• BMB Reports
• /
• v.48 no.10
• /
• pp.577-582
• /
• 2015

Cyclopia subternata is a medicinal plant commonly used in traditional medicine to relieve pain. Here, the anticoagulant effects of scolymoside, an active compound in C. subternata, were examined by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT), and the activities of thrombin and activated factor X (FXa). The effects of scolymoside on plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) expression were evaluated in tumor necrosis factor (TNF)-α-activated human endothelial cells. Treatment with scolymoside resulted in prolonged aPTT and PT and the inhibition of thrombin and FXa activities and production. In addition, scolymoside inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. Scolymoside also elicited anticoagulant effects in mice, including a significant reduction in the PAI-1 to t-PA ratio. Collectively, these findings indicate that scolymoside possesses anticoagulant activities and could be developed as a novel anticoagulant.

• Biomolecules & Therapeutics
• /
• v.11 no.1
• /
• pp.41-50
• /
• 2003

General pharmacological properties of DA-8159, a new pyrazolopyrimidinone derivative were examined in laboratory animals to investigate its safety profile. The oral administration of DA-8159 (1, 5 or 30 mg/kg) in mice and rats had no effect on general behaviors and central nervous system of the animals in test systems, such as hexobarbital-induced sleeping time, motor coordination, normal body temperature, writhing syndromes induced by 0.75% acetic acid solution, chemo-shock produced by pentetrazole solution and rotar rod test. Anesthetized cats treated intravenously with DA-8159 (0.1, 0.3, 1, 3 or 10 mg/kg) showed transient and mild decrease in blood pressure. However, heart rate, respiration rate and tidal volume were not changed by intravenous DA-8159. In the isolated organs including ileum, heart (sinus rate of atria and contractility of papillary muscle), trachea of guinea pigs and phrenic nerve of rats, DA-8159 ($10^{-8}$ ∼$10^{-5}$ mg/L) did not elicit any effect or inhibitory action on the chemically or electrically stimulated contraction. DA-8159 did not influence gastric secretion, pH and total acid output in rats and intestinal propulsion in mice. The administration of DA-8159 in rats had no effect on the platelet aggregation induced by ADP in rabbit plasma, urinary volume and electrolyte ion ($Na^{+}$, $K^{+}$, $Cl^{-}$) excretion in rats. Prothrombin time (PT) of the rats showed a mild but significant increase after administration of DA-8159. Activated partial thromboplastin time (APTT), however, was not affected by DA-8159. These results indicate that DA-8159 does not exert any of serious pharmacological effects.

• Journal of Pharmaceutical Investigation
• /
• v.40 no.2
• /
• pp.117-123
• /
• 2010

Ibudilast, 3-isobutyryl-2-isopropyrazolo[1,5-a]pyridine, is a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It preferentially inhibits PDE 3A, PDE4, PDE10 and PDE11 as well as a number of the other PDE families, albeit to a lesser extent. Ibudilast is used clinically to treat bronchial asthma and cerebrovascular disorders. Thes e clinical uses are based on the ability of ibudilast to inhibit platelet aggregation, improve cerebral blood flow and attenuate allergic reactions. The purpose of the present study was to evaluate the bioequivalence of two ibudilast capsules, Ketas capsule (Handok Pharmaceuticals Co., Ltd.) and Pinatos capsule (Sam Chun Dang Pharm. Co., Ltd.), according to the guidelines of the Korea Food and Drug Administration (KFDA). The in vitro release of ibudilast from the two ibudilast formulations was tested using KP Apparatus method with various dissolution media. Twenty six healthy male subjects, 23.31${\pm}$1.09 years in age and 70.45${\pm}$8.51 kg in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After a single capsule containing 10 mg as ibudilast was orally administered, blood samples were taken at predetermined time intervals and the concentrations of ibudilast in serum were determined using HPLC/UV detector. The dissolution profiles of two formulations were similar in all tested dissolution media. The pharmacokinetic parameters such as $AUC_t$, $C_{max}$ and $T_{max}$ were calculated, and computer programs (Equiv Test and K-BE Test 2002) were utilized for the statistical analysis of the parameters using logarithmically transformed $AUC_t$, $C_{max}$ and untransformed $T_{max}$. The results showed that the differences between two formulations based on the reference drug, Ketas, were 6.99%, -2.48% and 9.93% for $AUC_t$, $C_{max}$ and $T_{max}$, respectively. There were no sequence effects between two formulations in these parameters. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log 0.8 to log 1.25 (e.g., log 0.8791~log 1.1861 and log 0.8347~log 1.1199 for $AUC_t$ and $C_{max}$, respectively). Thus, the criteria of the KFDA bioequivalence guideline were satisfied, indicating Pinatos capsule was bioequivalent to Ketas capsule.

