OBJECTIVE: To investigate the effects of removing microglia from spinal cord on nerve repair and functional recovery after spinal cord injury (SCI) in mice. METHODS: Thirty-nine 6-week-old female C57BL/6 mice were randomly divided into control group ( n=12), SCI group ( n=12), and PLX3397+SCI group ( n=15). The PLX3397+SCI group received continuous feeding of PLX3397, a colony-stimulating factor 1 receptor inhibitor, while the other two groups were fed a standard diet. After 14 days, both the SCI group and the PLX3397+SCI group were tested for ionized calcium binding adapter molecule 1 (Iba1) to confirm that the PLX3397+SCI group had completely depleted the spinal cord microglia. The SCI model was then prepared by clamping the spinal cord in both the SCI group and the PLX3397+SCI group, while the control group underwent laminectomy. Preoperatively and at 1, 3, 7, 14, 21, and 28 days postoperatively, the Basso Mouse Scale (BMS) was used to assess the hind limb function of mice in each group. At 28 days, a footprint test was conducted to observe the gait of the mice. After SCI, spinal cord tissue from the injury site was taken, and Iba1 immunofluorescence staining was performed at 7 days to observe the aggregation and proliferation of microglia in the spinal cord. HE staining was used to observe the formation of glial scars at the injury site at 28 days; glial fibrillary acidic protein (GFAP) immunofluorescence staining was applied to astrocytes to assess the extent of the injured area; neuronal nuclei antigen (NeuN) immunofluorescence staining was used to evaluate neuronal survival. And 5-hydroxytryptamine (5-HT) immunofluorescence staining was performed to assess axonal survival at 60 days. RESULTS: All mice survived until the end of the experiment. Immunofluorescence staining revealed that the microglia in the spinal cord of the PLX3397+SCI group decreased by more than 95% compared to the control group after 14 days of continuous feeding with PLX3397 ( P<0.05). Compared to the control group, the BMS scores in the PLX3397+SCI group and the SCI group significantly decreased at different time points after SCI ( P<0.05). Moreover, the PLX3397+SCI group showed a further decrease in BMS scores compared to the SCI group, and exhibited a dragging gait. The differences between the two groups were significant at 14, 21, and 28 days ( P<0.05). HE staining at 28 days revealed that the SCI group had formed a well-defined and dense gliotic scar, while the PLX3397+SCI group also developed a gliotic scar, but with a more blurred and loose boundary. Immunofluorescence staining revealed that the number of microglia near the injury center at 7 days increased in the SCI group than in the control group, but the difference between groups was not significant ( P>0.05). In contrast, the PLX3397+SCI group showed a significant reduction in microglia compared to both the control and SCI groups ( P<0.05). At 28 days after SCI, the area of spinal cord injury in the PLX3397+SCI group was significantly larger than that in SCI group ( P<0.05); the surviving neurons significantly reduced compared with the control group and SCI group ( P<0.05). The axonal necrosis and retraction at 60 days after SCI were more obvious. CONCLUSION The removal of microglia in the spinal cord aggravate the tissue damage after SCI and affecte the recovery of motor function in mice, suggesting that microglia played a neuroprotective role in SCI.
Animals ; Spinal Cord Injuries/surgery* ; Microglia/pathology* ; Female ; Mice ; Mice, Inbred C57BL ; Nerve Regeneration/drug effects* ; Spinal Cord/pathology* ; Pyrroles/administration & dosage* ; Aminopyridines/administration & dosage* ; Recovery of Function ; Disease Models, Animal ; Calcium-Binding Proteins/metabolism* ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors* ; Microfilament Proteins/metabolism* ; Glial Fibrillary Acidic Protein/metabolism*

