Batifiban, a synthetic cyclic peptide, is a potent platelet glycoprotein GPIIb/IIIa antagonist which may be useful in the treatment and prevention of acute coronary syndromes. The pharmacokinetics and pharmacodymanic (inhibition of platelet aggregation) effects, and tolerability of batifiban were investigated in healthy subjects following single bolus injection with doses of 55, 110, or 220 microg/kg, or multiple doses of an bolus followed intravenous infusion for 24 h (180 microg/kg plus 2.0 microg/min.kg, and 220 microg/kg plus 2.5 microg/min.kg) in this phase I clinical trial. Plasma levels of batifiban and areas under the curve were found to be proportional to doses. Batifiban was rapidly eliminated with a half-life of approximately 2.5 h. Significant differences were noted for plasma levels of batifiban and areas under the curve between males and females. No significant differences in the terminal half-life were found between males and females. Batifiban reversibly inhibited ex vivo platelet aggregation in a dose- and concentration-dependent manner, consistent with its mechanism as a GPIIb/IIIa antagonist. Single and multiple intravenous doses of batifiban were found to be safe and well tolerated in healthy subjects. These results support a bolus injection plus intravenous infusion regimen of batifiban for the treatment and prevention of acute coronary syndromes.
Injections, Intravenous ; Peptides, Cyclic/*pharmacokinetics ; Peptides, Cyclic/*pharmacology ; Platelet Aggregation Inhibitors/adverse effects ; Platelet Aggregation Inhibitors/*pharmacokinetics ; Platelet Aggregation Inhibitors/*pharmacology ; Platelet Glycoprotein GPIIb-IIIa Complex/*antagonists & inhibitors ; Young Adult

The present study was designed to determine the effects of puerarin pre-treatment on the pharmacokinetics of the oral anticoagulant agent warfarin and the antiplatelet agent clopidogrel in rats. In the treatment group, rats was gavaged with warfarin or clopidogrel after repeated treatment with puerarin at intraperitoneal doses of 20, 60, or 200 mg·kg(-1) for 7 days, while rats in the control group were administrated only with the same dose warfarin or clopidogrel. Plasma samples were obtained at the prescribed times and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). The results showed that rats treated with puerarin at all the test doses of 20, 60 and 200 mg·kg(-1) were found to affect the pharmacokinetics of warfarin, but not clopidogrel, suggesting a potential herb-drug interaction between puerarin and warfarin.
Animals ; Anticoagulants ; pharmacokinetics ; Chromatography, Liquid ; Clopidogrel ; Drug Administration Schedule ; Herb-Drug Interactions ; Injections, Intraperitoneal ; Isoflavones ; administration & dosage ; pharmacology ; Male ; Platelet Aggregation Inhibitors ; pharmacokinetics ; Rats ; Rats, Wistar ; Tandem Mass Spectrometry ; Ticlopidine ; analogs & derivatives ; pharmacokinetics ; Vasodilator Agents ; administration & dosage ; pharmacology ; Warfarin ; pharmacokinetics

OBJECTIVETo explore the effects of 2A-1-1 (purified component from Panax notoginsengs saponins) on the aggregation of and Ca2+ influx into human platelets.

METHODSThe aggregation of platelets was tested by nephelometry, Fura-2 fluorescent technique was used for detecting cell [Ca2+]i. The effects of 2A-1-1, nifedipine and SK&F96365 on Ca(2+) influx into human platelets induced by ADP or CPA were observed separately.

RESULTSNifedipine (< 20 micromol/L) could not inhibit platelet aggregation induced by ADP or the Ca(2+) influx induced by ADP or CPA. SK&F96365 at 20 micromol/L could inhibit the maximal aggregation of platelets induced by ADP with a inhibitory rate of 59.83%, at 15 micromol/L could inhibit the Ca2+ influx induced by CPA or ADP. 2A-1-1 (5, 10 and 20 micromol/L) could inhibit the maximal aggregation of platelets induced by ADP with the inhibitory rates of 47.06%, 53.47% and 71.52%, respectively. 2A-1-1 at 10 and 20 micromol/L could inhibit the Ca2+ influx induced by CPA or ADP.

CONCLUSIONS2A-1-1 can inhibit platelets aggregation, block the ROC (Receptor-dependent Ca2+ channels) and inhibit Ca2+ influx of human platelets.

