In-Suk Kim

Adding Cilostazol to Dual Antiplatelet Therapy Achieves Greater Platelet Inhibition than High Maintenance Dose Clopidogrel in Patients With Acute Myocardial Infarction Results of the Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With AMI (ACCEL-AMI) Study

Background—Optimal platelet inhibition is an important therapeutic adjunct in patients acute myocardial infarction (AMI) undergoing coronary stenting. Whether adjunctive cilostazol to dual antiplatelet therapy (triple antiplatelet therapy) can inhibit enhanced platelet reactivity in patients with AMI yet has not been determined. The aim of this study was to assess the degree of platelet inhibition by triple antiplatelet therapy in patients with AMI. Methods and Results—Immediately after emergency room arrival, patients with AMI received clopidogrel (600-mg loading dose, followed by 75 mg daily) and aspirin (300-mg loading dose and 200 mg daily throughout the study period). After patients underwent coronary stenting (n=90), they were randomly assigned to 1 of 3 groups before discharge: standard group, clopidogrel of 75 mg daily (n=30); high maintenance dose (MD) group, clopidogrel of 150 mg daily (n=30); and triple group, adjunctive cilostazol of 100 mg twice daily to clopidogrel of 75 mg daily (n=30). Platelet reactivity was assessed at predischarge and 30-day follow-up by conventional aggregometry and the VerifyNow P2Y12 assay. Predischarge platelet reactivities were similar in the 3 groups. At 30-day follow-up, inhibition of maximal aggregation with 20 &mgr;M ADP stimuli was 6.0% in the standard group, 19.1% in the high-MD group, and 42.4% in the triple group (P<0.001), whereas inhibition of late aggregation with 20&mgr;M ADP stimuli was 10.8%, 38.1%, and 66.4%, respectively (P<0.001). Similar results were demonstrated when 5 &mgr;M ADP was used. Furthermore, percent changes of P2Y12 reaction unit were significantly different among regimens (10.6% in the standard group, 30.7% in the high-MD group, and 43.0% in the triple group; P<0.001). With respect to high-postclopidogrel platelet reactivity (prespecified as 20 &mgr;M ADP-induced maximal aggregation >50% of light transmission), fewer patients in the triple group (13.3%) met the criteria as compared with those in the standard (76.7%) and high-MD groups (56.7%) at 30-day follow-up (P<0.001). In the triple group, there were more potent and consistent platelet inhibitions by all parameters as compared with the high-MD group except for percent changes of P2Y12 reaction unit (P=0.071). Conclusions—Among patients with AMI undergoing coronary stenting, triple antiplatelet therapy results in a greater antiplatelet effect at 30 days as compared with a high-MD clopidogrel or standard dual antiplatelet therapy.

Carriage of Cytochrome 2C19 Polymorphism Is Associated With Risk of High Post-Treatment Platelet Reactivity on High Maintenance-Dose Clopidogrel of 150 mg/day: Results of the ACCEL-DOUBLE (Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism) Study

OBJECTIVES This study sought to determine the impact of gene polymorphisms on platelet reactivity (PR) after clopidogrel 150 mg/day in patients treated with percutaneous coronary intervention (PCI). BACKGROUND Although high maintenance-dose (MD) clopidogrel reduces PR, it is unknown whether gene polymorphisms are related with the risk of high post-treatment PR (HPPR) after high-MD clopidogrel. METHODS We included mostly patients receiving high-MD clopidogrel after PCI from previously registered Gyeongsang National University Hospital data. A total of 126 PCI-treated patients receiving high-MD clopidogrel were enrolled. Platelet reactivity was assessed with conventional aggregometry and VerifyNow (Accumetrics Inc., San Diego, California) after receiving clopidogrel 150 mg/day for at least 1 month. CYP3A5, CYP2C19, and ABCB1 genotyping was performed. We defined HPPR as 5 micromol/l adenosine diphosphate (ADP)-induced maximal PR (PR(max)) >50%. RESULTS CYP3A5 and ABCB1 polymorphisms did not influence PR. Carriers of CYP2C19 variant (*2 or *3) (n = 80) had significantly higher 5 and 20 micromol/l ADP-induced PR(max) than did noncarriers (n = 46) (40.7 +/- 16.8% vs. 30.3 +/- 12.6%, p < 0.001; 54.2 +/- 16.2% vs. 40.5 +/- 15.8%, p < 0.001, respectively). Late PR and VerifyNow results indicated consistently greater measures in carriers versus noncarriers of CYP2C19 variant. All platelet measures proportionally increased according to the number of CYP2C19 variant alleles. Twenty-seven (21.4%) patients met the criteria for HPPR. Prevalence of HPPR was 8.7%, 21.7%, and 50.0% in carriers of 0, 1, and 2 CYP2C19 variant alleles, respectively (p < 0.001). By multivariate analysis, carriage of CYP2C19 variant was a significant predictor of HPPR (odds ratio: 5.525, 95% confidence interval: 1.333 to 23.256, p = 0.018). CONCLUSIONS Among PCI-treated patients receiving high-MD clopidogrel, carriage of CYP2C19 variant relates to increased PR and predicts risk of HPPR. (Adjunctive Cilostazol Versus High Maintenance-dose ClopidogrEL in Acute Myocardial Infarction [AMI] Patients According to CYP2C19 Polymorphism [ACCELAMI2C19]; NCT00915733; and Comparison of Platelet Inhibition With Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel According to Hepatic Cytochrome 2C19 Allele (CYP2C19) Polymorphism [ACCEL2C19]; NCT00891670).

