Clopidogrel Research Articles

COST-MINIMIZATION ANALYSIS OF VARIOUS PHARMACEUTICAL ALTERNATIVES OF CLOPIDOGREL BISULFATE

Heart disease is widespread, and accounts for a quarter of all deaths in the US. Clopidogrel is used extensively for various cardiac conditions but has a high price. Cost-minimization analysis (CMA) differentiates alternative therapies based on price, given that all of the interventions have exactly the same health effects and must be bioequivalent when it comes to health benefits and adverse effects. Dissolution studies, using four marketed products, were conducted using a six stage, type II dissolution apparatus. Samples were analyzed at 240nm using a UV-VIS spectrophotometer. Concentration values of each sample, taken after 30 minutes were calculated from the calibration curve constructed with Clopidogrel Bisulfate RS. ANOVA was used to analyze any significant differences between the means of active dissolved. Plavix was found to have the highest percentage release of 97% but Ogrel had the least SEM of 3.9 with a percentage release of 95%. Lowplat and Pidogrel, although showed average percent releases of greater than 85%, their SEM and stand deviations were large showing widespread variations in unit contents. ANOVA gave a p>0.05, indicating a non-statistically significant difference between the means of active dissolved hence proving bioequivalence. CMA concluded that Ogrel may be used instead of the more expensive Plavix.

ASpirin and Plavix Following Coronary Artery Bypass Grafting (ASAP-CABG): A Randomized, Double-Blind, Placebo-Controlled Pilot Trial

1 Cardiology Service, San Antonio Military Medical Center, 3551 Roger Brooke Drive, San Antonio, Texas 78234-6200, USA. 2 Louisiana State University, New Orleans, LA, USA. 3 Geisinger Medical Center, Danville, PA, USA. Cardiology Service, Walter Reed National Military Medical Center, Bethesda, MD, USA. 5 Department of Radiology, Miami Cardiac and Vascular Institute, Baptist Health South Florida, Miami, FL, USA. 6 Division of Cardiology, University of Washington, Seattle, WA, USA.

Comparison of the antiplatelet effect of clopidogrel benzene sulfonate and clopidogrel hydrogen sulfate in stable coronary heart disease.

Clopidogrel hydrogen sulfate (CHS) is a thienopyridine, which can be used to prevent cardiovascular complications alone or in combination with acetyl salicylic acid as an important antiplatelet agent. Clopidogrel benzene sulfonate (CB) is a special clopidogrel salt that can be used as a conventional drug for antiplatelet effects, but the mechanism is still unknown. This study aimed to compare the antiplatelet effects of CHS and CB in stable coronary artery disease patients. Stable coronary artery disease patients (N = 119) were randomly divided into two groups receiving CHS (N = 67) or CB (N = 52). The patients were administered the drugs (600 mg dosage) and monitored for 12 to 14 h to detect antiplatelet effects. Antiplatelet response was evaluated by the P2Y12 response unit (PRU) and P2Y12 suppression percentage. In addition, all patients' CYP2C19*2, CYP2C19*3, and CYP3A5 polymorphisms were studied. Similar clinical manifestations were observed in the two groups. No obvious difference was detected in the platelet levels of patients given CHS or CB. The antiplatelet response (PRU and P2Y12 evaluation) of the patients using CHS and CB was not significantly different. In the two groups, the CYP2C19*2 polymorphic heterozygote number and antiplatelet response were similar. CB and CHS presented similar antiplatelet effects in stable coronary artery disease patients, and there was no difference in the CYP2C19*2 heterozygous polymorphism.

