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. METHODS: Patients with de novo DLS, aged ≥ 65 years, who had LBP with visual analog scale (VAS) of ≥ 50 for ≥ 6 months with intervertebral vacuum on computed tomography and bone marrow edema (BME) on magnetic resonance imaging were included. The clinical outcomes were evaluated using VAS and the Oswestry Disability Index (ODI) at baseline, 1, 6, 12, 24 months, and at the final follow-up. The course of BME was also evaluated. RESULTS: One hundred and one patients underwent PIPI and 61 received nonoperative treatment. The mean follow-up duration after PIPI and nonoperative treatment was 63.7 ± 32.4 and 43.9 ± 20.9 months, respectively. VAS and ODI after PIPI were significantly improved compared to post-nonoperative treatment. BME decreased substantially in the PIPI group and it was significantly correlated with VAS and ODI improvement. Following PIPI, LBP recurred in 28 patients (35%). LBP recurrence was identified at the same level of PIPI in 10 patients, at the adjacent level of PIPI in 11 patients, and at the non-adjacent level of PIPI in seven patients. Eighteen patients underwent additional PIPIs, and both VAS and ODI were significantly improved after additional PIPIs. CONCLUSION: Bone marrow lesions of the endplate are strongly associated with the presence of LBP. PIPI can be considered as an effective, safe and repeatable treatment for LBP in elderly DLS patients.

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. Therefore, avoiding such compounds during early research stages would contribute to identifying compounds with a higher chance of success in the clinic. To evaluate the interaction profile against a wide variety of targets, we constructed a small-scale promiscuity panel (PP) consisting of eight targets (ROCK1, PDE4D2, GR, PPARγ, 5-HT2B, adenosine A3, M1, and GABAA) that were selected from diverse gene families. The validity of this panel was confirmed by comparison with the promiscuity index evaluated from larger-scale panels. Analysis of data from the PP revealed that both lipophilicity and basicity are likely to increase promiscuity, while the molecular weight does not significantly contribute. Additionally, the promiscuity assessed using our PP correlated with the occurrence of both in vitro cytotoxicity and in vivo toxicity, suggesting that the PP is useful to identify compounds with fewer toxicity concerns. In summary, this small-scale and cost-effective PP can contribute to the identification of safer compounds that would lead to a reduction in drug attrition due to safety issues.

Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF1 receptor antagonist.

Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF1) receptor (IC50=9.5nM) and in vitro antagonistic activity (IC50=88nM) but is rapidly metabolized by human hepatic microsomes (182µL/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity. Structure-activity relationship (SAR) studies considering in vitro metabolic stability revealed that 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole 24d was more stable in human microsomes (87µL/min/mg) than compound 1. Compound 24d demonstrated potent CRF binding inhibitory activity (IC50=4.1nM), in vitro antagonistic activity (IC50=44nM), and slow dissociation from the CRF1 receptor. Orally administered compound 24d (6-24µmol/kg) showed ex vivo CRF1 receptor binding in the rat pituitary, olfactory bulb, and frontal cortex and suppressed stress-induced adrenocorticotropic hormone (ACTH) secretion. In this report, we discuss SAR studies on the metabolic stability as well as CRF binding inhibitory activity of the benzimidazole series as CRF1 receptor antagonists and the pharmacological profiles of compound 24d.

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. We developed a novel treatment procedure, termed percutaneous intervertebral-vacuum polymethylmethacrylate injection (PIPI). METHODS: We included patients with de novo DLS aged ≥65 years who had LBP with a visual analogue scale (VAS) score of >50 for ≥6 months with intervertebral vacuum and vertebral bone marrow edema (BME) defined on fat-saturated T2-weighted or gadolinium-enhanced T1-weighted magnetic resonance imaging. The primary outcomes were evaluated using the VAS score and modified Oswestry Disability Index (ODI). As an objective measurement, we scored BME on magnetic resonance imaging. RESULTS: Between August 2004 and July 2011, 109 patients underwent PIPI and 53 received nonoperative treatment. At 1 month, mean improvements in VAS scores were -55.3 (95% CI, -60.5 to -50.1) and -1.9 (CI, -7.7 to 3.8) and mean improvements in ODI were -22.7 (CI, -27.3 to -18.2) and -0.6 (CI, -6.6 to 5.4) for the PIPI and nonoperative groups, respectively. At 2 years, mean improvements in VAS scores were -52.2 (CI, -59.9 to -44.4) and -4.0 (CI, -10.9 to 3.0) and mean improvements in ODI were -20.7 (CI, -27.3 to -14.5) and -1.0 (CI, -7.7 to 5.7) for the PIPI and nonoperative groups, respectively. BME substantially decreased in the PIPI group compared with the nonoperative group (P <0.001) and correlated with VAS score and ODI improvements (VAS score: r = 0.502, P <0.001; ODI: r = 0.372, P <0.001). CONCLUSION: PIPI improved treatment for LBP, with a sustained clinical benefit for at least 2 years. LEVEL OF EVIDENCE: 3.