Adenosine Diphosphate ; pharmacology ; Adult ; Blood Platelets ; cytology ; drug effects ; metabolism ; Calcium ; metabolism ; pharmacokinetics ; Calcium Channel Blockers ; pharmacology ; Dose-Response Relationship, Drug ; Female ; Ginsenosides ; pharmacology ; Humans ; Imidazoles ; pharmacology ; Indoles ; pharmacology ; Male ; Nifedipine ; pharmacology ; Platelet Aggregation ; drug effects ; Platelet Aggregation Inhibitors ; pharmacology

PURPOSE: Clopidogrel is a prodrug that requires transformation into an active metabolite by cytochrome P450 (CYP) in the liver in order to irreversibly inhibit the P2Y12 adenosine diphosphate platelet receptor. CYP2C19 polymorphism has been reported to correlate with reduced antiplatelet activity of clopidogrel in coronary artery disease. We assessed the association between CYP2C19 polymorphism and clopidogrel resistance in patients with cerebrovascular disease. MATERIALS AND METHODS: We retrospectively gathered data from patients who experienced cerebrovascular disease, received clopidogrel, and were tested for clopidogrel resistance and CYP2C19 polymorphism. Clopidogrel resistance was tested by the VerifyNow P2Y12 system, and the CYP2C19 polymorphism was tested by the Seeplex CYP2C19 ACE Genotyping system. Clopidogrel resistance was expressed in P2Y12 reaction units (PRU) and percent inhibition. High PRU and low percent inhibition suggests clopidogrel resistance. CYP2C19 polymorphisms were expressed as extensive, intermediate, and poor metabolizers. Clopidogrel resistance was assessed according to the subgroup of CYP2C19 polymorphism. RESULTS: A total of 166 patients were evaluated. The PRU values of extensive CYP2C19 metabolizers (195.0+/-84.9) were significantly lower than those of intermediate and poor metabolizers (237.9+/-88.0, 302.2+/-58.9). The percent inhibition of extensive metabolizers (44.6+/-21.8) was significantly higher than that of intermediate and poor metabolizers (30.5+/-21.5, 14.0+/-13.4). CONCLUSION: Intermediate and poor metabolizing CYP2C19 polymorphism is associated with reduced clopidogrel antiplatelet activity in patients with cerebrovascular disease. The clinical implications of this finding require further investigation.
Aged ; Aryl Hydrocarbon Hydroxylases/*genetics/metabolism ; Cerebrovascular Disorders/*drug therapy/*enzymology/genetics ; Drug Resistance/genetics ; Female ; Humans ; Male ; Middle Aged ; Platelet Aggregation Inhibitors/pharmacokinetics/*therapeutic use ; Polymorphism, Single Nucleotide ; Retrospective Studies ; Ticlopidine/*analogs & derivatives/pharmacokinetics/therapeutic use

BACKGROUND: Previously, the inhibition of coronary restenosis with Abciximab (ReoPro (R) ) -coated stent in a porcine model was reported. ReoPro (R) inhibits platelet aggregation, the proliferation of vascular smooth muscle cells and the inflammatory reaction. METHODS: A prospective randomized trial was performed to compare two types of stent for revascularization in the native coronary artery. The primary effective end points were major adverse coronary events (MACE) : cardiac death, acute myocardial infarction, target vessel revascularization (TVR) and restenosis at the 6-month clinical and angiographic follow-ups. RESULTS: One hundred and fifty-five patients were enrolled between August 2001 and June 2003. The mean ages (56.0 +/- 10.0 vs. 56.9 +/- 10.8 years), baseline diameter of stenosis and minimal luminal diameter were no different between the two groups. There was one myocardial infarction and revascularization during the hospital stay in control stent group. During the clinical follow-up there were two myocardial infarctions in control group. Follow-up coronary angiograms were performed in 62.3% (48/77) and 65.4% (51/78) of the coated and control groups, respectively. The diameter of stenosis and late loss were significantly less in the ReoPro (R) -coated stent group compared with the controls (16.4 +/- 5.8% vs. 34.3 +/- 6.1%, p=0.009; and 0.33 +/- 0.28 mm vs. 0.88 +/- 0.41 mm; p=0.002). The restenosis and TVR rates of the ReoPro (R) -coated stent were relatively lower compared with the control stent [14.6% (7/48) vs. 29.4% (15/51), p=0.062; and 9.2% (7/76) vs. 14.7% (11/75) ; p=0.327]. CONCLUSION: A ReoPro (R) -coated stent is safe, and may be effective in the prevention of coronary restenosis.
Antibodies, Monoclonal/pharmacokinetics/*therapeutic use ; Coated Materials, Biocompatible/pharmacokinetics/*therapeutic use ; Coronary Arteriosclerosis/*surgery ; Coronary Restenosis/epidemiology/prevention & control ; Female ; Humans ; Immunoglobulins, Fab/*therapeutic use ; Korea/epidemiology ; Male ; Middle Aged ; Platelet Aggregation Inhibitors/pharmacokinetics/*therapeutic use ; Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors ; Prospective Studies ; Research Support, Non-U.S. Gov't ; *Stents