Micellar High Performance Liquid Chromatographic Determination of a Binary Mixture of Rivaroxaban and Clopidogrel and Application to Biological Fluids

A selective and short time consuming cost effective micellar high performance liquid chromatographic technique is created for the separation and simultaneous assay of two antiplatelet drugs, Rivaroxaban (RIV) with Clopidogrel (CLP). The developed and validated method is characterized by its simplicity, sensitivity and rapidness. Chromatographic study is performed on a 3 mm × 4.6 mm i.d., 2 μm pore size highly porous monolithic (chromolith® reversed phase) column to obtain good chromatographic separation using a mixture of 0.185 M sodium dodecyl sulphate (SDS), 8% n-propanol, 0.3% triethylamine (TEA) as a mobile phase, adjusted at pH 4.0 using 0.02 M orthophosphoric acid and pumped at a flow rate of 1 mL/min. using UV detector at 235 nm. The internal standard (IS) of choice was Raloxifen (RAL) and separation was performed at room temperature. Good linearity for the proposed method was obtained over the ranges of 0.3-9.0 μg/mL and 0.5-25.0 μg/mL with limits of detection (LOD) of 0.05, 0.16 μg/mL and limits of quantitation (LOQ) of 0.16, 0.49 μg/mL for rivaroxaban and clopidogrel, respectively and retention time was 1.9 and 5min., respectively. Simultaneous analysis of the studied drugs in their laboratory prepared mixture and tablet was done as an application for the proposed method showing satisfactory results. Also biological fluids were assayed using the proposed method for the determination of rivaroxaban in human plasma and for both drugs in human urine with no need for previous extraction. The data obtained by the proposed method was statistically evaluated and compared with the reference one showing good accuracy and precision of the proposed method.

Percutaneous left atrial appendage occlusion - treatment outcomes and 6 months of follow-up - a single-center experience.

AimTo present the results of treatment and evaluate 6 months of follow-up in a group of patients with non-valvular atrial fibrillation, who underwent the procedure of percutaneous left atrial appendage occlusion (PLAAO).Material and methodsPercutaneous left atrial appendage occlusion was performed in 34 patients with non-valvular atrial fibrillation and contraindications for oral anticoagulation therapy. The risk of thromboembolic and bleeding complications was determined based on the CHA2DS2VASc and HAS-BLED scales. The Amplatzer Amulet system from St. Jude Medical was used. On the first postoperative day, all patients were started on double antiplatelet therapy with 75 mg/day of acetylsalicylic acid (ASA) and 75 mg/day of clopidogrel (CLO). On the 30th postoperative day, the efficacy of the antiplatelet therapy was assessed with impedance aggregometry using a Multiplate analyzer (Roche). Echocardiographic examinations were performed intraoperatively and on the first postoperative day; subsequently, follow-up examinations were conducted 1 and 6 months after the implantation.ResultsIn all patients, proper occluder position was observed throughout the follow-up. No leakage or thrombi around the implants were found. No strokes or bleeding complications associated with the antiplatelet therapy were observed. Multiplate assessment of platelet activity was conducted in 20 out of 34 patients. The efficacy of ASA treatment was demonstrated in all patients; no response to clopidogrel treatment was observed in 5 out of 20 patients. One patient suffered from cardiac tamponade, which required the performance of full sternotomy. Local complications (hematomas of the inguinal region) were observed in 3 patients. One of the patients died for reasons unrelated to the procedure.ConclusionsPercutaneous left atrial appendage occlusion is an effective procedure in patients with non-valvular atrial fibrillation and contraindications for chronic anticoagulation therapy. Further observation is necessary to evaluate the longterm results.

The predictive value of multiple electrode platelet aggregometry for postoperative bleeding complications in patients undergoing coronary artery bypass graft surgery.

