Development of Low Molecular Weight Ligands for Integrin αvß3.

We designed and synthesized non-peptide organic molecular ligands for integrin αvß3. Candidate ligands featured amidino analog and carboxy groups as binding sites on either side of a spacer, which consisted of benzophenone or an analog, such as diphenyl sulfide, diphenyl sulfoxide, diphenyl sulfone, or diphenyl ether. Competitive binding assays to integrin αvß3 with respect to [125I]echistatin were used to determine inhibitory activity of the synthetic ligands. Ligands bearing 2-aminobenzimidazoyl and glycyl groups separated by a benzophenone spacer demonstrated more potent binding than did a linear Arg-Gly-Asp (RGD) tripeptide that represents the native integrin αvß3 binding motif. Ligands possessing 2-aminobenzimidazoyl and carboxy groups and diphenyl sulfoxide or diphenyl ether spacers inhibited binding of [125I]echistatin with IC50 values similar to that of the linear RGD tripeptide.

Risk of major bleeding at different PT-INR ranges in elderly Japanese patients with non-valvular atrial fibrillation receiving warfarin: a nested case-control study.

BACKGROUND: Debate continues about the optimal anticoagulation level for elderly Japanese patients with non-valvular atrial fibrillation (NVAF) receiving warfarin. The Japanese Circulation Society guideline has recommended prothrombin time-international normalized ratios (PT-INR) of 1.6 - 2.6 for elderly patients and 2.0 - 3.0 for non-elderly patients, because previous observational studies indicated increased risk of bleeding when the ratio exceeded 2.6. We aimed to reappraise the relationship between PT-INR and the risk of major bleeding in elderly Japanese patients. METHODS: From the electronic medical records, we selected a cohort of elderly (age ≥ 70 years) Japanese patients with NVAF who were prescribed warfarin for the prevention of thromboembolic diseases between November 2010 and March 2014 at Kanto Rosai Hospital. We identified those who developed major bleeding (cases). For each case, we randomly selected two matched controls by adopting a risk-set sampling method defined by calendar date, age, gender, length of warfarin administration, and the prescriber of warfarin. The risk of major bleeding in patients having PT-INR ≤ 1.49, 1.50 - 1.99, 2.00 - 2.49 (the reference), 2.50 - 2.99, and ≥ 3.00 were compared using the conditional logistic regression method. The study protocol was approved by the IRB before the study was begun. RESULTS: Among the cohort of 806 elderly patients, we identified 32 cases and selected 64 matched controls. The overall incidence of major bleeding was 3.5 per 100 patient-years. The odds ratios (95 % confidence intervals) for the risk of developing major bleeding in patients with PT-INR ≤ 1.49 (n = 20), 1.50 - 1.99 (n = 32), 2.00 - 2.49 (n = 18), 2.50 - 2.99 (n = 10), and ≥ 3.00 (n = 16) were 1.0 (0.2, 5.9), 0.3 (0.1, 1.9), 1.0 (reference), 1.2 (0.2, 8.4), and 19.8 (2.0, 198.9), respectively, with a significant difference between ≥ 3.00 and reference. CONCLUSIONS: Among elderly Japanese patients with NVAF, PT-INR 2.0 - 3.0 may be associated with a clinically permissible risk of major bleeding while PT-INR ≥ 3.00 a significant risk. Further studies are warranted to determine whether the risk of major bleeding is significantly lower for PT-INR 2.50 - 2.99 than for PT-INR ≥ 3.00.

Longitudinal extent of lipid pool assessed by optical coherence tomography predicts microvascular no-reflow after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction.

BACKGROUND: Distal embolization during percutaneous coronary intervention (PCI) may deteriorate microvascular reperfusion in patients with ST-elevation myocardial infarction (STEMI). Reperfusion at the coronary microvascular level is important for STEMI and culprit plaque is associated with distal embolization and microvascular reperfusion. ST-segment resolution (ST-R) in the electrocardiogram reflects microvascular reperfusion after primary PCI. Longitudinal extent of lipid pool assessed by optical coherence tomography (OCT) may predict the risk of failure of microvascular reperfusion after primary PCI. METHODS AND RESULTS: This study consisted of 39 patients with STEMI who underwent primary PCI within 24h after the onset of chest pain. Immediately after thrombectomy, OCT was performed and length of lipid pool was measured. Microvascular reperfusion after primary PCI was assessed by ST-R, which was defined as >50% decrease in ST elevation at 1h after primary PCI. There were 23 patients with ST-R and 16 patients without ST-R, with no significant difference in baseline clinical and angiographical variables between the 2 groups. Final thrombolysis in myocardial infarction 3 flow was obtained in all of the patients. Peak creatine kinase was significantly higher in the ST-R (-) group than in the ST-R (+) group (p=0.01). Length of lipid pool was 10.1 ± 2.8mm in the ST-R (-) group and 7.8 ± 3.2mm in the ST-R (+) group (p=0.02). In receiver operating characteristics curve assessing the ability of length of lipid pool to predict ST-R, area under the curve was 0.74 (p=0.02). Length of lipid pool >9.0mm best predicted the absence of ST-R with sensitivity 88% and specificity 78%. CONCLUSIONS: These findings suggest that length of lipid pool estimated by OCT may predict microvascular no-reflow after primary PCI.

Factors exacerbating peripheral neuropathy induced by paclitaxel plus carboplatin in non-small cell lung cancer.

No established supportive therapy to prevent and treat chemotherapy-induced peripheral neuropathy (PN) is available. Minimizing the severity of PN is therefore critical in clinical use. We aimed to determine when and how often PN occurs in association with paclitaxel plus carboplatin (PC therapy), a regimen used to treat non-small cell lung cancer, and factors that exacerbate this condition. Patients who received PC therapy for non-small cell lung cancer at the Japanese Foundation for Cancer Research, Cancer Institute Hospital, between May 20, 2009, and November 30, 2010, were included. PN was evaluated by the study pharmacist using specific questions based on the Common Terminology Criteria for Adverse Events Version 3.0. Univariate analysis was used to compare a group with no, Grade 1, or Grade 2 PN (non-serious) and a group with Grade 3 PN (serious). Analyses were conducted using the Cox proportional hazard model with patient characteristics having p < or = 0.20 when assessed as independent variables. Of 50 patients, 38 (76.0%) developed PN by day 6 of the first course of anticancer treatment. Grade 3 PN had an incidence of 25.0% in the fourth course. In multivariate analysis with the Cox proportional hazard model, pack-year [hazard ratio = 1.029; 95% confidence interval (CI): 1.009-1.050, p = 0.005] and creatinine clearance (hazard ratio = 0.957; 95% CI: 0.920-0.996, p = 0.031) were significant factors. A high pack-year and a low creatinine clearance exacerbated PN in patients treated with PC. PN must be carefully evaluated in patients with exacerbating factors.