Regulatory guideline for biosimilar products in Korea

AbstractThe regulatory framework of biosimilar products in Korea is a 3-tiered system: 1) Pharmaceutical Affairs Act; 2) Notification of the regulation on review and authorization of biological products; 3) Guideline on evaluation of biosimilar products. A biosimilar product is regulated under the same regulation as biological products. The difference from new biological product is that biosimilar product requires full comparability data with reference product. Based on these data, some of the non-clinical and clinical data could be abbreviated. As Korean guideline for biosimilar products was developed along with that of the WHO’s, most of the recommendations were based on similar principle except the clinical evaluation to demonstrate similarity. No biosimilar products are licensed yet, however, 4 IND products have been approved for phase I or III clinical trials. The addressed issues during review were as follows: acceptability of reference products manufactured in different sites, determination of acceptable criteria for differences and selection of analytical tests for the comparability exercise to detect potential differences in quality attributes, relevant species for non-clinical study, and duration of toxicity study, etc. These and other future issues will be dealt with scientific advancement, experiences of collaborating work with WHO or other NRAs, which will be reflected in the guidelines on regulations of biosimilar products in Korea

The impact of sagittal balance on clinical results after posterior interbody fusion for patients with degenerative spondylolisthesis: A Pilot study

<p>Abstract</p> <p>Background</p> <p>Comparatively little is known about the relation between the sagittal vertical axis and clinical outcome in cases of degenerative lumbar spondylolisthesis. The objective of this study was to determine whether lumbar sagittal balance affects clinical outcomes after posterior interbody fusion. This series suggests that consideration of sagittal balance during posterior interbody fusion for degenerative spondylolisthesis can yield high levels of patient satisfaction and restore spinal balance</p> <p>Methods</p> <p>A retrospective study of clinical outcomes and a radiological review was performed on 18 patients with one or two level degenerative spondylolisthesis. Patients were divided into two groups: the patients without improvement in pelvic tilt, postoperatively (Group A; n = 10) and the patients with improvement in pelvic tilt postoperatively (Group B; n = 8). Pre- and postoperative clinical outcome surveys were administered to determine Visual Analogue Pain Scores (VAS) and Oswestry disability index (ODI). In addition, we evaluated full spine radiographic films for pelvic tilt (PT), sacral slope (SS), pelvic incidence (PI), thoracic kyphosis (TK), lumbar lordosis (LL), sacrofemoral distance (SFD), and sacro C7 plumb line distance (SC7D)</p> <p>Results</p> <p>All 18 patients underwent surgery principally for the relief of radicular leg pain and back pain. In groups A and B, mean preoperative VAS were 6.85 and 6.81, respectively, and these improved to 3.20 and 1.63 at last follow-up. Mean preoperative ODI were 43.2 and 50.4, respectively, and these improved to 23.6 and 18.9 at last follow-up. In spinopelvic parameters, no significant difference was found between preoperative and follow up variables except PT in Group A. However, significant difference was found between the preoperative and follows up values of PT, SS, TK, LL, and SFD/SC7D in Group B. Between parameters of group A and B, there is borderline significance on preoperative PT, preoperative LL and last follow up SS.</p> <p>Correlation analysis revealed the VAS improvements in Group A were significantly related to postoperative lumbar lordosis (Pearson's coefficient = -0.829; p = 0.003). Similarly, ODI improvements were also associated with postoperative lumbar lordosis (Pearson's coefficient = -0.700; p = 0.024). However, in Group B, VAS and ODI improvements were not found to be related to postoperative lumbar lordosis and to spinopelvic parameters.</p> <p>Conclusion</p> <p>In the current series, patients improving PT after fusion were found to achieve good clinical outcomes in degenerative spondylolisthesis. Overall, our findings show that it is important to quantify sagittal spinopelvic parameters and promote sagittal balance when performing lumbar fusion for degenerative spondylolisthesis.</p

High dose therapy followed by autologous peripheral blood stem cell transplantation as a first line treatment for multiple myeloma: a Korean Multicenter Study.

