Open-Label Randomized Trial Comparing Oral Anticoagulation With and Without Single Antiplatelet Therapy in Patients With Atrial Fibrillation and Stable Coronary Artery Disease Beyond 1 Year After Coronary Stent Implantation.

BACKGROUND: Despite recommendations in the guidelines and consensus documents, there has been no randomized controlled trial evaluating oral anticoagulation (OAC) alone without antiplatelet therapy (APT) in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after coronary stenting. METHODS: This study was a prospective, multicenter, open-label, noninferiority trial comparing OAC alone to combined OAC and single APT among patients with atrial fibrillation beyond 1 year after stenting in a 1:1 randomization fashion. The primary end point was a composite of all-cause death, myocardial infarction, stroke, or systemic embolism. The major secondary end point was a composite of the primary end point or major bleeding according to the International Society on Thrombosis and Haemostasis classification. Although the trial was designed to enroll 2000 patients during 12 months, enrollment was prematurely terminated after enrolling 696 patients in 38 months. RESULTS: Mean age was 75.0±7.6 years, and 85.2% of patients were men. OAC was warfarin in 75.2% and direct oral anticoagulants in 24.8% of patients. The mean CHADS2 score was 2.5±1.2. During a median follow-up interval of 2.5 years, the primary end point occurred in 54 patients (15.7%) in the OAC-alone group and in 47 patients (13.6%) in the combined OAC and APT group (hazard ratio, 1.16; 95% CI, 0.79-1.72; P=0.20 for noninferiority, P=0.45 for superiority). The major secondary end point occurred in 67 patients (19.5%) in the OAC-alone group and in 67 patients (19.4%) in the combined OAC and APT group (hazard ratio, 0.99; 95% CI, 0.71-1.39; P=0.016 for noninferiority, P=0.96 for superiority). Myocardial infarction occurred in 8 (2.3%) and 4 (1.2%) patients, whereas stroke or systemic embolism occurred in 13 (3.8%) and 19 (5.5%) patients, respectively. Major bleeding occurred in 27 (7.8%) and 36 (10.4%) patients, respectively. CONCLUSIONS: This randomized trial did not establish noninferiority of OAC alone to combined OAC and APT in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after stenting. Because patient enrollment was prematurely terminated, the study was underpowered and inconclusive. Future larger studies are required to establish the optimal antithrombotic regimen in this population. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01962545.

Analysis of Temporal Changes in Dural Sac Morphology After XLIF Indirect Decompression.

STUDY DESIGN: Retrospective study. OBJECTIVE: To investigate temporal changes in dural sac morphology after extreme lateral interbody fusion (XLIF) indirect decompression for central lumbar spinal stenosis and to study the factors influencing the changes. METHODS: The morphology of the dural sac was categorized into 4 grades (A, minor; B, moderate; C, severe; and D, extreme) by partially modifying Schizas classification (m-Schizas). The study involved 38 patients and 47 intervertebral spaces treated with indirect decompression (grade C or D). We evaluated m-Schizas before surgery, immediately after surgery, and at final follow-up. We performed a statistical analysis on the risk factors of grade C or D stenosis (poor morphological improvement) at final follow-up. The factors evaluated were preoperative dural sac cross-section area (CSA), diagnosis, cage size, location of cage insertion, locked facets, bony lateral recess stenosis, end plate injury, and changes in the posterior disc height (PDH) and disc angle (DA). RESULTS: On morphological evaluation, improvement to grade A or B was seen in 10 intervertebral spaces (21.2%) immediately after the surgery, and improvement was achieved in 38 intervertebral spaces (80.8%) at final follow-up. The risk factor of poor morphological improvement was found to be small preoperative dural sac CSA (odds ratio 1.32, P < .002). CONCLUSIONS: After XLIF indirect decompression, the morphological improvement of the dural sac was remodeled with time and further expansion was seen in many patients. However, the study suggested that sufficient morphological improvement may not be achieved in spinal stenosis whose preoperative state is severe.

Novel prodrugs of decitabine with greater metabolic stability and less toxicity.

BACKGROUND: DNA demethylation therapy is now used in practice for hematological tumors and is being developed for solid tumors. Nevertheless, it is difficult to achieve stable pharmacokinetics with the current DNA-demethylating agents, azacitidine (AZA) and decitabine (DAC), because of their rapid deamination by cytidine deaminase in vivo and spontaneous hydrolytic cleavage. Here, we aimed to develop metabolically stable prodrugs of AZA and DAC as novel DNA-demethylating agents. RESULTS: Thirty-five 5'-O-trialkylsilylated AZAs/DACs were synthesized with potential resistance to deamination. Out of these, 11 compounds exhibited demethylating activity similar to that of DAC and guadecitabine, and a suitable aqueous solubility. Pharmacokinetic analysis in mice showed that OR-2003 displayed the highest serum concentration and the area under the curve in an intraperitoneal experiment, whereas OR-2100 exhibited high stability to cytidine deaminase. Treatment of cells with OR-2003 and OR-2100 depleted DNA methyltransferase 1 completely and induced both gene-specific and genome-wide demethylation. The treatment suppressed the growth of multiple types of cancer cells and induced re-expression of tumor suppressor genes. The anti-tumor effect and DNA demethylation effect of OR-2003 and OR-2100 were comparable to that of DAC with fewer adverse effects in vivo. CONCLUSIONS: We developed two novel prodrugs of DAC that exhibited greater stability, comparable DNA demethylation activity, and less toxicity. These compounds are expected to overcome the difficulty in achieving stable pharmacokinetics in patients, leading to maximum DNA demethylation activity with minimum adverse effects.