Adding Cilostazol to Dual Antiplatelet Therapy Achieves Greater Platelet Inhibition than High Maintenance Dose Clopidogrel in Patients With Acute Myocardial Infarction

Background—Optimal platelet inhibition is an important therapeutic adjunct in patients acute myocardial infarction (AMI) undergoing coronary stenting. Whether adjunctive cilostazol to dual antiplatelet therapy (triple antiplatelet therapy) can inhibit enhanced platelet reactivity in patients with AMI yet has not been determined. The aim of this study was to assess the degree of platelet inhibition by triple antiplatelet therapy in patients with AMI. Methods and Results—Immediately after emergency room arrival, patients with AMI received clopidogrel (600-mg loading dose, followed by 75 mg daily) and aspirin (300-mg loading dose and 200 mg daily throughout the study period). After patients underwent coronary stenting (n=90), they were randomly assigned to 1 of 3 groups before discharge: standard group, clopidogrel of 75 mg daily (n=30); high maintenance dose (MD) group, clopidogrel of 150 mg daily (n=30); and triple group, adjunctive cilostazol of 100 mg twice daily to clopidogrel of 75 mg daily (n=30). Platelet reactivity was assessed at predischarge and 30-day follow-up by conventional aggregometry and the VerifyNow P2Y12 assay. Predischarge platelet reactivities were similar in the 3 groups. At 30-day follow-up, inhibition of maximal aggregation with 20 &mgr;M ADP stimuli was 6.0% in the standard group, 19.1% in the high-MD group, and 42.4% in the triple group (P<0.001), whereas inhibition of late aggregation with 20&mgr;M ADP stimuli was 10.8%, 38.1%, and 66.4%, respectively (P<0.001). Similar results were demonstrated when 5 &mgr;M ADP was used. Furthermore, percent changes of P2Y12 reaction unit were significantly different among regimens (10.6% in the standard group, 30.7% in the high-MD group, and 43.0% in the triple group; P<0.001). With respect to high-postclopidogrel platelet reactivity (prespecified as 20 &mgr;M ADP-induced maximal aggregation >50% of light transmission), fewer patients in the triple group (13.3%) met the criteria as compared with those in the standard (76.7%) and high-MD groups (56.7%) at 30-day follow-up (P<0.001). In the triple group, there were more potent and consistent platelet inhibitions by all parameters as compared with the high-MD group except for percent changes of P2Y12 reaction unit (P=0.071). Conclusions—Among patients with AMI undergoing coronary stenting, triple antiplatelet therapy results in a greater antiplatelet effect at 30 days as compared with a high-MD clopidogrel or standard dual antiplatelet therapy.

Diversity of Ampicillin Resistance Genes and Antimicrobial Susceptibility Patterns in Haemophilus influenzae Strains Isolated in Korea

ABSTRACT By Etest determination of the susceptibilities of 229 Haemophilus influenzae strains isolated in Korea to 10 antibiotics, the isolates were found to be antibiotic nonsusceptible in the following order: ampicillin (58.1%), trimethoprim-sulfamethoxazole (52%), cefaclor (41.1%), clarithromycin (25.8%), chloramphenicol (14.0%), amoxicillin-clavulanic acid (13.5%), meropenem (11.7%), cefixime (10.9%), cefuroxime (9.2%), and levofloxacin (1.3%). The prevalences of each resistance class were 23.6% for β-lactamase-negative ampicillin-susceptible (BLNAS) strains; 37.6% for strains with the TEM-1 type β-lactamase gene; 1.3% for strains with the ROB-1 type β-lactamase gene; 29.3% for the β-lactamase-negative ampicillin-resistant (BLNAR) strains with a mutation in the ftsI gene, which encodes PBP 3; and 8.3% for β-lactamase-positive amoxicillin-clavulanate-resistant (BLPACR) strains, which showed both resistance mechanisms (i.e., a β-lactamase gene and a mutation in the ftsI gene). The MIC50s of all β-lactams, including cephem and meropenem agents, for the BLNAR strains were two to three times higher than those for the BLNAS strains. This study confirms that the prevalence of BLNAR and BLPACR strains is relatively high and for the first time confirms the presence of H. influenzae strains carrying blaROB-1 in Korea. Even though mutations in another gene(s) might be involved in β-lactam resistance, these results suggest that mutations in the ftsI gene are important for the development of resistance to β-lactams in H. influenzae strains in Korea.