We conducted a phase II multicenter trial to estimate the response and survival of patients with newly diagnosed multiple myeloma to high dose melphalan therapy followed by autologous peripheral blood stem cell transplantation. Eligible patients who had undergone induction with vincristine, adriamycin and dexamethasone (VAD) should have adequate cardiac, pulmonary and renal function (creatinine <2 mg/dL). Melphalan at 200 mg/m2 was used as a conditioning regimen. Eighty patients were enrolled from 13 centers. The median age of the patients was 53 yr (range; 20 to 68 yr). The initial stage was IA/IIA/IIB/IIIA/IIIB in 3/8/1/54/14 patients, respectively. Beta2-microglobulin, CRP and LDH were increased in 74, 42 and 34% of the patients examined. Cytogenetic data were available in 30 patients, and 6 patients showed numeric or structural abnormalities. Two therapy-related mortalities occurred from infection. Among the 78 evaluable patients, CR/PR/MR/NC/PD were achieved in 48/26/2/1/1 patients, respectively. After a median follow-up of 30 months, the median overall and event-free survivals were 66 months (95% CI: 20-112) and 24 months (95% CI: 18-29), respectively. This study verifies the efficacy and feasibility of high dose melphalan therapy with autologous stem cell transplantation in newly diagnosed multiple myeloma

miR-140-5p suppresses BMP2-mediated osteogenesis in undifferentiated human mesenchymal stem cells

AbstractHuman mesenchymal stem cells (hMSCs) have self-renewal and differentiation capabilities but the regulatory mechanisms of MSC fate determination remain poorly understood. Here, we aimed to identify microRNAs enriched in hMSCs that modulate differentiation commitments. Microarray analysis revealed that miR-140-5p is commonly enriched in undifferentiated hMSCs from various tissue sources. Moreover, bioinformatic analysis and luciferase reporter assay validated that miR-140-5p directly represses bone morphogenic protein 2 (BMP2). Furthermore, blocking miR-140-5p in hMSCs increased the expression of BMP signaling components and critical regulators of osteogenic differentiation. We propose that miR-140-5p functionally inhibits osteogenic lineage commitment in undifferentiated hMSCs

Two Methods of Setting Positive End-expiratory Pressure in Acute Lung Injury: An Experimental Computed Tomography Volumetric Study

This study was conducted to observe effects of two methods of setting positive end-expiratory pressure (PEEP) based on the pressure-volume (PV) curve. After lung injury was induced by oleic acid in six mongrel adult dogs, the inflation PV curve was traced and the lower inflection point (LIP) was measured. The 'PEEPINF' was defined as LIP+2 cmH2O. After recruitment maneuver to move the lung physiology to the deflation limb of PV curve, decremental PEEP was applied. The lowest level of PEEP that did not result in a significant drop in PaO2 was defined as the 'PEEPDEF'. Arterial blood gases, lung mechanics, hemodynamics, and lung volumes (measured on computed tomography during end-expiratory pause) were measured at PEEP of 0 cmH2O, PEEPINF and PEEPDEF sequentially. The median PEEPINF was 13.4 cm H2O (interquartile range, 12.5-14.3) and median PEEPDEF was 12.0 cm H2O (10.0-16.5) (p=0.813). PEEPDEF was associated with significantly higher PaO2 and lung volumes, and significantly lower shunt fraction and cardiac index when compared to PEEPINF (p<0.05). Setting the PEEP based on the deflation limb of the PV curve was useful in improving oxygenation and lung volumes in a canine lung injury model

Titanium dioxide induces apoptotic cell death through reactive oxygen species-mediated Fas upregulation and Bax activation

