anticonvulsant effect up to 1200 mg/kg p.o. However, the compound has hypothermic and analgesic effect. When administered intravenously in rabbits, aspalatone did not affect blood pressure, heat rate and respiration rate and depth, and it did not inhibit transient hypotensive effect of acetylcholine. The compound did not affect isolated guinea-pig ileum and tracheal strip at a concentration of 1${\times}$$10^{-4}$, and did not inhibit histamine-induced contraction of guinea-pig ileum. It also did not affect isolated rat stomach fundus and estrogenated rat uterus at 1${\times}$$10^{-4}$, and did not inhibit contraction produced by acetylcholine or oxytocin. The pupil size and intestinal propulsion were not influenced at a large dose of was shown. The compound showed a slight increase in urine volume and led to decreased excretion of potassium in urine of rats. The results suggest that aspalatone may have no considerable adverse effects in general pharmacological aspect.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1994.04a
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• pp.236-236
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• 1994

Acetylsalicylic acid (ASA)와 고려홍삼의 항산화 성분인 maltol을 축합하여 신물질 aspalatone을 합성하고, 흰쥐에서의 지혈시간 연장 효과, 항혈소판 응집 억제 (in Vitro, ex ViVO) 효과 및 생쥐의 혈전 모델을 이용한 항혈전 (in vivo) 효과를 연구하였다. SD계 웅성 흰쥐에 15 mg/kg의 낮은 용량으로 경구투여 할 경우, aspalatone과 ASA는 각각 최소한 8일 연속투여후 지혈시간을 유의적으로 연장시켰으며 같은 용량으로 10일 간 경구투여. 하였을 때, aspalatone 투여군은 대조군에 비하여 지혈시간이 57% (p<0.005) 연장된 반면, ASA 투여군은 44% 연장되었다. 반면, aspalatone의 아세칠 기를 갖지 않는 salicylic acid maltnl ester는 같은 용량에서 지혈시간을 유의적으로 연장시키지 않았다. Aspalatone은 in vitro에서 collagen에 의해 유도된 흰쥐 혈소판 응집을 강력하게 억제하였으나 (IS$_{50}$ = 0.18 mM), ASA와 마찬가지로 ADP에 의한 응집은 억제하지 않았다. Aspalatnne과 다른 대조약물들의 ex vivo에서의 혈소판 응집 억제능은 ASA>dipyridamdle(equation omitted)aspalatone>ticlopidine의 순이었다. 1회 경구투여로 aspalatone은 생쥐의 collagen에 의한 혈전에 기인하는 치사율을 억제하였다 (ED$_{50}$ = 32mg/kg). Aspalatone을 10일 간 투여하면 유효용량이 현저히 감소하여 20 mg/kg에서 치사율을 90% (p<0.001) 억제하였으며, 이러한 항혈전 효과는 투여중단 4일 후에도 지속되었다. 또한, 경구투여시 위궤양을 유발하는 ASA (ulcer index : 29 mm 200 mg/kg p.o.)와는 다르게 aspalatone은 위궤양을 유발하지 않는다는 장점을 갖는다 (0.71 mm, 800 mg/kg p.o.). In vitro에서 malondialdehyde 생성 억제를 지표로 한 aspalatone의 항산화 활성 ($IC_{50}$/ = 0.11 mM)은 maltol ($IC_{50}$/ = 0.084 mM)과 유산하다. 이러한 실험결과를 토대로 하여 aspalatone을 위궤양을 유발하지 않는 항혈전 신약으로 개발하기 위한 연구가 진행 중이다.

• YAKHAK HOEJI
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• v.39 no.5
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• pp.565-568
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• 1995

A new antiplatelett agent, aspalatone ([3-(2-methyl-4-pyronyl)]-2-acetyloxybenzoate) was demonstrated to inhibit MDA generation from arachidonic acid catalyzed by partially purified bovine seminal vesicle cyclooxygenase. This inhibition was also observed with acetylsalicylic acid. The results suggest that the mechanism for the antiplatelet effect of aspalatone is, like acetylsalicylic acid, due to its inhibition of cyclooxygenase.

• Archives of Pharmacal Research
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• v.17 no.3
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• pp.166-169
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• 1994

The anti-inflammatory activity of acetylsalicylic acid maltol ester (aspalatone), a potential anti-thombotic agent, was studied using the several experimental animal models of inflammation. By oral administration, aspalatone was found to possess the weak anti-inflammatory activity in models of an acute inflammation, in which aspalatone showed approximately one-third to one-fourth of the anti-inflammatory activity of aspirin. Aspalatone (200 mg/kg/day) and aspirin (50 mg/kg/day), however, did not show the inhibitory activity against granuloma fomation and adjuvant-induced arthritis.

