Use of combined treatment of 3rd-generation cephalosporin, azithromycin and antiviral agents on moderate SARs-CoV-2 patients in South Korea: A retrospective cohort study.

OBJECTIVES: To assess efficacy and safety of the combined treatment of antibiotics (3rd-generation cephalosporin and azithromycin) and antiviral agents (lopinavir/ritonavir or hydroxychloroquine) on moderate COVID-19 patients in South Korea. METHODS: A retrospective cohort study of the 358 laboratory-confirmed SARS-CoV-2 (COVID-19) patients was conducted. 299 patients met inclusion criteria for analysis. Propensity score matching (PSM) and Cox regression method were used to control and adjust for confounding factors. Mild to moderate COVID-19 patients were managed with either CA/LoP (cephalosporin, azithromycin, and lopinavir/ritonavir) (n = 57), CA/HQ (cephalosporin, azithromycin, and hydroxychloroquine) (n = 25) or standard supportive care (n = 217). We analyzed the association between treatment group and standard supportive group in terms of three endpoints: time to symptom resolution, time to viral clearance, and hospital stay duration. Using propensity-score matching analysis, three rounds of propensity-matching analysis were performed to balance baseline characteristics among three cohorts. RESULTS: Kaplan-Meier curves fitted using propensity score-matched data revealed no significant differences on time to symptom resolution, time to viral clearance, hospital stay duration among the three treatment arms (CA/LoP vs Standard, log-rank p-value = 0.2, 0.58, and 0.74 respectively for the three endpoints) (CA/HQ vs Standard, log-rank p-value = 0.46, 0.99, and 0.75 respectively). Similarly, Cox regression analysis on matched cohorts of CA/LoP and standard supportive group showed that hazard ratios of time to symptom resolution (HR: 1.447 [95%-CI: 0.813-2.577]), time to viral clearance(HR: 0.861, [95%-CI: 0.485-1.527]), and hospital stay duration (HR: 0.902, [95%-CI: 0.510-1.595]) were not significant. For CA/HQ and standard supportive group, hazard ratios of the three endpoints all showed no statistical significance (HR: 1.331 [95%-CI:0.631-2.809], 1.005 [95%-CI:0.480-2.105], and 0.887, [95%-CI:0.422-1.862] respectively). No severe adverse event or death was observed in all groups. CONCLUSIONS: Combined treatment of 3rd cephalosporin, azithromycin and either low-dose lopinavir/ritonavir or hydroxychloroquine was not associated with better clinical outcomes in terms of time to symptom resolution, time to viral clearance, and hospital stay duration compared to standard supportive treatment alone. Microbiological evidence should be closely monitored when treating SARS-CoV-2 patients with antibiotics to prevent indiscreet administration of empirical antimicrobial treatments.

Pulsed radiofrequency application reduced mechanical hypersensitivity and microglial expression in neuropathic pain model.

OBJECTIVE: Pulsed radiofrequency (PRF) procedure has been used in clinical practice for the treatment of chronic neuropathic pain conditions without neuronal damage. The purpose of this study was to investigate the changes in pain response and glial expression after the application of PRF on a dorsal root ganglion (DRG) in a neuropathic pain model. DESIGN: A neuropathic pain model (14 female Sprague-Dawley [SD] rats; 200-250 g) was made by a unilateral L5 spinal nerve ligation (SNL) and transection on the distal side of the ligation. The development of mechanical and cold hypersensitivity on the hindpaw was established postoperative day 9 (POD 9). The rats were then randomly assigned to the PRF (+) and the PRF (-) groups. Furthermore, PRF (2 bursts/s, duration = 20 milliseconds, output voltage = 45 V) was applied on the ipsilateral DRG for 180 seconds, with a maximum temperature of 42°C, at POD 10. Pain behaviors were tested throughout the 12 days after PRF. We also examined the changes of the spinal glial expression by immunohistochemistry. RESULTS: Significant reduction of mechanical hypersensitivity in the PRF (+) group was observed from day 1 after a single PRF procedure and was maintained throughout the following 12 days. Immunoreactivity for OX42 in the ipsilateral dorsal horn also decreased compared with that of the PRF (-) group. However, cold hypersensitivity and glial fibrillary acidic protein (GFAP) immunoreactivity in the dorsal horn was not affected by a PRF procedure. CONCLUSIONS: Our result demonstrated that the mechanical hypersensitivity, induced by L5 SNL, was attenuated by a PRF procedure on the ipsilateral DRG. This analgesic effect may be associated with an attenuation of the microglial activation in the dorsal horn.

