Long-term outcome of targeted therapy for low back pain in elderly degenerative lumbar scoliosis.

Purpose: Treatment of low back pain (LBP) associated with elderly degenerative lumbar scoliosis (DLS) remains controversial. We have developed percutaneous intervertebral-vacuum polymethylmethacrylate injection (PIPI) targeting to the intervertebral vacuum as a minimally invasive surgery. The present study compared the long-term clinical outcomes of PIPI to that of nonoperative treatment.

Small-Scale Panel Comprising Diverse Gene Family Targets To Evaluate Compound Promiscuity.

Despite the recent advances in the life sciences and the remarkable investment in drug discovery research, the success rate of small-molecule drug development remains low. Safety is the second most influential factor of drug attrition in clinical studies; thus, the selection of compounds with fewer toxicity concerns is crucial to increase the success rate of drug discovery. Compounds that promiscuously bind to multiple targets are likely to cause unexpected pharmacological activity that may lead to adverse effects.

Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF receptor antagonist.

Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF) receptor (IC=9.5nM) and in vitro antagonistic activity (IC=88nM) but is rapidly metabolized by human hepatic microsomes (182μL/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity.

Targeted Therapy for Low Back Pain in Elderly Degenerative Lumbar Scoliosis: A Cohort Study.

Study Design: Prospective cohort study.

Objective: To compare the novel treatment procedure with nonoperative treatment for low back pain (LBP) in elderly patients with degenerative lumbar scoliosis (DLS).

Summary Of Background Data: Treatment of LBP associated with elderly DLS is controversial.

Bone Marrow Edema and Low Back Pain in Elderly Degenerative Lumbar Scoliosis: A Cross-Sectional Study.

Study Design: Cross-sectional study.

Objective: To examine whether bone marrow edema is associated with low back pain in elderly patients with degenerative lumbar scoliosis.

Summary Of Background Data: The cause of low back pain in degenerative lumbar scoliosis is unclear.

Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor.

Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems and the contribution of each site to efficacy has not been clarified. This report describes the development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate the contribution of the peripheral site to increasing urethral resistance in rats.

Clarification of P-glycoprotein inhibition-related drug-drug interaction risks based on a literature search of the clinical information.

1. Recently, the Food and Drug Administration (FDA) and European Medicines Agency have shown decision trees to determine whether a drug candidate is an inhibitor of P-glycoprotein (P-gp). However, there has been no clear information on whether P-gp inhibition can be significant in clinical drug-drug interactions (DDIs).

Risk assessment of drug-drug interactions using hepatocytes suspended in serum during the drug discovery process.

1. This study optimized the reported approach for the prediction of drug-drug interactions (DDIs) using hepatocytes suspended in serum (HHSS) and provided a practical usage of HHSS in the early and late phases of drug discovery. 2.

Medium-term clinical results of microsurgical lumbar flavectomy that preserves facet joints in cases of lumbar degenerative spondylolisthesis: comparison of bilateral laminotomy with bilateral decompression by a unilateral approach.

Study Design: A retrospective study of medium-term results.

Objective: To describe a technique for posterior decompression using microsurgical lumbar flavectomy (MLF) without facetectomy, which is based on the anatomic features of the ligamentum flavum, and to examine the clinical outcomes of patients with lumbar spinal spondylolisthesis with lower extremity symptoms rather than low back pain, who underwent this procedure by 2 different approaches.

Summary Of Background Data: Posterior decompression with fusion has been the optimal and standard operative treatment for lumbar degenerative spondylolisthesis.

Evaluation of cytochrome P450-mediated drug-drug interactions based on the strategies recommended by regulatory authorities.

Herein, we aimed to evaluate the recently proposed risk assessment strategies of a cytochrome P450 (CYP) mediated drug-drug interaction (DDI) according to the European Medicines Evaluation Agency (EMEA) draft guideline, and discuss the differences between this guideline and the Food and Drug Administration (FDA) draft guidance. A retrospective study on reported 35 clinical DDI cases revealed that the EMEA assessment successfully predicts moderate-to-strong DDIs, i.e.

Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer.

A novel naphthylmethylimidazole derivative 1 and its related compounds were identified as 17,20-lyase inhibitors. Based on the structure-activity relationship around the naphthalene scaffold and the results of a docking study of 1a in the homology model of 17,20-lyase, the 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole derivative (+)-3c was synthesized and identified as a potent and highly selective 17,20-lyase inhibitor. Biological evaluation of (+)-3c at a dose of 1mg/kg in a male monkey model revealed marked reductions in both serum testosterone and dehydroepiandrosterone concentrations.

A 96-well plate assay for CYP4503A induction using cryopreserved human hepatocytes.

A reliable and practical CYP3A induction assay with cryopreserved human hepatocytes in a 96-well format was developed. Various 96-well plates with different basement membrane were evaluated using prototypical inducers, rifampicin, phenytoin, and carbamazepine. Thin-layer (TL) Matrigel was found to yield the highest basal and induced levels of CYP3A activity as determined by testosterone 6β-hydroxylation.

The autotomy relief effect of a silicone tube covering the proximal nerve stump.

A technique of covering the proximal nerve stump (PNS) has been reported as a preventative method or treatment for neuroma. However, its detailed pain relief mechanism remains unknown. We created a silicone tube model in which the PNS of the rat sciatic nerve was introduced into the tube, whereas the controls had no tube.

Knee joint position sense in compressive myelopathy.

Study Design: The knee joint position sense (JPS) and kinesthesia were measured in patients with compressive myelopathy.

Objectives: To find out how the knee JPS and kinesthesia are useful to evaluate lower limb function in patients with compressive myelopathy.

Summary Of Background Data: No previous reports have been written on the quantitative analysis of knee joint proprioception in myelopathy patients.

Morphological changes of the ligamentum flavum as a cause of nerve root compression.

The ligamentum flavum is considered to be one of the important causes of radiculopathy in lumbar degenerative disease. Although there have been several reports anatomically examining the positional relationship between the ligamentum flavum and nerve root, there are few reports on ventral observation. The purpose of this study is to clarify the shape of the ligamentum flavum seen ventrally, and to obtain anatomic findings related to nerve root compression.

The pathology of ligamentum flavum in degenerative lumbar disease.

Study Design: A pathologic study of the ligamentum flavum in degenerative lumbar disease.

Objectives: To elucidate the clinical significance of each pathologic finding of the ligamentum flavum.

Summary Of Background Data: In many reports, researchers observed the ligamentum flavum removed partially during surgery and did not evaluate the whole image of the ligamentum flavum.

Characterization of the CYP2C8 active site by homology modeling.

To compare the features of the active sites of CYP2C8, CYP2C9, and CYP2C19, homology modeling was performed based on the crystallographic coordinates of mammalian CYP2C5. It was found that CYP2C8 has a much larger pocket than the other forms due to the existence of an additional pocket. The approach to the additional pocket is comprised of Ile102, Ser114, Leu208, Val366, and Ile476, and the side chains of Ser114, Val366, and Ile476, which are smaller than the corresponding residues in the other CYPs, enable access to the pocket.

Characterization of the CYP3A4 active site by homology modeling.

Human microsomal cytochrome P450s participate in drug metabolism and detoxification. Among them, CYP3A4 is the most important isoform for drug-drug interactions. To gain a better understanding of the active site, a homology model of CYP3A4 was constructed based on the crystallographic coordinates of mammalian CYP2C5.