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. METHODS: A total of 120 degenerative lumbar scoliosis patients 65 years of age or older were evaluated. Radiography, computed tomography (CT), magnetic resonance imaging (MRI), and tender point examination in the lumbar spine were performed. On MRI, coronal gadolinium-contrasted T1- or T2-weighed fat-saturated images were used to score the size of bone marrow edema. The prevalence of bone marrow edema in patients with and without low back pain was compared; in patients with low back pain, we tested whether the locations of lumbar tender point were consistent with that of bone marrow edema. RESULTS: Bone marrow edema was found in 62 of 64 (96.9%) patients with low back pain compared with 21 of 56 (37.5%) patients without it (P < 0.001). Bone marrow edema located more frequently on the concave side than on the convex side of scoliosis (P < 0.001). Among patients with low back pain, bone marrow edema score was associated with low back pain severity (r = 0.724; P < 0.001), and the location of lumbar tender point were consistent with that of bone marrow edema (κ value = 0.745; P < 0.001). CONCLUSION: Bone marrow edema on MRI was closely associated with the presence of low back pain in elderly degenerative lumbar scoliosis. LEVEL OF EVIDENCE: 4.

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. (6S,7R)-1,4-Oxazepane derivative 7 exhibited noradrenaline transporter inhibition with high selectivity against inhibitions of serotonin and dopamine transporters. A replacement of hydroxyl with acetamide group contributed to enhancement of peripheral selectivity by increasing molecular polarity. Compound 12, N-{[(6S,7R)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl}acetamide 0.5 fumarate, which showed effectively no brain penetration in rats, increased urethral resistance in a dose-dependent manner and exhibited a maximal effect on par with esreboxetine. These results demonstrate that the urethral resistance-increasing effects of NRI in rats are mainly caused by the inhibition of noradrenaline transporters in the peripheral sites.

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). The purpose of this study was to confirm the effect of P-gp inhibition through comprehensive analysis of the clinical DDI studies. 2. Clinical information on P-gp inhibition was collected using the University of Washington Metabolism and Transport Drug Interaction Database™. The risks of P-gp inhibition-related DDI were qualitatively evaluated in terms of the contribution of CYP3A inhibition. The degrees of DDI risk were categorized using the area under the plasma concentration-time curve increase ratio (AUCR), according to the FDA DDI criteria. 3. When both P-gp and CYP3A were inhibited, the DDI risks were potent in 25% of the studies. When CYP3A inhibition did not contribute to the DDI, no study was categorized as potent DDI risk, and the detailed analysis revealed that AUCRs were basically <3.0. The DDI risk caused by P-gp inhibition solely would be limited, although the use of P-gp substrates with narrow therapeutic range should be carefully controlled.

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. First, the IC50 was determined using HHSS and evaluated as a qualitative index for DDI risks in the early phase. A retrospective study on clinical DDI cases revealed that inhibitors with IC50 < 100 µmol/L caused clinical DDIs while those with IC50 > 100 µmol/L showed weak or no potential for DDIs. Meanwhile, a pragmatic cutoff value could not be determined using previously reported Ki values of recombinant human cytochrome P450s. 3. Second, for a more substantial DDI risk assessment in the later phase, quantitative predictions of clinical DDI based on a static model were attempted by optimizing the most appropriate inhibitor concentration ([I]). The use of hepatic input plasma concentrations as a surrogate for [I] achieved the most successful predictions of the magnitude of increase in the AUC (within a 2-fold range of the observed values for 93.8% of inhibitors). 4. Through this study, we proposed the practical application of HHSS for an effective workflow to explore and profile candidates with less DDI liability.

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. Alternatively, minimally invasive procedures have been used for the treatment of lumbar degenerative spondylolisthesis with favorable outcomes. METHODS: A bilateral laminotomy (BL group) was performed on 44 consecutive patients, and bilateral decompression by a unilateral approach (BDU group) was performed on 23 consecutive patients. The mean follow-up period was 7.0 years. The Japanese Orthopaedic Association score and recovery rate were obtained, and radiographic assessment was performed using plain radiograms on the lateral view while standing in flexion, neutral, and extension postures before surgery and at the final follow-up. RESULTS: The Japanese Orthopaedic Association score at the final follow-up was improved in the BL and BDU groups, compared with that before MLF. The mean recovery rate was 72.4% and 68.4%, respectively. The mean % slip increased at the final follow-up, compared with that before surgery in both groups, except for the % slip in the extension posture in the BDU group. However, there was no significant difference in the dynamic % slip in the flexion-extension posture between before surgery and at the final follow-up. CONCLUSIONS: Clinical and radiologic parameters were not significantly different between the 2 groups. This technique of MLF using either approach did not increase the dynamic % slip and showed favorable medium-term clinical results in cases of 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. drugs that cause more than 2-fold increase in the area under the curve in the presence and absence of CYP inhibitor (AUC(i)/AUC); however, EMEA tends to overlook weak DDIs with AUC(i)/AUC ≤ 2 to > 1.25. For CYP3A4 inhibitors, even clinically insignificant DDIs were overemphasized if the intestinal DDI is considered. The differences between unbound fraction in plasma and microsomes account for the discrepancies in DDI risk assessment results between EMEA and FDA assessments. Comparing two assessment results for CYP2D6 and CYP2C9 inhibitors, the FDA assessment suggested potential DDI risks for sulphinpyrazone and amitriptyline, while the EMEA assessment indicated no potential risk for these drugs. Through a retrospective study, we showed practical differences in the DDI assessment strategies of EMEA and FDA and suggested improvements in their current strategies.