The cytochrome 2C19*2 and *3 alleles attenuate response to clopidogrel similarly in East Asian patients undergoing elective percutaneous coronary intervention

INTRODUCTION Carriage of CYP2C19*2 allele is associated with diminished platelet response to clopidogrel. However, the loss-of-function impact of CYP2C19*3 allele on antiplatelet effect of clopidogrel has not been definitely verified. We conducted this study to compare decreased response to clopidogrel according to carriage of CYP2C19*2 vs. *3 allele. MATERIALS AND METHODS The study included 190 consecutive Korean patients undergoing elective percutaneous coronary intervention. Light transmittance aggregometry and the VerifyNow P2Y(12) assay were used to assess platelet reactivity (PR) at least 12 hours after 300-mg loading of clopidogrel. The cutoff of high on-treatment PR (HPR) was defined as 5 μmol/L ADP-induced PR >50%. CYP2C19 genotype was analyzed by the SNaPshot method. RESULTS Carriers of at least one CYP2C19 variant allele were 115 patients (60.5%), and allelic frequency of CYP2C19*2 and *3 was 30.3% and 6.8%, respectively. PR and the rate of HPR increased proportionally according to the number of CYP2C19 variant allele. Carriage of CYP2C19 variant allele was an only independent predictor of HPR in multivariate analysis. When we compare the effect of allelic carriage, there were no significant differences in platelet measures and the rate of HPR between carriers of CYP2C19*2 and/or *3 allele(s) whether they were intermediate or poor metabolizers. CONCLUSION Carriage of CYP2C19*3 allele is associated with diminished antiplatelet effect of clopidogrel, which may be as potent as the loss-of-function effect of CYP2C19*2 allele.

Platelet Inhibition by Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel in Patients With Acute Myocardial Infarction According to Cytochrome P450 2C19 Genotype

OBJECTIVES The aim of this study was to assess the degree of platelet inhibition by adjunctive cilostazol in patients with acute myocardial infarction (AMI) according to hepatic cytochrome P450 2C19 (CYP2C19) genotype. BACKGROUND Although adjunctive cilostazol intensifies platelet inhibition in AMI patients, it is not established whether this regimen can be free from the effect of CYP2C19 loss-of-function variants (*2/*3). METHODS We randomly assigned 126 AMI patients with available CYP2C19 genotyping to receive adjunctive cilostazol (triple group; n = 64) or high maintenance-dose (MD) clopidogrel of 150 mg/day (high-MD group; n = 62). Using conventional aggregometry and VerifyNow (Accumetrics Inc., San Diego, California), platelet reactivity was measured at pre-discharge and 30-day follow-up. Primary endpoint was change in maximal platelet aggregation (ΔAgg(max)) between pre-discharge and 30-day follow-up. High on-treatment platelet reactivity (HPR) was defined as 20 μmol/l adenosine diphosphate-induced maximal platelet aggregation (Agg(max)) >59%. RESULTS In noncarriers, despite numerically greater inhibition by adjunctive cilostazol, changes in platelet measures and the rate of HPR did not significantly differ between the 2 groups. In carriers, ΔAgg(max) after 5 and 20 μmol/l adenosine diphosphate stimuli was significantly higher in the triple (n = 39) versus high-MD group (n = 38) (21.8 ± 13.9% vs. 9.0 ± 13.3%, p < 0.001, and 24.2 ± 17.2% vs. 7.7 ± 15.5%, p < 0.001, respectively). Likewise, changes in late platelet aggregation and P2Y12 reaction unit were consistently greater in the triple versus high-MD group. Fewer patients in the triple group met the criteria of HPR at 30-day follow-up than in the high-MD group (15.4% vs. 44.7%, p = 0.005). CONCLUSIONS Compared with high-MD clopidogrel, adjunctive cilostazol significantly enhances platelet inhibition and reduces the rate of HPR, especially in AMI patients with CYP2C19 loss-of-function variants. (Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel in Acute Myocardial Infarction (AMI) Patients According to CYP2C19 Polymorphism [ACCELAMI2C19]; NCT00915733).