• Tuberculosis and Respiratory Diseases
• /
• v.45 no.6
• /
• pp.1265-1276
• /
• 1998

Background : Nitric oxide(NO) is an endogenously produced free radical that plays an important role in regulating vascular tone, inhibition of platelet aggregation and white blood cell adhesion to endothelial cells, and host defense against infection. The highly reactive nature of NO with oxygen radicals suggests that it may either promote or reduce oxidant-induced cell injury in several biological pathways. Oxidant injury and interactions between pulmonary vascular endothelium and leukocytes are important in the pathogenesis of acute lung injury, including acute respiratory distress syndrome(ARDS). In ARDS, therapeutic administration of NO is a clinical condition providing exogenous NO in oxidant-induced endothelial injury. The role of exogenous NO from NO donor or the suppression of endogenous NO production was evaluated in oxidant-induced endothelial injury. Method : The oxidant injury in cultured rat lung microvascular endothelial cells(RLMVC) was induced by hydrogen peroxide generated from glucose oxidase(GO). Cell injury was evaluated by $^{51}$chromium($^{51}Cr$) release technique. NO donor, such as S-nitroso-N-acetylpenicillamine(SNAP) or sodium nitroprusside(SNP), was added to the endothelial cells as a source of exogenous NO. Endogenous production of NO was suppressed with N-monomethyl-L-arginine(L-NMMA) which is an NO synthase inhibitor. L-NMMA was also used in increased endogenous NO production induced by combined stimulation with interferon-$\gamma$(INF-$\gamma$), tumor necrosis factor-$\alpha$(TNF-$\alpha$), and lipopolysaccharide(LPS). NO generation from NO donor or from the endothelial cells was evaluated by measuring nitrite concentration. Result : $^{51}Cr$ release was $8.7{\pm}0.5%$ in GO 5 mU/ml, $14.4{\pm}2.9%$ in GO 10 mU/ml, $32.3{\pm}2.9%$ in GO 15 mU/ml, $55.5{\pm}0.3%$ in GO 20 mU/ml and $67.8{\pm}0.9%$ in GO 30 mU/ml ; it was significantly increased in GO 15 mU/ml or higher concentrations when compared with $9.6{\pm}0.7%$ in control(p < 0.05; n=6). L-NMMA(0.5 mM) did not affect the $^{51}Cr$ release by GO. Nitrite concentration was increased to $3.9{\pm}0.3\;{\mu}M$ in culture media of RLMVC treated with INF-$\gamma$ (500 U/ml), TNF-$\alpha$(150 U/ml) and LPS($1\;{\mu}g/ml$) for 24 hours ; it was significantly suppressed by the addition of L-NMMA. The presence of L-NMMA did not affect $^{51}Cr$ release induced by GO in RLMVC pretreated with INF-$\gamma$, TNF-$\alpha$ and LPS. The increase of $^{51}Cr$ release with GO(20 mU/ml) was prevented completely by adding 100 ${\mu}M$ SNAP. But the add of SNP, potassium ferrocyanate or potassium ferricyanate did not protect the oxidant injury. Nitrite accumulation was $23{\pm}1.0\;{\mu}M$ from 100 ${\mu}M$ SNAP at 4 hours in phenol red free Hanks' balanced salt solution. But nitrite was not detectable from SNP upto 1 mM The presence of SNAP did not affect the time dependent generation of hydrogen peroxide by GO in phenol red free Hanks' balanced salt solution. Conclusion : Hydrogen peroxide generated by GO causes oxidant injury in RLMVC. Exogenous NO from NO donor prevents oxidant injury, and the protective effect may be related to the ability to release NO. These results suggest that the exogenous NO may be protective on oxidant injury to the endothelium.