Changes in expression of mRNA for interleukin-8 and effects of interleukin-8 receptor inhibitor in the spinal dorsal horn in a rat model of lumbar disc herniation.

STUDY DESIGN: Autologous nucleus pulposus obtained from coccygeal intervertebral discs was grafted on the proximal of L5 dorsal root ganglion. Pain behavior, mRNA expression of Interleukin-8 (IL-8), and immunohistochemical changes were assessed. OBJECTIVE: The purpose of this study is to investigate temporal changes of IL-8 expression in the spinal cord and dorsal root ganglion and the pain-related behaviors with time course and to elucidate whether repertaxin (IL-8 receptor inhibitor) attenuates pain-related behaviors in a rat model of lumbar disc herniation. SUMMARY OF BACKGROUND DATA: Inflammatory mediators like cytokines and chemokines have been implicated in radicular pain because of disc herniation. IL-8, known as CXCL8, is a chemokine, which has been reported to be associated with painful degenerative disc disorders and chronic inflammatory pain states. METHODS: Lumbar disc herniated rat model was made by implantation of the autologous nucleus pulposus, harvested from the coccygeal vertebra of each tail, on the left L5 nerve root just proximal to the dorsal root ganglion. Rats were tested for mechanical allodynia and thermal hyperalgesia at 2 days before surgery, and on days 1, 5, 10, 20, 30, 40, 50, and 60 postoperatively. Experimental group was intrathecally injected with the IL-8 receptor inhibitor at L5 level on postoperative day 10. Mechanical allodynia of the plantar surface of both hindpaw was tested on 30 minutes, 1, 3 hours, 1, 3, 5, and 10 days after administration. For the staining of astrocytes and microglia, immunohistochemical study was done 20 days after surgery. RESULTS: Mechanical allodynia in ipsilateral hindpaw developed 1 day after surgery and lasted until 60 days and thermal withdrawal latency decreased significantly on the ipsilateral side 10 days after surgery and gradually increased through day 60. The IL-8 receptor inhibitor attenuated the mechanical allodynia caused by nucleus pulposus when it was administered on postoperative day 10 and reduced microglial activation and phosphorylated form of mitogen-activated protein kinase (pERK) expression in the spinal dorsal horn. CONCLUSION: IL-8 might be a potential therapeutic target in chronic radicular neuropathic pain because of disc herniation, CXCL8 inhibitor could be one of its promising therapeutic agents.

Abnormal spontaneous activities on needle electromyography and their relation with pain behavior and nerve fiber pathology in a rat model of lumbar disc herniation.

