• Toxicological Research
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• v.14 no.4
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• pp.547-555
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• 1998

The subchronic toxicity of a combined preparation of ticlopidine and ginkgo biloba extract (EGb 761) mixed in a ratio of 10: 4 was examined in male and female Sprague-Dawley rats. Rats were treated with the test substance at a dose of 52 mg/kg, 156 mg/kg, or 467 mg/kg intragastrically for 30 consecutive days. Control rats were treated with vehicle only. Each group consisted of 10 rats. No death or abnormal clinical signs were observed throughout the administration period. A transient decrease in body weight gain and food intake was observed in the rats treated with the high dose (467 mg/kg), which was recovered to normal in a week. There were no drug-related differences in urinalysis and hematological results. A significant increase in serum total cholesterol and total protein was observed in both sexes of the rats treated with a dose of 467 mg/kg daily, but all the other values obtained in serum chemistry appeared to be within normal range. A dose dependent increase in liver weight was observed in both male and female rats. Relative kidney weight was also increased in the high dose groups. There was no gross pathological finding at terminal sacrifice. Microscopic histopathological examination did not show any lesion in terms of correlation with administration of the test substance. The results suggest that under the conditions employed in this study no observable effect level (NOEL) of the test substance be 52 mg/kg/day.

• Toxicological Research
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• v.16 no.4
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• pp.293-301
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• 2000

Toxicity of a combined preparation of ticlopidine and ginkgo biloba extract (EGb 761) in a ratio of 10: 4 was examined in male and female Sprague-Dawley rats. Rats were treated with the test substance intragastrically at a dose of 0 mg/kg, 17 mg/kg, 52 mg/kg or 156 mg/kg for 91 consecutive days. No death or abnormal clinical sign was observed throughout the administration period. There was no difference in body weight gain, food intake or water consumption among different dose groups. Test sub-stance-related differences were not observed in urinalysis. In hematological results mean corpuscular hemoglobin (MCH) of low and high dose male group was increased. Prothrombin time of medium and high dose female group was decreased. A significant increase in serum total cholesterol was observed in both sexes of rats treated with a daily dose of 156 mg/kg, but all the other values obtained in serum chemistry appeared to be within normal ranges. A dose dependent increase in the relative liver and kidney weights was observed in both male and female rats. There were no gross pathological findings at terminal sacrifice. Microscopic histopathological examination did not show any lesion associated with administration of the test substance. The results suggest that under the conditions employed in this study no observable effect level (NOEL) of the test substance be greater than 17 mg/kg/day, but less than 52 mg/kg/day.

• Korean Journal of Clinical Pharmacy
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• v.22 no.1
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• pp.1-8
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• 2012

항혈소판제인 티크로피딘과 항고혈압제인 니칼디핀과의 약동학적 상호작용 연구를 위하여 티크로피딘 (3 또는 10 mg/kg)과 니칼디핀의 경구 (4 mg/kg) 및 정맥 (12 mg/kg) 투여하여 본 연구를 시행하였다. 연구방법: 티크로피딘이 cytochrome P450 (CYP) 3A4 활성과 P-glycoprotein (P-gp)의 활성에 미치는 영향도 평가하였다. 결 과: 티크로피딘과 니칼디핀의 병용투여 시 티크로피딘이 니칼디핀의 약물동태 파라미터에 미치는 결과는 다음과 같다. 티크로피딘은 CYP3A4 효소의 활성을 저해 하였으나 P-gp활성에는 영향을 미치지 못하였다. 니칼디핀의 혈중농도곡선하면적 (AUC)는 대조군에 비해 티크로피딘 10 mg/kg 병용투여군에서 유의성 (p < 0.05)있게 증가되었다. 상대적 생체이용률 (RB)은 티크로피딘 병용투여군에서 115-143%로 증가하였다. 결 론: 본 논문에서 흰쥐에 티크로피딘과 니칼디핀을 병용경구투여 시 니칼디핀의 생체이용률 (bioavailability)이 유의성 (p < 0.05)있게 증가된 것은 티크로피딘이 대사효소인 CYP3A4를 억제하여 소장과 간장에서 초회통과효과 (first-pass metabolism)를 감소 시켰기 때문인 것으로 사료된다. 본 실험결과를 토대로 인체에서 티크로피딘과 니칼디핀의 상호작용을 검토한 후 투여용량을 조절하는 것이 바람직하다고 사료된다.

• Journal of Chest Surgery
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• v.17 no.4
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• pp.672-677
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• 1984

Thromboembolism is a major cause of morbidity and death following implantation of cardiac prosthetic devices. Effective systemic anticoagulation is very important. The presence of thrombus can often be detected by pulmonary edema associated with the disappearance of valve clicks. 2-D echocardiography and phonocardiography are also valuable tools. The most common treatment is reoperation and replacement after discovery early. We have experienced one death of fatal thromboembolism after St. Jude valve replacement was done in 48 years old male diagnosed of severe mitral stenosis. He was treated with warfarin, aspirin, ticlopidine for 10 weeks but died suddenly. At autopsy, valve dysfunction was seen due to organic thrombus arising from atrial septum and confirmed with microscopic findings.

