Adenosine diphosphate/ADP receptor

Ticlopidine HCl inhibits platelet aggregation with IC50 of ~2 μM in men. Ticlopidine HCl, when orally administered to rats, results 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.

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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].

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.

Cell Proliferation Assay[4]
Cell Types: Human endothelial cells
Tested Concentrations: 30 and 150 µM
Incubation Duration: 2, 6; 10 days
Experimental Results: Treated cells grow slower if compared with controls and this effect correlates with the concentration of Ticlopidine in the culture medium.

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 rate is greater than 80%. Food can increase absorption by approximately 20%.
Excretion Route
Ticlopidine is primarily excreted in urine (60%), with a small amount excreted in feces (23%).
Volume of Distribution
Volume of distribution was not quantified.
Clearance
Clearance of ticlopidine was not quantified, but it decreases with age.

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Metabolism/Metabolites
Ticlopidine is primarily metabolized in the liver, with only trace amounts of intact drug detected. At least 20 metabolites have been identified.
Known human metabolites of ticlopidine include ticlopidine S-oxide and thienodihydropyridinium.

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Biological Half-Life
After a single 250 mg dose, the half-life is approximately 7.9 hours in subjects aged 20 to 43 years and approximately 12.6 hours in subjects aged 65 to 76 years. After repeated administration (250 mg twice daily), the half-life was approximately 4 days in subjects aged 20 to 43 years and approximately 5 days in subjects aged 65 to 76 years.

Hepatotoxicity
During ticlopidine treatment, approximately 4% of patients experience elevated serum enzymes. These elevations are usually mild, asymptomatic, and rarely require dose adjustment or discontinuation. Ticlopidine is also associated with clinically significant acute liver injury. Although these reactions are rare, more than 50 cases have been reported in the literature, some of which are severe. Symptoms usually appear within 6 weeks (range 1 to 24 weeks), with fatigue, jaundice, and pruritus as the main manifestations. The most common pattern of elevated liver enzymes is cholestatic (approximately 75%), but mixed or hepatocellular liver enzyme elevations have also been reported. Immune allergic reactions, such as fever, rash, and eosinophilia, may occur but are uncommon and, if they do occur, are usually mild. Autoantibody formation is rare. Liver biopsy usually shows cholestatic hepatitis with mixed cellular infiltration. Most cases are self-limiting and resolve within 1 to 3 months, but there are isolated cases of persistent jaundice or abnormal liver function, including at least one suspected case of disappearing bile duct syndrome, which ultimately requires liver transplantation. Ticlopidine treatment is also associated with aplastic anemia and thrombotic thrombocytopenic purpura (TTP), which can be severe and even fatal; these patients may also have cholestatic liver damage.

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Protein Binding
Reversible binding (98%) to plasma proteins, primarily serum albumin and lipoproteins. Binding to albumin and lipoproteins is unsaturated over a wide concentration range. Ticlopidine also binds to α1-acid glycoproteins (approximately 15% or less).

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Women TDLo oral 350 mg/kg/5 weeks - once a week
Women TDLo oral 1896 mg/kg/26 weeks
65335 women TDLo oral 1896 mg/kg/26 weeks Liver: Jaundice, cholestatic; Gastrointestinal: Nausea or Vomiting Clinical Pharmacy, 12(398), 1993 [PMID:8403812]
65335 women TDLo oral 49 mg/kg/1 week - once a week Liver: Jaundice, cholestatic; Liver: Impaired liver function tests, American Journal of Hospital Pharmacy, 51(1821), 1994 [PMID:7942916]
65335 women, oral TDLo 189 mg/kg/17 days - Liver: Cholestatic jaundice; Liver: Impaired liver function, American Journal of Hospital Pharmacy, 51(1821), 1994 [PMID:7942916]
65335 females, LDLo not reported 180 mg/kg/18 days - Liver: Impaired liver function; Blood: Aplastic anemia; Skin and appendages (skin): Other dermatitis: Post-systemic exposure, American Journal of Hematology, 59(260), 1998;
65335 rats, oral LD50 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 form of ticlopidine, a thienopyridine derivative with anticoagulant properties. Ticlopidine hydrochloride irreversibly inhibits adenosine diphosphate (ADP)-induced platelet-fibrinogen binding by binding to the glycoprotein (GP) IIb/IIIA complex. The GP IIb/IIIA complex is one of the two purinergic receptors activated by ADP. Inhibition of receptor activation leads to inhibition of adenylate cyclase, thereby reducing cyclic adenosine monophosphate (cAMP) levels, which in turn interferes with platelet membrane function and affects platelet-platelet interactions, the release of platelet granule components, and prolongs bleeding time. It is a potent platelet aggregation inhibitor commonly used in coronary artery stenting. See also: Ticlopidine (containing the active moiety). Ticlopidine is a novel platelet aggregation inhibitor. This study investigated the efficacy of the drug in 55 subjects, including healthy volunteers and hospitalized patients. The drug takes 24 to 48 hours to take effect and lasts for more than 3 days. The study examined the dose-response relationship of oral doses ranging from 250 mg to 1000 mg over one week; the results showed that oral administration of 450 mg/day inhibited 2 μM ADP-induced platelet aggregation by up to 50%. The drug had no effect on collagen-induced platelet aggregation, but had a slight effect on platelet adhesion. The clinical tolerability of patients was assessed by oral administration of up to 500 mg ticlopidine daily over several weeks, and the results showed no significant side effects and no changes in safety indicators. [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

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

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.33 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (8.33 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 8.33 mg/mL (27.74 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)