IntroductionPostoperative bleeding is one of the most serious complications of cardiac surgery and requires transfusion of blood or blood products. Acetylsalicylic acid (ASA) and clopidogrel (CLO) are the two most commonly used antiplatelet agents; when used in combination (i.e., as dual antiplatelet therapy [DAPT]), they exert a synergistic effect. Dual antiplatelet therapy, however, significantly increases the risk of postoperative bleeding. The effect of antiplatelet therapy can be monitored by platelet aggregation testing. One of the most commonly methods used for assessing platelet reactivity is multiple electrode aggregometry (MEA) which can be performed with the use of Multiplate analyzer. Although the method has long been used in interventional cardiology to assess the effect of antiplatelet therapy, it is not available at cardiac surgery departments as a standard diagnostic procedure. The aim of the study was to establish the frequency of bleeding complications following coronary artery bypass graft (CABG) surgery in patients on single antiplatelet therapy (SAPT) and patients on DAPT and to determine the usefulness of routine measurement of platelet responsiveness before CABG surgery in patients receiving antiplatelet therapy.Material and methodsA consecutive cohort of 200 patients referred for elective surgical treatment of stable coronary artery disease was enrolled (100 consecutive patients on SAPT [ASA 75 mg/day] and 100 consecutive patients on DAPT [ASA 75 mg/day + CLO 75 mg/day]). All subjects continued their antiplatelet therapy until the day before surgery. For each subject, platelet aggregation testing in the form of an ASPI test and an ADP test was performed on the Multiplate analyzer. Each subject underwent coronary artery bypass grafting surgery. For the primary and secondary endpoints in our study we adopted the definition provided in ‘Standardised Bleeding Definitions for Cardiovascular Clinical Trials: A Consensus Report from the Bleeding Academic Research Consortium’ (‘Circulation’, 2011) for BARC type 4 bleeding (i.e. CABG-related bleeding).ResultsAn ROC curve was constructed for the ASPI test and ADP test for a total of 200 patients. No significant correlations were demonstrated between the ASPI test results and either the primary endpoint or the secondary endpoints. A correlation was found between the ADP test results and the composite primary endpoint and each of the secondary endpoints. The primary endpoint of major postoperative bleeding occurred in 16 subjects. From the ROC curve, we established the optimal cut-off value for the ADP test of 26 U at sensitivity of 72%, specificity of 69%, positive predictive value of 69.90%, and negative predictive value of 71.13%.ConclusionsIn patients on antiplatelet therapy, an ADP test result of < 26 U is strongly predictive of serious bleeding complications after CABG surgery. The MEA ADP test allows to identify the group of patients at an increased risk of postoperative bleeding.

Formulation Development and Comparative Study of Clopidogrel Bisulfate Matrix Formulations

The objective of this study was to design matrix tablets for oral sustained release of clopidogrel bisulfate and to investigate the sustained release behavior of the matrix tablets. Matrices were prepared by direct compression technique, melt method and microencapsulation using sodium carboxymethylcellulose, carnuba wax and ethyl cellulose as a release retardant. The FT-IR analysis indicated the stability and compatibility of drug with excipients. The formulation was optimized on the basis of acceptable tablet properties and invitro drug release. The resulting formulations produced tablets with optimum hardness, uniform thickness, consistent weight uniformity and low friability. The results of dissolution studies indicated that formulations F2 batch exhibited good drug release pattern to provide sufficient concentration for achieving satisfactory therapeutic value for extended period of time. The drug release from F2 formulation was sustained upto 12 hrs. Tablet Fitting in-vitro drug release data from optimized matrix formulation to Korsmeyer Pappas model equation indicated that diffusion and erosion could be mechanism of drug release. Matrix tablet F2 showed no change in physical appearance, drug content after storage 40°C, 75% RH for 3 months.

Comparative effectiveness research: what kind of studies do we need?

Comparative effectiveness research (CER) is increasingly popular, yet discussions of its conduct and consequences often overlook the extensive history of comparing different therapeutic options in patient-oriented research. In particular, research in the Department of Veterans Affairs (VA) has included a decades-long focus on generating information that can enhance medical decision making and improve health outcomes. Categories of such research include multisite randomized controlled trials (conducted by the Cooperative Studies Program) and observational studies involving either primary or secondary data collection. As representative examples from cardiology, a landmark VA clinical trial published in the 1970s evaluated the benefits of coronary artery bypass grafting surgery among patients with angina; a VA trial initiated in the 1990s, and identified formally as CER, demonstrated that percutaneous coronary intervention is not superior to optimal medical therapy; and a database investigation using information from the VA electronic medical record system in the 2000s found that use of proton pump inhibitor medication is associated with the attenuation of the benefits of clopidogrel among patients hospitalized for acute coronary syndrome. A review of these (and other) selected projects, based on their type of study design, serves to highlight the strengths, limitations, and potential of CER.

