Adenosine diphosphate/ADP receptor

体外活性：盐酸噻氯匹定是噻吩并吡啶家族的一种抗血小板药物。盐酸噻氯匹定通过阻断 ADP 受体来改变血小板膜的功能，从而抑制血小板聚集。这可以防止糖蛋白 IIb/IIIa 的构象变化，从而使血小板与纤维蛋白原结合。 Ticlopidine HCl 通过激活环化酶的基础活性和 PGE1 刺激的活性，抑制血小板聚集和内源性底物合成前列腺素，防止 PGE2 诱导的环化酶活性抑制，从而增加血小板 c-AMP 水平。

盐酸噻氯匹定可抑制男性血小板聚集，IC50 约为 2 μM。当大鼠口服盐酸噻氯匹定时，通过增加血小板膜中的环化酶与 PGE1 的亲和力，导致基础和前列腺素 E1 (PGE1) 刺激的腺苷酸环化酶活性的激活，尽管它不能影响腺苷或氟化钠刺激的腺苷酸环化酶活性。

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当对大鼠口服噻氯匹啶时，通过增加血小板膜中环化酶对PGE1的亲和力，导致基础和前列腺素E1（PGE1）刺激的腺苷酸环化酶活性的激活，尽管它没有影响腺苷或氟化钠刺激的酶活性。在洗涤过的血小板中，噻氯匹啶还激活了基础和PGE1刺激的环化酶活性，并防止了低浓度PGE2引起的环化活性降低。此外，噻氯匹啶抑制了凝血酶诱导的血小板丙二醛的形成，但未能抑制外源性花生四烯酸引起的丙二醛的形成。腺苷3'，5'-环磷酸（c-AMP）：噻氯匹啶治疗对血小板裂解物的磷酸二酯酶活性没有显著影响。这些发现表明，噻氯匹啶通过激活环化酶的基础和PGE1刺激的活性，抑制血小板聚集和内源性底物前列腺素合成，防止PGE2诱导的环化酶活性降低，从而增加血小板c-AMP水平[2]。

盐酸噻氯匹啶是噻氯匹定的盐酸盐形式，噻氯匹定是一种具有抗凝血特性的噻吩并吡啶衍生物。盐酸噻氯匹啶通过与糖蛋白（GP）IIb/IIIA复合物结合，不可逆地抑制二磷酸腺苷（ADP）诱导的血小板纤维蛋白原结合，糖蛋白是ADP激活的两种嘌呤能受体之一。受体激活的抑制会导致腺苷酸环化酶的抑制，导致环磷酸腺苷水平降低，从而干扰血小板膜功能和随后的血小板-血小板相互作用、血小板颗粒成分的释放和出血时间的延长。

细胞增殖测定[4]
细胞类型： 人内皮细胞
测试浓度： 30 和 150 µM
孵育时间： 2, 6; 10 天
实验结果：与对照组相比，处理过的细胞生长较慢，这种效应与培养基中噻氯匹定的浓度相关。

Ticlopidine, when orally administered to rats, resulted in activation of basal and prostaglandin E1 (PGE1)-stimulated adenylate cylase activity through increase in affinity of the cyclase in platelet membrane to PGE1, although it failed to affect adenosine- or sodium fluoride-stimulated activity of the enzyme. In washed platelets, Ticlopidine also activated basal and PGE1-stimulated activity of the cyclase and prevented reduction in the cyclase activity caused by low concentrations of PGE2. Furthermore, Ticlopidine inhibited malondialdehyde formation in platelets induced by thrombin but failed to inhibit that caused by exogenous arachidonic acid. Adenosine 3',5'-cyclic monophosphate (c-AMP): phosphodiesterase activity of platelet lysate was not significantly affected by Ticlopidine treatment. These findings indicate that Ticlopidine inhibits platelet aggregation and prostaglandin synthesis from endogenous substrate through activating basal and PGE1-stimulated activity of the cyclase, preventing PGE2-induced depression of the cyclase activity and thus increasing platelet c-AMP level.[2]

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Ticlopidine is a new platelet aggregation inhibitor. The effect of this drug was studied on 55 subjects, healthy volunteers and hospitalized patients. The action requires 24 to 48 hr to appear, and lasts more than 3 days. A dose-effect relationship was studied with oral daily doses ranging from 250 to 1,000 mg during 1 wk; it showed a 50% inhibition on adenosine diphosphate (ADP)-induced aggregation at 2 muM concentration on an oral daily dose of 450 mg. No action was found on collagen-induced aggregation, and a mild effect was observed on platelet adhesiveness. Clinical tolerance was assessed in patients given ticlopidine in oral doses up to 500 mg/day during several weeks, showing no overt side effects and no change in the safety parameters.[1]

Absorption
Absorption is greater than 80%. Food increases absorption by approximately 20%.

Route of Elimination
Ticlopidine is eliminated mostly in the urine (60%) and somewhat in the feces (23%).

Volume of Distribution
The volume of distribution was not quantified.

Clearance
Ticlopidine clearance was not quantified, but clearance decreases with age.

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Metabolism / Metabolites
Ticlopidine is metabolized extensively by the liver with only trace amounts of intact drug detected. At least 20 metabolites have been identified.

Ticlopidine has known human metabolites that include Ticlopidine S-oxide and Thienodihydropyridinium.

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Biological Half-Life
Half-life following a single 250-mg dose is approximately 7.9 hours in subjects 20 to 43 years of age and 12.6 hours in subjects 65 to 76 years of age. With repeated dosing (250 mg twice a day), half-life is about 4 days in subjects 20 to 43 years of age and about 5 days in subjects 65 to 76 years of age.