STUDY DESIGN: This longitudinal experimental study was conducted to investigate electrophysiologic characteristics, pain behavior, and histological changes in a rat model of lumbar disc herniation. OBJECTIVE: To observe abnormal spontaneous activity (ASA) on needle electromyography (EMG) and to determine its relation with neuropathic pain behavior and histological changes longitudinally in a rat model of lumbar disc herniation. SUMMARY OF BACKGROUND DATA: Needle EMG is generally performed to determine the existence and the degree of radiculopathy caused by disc herniation. The local application of autologous nucleus pulposus to the spinal nerve has been shown to induce neuropathic pain. However, little is known about the relations between neuropathic pain and abnormal EMG findings and the manner in which they change with time in rat models of lumbar disc herniation. METHODS: Twenty-five Sprague-Dawley rats were randomly assigned to either sham or experimental groups. In the experimental group, autologous nucleus pulposus was grafted on the left L5 dorsal root ganglion. All rats were evaluated for mechanical allodynia and thermal hyperalgesia and underwent needle EMG examinations before and on days 1, 5, 10, 20, 30, 40, and 50 after surgery. Morphologic changes of L5 spinal nerves and of sciatic nerves were assessed by toluidine blue staining on days 1, 5, and 50 after surgery. RESULTS: A dramatic decrease in mechanical withdrawal threshold and in thermal withdrawal latency was observed on day 1 after surgery, and these changes persisted until day 50 after surgery. ASAs on needle EMG were observed on day 1 (33%), peaked on day 5 (93%), and gradually decreased from day 10 (69%) to day 40 (18%) after surgery. Pathologic findings of nerve fibers, such as swelling of myelin sheaths, demyelination, and degeneration of axoplasms were observed from day 1. These findings were exaggerated on day 5 and then diminished but were still evident on day 50. CONCLUSION: Neuropathic pain and pathologic changes in spinal nerve fibers probably remain even after ASAs in EMG have disappeared in our rat model of lumbar disc herniation. These results provide baseline data concerning the natural courses of electrophysiologic findings and of radicular pain in patients with intervertebral disc herniation.

Changes in spinal cord expression of fractalkine and its receptor in a rat model of disc herniation by autologous nucleus pulposus.

STUDY DESIGN: Behavior, mRNA and immunohistochemical assessment of the expression of fractalkine (CX3CL1) and its receptor (CX3CR1) in a rat model of disc herniation by autologous nucleus pulposus (NP) implantation. OBJECTIVE: To evaluate the changes in expression of fractalkine and its receptor in the spinal cord and their association with pain behavior in a rat model of disc herniation. SUMMARY OF BACKGROUND DATA: Chemokines have recently been implicated in the pathophysiology of neuropathic pain. They mediate astrocytic migration and microglial proliferation, which are involved in the regulation of nociceptive transmission. Fractalkine is a chemokine, which participates in the mechanisms of neuropathic pain as a mediator of neuron-glia interactions. METHODS: Sixty-six rats (NP-treated = 47, sham = 19) were implanted with autologous NP (approximately 3 mg) on the left L5 nerve root, just proximal to the dorsal root ganglion and tested for thermal hyperalgesia and mechanical allodynia before surgery and on days 1, 5, 10, 20, and 30 after surgery. The changes of expression of fractalkine and its receptor in the spinal cord were studied using real time PCR and immunohistochemistry. RESULTS: Rats developed ipsilateral mechanical allodynia at day 1 and bilateral thermal hyperalgesia at day 5 after surgery, and these changes in sensitivity persisted throughout the observation period. The expression of mRNA for fractalkine in the spinal cord was increased by day 5 and remained upregulated for the duration of the experiment. The immunostaining for fractalkine increased in neurons and astrocytes and that for the fractalkine receptor increased in microglia in the dorsal horn ipsilateral to the disc herniation. CONCLUSION: Our results indicate that autologous implantation of NP induces thermal hyperalgesia and mechanical allodynia, and leads to an upregulation of fractalkine and its receptor in spinal neurons and glia, implicating fractalkine in association with radicular pain.

Gabapentin effect on neuropathic pain compared among patients with spinal cord injury and different durations of symptoms.