Bioequivalence of clopidogrel hydrogen sulfate tablets in healthy Chinese volunteers.

We aimed to evaluate the bioequivalence of clopidogrel in healthy Chinese volunteers after administration of a single oral dose. We administered a single oral dose of 75 mg clopidogrel (test and reference) to 32 healthy Chinese volunteers according to an open, randomized, crossover design. The concentration of clopidogrel acid (carboxylic metabolite of clopidogrel) in the plasma was determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bioequivalence of the test and reference preparations were calculated using analysis of variance and one-sided t-test by using the DAS 2.0 software. The pharmacokinetic parameters of the test and reference preparations were as follows: peak plasma concentration (Cmax), 1351.101 ± 654.955 ng/mL and 1184.652 ± 607.713 ng/mL; area under the curve, 2642.017 ± 1093.848 ng·h/mL and 2780.666 ± 1283.100 ng·h/mL; and time to reach Cmax (Tmax), 0.789 ± 0.318 h and 0.953 ± 0.633 h, respectively. The relative bioavailability of the formulation was 101.7 ± 35.3%, which indicated that the test preparation was bioequivalent to the reference drug.

The mechanism and risk factors of clopidogrel-induced liver injury

Context and objective: Clopidogrel (CLP) is a prodrug which is widely used as a platelet aggregation inhibitor. Hepatotoxicity is rare but a potentially serious adverse reaction that is associated with CLP. Thiophene in CLP (the thienopyridine derivative) is a group that is easily oxidated by cytochrome P450 enzymes (CYP450s) to generate reactive metabolites (RMs), it may be implicated in the mechanism of CLP-induced hepatotoxicity. CYP2C19 and CYP2B6 are important CYP450s involved in the metabolism and activation of CLP, and the aim of this study is to investigate whether the metabolites of CYP2C19 and CYP2B6 are associated with the CLP-induced liver injury. Method: Primary rat hepatocytes are applied to evaluate the hepatotoxicity of CLP. Glutathione-depleted mouse model is used to evaluate whether this toxicity of CLP is metabolized by CYP450s. We also used HepG2 cells co-incubated with recombinant CYP2B6 and CYP2C19 enzymes to further assess whether the metabolites of CYP2C19 and CYP2B6 are associated with the CLP-induced hepatocellular toxicity. Result: CLP in high dose (100 μM and 300 μM) showed cytotoxicity in primary rat hepatocytes assay. Administration of CLP with l-buthionine-S, R-sulfoxinine (BSO) for seven days enhanced the liver injury of CLP. The level of ALT, AST and TBIL in plasma increased significantly, and the histopathological results showed the obvious liver injury; Pretreatment of 1-aminobenzotriazole, a nonspecific inhibitor of CYP450s, suppressed CLP-induced hepatotoxicity; CLP showed a dose-dependent toxicity in HepG2/CYP2C19 enzyme and HepG2/CYP2B6 enzyme models. Conclusion: High activities of CYP2C19 and CYP2B6 are the risk factors for hepatocellular toxicity of CLP.

Meta-analysis on the efficacy and adverse events of aspirin plus clopidogrel versus aspirin-monotherapy in patients with ischemic stroke or transient ischemic attack