• YAKHAK HOEJI
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• v.56 no.5
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• pp.288-292
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• 2012

The aim of the paper is to ameliorate old research methods of Korean Pharmaceutical Codex to adjust the newest scientistic level which is necessary to maintain quality of medical supplies effectively. After reviewing result of Establishment of Dissolution Specifications for Generic Drugs in Korea Pharmaceutical Codex Monograph, there are two items chosen for the methods - Establishment of Dissolution Specifications for Generic Drugs in Korea Pharmaceutical Codex Monograph which KFDA researched in 2010, arranged new measuring standard by having an experiment to set measuring method after obtaining each item. According to the result, The experiment includes a measuring method of two items; Nafronyl Oxalate Capsules, and Ticlopidine Hydrochloride Tablets. The research is ameliorated by research methods through several experiments such as High Performance Liquid Chromatography validation, preparing items, implement of trial-experiment and authentic experiment, and experiment on measuring method of regulations of Korea Pharmaceutical Codex. The experiments are taken opinions of experts in KFDA into consideration and wrote out a report of the new measuring method on each last item. The report is combined as each two experiment sections of analyzing method to maintain the quality on the basis of the research in 2010 on setting of dissolution specifications for oral solid dosage forms. The result of measuring method of medical supplies through modernizing trial method of oral solid dosage forms is available to be accurate. In conclusion, this study could contribute to promotion of public health by organizing a basis for safe and high quality of medical supplies in domestic market.

• Journal of Chest Surgery
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• v.20 no.3
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• pp.512-519
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• 1987

In the department of chest surgery of Pusan National University hospital cardiac valve surgery was done in 118 cases from March, 1982, to June, 1986. Among these, 90 were mitral valve replacement, 9 mitral commissurotomy, 5 mitral valvuloplasty, 4 aortic valve replacement, 4 double valve replacement, 4 mitral annuloplasty, one mitral annuloplasty with commissurotomy and valvuloplasty. 48 were male and 70 were female and age distribution ranged from 6 to 57 years [mean 30.6 years]. Early death within 30 days after operation was 14 cases: 10 had mitral valve replacement, 2 double valve replacement and 2 mitral annuloplasty respectively. Confirmed causes of death were low cardiac output syndrome in 9 cases, congestive heart failure in one case, cardiac tamponade in one case, malfunction of valve in one case, cardiac rupture in one case and renal failure in one case. The 104 cases were followed up for a total 190 years and range was from 2 to 54 months [Mean*SD: 21.9*16.5 months]. During follow-up period, 2 late deaths were developed: one was due to subdural hematoma and the other was congestive heart failure combined with fulminant hepatitis. Anticoagulation therapy was done with warfarin to the level of 20 to 40% of normal prothrombin time in 53 cases, dipyridamole and aspirin in 18 cases, or ticlopidine hcl in 15 cases. The frequency of bleeding due to anticoagulation therapy was 1.0% episodes per patient-years: one was in warfarin group and another was in dipyridamole and aspirin group. Among the studied 102 cases, 93 cases [91.2%] of patients were in NYHA class I or II during follow up period.

• 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.

• Journal of Yeungnam Medical Science
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• v.15 no.2
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• pp.350-358
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• 1998

Antiphospholipid antibody syndrome(APS) is a well-known clinical syndrome characterized by recurrent arterial or venous thromboses, recurrent fetal loss, thrombocytopenia, together with high titers of sustained anticardiolipin antibody(aCL) or lupus anticoagulant(LA). Although systemic lupus erythematosus(SLB) and APS may coexist, a high proportion of patients manifesting the APS do not suffer from classical lupus or other connective tissue disease. The patient has been defined as having a primary antiphospholipid antibody syndrome. We experienced one case of primary APS with recurrent fetal loss, recurrent cerebral infarctions, positive anticardiolipin antibody IgG and fluttering vegetation on the mitral valve, without other connective tissue diseases including SLE. Forty-three old female had 2 out of 11 criteria for the diagnosis of SLE, such as thrombocytopenia and positive antinuclear antibody, but did not meet whole criteria. The patient was treated with ticlopidine, and anticoagulant therapy was recommended.

• Journal of Yeungnam Medical Science
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• v.18 no.1
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• pp.51-58
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• 2001