Dual-Priming Oligonucleotide-Based Multiplex PCR for the Detection of Helicobacter pylori and Determination of Clarithromycin Resistance with Gastric Biopsy Specimens

Background:  Assessment of Helicobacter pylori (H. pylori) clarithromycin resistance has rarely been performed routinely despite an increasing resistance rate. Our aim was to develop and evaluate the use of dual‐priming oligonucleotide (DPO)‐based multiplex polymerase chain reaction (PCR) to detect point mutations in the 23S rRNA gene responsible for clarithromycin resistance of H. pylori.

The CYP2C19*2 and CYP2C19*3 polymorphisms are associated with high post‐treatment platelet reactivity in Asian patients with acute coronary syndrome

Table S1. Data summary for coronary artery disease (CAD) patients including lipid profile, juxtaposed with the individual plasma total tissue factor potential (tTFp) values (expressed as percentage of normal plasma pool), and ACTI-FXa values (pmol L). Underlined/italics: patients presenting with diabetes. Fig. S1. Characterization immunoblot, using high-affinity tissue factor (TF) capture antibody SATF-IG 160. Left panel: detection of recombinant human TF forms. Right panel: detection of TF forms in human monocytic cells (THP-1); numbers on top indicate the amounts of cell lysate. Multiple bands of distinct apparent molecular weight, present between the major bands corresponding to full length TF (flTF) and alternatively spliced TF (asTF), most likely reflect variable glycosylation and/or propeptide processing of the two TF forms. Fig. S2. Compartmentalization of human plasma (normal plasma pool), following ultracentrifugation. The microparticle pellet is clearly visible at the bottom of the tube, spreading to the wall. Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.

Incidence and clinical significance of human parvovirus B19 infection in kidney transplant recipients

Abstract:  Human parvovirus B19 (B19) infection has been known to cause chronic anemia, pure red cell aplasia (PRCA), glomerulopathy, and allograft dysfunction in kidney transplant (KT) recipients. The aim of this study was to evaluate the incidence and clinical significance of B19 infection in KT recipients. A total of 537 serum samples from 167 KT recipients were included in the present study. The incidence of B19 infection was based on either qualitative polymerase chain reaction (PCR) or quantitative PCR with LightCycler Parvovirus B19 Quantitation kit. Clinical significance of B19 infection was investigated by a retrospective review of hemoglobin (Hb) levels and the results of kidney and bone marrow biopsies. The overall PCR positive rate was 18.3% (98/537), and 52 of 167 (31.1%) KT recipients showed at least one positive PCR. In addition, 20 of 167 subjects (12.0%) showed PCR‐positivity more than two consecutive times, and they had significantly lower Hb levels than those with negative or one positive PCR (p < 0.0001). Furthermore, two patients suffered from PRCA, which was confirmed by bone marrow biopsy. However, B19 infection did not seem to affect the graft outcome. In conclusion, the B19 infection in KT recipients was not uncommon and was associated with low Hb levels and PRCA after KT.

Glutathione-S-transferase genotypes influence the risk of chemotherapy-related toxicities and prognosis in Korean patients with diffuse large B-cell lymphoma

Polymorphisms in detoxification enzymes of the glutathione S-transferase (GST) family are associated with treatment response, resistance, and drug-related toxicity, all of which affect final clinical outcome. In this study, we investigated the influence of the genetic polymorphisms GSTM1, GSTT1, and GSTP1 on treatment response in 94 Korean patients with de novo diffuse large B-cell lymphoma, who had received rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) as a front-line regimen. Deletions of the GSTM1 and GSTT1 genes were detected using a multiplex polymerase chain reaction technique, and the functional GSTP1 polymorphism, Ile(105)Val, was genotyped using the TaqMan assay. The treatment response rate did not differ according to GST polymorphisms. Patients with the GSTT1-null genotype, however, showed more frequent grade III-IV chemotherapy-related toxicities, including leukocytopenia [odds ratio (OR)=3.1; 95% confidence interval (95%CI), 1.2-8.0; P=0.025], fever (OR=5.3; 95% CI, 1.4-19.7; P=0.009), and mucositis (OR=4.6; 95% CI, 1.4-15.1; P=0.012). Patients with the GSTM1/T1 double-null genotype had more grade III-IV thrombocytopenia (OR=7.8; 95% CI, 1.5-41.1; P=0.002) compared to those with other genotypes. In male patients, the GSTM1/T1 double-null genotype was associated with a shorter event-free survival period (P=0.02). This study suggests that GSTT1 deletion may significantly increase the risk of drug-related toxicity after R-CHOP chemotherapy in patients with DLBCL, and is associated with worse prognosis in males.