Background: Titanium dioxide (TiO2) has been widely used in many areas, including biomedicine, cosmetics, and environmental engineering. Recently, it has become evident that some TiO2 particles have a considerable cytotoxic effect in normal human cells. However, the molecular basis for the cytotoxicity of TiO2 has yet to be defined.Methods and results: In this study, we demonstrated that combined treatment with TiO2 nanoparticles sized less than 100 nm and ultraviolet A irradiation induces apoptotic cell death through reactive oxygen species-dependent upregulation of Fas and conformational activation of Bax in normal human cells. Treatment with P25 TiO2 nanoparticles with a hydrodynamic size distribution centered around 70 nm (TiO2P25-70) together with ultraviolet A irradiation-induced caspase-dependent apoptotic cell death, accompanied by transcriptional upregulation of the death receptor, Fas, and conformational activation of Bax. In line with these results, knockdown of either Fas or Bax with specific siRNA significantly inhibited TiO2-induced apoptotic cell death. Moreover, inhibition of reactive oxygen species with an antioxidant, N-acetyl-L-cysteine, clearly suppressed upregulation of Fas, conformational activation of Bax, and subsequent apoptotic cell death in response to combination treatment using TiO2P25-70 and ultraviolet A irradiation.Conclusion: These results indicate that sub-100 nm sized TiO2 treatment under ultraviolet A irradiation induces apoptotic cell death through reactive oxygen species-mediated upregulation of the death receptor, Fas, and activation of the preapoptotic protein, Bax. Elucidating the molecular mechanisms by which nanosized particles induce activation of cell death signaling pathways would be critical for the development of prevention strategies to minimize the cytotoxicity of nanomaterials.This work was supported by the Korea Ministry of Environment and The Eco-Technopia 21 Project (091-091-081)

Efficacy of Antibiotics Sprayed into Surgical Site for Prevention of the Contamination in the Spinal Surgery

Study DesignRetrospective study.PurposeTo evaluate the effect of intraoperative wound application of vancomycin on preventing surgical wound contamination during instrumented lumbar spinal surgery.Overview of LiteraturePostoperative infection is the one of the most devastating complications of lumbar surgery. There are a few reports showing the benefits of intraoperative wound application of vancomycin during spinal surgery. However, there is no report about the effectiveness of local vancomycin instillation in prevention of surgical wound contamination.MethodsEighty-six patients underwent instrumented lumbar spinal surgery. Mean patient age was 65.19 years (range, 23-83 years). There were 67 females and 19 males. During surgery, vancomycin powder was applied into the surgical site before closure in 43 patients (antibiotic group) and vancomycin powder was not applied into the surgical site before closure in 43 patients (control group). The tip of the surgical drain was cultured to evaluate surgical wound contamination. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured on the first, third, seventh, and fourteenth day after the operation.ResultsWe found two patients with a positive culture from the tip of surgical drains in the antibiotic group, and one patient with a positive culture from the tip of the surgical drain in the control group. Postoperative ESR and CRP levels did not show significant differences between the two groups. On the third postoperative day, ESR in patients of the antibiotic group was more significantly decreased than that in patients of the control group, while CRP level did not show a significant difference between the two groups.ConclusionsThere was no evidence to suggest that intraoperative vancomycin application is effective in decreasing the risk of postoperative wound infection after instrumented posterior lumbar fusion surgery

Fixed Subaortic Stenosis In Infants and Children

Fixed subaortic stenosis(FSS) is important because of not only obstruction but also aortic insufficiency. This study was performed to find out the characteristics and combined anomalies of FSS. Echocardiographic and clinical data were reviewed in 31 children who were diagnosed as FSS between March 1985 and February 1991 (age: 2months-12yr7months, M:F = 2:1). Cardiac defects were associated in 26(84%) and the majority of the cases were related to VSD(VSD only: 14 cases, VSD with other anomalies: 7 cases). The type of VSD was perimembranous in 86%(18/21) and subarterial in 14%(3/21). Aortic insufficiency(AO was present in 13 cases(42%) and the degree of AI was usually mild. The mean pressure gradient between the left ventricle and the aorta was 21mmHg by cardiac catheterization in 27. Operative resection was done in 20; 11 during the correction of major defects, 4 for AI, 5 for significant pressure gradient. The pathologic findings of 13 were mainly fibrosis and hypertrophied myocardium. In conclusion, because of the possible association with other cardiac defects, especially perimembranous VSD and its co~rt features, it is recommended to pay attention to the coexistence of FSS during the evaluation of cardiac defects