BACKGROUND: Clopidogrel has been widely used to prevent recurrent ischemia in patients with acute coronary syndrome (ACS). However, inter-individual variability in response to clopidogrel has been a problem in the clinical setting. The aim of the present study was to investigate the frequency of clopidogrel resistance and to determine the clinical, pharmacokinetic, and pharmacogenetic factors for clopidogrel resistance in Korean patients with ACS. METHODS: Clinical information, such as the underlying diseases and concurrent medications, of 114 patients with ACS who received clopidogrel therapy was studied. The degree of inhibition of platelets was assessed using the VerifyNow assay (Accumetrics, USA). The patients who showed less than 20% inhibition of platelets were defined as non-responders to clopidogrel treatment. Steady state plasma concentrations of clopidogrel were measured using HPLC/tandem mass spectrometry. CYP2C19 genotyping was also performed. RESULTS: A wide inter-individual variability was observed in platelet inhibition (0-76%); 56 patients (49%) showed less than 20% inhibition. There were no differences between the patients' history of diabetes mellitus and concurrent medications as well as the plasma concentrations of clopidogrel of the responders and non-responders. CYP2C19 variants, including CYP2C19*2 and CYP2C19*3, were more commonly observed in the non-responders than in the responders (P value<0.0001). CONCLUSIONS: The response to clopidogrel was highly variable in Korean patients with ACS. The results of the present study confirmed that the genetic polymorphism of CYP2C19 could be important in clopidogrel response. However, further studies are required to investigate other likely factors involved in clopidogrel resistance.
Acute Coronary Syndrome/complications/*drug therapy/genetics ; Adult ; Aged ; Aged, 80 and over ; Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors/genetics/metabolism ; Asian Continental Ancestry Group/*genetics ; Diabetes Complications ; Drug Resistance ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Platelet Aggregation Inhibitors/blood/pharmacokinetics/*therapeutic use ; Polymorphism, Genetic ; Republic of Korea ; Ticlopidine/*analogs & derivatives/blood/pharmacokinetics/therapeutic use

The combined use of batifiban, a synthetic platelet GPII b/ IIIa receptor antagonist, and antithrombin agents is an attractive option for the treatment of patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS) and those scheduled for percutaneous coronary intervention. To observe whether antithrombin agents affect the pharmacokinetic and pharmacodynamic properties of batifiban in combination therapy and optimize clinical administration dosage of batifiban, an open-label and parallel study was conducted. Thirty healthy subjects were randomly divided into three groups, which were sequentially treated with batifiban alone, or oral coadministration of clopidogrel, aspirin and UFH, or batifiban coadministered with these antithrombin agents. Blood samples were collected at pre-specified time points. The evaluation index included the inhibition of platelet aggregation and pharmacokinetic parameters. The pharmacokinetic parameters of batifiban and batifiban coadministered with antithrombin agents showed no significant differences. The mean inhibition rate of platelet aggregation (%) suggested that neither batifiban alone nor antithrombin agents alone could provide such potent inhibition rate (>80%) to obtain the best clinical efficacy, but they had a synergistic effect on platelet inhibition. No serious adverse effects were observed. The results in these healthy subjects suggest that batifiban coadministrated with antithrombin agents could achieve optimum clinical treatment effect for patients with NSTE ACS, and also those scheduled for percutaneous coronary intervention.
Administration, Oral ; Adolescent ; Adult ; Area Under Curve ; Aspirin ; administration & dosage ; pharmacology ; China ; Drug Administration Schedule ; Female ; Fibrinolytic Agents ; administration & dosage ; pharmacology ; Heparin ; administration & dosage ; pharmacology ; Humans ; Infusions, Intravenous ; Injections, Intravenous ; Male ; Metabolic Clearance Rate ; drug effects ; Peptides, Cyclic ; administration & dosage ; pharmacokinetics ; Platelet Aggregation Inhibitors ; administration & dosage ; pharmacokinetics ; Ticlopidine ; administration & dosage ; analogs & derivatives ; pharmacology ; Time Factors ; Young Adult

Four crystalline forms of clopidogrel bisulfate were characterized by analytical techniques. Aiming to research the absorption characteristics of clopidogrel bisulfate polymorphs after taken orally by rat, and to estimate the influence of crystal form to pharmacodynamic action, four crystalline forms of clopidogrel bisulfate were administered intragastrically to rats, and high performance liquid chromatography (HPLC) was used to measure the contents of clopidogrel bisulfate and its metabolite in rat plasma. The metabolite of clopidogrel bisulfate was detected in rat plasma. There were significant deviations among four crystalline forms in the areas under curve of the metabolite of clopidogrel bisulfate. We concluded that the different crystal forms of clopidogrel bisulfate showed different pharmacokinetic characteristics, which might affect pharmacodynamic action.
Absorption ; Administration, Oral ; Animals ; Area Under Curve ; Calorimetry, Differential Scanning ; Chromatography, High Pressure Liquid ; Crystallization ; Male ; Platelet Aggregation Inhibitors ; administration & dosage ; chemistry ; pharmacokinetics ; Random Allocation ; Rats ; Rats, Wistar ; Spectrophotometry, Infrared ; Ticlopidine ; administration & dosage ; analogs & derivatives ; blood ; chemistry ; pharmacokinetics ; X-Ray Diffraction