To present the systematic assessment on the efficacy and bleeding adverse events of dual-antiplatelet therapy with aspirin and clopidogrel versus aspirin-mono-antiplatelet therapy in patients with ischemic stroke or transient ischemic attack. Retrieve randomized controlled trials conformed to the inclusion and exclusion criteria in Cochrane Library, Medline, Embase, and Web of Science electronic database, between January 1, 1998 and April 1, 2015. Cochrane Collaboration was used to assess the methodological quality of the included research papers. Stratification analysis was performed on factors as: race, subtypes of the disease, duration of follow-up and with or without clopidogrel loading dose, of the patients. A total of 7 studies were eligible for analysis, including 14 022 study objects. Data from Meta-analysis showed that dual-antiplatelet therapy, when compared to the mono-therapy group, could reduce the risk of recurrent stroke (RR=0.71, 95%CI: 0.61-0.84, P<0.001) , at the same time, increase the risk of bleeding events (RR=1.60, 95%CI: 1.46-1.76, P<0.001). Data derived from the Hierarchical analysis showed that the risk of stroke recurrence in Chinese population (RR=0.55, 95%CI: 0.34-0.89) was lower than recorded in other populations (RR=0.78, 95%CI: 0.66-0.93) , with the risks of bleeding events as RR=1.41 (95%CI: 1.01-1.96) and RR=1.62 (95%CI: 1.47-1.79) , respectively. Risk of recurrence among the group with clopidogrel loading dose (RR=0.69, 95%CI: 0.58-0.81) was less than those without (RR=0.74, 95%CI:0.56-0.99). The risks of occurrence on bleeding events were RR=1.59 (95%CI: 1.10-2.30) and RR=1.60 (95%CI: 1.46-1.77) , respectively. The combined therapy of aspirin and clopidogrel could reduce the risk of recurrence of ischemic stroke and TIA patients, but increase the risk of bleeding, when compared to the group that using aspirin alone for the therapy. In Chinese population, the combined therapy seemed more effective than using aspirin alone in reducing the recurrence of stroke, but without increasing the risk of bleeding.

Antiplatelet Efficacy of Fixed-Dose Aspirin-Clopidogrel Combination in Patients with Stable Coronary Artery Disease Treated with Drug-Eluting Stent Implantation.

A fixed-dose combination (FDC) of aspirin and clopidogrel bisulfate may improve medication adherence. However, the absence of data on the relative antiplatelet efficacy of FDC and separate dual pills (SDP) of aspirin and clopidogrel in real-world patients with stable coronary artery disease is a major factor retarding clinical introduction of such an FDC. This was a single-centre, randomized, open-label, parallel-group, non-inferiority trial. Patients who maintained a regimen of separate aspirin and clopidogrel pills for at least 1year after drug-eluting stent implantation without adverse events were enrolled. Patients were randomly assigned to either the FDC group or the SDP group. Antiplatelet efficacy and tolerability were assessed at baseline and at 4weeks. Of the 93 enrolled patients, 83 (FDC group: n=42; SDP group: n=41) completed the study. The difference in the changes in P2Y12 percentage inhibition did not exceed the predetermined value for inferiority [mean difference -1.7; 95% confidence interval (CI) -6.9 to 4.5, p<0.001 for non-inferiority]. The changes from baseline to 4weeks in P2Y12 reaction units (PRU) (mean difference 9.7PRU, p=0.46), maximal platelet aggregation (mean difference 2.0%, p=0.44) and aspirin reaction units (ARU) (mean difference -2.3ARU, p=0.88) did not differ significantly between the treatment groups. The tolerability of the FDC formulation was similar to that of SDP therapy (p=0.68). In patients with prior percutaneous coronary intervention, the antiplatelet efficacy of the aspirin/clopidogrel FDC was non-inferior to that of SDP and the tolerability of the two regimens was similar after 4weeks of treatment.

Cerebrovascular Ischemic Events in Patients With Advanced Renal Cell Carcinoma Treated With Anti-Angiogenic Tyrosine Kinase Inhibitors: A Report on Two Cases With Different Outcomes