Background: Cholestatic hepatitis is failure of bile to reach the duodenum with hepatocellular damage and no demonstable obstruction of the major bile ducts. The prognosis is usually good with recovery in less than 4 weeks after withdrawal of the offending drug. However, a prolonged course lasting over 3 months is possible and, in rare cases, progression to ductopenia with development of a vanishing bile duct syndrome occurs. A differential diagnosis with other causes of Chronic liver disease is needed. Materials and Methods: From January 1991 through January 2000, 14 patients diagnosed as cholestatic hepatitis by liver biopsy were included. The possible causative drug, clinical features, laboratory findings, and progression of cholestatic hepatitis were evaluated. The semiquantitative study of liver lesions was performed by two independent observers. Results: Causes of cholestatic hepatitis are 5 cases of oriental medicine, 3 cases of anti-tuberculosis medication, 1 case of ticlopidine and antibiotics and 4 cases of unknown causes. The clinical features of cholestatic hepatitis were jaundice, itching, urine color change, and general weakness. During 6 to 30 months, LFT of 5 patients showed prolonged elevation. Elevated total cholesterol ${\geq}$250 mg/dL in 6 patients, pheripheral blood eosinophilia in 5 patients, auto-antibody positive in 6 patients were observed respectively. The biopsies showed intralobular bilirubinostasis with a mixed portal inflammatory infiltration. Conclusion: In cholestatic hepatitis, durations of abnormal LFT are variable regardless of causative drugs. If cholestatic hepatitis progresses toward chronic course, viral hepatitis, primary biliary cirrhosis, and autoimmune hepatitis should be differentially diagnosed and sequential liver biopsies are needed.

• The Journal of Dong Guk Oriental Medicine
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• v.8 no.2
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• pp.115-129
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• 2000

The cause that the increase of animality fat intakes, under exercise, fatness, adding the stress, advanced age etc., the occurrence rate of the circulation system disease has been increased. And the thrombosis importantly came to the front as the risk factor of these circulation system's disease. Nowadays, the ischemic disease has especially discussed, for example the angina or myocardial infarction, originated in thrombosis that came from the platelet aggregation. In the western medicine, as the cure and prevention, using the aspirin or ticlopidine for platelet aggregation suppressant. But in the , the curing method must be used properly according to the pectoralgia or heartache's kind, state, grade. The platelet do not attache to the normal hemangioendothelial cell. But when it stimulated by endothelium peronia and so on, it attache to the injury endothelium or rise aggregation between the platelet. On this time, it secrete the platelet aggregation inducer as like ADP, thromboxane A2 from the inside of platelet. So it has first defensive function through the aggregation augment that prevent the celerity consumption of blood. But the activation of abnormal platelet occur the platelet grume and thrombogenesis. So it bring up the occlusive angiosis, so to speak, cardiovascular disease, cerebrovascular disease, arterial sclerosis. In oriental medicine, the thrombosis in the category of blood stasis and this blood stasis present the generalise or local blood circulation disturbance that generated by all kinds of pathological fact or blood stream retention accompanying with a series of syndrome. As the syndrome, stabbing pain fixed at certain region, squamous and dry skin, fullness and pain of the chest and hypochondrium, firmness and fullness of the lower abdomen, black stool, dark purple tongue or with ecchymoses and petechiae etc.. has been created. And it becomes the pathopoiesis cause that the convulsion and palpitation, severe palpitatiion, tympanites, the symtom complex with a mass or swelling in the abdomen, insanity, stricken by wind etc.. Moreover, it used the drugs for invigorating blood circulation and eliminating blood stasis or drugs for removing blood stasis for all kinds of syndrome through the blood stasis. And the drugs for activating the blood circulation, such as Salviae Radix, Angelicae Sinensis Radix, Persicae Semen, Achyranthis Radix, Cnidii Rhizoma, Carthami Flos are used for that. And it is used to the herbs of insects that has strong effect about the disintergrating blood stasis such as Hirudo, Scolopendrae Corpus, Buthus, Lumbricus etc.. On this study, It used Geijibokryunghwan(GBH) and the consisting herbs to investigate the influence of platelet aggregation about drugs that used to improvement various symptoms created by the thrombosis in oriental medicine. GBH formula has as formula recorded in the , action of 'eleminating the evil and not impairment of healthy energy' and 'promoting the flow of QI and cold and heat, so used for the expel blood stasis herbs from the ancient. Therefore we investigated the restraint effect of GBH and the consisting herbs about the platelet agregation induced to the ADP, AA or collagen. The conclusion is following. 1. When it added the aggregation inducer after that it added GBH and individual consisting herbs in the PRP, GBH showed the (+) inhibition effect on the platelet aggregation and it showed the (+) inhibition effect in the individual consisting herbs as like Paeoniae Radix and Moutan Cortex Radicis. 2. It showed the (+), (+,++) inhibition effect on the platelet aggregation in Paeoniae Radix Hoelen, Paeoniae Radix Moutan Cortex Radicis, Hoelen Moutan Cortex Radicis etc. 3. In the aggregation inhibition activating on the difference of density, GBH showed strong inhibition effect to the aggregation state induced to collagen, and it showed the inhibition effect in the individual consisting herbs as like Paeoniae Radix and Moutan Cortex Radicis about the aggregation induced by the collagen. 4. It showed the strong inhibition effect about the aggregation induced by the collagen in Paeoniae Radix Hoelen, Paeoniae Radix Moutan Cortex Radicis, Hoelen Moutan Cortex Radicis etc Like this, as confirm GBH and the individual consisting herb's inhibition effect of platelet aggregation, We considerated that GBH and the individual consisting herbs have practical applicational value of clinical trial in the thrombosis caused by platelet aggregation.