Comparison of Clinical and Radiologic Results of Mini-Open Transforaminal Lumbar Interbody Fusion and Extreme Lateral Interbody Fusion Indirect Decompression for Degenerative Lumbar Spondylolisthesis.

STUDY DESIGN: Retrospective study. PURPOSE: In this study, we compared the postoperative outcomes of extreme lateral interbody fusion (XLIF) indirect decompression with that of mini-open transforaminal lumbar interbody fusion (TLIF) in patients with lumbar degenerative spondylolisthesis. OVERVIEW OF LITERATURE: There are very few reports examining postoperative results of XLIF and minimally invasive TLIF for degenerative lumbar spondylolisthesis, and no reports comparing XLIF and mini-open TLIF. METHODS: Forty patients who underwent 1-level spinal fusion, either by XLIF indirect decompression (X group, 20 patients) or by mini-open TLIF (T group, 20 patients), for treatment of lumbar degenerative spondylolisthesis were included in this study. Invasiveness of surgery was evaluated on the basis of surgery time, blood loss, hospitalization period, and perioperative complications. The Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOABPEQ), disc angle (DA), disc height (DH), and slipping length (SL) were evaluated before surgery, immediately after surgery, and at 12 months after surgery. Cross-sectional spinal canal area (CSA) was also measured before surgery and at 1 month after surgery. RESULTS: There was no significant difference between the groups in terms of surgery time or hospitalization period; however, X group showed a significant decrease in blood loss (p<0.001). Serious complications were not observed in either group. In clinical assessment, no significant differences were observed between the groups with regard to the JOABPEQ results. The change in DH at 12 months after surgery increased significantly in the X group (p<0.05), and the changes in DA and SL were not significantly different between the two groups. The change in CSA was significantly greater in the T group (p<0.001). CONCLUSIONS: Postoperative clinical results were equally favorable for both procedures; however, in comparison with mini-open TLIF, less blood loss and greater correction of DH were observed in XLIF.

Discovery of diphenyloxazole and Ndelta-Z-ornithine derivatives as highly potent and selective human prostaglandin EP(4) receptor antagonists.

Two novel classes of diphenyloxazole and Ndelta-Z-ornithine derivatives as highly potent and selective EP(4) antagonists have been discovered. The optimized diphenyloxzole 8 and Ndelta-Z-ornithine 11 effectively competed with [(3)H]PGE(2) binding to human recombinant EP(4), with K(i) values of 0.30 nM and 0.91 nM, respectively, and were selective for all members of the human prostanoid receptor family. 8 was shown to exhibit good pharmacokinetic properties in rats and dogs and potent inhibitory activity toward in vitro PGE(2)-promoted IgE synthesis.

Systematic evaluation of vascular access by color-Doppler ultrasound decreased the incidence of emergent vascular access intervention therapy and X-ray exposure time: a single-center observational study.

Arteriovenous fistula has superior patency over other accesses, but vascular access intervention therapy (VAIVT) for stenosis or thrombosis still remain major reasons for hospital admission of dialysis patients. The aim of this study was to examine the usefulness of systematic evaluation of vascular access by color-Doppler ultrasound (CDUS). This study was a single-center observational design study. We planned screening CDUS to evaluate all vascular accesses once per year, and additionally, follow-up CDUS of post-interventional patients 1 month, 3 months and 6 months after their recent VAIVT. This systematic evaluation was started from September 2009. The observational period between September 2008 and August 2009 was defined as period A. The observational period between September 2009 and August 2010 was defined as period B. We compared the incidence of emergent VAIVT and X-ray exposure time during the period A to B. 131 patients with AV fistula were assigned. 13 patients were excluded due to death, hospital transfer or re-operation of their accesses. During period A, 57 VAIVTs were carried out, and 37 cases (65%) were emergent. During period B, 42 VAIVTs were carried out, and 11 cases (25%) were emergent. The incidence of emergent intervention therapy was lower during period B than period A (P < 0.001). The amount of X-ray exposure time per patient was decreased in patients who received VAIVT during both periods (P < 0.03). Systematic evaluation of vascular access by CDUS decreased the incidence of emergent VAIVT and X-ray exposure time.