Small-molecule tyrosine kinase inhibitors (TKIs), targeting tumor angiogenesis, have revolutionized the treatment of advanced renal cell carcinoma (RCC) over the last decade. Their rationale is that most clear cell RCCs have alterations in the Von Hippel-Lindau (VHL) gene pathway that leads to over-expression of pro-angiogenic factors such as vascular endothelial growth factor and platelet-derived growth factor that drive tumor growth and dissemination. The toxicity profile of these therapies, whilst generally mild and manageable, is quite distinct from that of conventional cytotoxic chemotherapy and immunotherapy. Arterial thrombotic events have been reported with pazopanib and axitinib (1-2% incidence) and patients with recent vascular events have been excluded from phase III trials of these drugs in RCC. We report two cases of cerebral infarction likely related to these treatments in female patients without any history of macrovascular disease or any conventional risk factors such as hyperlipidemia, hypertension or diabetes mellitus. Treatment-related arterial thromboembolism may develop rapidly and unpredictably in these patients and consideration should be given to aggressively monitoring and modifying any pre-existing vascular risk factors. Older patients with risk factors for vascular disease or with a prior history of such events must have an informed discussion regarding the risks and benefits of treatment. It remains to be seen whether prophylactic anti-platelet therapies such as aspirin, dipyridamole or clopidogrel might reduce the risk of stroke in these patients with an acceptable risk of bleeding. J Med Cases. 2015;6(10):463-467 doi: http://dx.doi.org/10.14740/jmc2289w

Clopidogrel attenuates lithium-induced alterations in renal water and sodium channels/transporters in mice.

Lithium (Li) administration causes deranged expression and function of renal aquaporins and sodium channels/transporters resulting in nephrogenic diabetes insipidus (NDI). Extracellular nucleotides (ATP/ADP/UTP), via P2 receptors, regulate these transport functions. We tested whether clopidogrel bisulfate (CLPD), an antagonist of ADP-activated P2Y(12) receptor, would affect Li-induced alterations in renal aquaporins and sodium channels/transporters. Adult mice were treated for 14 days with CLPD and/or Li and euthanized. Urine and kidneys were collected for analysis. When administered with Li, CLPD ameliorated polyuria, attenuated the rise in urine prostaglandin E2 (PGE2), and resulted in significantly higher urinary arginine vasopressin (AVP) and aldosterone levels as compared to Li treatment alone. However, urine sodium excretion remained elevated. Semi-quantitative immunoblotting revealed that CLPD alone increased renal aquaporin 2 (AQP2), Na-K-2Cl cotransporter (NKCC2), Na-Cl cotransporter (NCC), and the subunits of the epithelial Na channel (ENaC) in medulla by 25-130 %. When combined with Li, CLPD prevented downregulation of AQP2, Na-K-ATPase, and NKCC2 but was less effective against downregulation of cortical α- or γ-ENaC (70 kDa band). Thus, CLPD primarily attenuated Li-induced downregulation of proteins involved in water conservation (AVP-sensitive), with modest effects on aldosterone-sensitive proteins potentially explaining sustained natriuresis. Confocal immunofluorescence microscopy revealed strong labeling for P2Y(12)-R in proximal tubule brush border and blood vessels in the cortex and less intense labeling in medullary thick ascending limb and the collecting ducts. Therefore, there is the potential for CLPD to be directly acting at the tubule sites to mediate these effects. In conclusion, P2Y(12)-R may represent a novel therapeutic target for Li-induced NDI.

Proton-Pump Inhibitors for Patients on Dual Antiplatelet Therapy?

Dual antiplatelet therapy (DAPT) with clopidogrel and low-dose aspirin is known to increase risk for gastrointestinal (GI) events. Previously, data

Clinical application of Gore stent graft for the treatment of spontaneous extracranial internal carotid artery aneurysms

Objectives To investigate the methods of using Gore stent graft for minimally invasive treatment of spontaneous extracranial internal carotid artery aneurysms and to evaluate its efficacy. Methods There were 6 patients in this group, including 2 females and 4 males. Before procedure, the patients orally took clopidogrel bisulfate 75 mg and aspirin 100 mg once a day for 3 days. Using the coaxial technique, loach guidewire guided Neuro catheter through the extracranial segment of internal carotid artery to distal aneurysm during the procedure. Amplatz exchange wire was delivered through a Neuron guiding catheter to the distal internal carotid artery aneurysm as the stent delivery support guidewire. After the withdrawal of the guiding catheter, the Gore stent graft was delivered to the distal aneurysm via the Amplatz exchange wire and the stent was released for internal carotid artery angioplasty of the aneurysmal segment. Angiography was reexamined at 3 months after procedure. Results There were 6 patients with 8 aneurysms in this group. They were treated for 7 times. Four patients had intracranial ischemia and one had intracranial hemorrhage. One was found during the physical examination. The lesions in 3 of them were on the left sides, 2 were on the right sides, and 1 had bilateral lesions. The stents of 5 patients were in place satisfactorily in this group. The angiopoiesis was good after stent releasing. There was no aneurysm development. The patients had no recurrence and luminal stenosis after reexamination. The stent of one patient failed in place because of local vascular excessive tortuosity and was treated with surgery. Conclusions Gore stent graft for the treatment of extracranial internal carotid artery aneurysms has the advantages of mini-invasion, simple operation, and definite curative effect, especially suitable for the long segment aneurysm and the lesions near the segment of skull base. Key words: Extracranial internal carotid artery aneurysm; Spontaneity; Covered stent; Angioplasty