Hepatotoxicity
Ticlopidine has been associated with serum enzyme elevations in approximately 4% of patients during therapy. These elevations are usually mild, asymptomatic and rarely require dose modification or stopping. Ticlopidine has also been associated with clinically apparent, acute liver injury. While these reactions are rare, more than 50 instances have been reported in the literature and some have been severe. The onset of symptoms is typically within 6 weeks (range 1 to 24 weeks) and marked by onset with fatigue, jaundice and itching. The usual pattern of liver enzyme elevations is cholestatic (~75%), but cases with mixed or hepatocellular enzyme elevations have also been described. Immunoallergic features such as fever, rash and eosinophilia can occur but are not common and, if present, are usually mild. Autoantibody formation is rare. Liver biopsy usually shows cholestatic hepatitis with mixed cellular infiltrates. Most cases are self-limited with recovery within 1 to 3 months, but isolated cases of prolonged jaundice or liver test abnormalities have been described, including at least one case of probable vanishing bile duct syndrome that eventually required liver transplantation. Ticlopidine therapy has also been associated with aplastic anemia and thrombotic thrombocytopenic purpura (TTP) that can be severe and lead to death; these patients may also have accompanying cholestatic liver injury.

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Protein Binding
Binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein (about 15% or less).

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women TDLo oral 350 mg/kg/5W-I
women TDLo oral 1896 mg/kg/26W

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65335 women TDLo oral 1896 mg/kg/26W LIVER: JAUNDICE, CHOLESTATIC; GASTROINTESTINAL: NAUSEA OR VOMITING Clinical Pharmacy., 12(398), 1993 [PMID:8403812]
65335 women TDLo oral 49 mg/kg/1W-I LIVER: JAUNDICE, CHOLESTATIC; LIVER: LIVER FUNCTION TESTS IMPAIRED American Journal of Hospital Pharmacy., 51(1821), 1994 [PMID:7942916]
65335 women TDLo oral 189 mg/kg/17D- LIVER: JAUNDICE, CHOLESTATIC; LIVER: LIVER FUNCTION TESTS IMPAIRED American Journal of Hospital Pharmacy., 51(1821), 1994 [PMID:7942916]
65335 women LDLo unreported 180 mg/kg/18D- LIVER: LIVER FUNCTION TESTS IMPAIRED; BLOOD: APLASTIC ANEMIA; SKIN AND APPENDAGES (SKIN): DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE American Journal of Hematology., 59(260), 1998
65335 rat LD50 oral 1780 mg/kg Medical Pharmacy., 15(272), 1981

[1]. Clin Pharmacol Ther.1975 Oct;18(4):485-90;
[2]. Thromb Haemost.1979 Apr 23;41(2):436-49.

Ticlopidine Hydrochloride is the hydrochloride salt form of ticlopidine, a thienopyridine derivative with anticoagulant property. Ticlopidine hydrochloride irreversibly inhibits adenosine-diphosphate (ADP)-induced platelet-fibrinogen binding by binding to the glycoprotein (GP) IIb/IIIA complex, one of the two purinergic receptors activated by ADP. Inhibition of the receptor activation causes the inhibition of adenylyl cyclase, results in decreased levels of cyclic adenosine monophosphate and thereby interferes with platelet membrane function and subsequent, platelet-platelet interaction, release of platelet granule constituents and prolongation of bleeding time.
An effective inhibitor of platelet aggregation commonly used in the placement of STENTS in CORONARY ARTERIES.
See also: Ticlopidine (has active moiety).

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Ticlopidine is a new platelet aggregation inhibitor. The effect of this drug was studied on 55 subjects, healthy volunteers and hospitalized patients. The action requires 24 to 48 hr to appear, and lasts more than 3 days. A dose-effect relationship was studied with oral daily doses ranging from 250 to 1,000 mg during 1 wk; it showed a 50% inhibition on adenosine diphosphate (ADP)-induced aggregation at 2 muM concentration on an oral daily dose of 450 mg. No action was found on collagen-induced aggregation, and a mild effect was observed on platelet adhesiveness. Clinical tolerance was assessed in patients given ticlopidine in oral doses up to 500 mg/day during several weeks, showing no overt side effects and no change in the safety parameters.[1]

C14H14CLNS.HCL

300.25

299.03

C, 56.01; H, 5.04; Cl, 23.61; N, 4.67; S, 10.68

53885-35-1

55142-85-3; 53885-35-1 (HCl)

65335

Typically exists as solid at room temperature

367.3ºC at 760 mmHg

205°C

175.9ºC

4.699

31.48

1

2

2

18

261

0

ClC1=C([H])C([H])=C([H])C([H])=C1C([H])([H])N1C([H])([H])C2C([H])=C([H])SC=2C([H])([H])C1([H])[H].Cl[H]

MTKNGOHFNXIVOS-UHFFFAOYSA-N

InChI=1S/C14H14ClNS.ClH/c15-13-4-2-1-3-11(13)9-16-7-5-14-12(10-16)6-8-17-14;/h1-4,6,8H,5,7,9-10H2;1H

5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride

Ticlodix; Ticlodone; Panaldine; TICLOPIDINE HYDROCHLORIDE; 53885-35-1; Ticlopidine HCL; Panaldine; Tiklid; 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride; Tiklyd; EINECS 258-837-4; Tiklid; Ticlopidine; Ticlopidine HCl; 53 32C; 53-32C; 5332C; trade name Ticlid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (8.33 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (8.33 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 3 中的溶解度: 8.33 mg/mL (27.74 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶 (<60°C).

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
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