Hepatocyte-protective and anti-oxidant effects of rifampicin on human chronic hepatitis C and murine acute hepatocyte disorder.

Rifampicin (RFP) is a semisynthetic antibiotic derived from the rifamycins and is one of the most commonly used pharmaceutical compounds worldwide in the treatment of tuberculosis. We previously reported that low-dose and long-term oral administration of RFP to 6 hepatitis C virus-related liver cirrhosis patients who were at high risk for presenting with hepatocellular carcinoma (HCC) resulted in a marked suppression of the occurrence of HCC without showing an adverse effect. The underlying mechanism was found to be due to the anticancer effect based on the potent anti-angiogenic properties of RFP. The present study revealed that RFP has an additional hepatocyte-protective effect by lowering the release of hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in chronic hepatitis C patients. Experimentally, we were able to show that RFP had hepatocyte-protective effects in acute hepatocyte disorder models of mice and rats induced by concanavalin A and by D-galactosamine, respectively: RFP significantly prevented an increase in the levels of ALT, AST and lactate dehydrogenase in these animal models. In addition, we found that RFP had a strong anti-oxidant action which was approximately three times stronger than the action of silibinin, an anti-inflammatory agent of human hepatic stellate cells, implicating that the hepatocyte-protective effects of RFP are mediated by its anti-oxidant activity. These results reveal that oral administration of RFP exerts not only a prophylactic effect on the occurrence or recurrence of HCC for an extensive period of time, but also exerts hepatocyte-protective effects on both human chronic hepatitis C and acute hepatocyte disorder in rodent models, and the anti-oxidant activity of RFP is implicated to participate in the latter effects.

Rifampicin as an oral angiogenesis inhibitor targeting hepatic cancers.

Angiogenesis is an important therapeutic target in cancer, and to fully exploit its therapeutic potential, combination chemotherapeutic/antiangiogenic regimens should be optimized and delivered earlier to more patients. Ideally, this could be done by a single potent oral agent with established safety. Rifampicin, a semisynthetic antibiotic derived from the rifamycins, is one of the most commonly used pharmaceutical compounds worldwide in the treatment of tuberculosis. Here, we present the effects of oral rifampicin on human cancer progression and its antiangiogenic properties, which were comparable to the angiogenesis inhibitor endostatin. Clinically, low-dose p.o. administration of rifampicin to six high-risk patients with hepatitis C virus-related liver cirrhosis resulted in a single occurrence of hepatocellular carcinoma during the follow-up period of 97.3 +/- 29.1 (mean +/- SD) months. Experimentally, rifampicin rapidly and markedly down-regulated the expression of a wide spectrum of angiogenesis-associated genes in growing human microvascular endothelial cells, thereby suppressing endothelial cell proliferation and migration. Rifampicin, at higher concentrations, also directly inhibited the growth of a variety of human cancer cells. P.o. administration of rifampicin significantly inhibited in vivo growth and metastases of subcutaneous human cancer xenografts. Thus, the potent antiangiogenic properties of oral rifampicin therapy were effective in suppressing cancer progression. It provides a promising new addition to antiangiogenic strategies for designing human cancer therapies. Considering the clinical pharmacokinetics of rifampicin, which enters the enterohepatic circulation and undergoes subsequent hepatic accumulation, it may be especially beneficial as an antitumor agent targeting hepatobiliary tumors.

Verapamil, a Ca2+ entry blocker, targets the pore-forming subunit of cardiac type KATP channel (Kir6.2).

This study investigated the mechanism by which verapamil, which blocks 10R1, l-type Ca2+ channel and the HERG channel, blocks ATP-sensitive K+ (K(ATP)) channels. In whole cell patch experiments, verapamil reversibly inhibited cardiac type K(ATP) (Kir6.2/SUR2A) channels previously activated by 100-micromol/L pinacidil. In inside-out patch experiments, verapamil inhibited the C-terminal truncated form of Kir6.2 (Kir6.2DeltaC36) in a concentration-dependent manner; half-maximal inhibition (IC(50)) was obtained at 11.5 +/- 2.8 micromol/L when Kir6.2DeltaC36 was expressed without SUR2A. Verapamil also inhibited Kir6.2/SUR2A with a similar potency; IC(50) was 8.9 +/- 2.1 micromol/L for Kir6.2/SUR2A (not statistically different from the value for Kir6.2DeltaC36 alone). Thus, verapamil appeared to target the pore-forming subunit Kir6.2 rather than SUR2A, a member of ABC superfamily. Verapamil did not decrease the single-channel conductance, but increased the closed time of Kir6.2/SUR2A. The mutations of Kir6.2DeltaC36 (Kir6.2DeltaC36-R50G, -K185Q, -G334D), which have much lower ATP sensitivity, had no significant effect on verapamil block, suggesting that the site at which verapamil mediates K(ATP) channel inhibition is not identical with that involved in ATP block.