Effects of Clopidogrel and Proton Pump Inhibitors on Cardiovascular Events in Patients with Type 2 Diabetes Mellitus after Drug-Eluting Stent Implantation: A Nationwide Cohort Study.

ObjectiveTo investigate whether there is an increased risk of cardiac events in diabetic patients with a combined therapy of clopidogrel (CLO) and proton pump inhibitors (PPIs) after drug-eluting stent (DES) deployment.MethodsBy using National Health Insurance Research Database, all patients who received CLO with or without PPI therapy within 90 days after undergoing DES (limus-eluting or paclitaxel-eluting stents) deployment were enrolled. Endpoints were acute coronary syndrome (ACS) and readmission for revascularization (percutaneous coronary intervention or coronary artery bypass graft surgery) after 3, 6, and 12 months.ResultsA total of 6,603 diabetic patients received LESs (5,933 in the CLO subgroup and 670 in the CLO plus PPIs subgroup), and 3,202 patients received PESs (2,923 in the CLO subgroup and 279 in the CLO plus PPIs subgroup). The patients who received CLO plus PPIs were at higher risk of ACS than those receiving CLO within 1 year after DES deployment (LESs: 6-month hazard ratio [HR] = 1.63, and 1-year HR = 1.37; PESs: 3-month HR = 1.72). Patients with a history of ACS who received CLO plus PPIs were at higher risk of ACS after LES implantation (HR = 1.55) than those in the CLO group.ConclusionIn “real-world” diabetic patients with LES deployment, the combination of PPIs and CLO is associated with higher rates of ACS after 6 months and 1 year. Even after correction for confounding factors, concomitant PPI use remained an independent predictor of cardiac events, emphasizing the clinical importance of this drug—drug interaction.

Clinical efficacies of laparoscopic distal pancreatectomy with laparoscopic splenectomy for the treatment of malignant tumor in the body and tail of pancreas

Objective To explore the clinical efficacies of laparoscopic distal pancreatectomy (LDP) with laparoscopic splenectomy (LS) for the treatment of malignant tumors in the body and tail of pancreas. Methods The clinical data of 37 patients with malignant tumors in the body and tail of pancreas who were admitted to the Third Affiliated Hospital of Guangzhou Medical University from June 2009 to December 2014 were retrospectively analyzed. LDP with LS was performed on all the patients under general anesthesia. The operation time, volume of intraoperative blood loss, postoperative complications, removal time of postoperative drainage tube, duration of hospital stay and results of pathological examinations were recorded. All the patients were followed up via outpatient examination and telephone interview up to May 2015. Results Thirty-seven patients received successful surgery without conversion to open surgery and perioperative death.Of 37 patients, 19 received splenectomy due to splenic artery and vein surrounded by masses of pancreatic body and tail, splenic ischemia after clamping or amputating of splenic artery and vein; 11 received splenectomy due to splenic hilum invasion, dense adhesions, unclear boundary and difficulty in preserving spleen; 7 received splenectomy due to splenic cystic occupying lesion.The operation time, volume of intraoperative blood loss and removal time of drainage tube were (232 ± 42) minutes, (330 ±160) mL and (5.0 ±2.0) days, respectively.Four patients were complicated with pancreatic leakage without obvious discomfort and discharged from hospital with a placement of drainage tube, and then drainage tubes were removed after 2 weeks.The mean duration of postoperative hospital stay was 7.5 days (range, 5.0-10.0 days). The results of pathological examination showed that resection margin was negative, moderate and low malignant intraductal papillary mucinous neoplasm (IPMN) was detected in 12 patients, mucinous cystic carcinoma in 9 patients, moderate and low malignant solid pesudopapillary neoplasm (SPN) in 7 patients, pancreatic ductal adenocarcinoma in 4 patients, pancreatic neuroendocrine cancer in 3 patients and acinic cell carcinoma in 2 patients. The number of detecting lymph node was (9 ±3). All the patients were followed up for a mean time of 9 months (range, 3-12 months) without recurrence of tumors. The platelet (PLT) of 37 patients was different levels of increasing. Of 21 patients with PLT >500 ×109/L, PLT was returned to normal range after aspirin and/or clopidogrel were taken orally. Conclusion LDP with LS is safe and feasible for malignant tumors in the body and tail of pancreas. Key words: Pancreatic neoplasms; Distal pancreatectomy; Splenectomy; Laparoscopy