• Archives of Pharmacal Research
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• v.19 no.5
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• pp.348-352
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• 1996

The antioxidant efficacy of aspalatone, a new antithrombotic agent, has been recognized in the neurotoxic model and in the cardiotoxic model in proliminary studies. We examined the specific activity of antiosidnat enzyme in the rat blood following administrations of aspirin, maltol, aspirin together with maltol, salicylmaltol (major metabolite of aspalatone) and aspalatone, respectively. Our assessment showed that salicylmaltol, maltol, aspalatone enhanced antiperoxidative activity. In addition, neither aspirin nor combination of aspirin and maltol, showed any significant effect on the activity of antioxidant enzyme. Because $H_{2}$$O_{2}$ accumulation may stimulate the thrombogenesis in blood, the result suggests that the induction of blood antiperoxidative activity produced by aspalatone may have beneficial effects on the thrombogenesis.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1994.04a
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• pp.235-235
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• 1994

NSAID의 대표적인 유도체인 acetylsalicylic acid(aspirin)은 항혈전 작용이 있다고 밝혀졌고, 주기적인 aspirin의 투여는 심근경색을 예방할 수 있음이 보고되었다. 그러나, 위궤양등 부작용의 발현이 심각하여 위의 목적에 입각한 aspirin의 장기적인 사용에 제약이 되고 있다. 이에 더욱 안전한 유도체인 aspalatone을 합성하였고, 이 물질은 낮은 궤양 유발능을 보이는 유망한 유도체로 개발중에 있다. 본 연구는 aspalatone의 in vivo 항염증 활성을 밝히기 위하여 시행하였다.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1993.04a
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• pp.123-123
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• 1993

Acetylsalicylic acid (aspirin)와 인삼의 항산화 성분인 maltol의 축합반응으로 합성된 신물질 Aspalatene이 저용량: 장기 복용시 항산화활성과 더불어 지혈시간 연장효과가 탁월함을 보고 한 바 있다. Aspalatone은 aspirin과는 달리, 장기 복용시에도 위궤양 유발 작용이 거의 나타나지 않으므로 말초순환개선제로서의 개발이 기대된다. 본 연구에서는 Aspalatone의 항혈전작용을 in vivo, ex vivo 및 in vitro에서 연구하였다. Mouse thromboembolism test를 이용한 in vivo실험에서 Aspalatone은 aspirin과 유사하게 collagen에 의한 치사를 유의적으로 감소시켰으며 ADP에 의한 치사에는 영향을 미치지 않았다. 또한 10일간의 장기 투여 실험에서는 저용량에서 영향을 미치지 않았다. 또한 10일간의 장기 투여 실험에서는 저용량에서 항혈전 작용을 나타내며 투여 중단 4일 후에도 약효가 유지되는 것을 밝혔다. 이는 Aspalatone이 aspirin과 같이 cycloosygenase에 작용하여 항혈전 작용을 나타냄을 강력히 시사하고 있다.

• Biomolecules & Therapeutics
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• v.8 no.4
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• pp.332-337
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• 2000

Physicochemical properties of aspalatone (acetylsalicylic acid maltol ester, AM), which has been recently found to have an antithrombotic effect, were studied in terms of solubility, dissolution, partition coefficient (Pc) and stability. The solubility of AM at 37$^{\circ}C$ was about 1.2 mg/ml and the P$_{c}$ value for n-octanol/water and chloroform/water was 11.4 and 382.6, respectively. Dissolution rates of AM at pH 1.2 and 6.8 were more than 80% within 30 min. The degradation of AM followed apparent first-order kinetics, and was dependent on temperature, pH and ionic strength. From the pH-rate profile, the optimal pH was found to be at around 4.0. Half-lives at pH 1.2 and 6.8 were 33.5 and 44.4 hr, respectively. The degradation rate of AM at pH 1.2 was somewhat faster than that of aspirin, but at pH 7.0, the degradation rate of AM was slower than that of aspirin.n.

• Journal of Pharmaceutical Investigation
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• v.30 no.4
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• pp.267-271
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• 2000

The effect of cyclodextrins on the solubility and stability of aspalatone (acetylsalicylic acid maltol ester, AM, CAS 147249-33-0), which has been recently found to have an antithrombotic effect, was investigated. The addition of ${\beta}-cyclodextrin\;({\beta}-CD),\;dimethyl-{\beta}-cyclodextrin\;(DMCD)\;or\;2-hydroxypropyl-{\beta}-cyclodextrin\;(HPCD)$ to the aqueous solution increased the solubility of AM concentration-dependently. From the phase solubility diagram, stability constants for $AM-{\beta}-CD$, -DMCD or -HPCD complexes were calculated to be 43.1, 78.3 and $53.0\;M^{-1}$. The addition of ${\beta}-CD$, DMCD or HPCD to AM solution retarded the degradation rate of AM in the acidic region. However, ${\beta}-CD$ and HPCD rather acted as an accelerator of degradation in the neutral and alkaline regions. DMCD had a stabilizing effect at all pHs studied.