STUDY DESIGN: This study evaluated the effect of gabapentin on neuropathic pain in patients with spinal cord injury. OBJECTIVE: To compare the effect of gabapentin on neuropathic pain refractory to conventional analgesics in patients with spinal cord injury and different durations of symptoms. SUMMARY OF BACKGROUND DATA: Neuropathic pain in patients with spinal cord injury severely compromises their quality of life. Gabapentin is a new antiepileptic drug that may additionally have a role in the treatment of neuropathic pain. So far, there has been little prospective research investigating the effect of gabapentin on neuropathic pain in patients after spinal cord injury or comparing gabapentin-treated patients with varying durations of symptoms after spinal cord injury. METHODS: The study included 31 patients who had experienced neuropathic pain associated with spinal cord injury or cauda equina syndrome. These subjects were divided into two groups. Group 1 (n = 13) was composed of patients whose duration of pain was less than 6 months, and Group 2 (n = 18) comprised patients whose symptoms of neuropathic pain had lasted more than 6 months. Although these patients had been treated with conventional analgesics such as antidepressants, anticonvulsants, membrane stabilizer, and neuroleptics, they reported that their condition did not improve after a medication trial of at least 2 weeks duration. In this study, conventional analgesics were continued at a therapeutic level, and gabapentin was administrated for an 18-day titration period followed by a 5-week maintenance period at a dosage of 1800 mg/day or the maximum tolerable dosage. The efficacy of gabapentin administration was gauged by a pain score and a sleep interference score using a 100-mm visual analogue scale (VAS) every 2 weeks. The scores of the two groups were compared every 2 weeks over the course of the 8-week study. RESULTS: The mean pain score and the mean sleep interference score for Group 1 decreased more than that of Group 2 during the interval between 2 to 8 weeks (P < 0.05). The mean pain score for Group 1 decreased from 7.3 +/- 0.5 initially to 3 +/- 0.6 after 8 weeks of treatment, whereas the corresponding score for Group 2 decreased from 7.6 +/- 0.4 to 5.1 +/- 0.6 ( < 0.05). The mean sleep interference score for Group 1 decreased from 5.7 +/- 0.9 initially to 1.8 +/- 0.8 after 8 weeks of treatment, whereas the corresponding score for Group 2 decreased from 5.9 +/- 0.8 to 4.2 +/- 0.7 (P < 0.05). As compared with the onset of this study, a decrease in pain score of 2 or more was reported at the completion of this study for 11 patients (100%) in Group 1 and 10 (71%) of 14 patients in Group 2. A decrease of 2 or more in sleep interference scores was reported for 8 (89%) of 9 patients with sleep interference in Group 1 and for 8 (62%) of 13 patients with sleep interference in Group 2. Some adverse effects such as somnolence were noted, but they were mild or moderate in intensity. CONCLUSIONS: Gabapentin may be effective in decreasing neuropathic pain refractory to conventional analgesics in some patients with spinal cord injury whose duration of symptoms is less than 6 months, although those with duration of symptoms longer than 6 months showed a significant decrease as well. The drug is unlikely to cause serious adverse effects that limit its use in patients with spinal cord injury.

Comparison of clinical outcomes and natural morphologic changes between sequestered and large central extruded disc herniations.

A prospective and longitudinal investigation concerning clinical outcomes and morphologic changes of large lumbar disc herniations by MR imaging. To compare the clinical outcomes and the natural morphologic changes of between sequestered and large central extruded disc herniations. The spontaneous disappearance or diminution of large herniated lumbar discs in the spinal canal is known. Poor clinical outcome and small changes of herniated discs have been shown for large central extruded disc herniations with conservative treatment. The study population consisted of 22 patients with sequestration and a large central as extrusion established by an MR imaging study. Seventeen (11 patients with sequestration, and 6 patients with a large central extrusion) patients underwent a follow-up MR imaging study. The size of the herniated disc was measured on serial MR imaging studies, and the changes in size were classified into four categories. Clinical evaluations were also performed using a visual analogue scale (VAS), the Oswestry low back pain disability questionnaire, the straight leg raising test (SLRT) and so forth. Both the sequestered and large central extruded disc herniations showed a successful clinical outcome after conservative treatment in 17 of 22 patients (77%) in total: 11 of 13 patients (85%) with sequestered disc herniations, and 6 of 9 patients (67%) with large central extruded disc herniations. VAS and Oswestry disability scoring showed a greater change in the group with sequestration than in the group with large central extrusions. In the group with sequestration, seven patients reported the disappearance of herniated disc materials, and four patients showed a marked decrease in the size of their herniated discs in follow-up MR images. However, in the group with large central extrusions, only two patients showed a decrease in the size of their herniated discs. Large central extruded disc herniations can be treated successfully by conservative treatment. Outcomes seemed to be as good as or slightly inferior to those of sequestered disc herniations. However, a greater morphologic decrease in the herniated discs occurred more frequently for sequestered disc herniations than for large central extruded disc herniations.