Solubility of Amorphous Clopidogrel Hydrogen Sulfate in Different Pure Solvents

At the temperature range (273.15 to 308.15) K, the solubility of amorphous clopidogrel hydrogen sulfate (CHS) in pure 1-butanol, 2-butanol, 2-propanol, methyl acetate, ethyl acetate, acetone, and methyl tert-butyl ether (MTBE) were experimentally measured. The order of solubility of amorphous CHS is 1-butanol > acetone > 2-propanol > 2-butanol > methyl acetate > ethyl acetate > MTBE, which is in good agreement with the orders of CHS crystalline forms in the literature. However, the solubility of the amorphous ones is dozens of times higher than that of crystals, respectively. In addition, the modified Apelblat equation was used to correlate the temperature with the mole fraction solubility. Finally, the thermodynamic parameters were calculated by the fitting parameters of the modified Van’t Hoff equation.

Research on detection method and clinical countermeasure of clopidogrel-resisted metabolism-related genes after interventional operation of coronary heart disease (CHD)

Objective Study on cytochrome P450 (CYP) 2C19 gene single nucleotide polymorphism and the clinical prognosis of coronary heart disease (CHD) patients with percutaneous coronary intervention (PCI) after long-term use of clopidogrel. Methods A total of 150 cases of CHD patients was chosen prospectively between January 2013 and June 2014 who were hospitalized and PCI. All patients accepted dual antiplatelet therapy. Platelet aggregation rate and platelet aggregation inhibition rate were detected before taking the medicine and after PCI, which were used to classify the patients into clopidogrel-resistance groups (CR) and non-clopidogrel-resistance group (NCR). CYP2C19 gene single nucleotide polymorphism type was determined. The patients in CR group accepted clinical intervention countermeasures and NCR group was used as control, and postoperative recurrence angina and bleeding at the one year of operation were observed. Results About 24.67% of patients with CHD with clopidogrel treatment, platelet aggregation rate cannot recover to normal. The correlation analysis showed CYP2C19*2 carriers had a significantly higher platelet aggregation rate. Comprehensive analysis found that CYP2C19*2, long-term smoking, increased platelet count, and diabetes were the independent risk factors that platelet aggregation rate cannot recover to normal. No significant differences were found in primary end point, secondary end points, and bleeding events between CR group after clinical intervention countermeasures and NCR group. Conclusions CYP2C19*2, long-term smoking, increased platelet count, and diabetes are the independent risk factors that platelet aggregation rate cannot be developed to standard. Patients with clopidogrel resistance, the clinical intervention countermeasures to strengthen antiplatelet therapy can improve high platelet reactivity after PCI in CHD patients, and does not increase the risk of bleeding. Key words: Cytochrome P-450 enzyme system/GE/ME; Polymorphism, single nucleotide; Angioplasty, transluminal, percutaneous coronary; Ticlopidine/AA/TU; Drug resistance; Coronary disease