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This study assessed the efficacy and safety of tofacitinib in Chinese patients with RA enrolled in Phase 3 and long-term extension (LTE) studies. Methods: ORAL Sync was a 1-year, randomized, placebo-controlled, Phase 3 trial. Patients received tofacitinib 5 or 10 mg twice daily (BID) or placebo advanced to tofacitinib 5 or 10 mg BID at 3 or 6 months. All patients remained on ≥1 background conventional synthetic disease-modifying antirheumatic drug. ORAL Sequel is an open-label LTE study (data-cut: March 2015; data collection and analyses were ongoing, and study database was not locked at the time of analysis; study was closed in 2017). Efficacy outcomes: American College of Rheumatology (ACR) 20/50/70 response rates and Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-4 [ESR]). Patient- and physician-reported outcomes: Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Physician Global Assessment of Arthritis, and pain (visual analog scale). Safety was assessed throughout. Results: ORAL Sync included 218 patients; 192 were subsequently enrolled into ORAL Sequel. In ORAL Sync, more patients achieved ACR20 (tofacitinib 5 mg BID, 67.4%; 10 mg BID, 70.6%; placebo, 34.1%) and DAS28-4 (ESR) <2.6 (tofacitinib 5 mg BID, 7.1%; 10 mg BID, 13.1%; placebo, 2.3%) with tofacitinib versus placebo at Month 6. Mean changes from baseline in HAQ-DI were greater with tofacitinib versus placebo at Month 6. In ORAL Sequel, efficacy was consistent to Month 48. Incidence rates for adverse events of special interest in tofacitinib-treated patients were similar to the global population. Conclusions: Tofacitinib significantly reduced signs/symptoms and improved physical function and quality of life in Chinese patients with moderate-to-severely active RA up to Month 48. The safety profile was consistent with the global population. Clinical Trial Identifier NCT00856544 and NCT00413699.
Administration, Oral ; Adult ; Aged ; Arthritis, Rheumatoid ; drug therapy ; Asian Continental Ancestry Group ; Female ; Humans ; Male ; Middle Aged ; Piperidines ; adverse effects ; therapeutic use ; Protein Kinase Inhibitors ; adverse effects ; therapeutic use ; Pyrimidines ; adverse effects ; therapeutic use ; Pyrroles ; adverse effects ; therapeutic use ; Surveys and Questionnaires ; Young Adult

OBJECTIVETo investigate the efficacy and safety of sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC) on a 2 weeks on/1 week off intermittent dosing schedule.

METHODSA total of 11 mRCC patients were enrolled to receive sunitinib 50 mg/day in 2 weeks on/1 week off schedule per 6 weeks till disease progression or intolerable toxicity occurred. The primary end point was progression free survival (PFS), the secondary end points were overall survival (OS), incidence of adverse effects and objective response.

RESULTSThe objective response rate in the 11 cases was 45.5% and disease control rate 72.7% (partial response n = 5, stable disease n = 3). Till the last follow up on Dec 2013, the median PFS was 17.0 months (95% CI 7.3 to 26.7 months), and median OS 26.0 months (95% CI 2.2 to 49.8 months). The common adverse events included leucopenia, thrombocytopenia, diarrhea, mucositis and hand-foot skin reaction. Dose reduction to 37.5 mg was seen only in 2 patients without discontinuation.

CONCLUSIONSSunitinib on an intermittent dosing schedule 2 weeks on /1 week off as first-line therapy for mRCC patients shows a good efficacy and tolerance, with less grade 3-4 drug-related toxicities and a tendency of prolonged PFS in mRCC patients.

Antineoplastic Agents ; administration & dosage ; pharmacology ; therapeutic use ; Carcinoma, Renal Cell ; drug therapy ; Disease-Free Survival ; Drug Administration Schedule ; Humans ; Indoles ; administration & dosage ; pharmacology ; therapeutic use ; Kidney Neoplasms ; drug therapy ; Pilot Projects ; Pyrroles ; administration & dosage ; pharmacology ; therapeutic use ; Treatment Outcome

BACKGROUND/AIMS: The aim of this study was to assess the efficacy and safety of tofacitinib (5 and 10 mg twice daily) in patients with active rheumatoid arthritis (RA). METHODS: A systematic review of randomized controlled trials (RCTs) that examined the efficacy and safety of tofacitinib in patients with active RA was performed using the Medline, Embase, and Cochrane Controlled Trials Register databases as well as manual searches. RESULTS: Five RCTs, including three phase-II and two phase-III trials involving 1,590 patients, met the inclusion criteria. The three phase-II RCTs included 452 patients with RA (144 patients randomized to 5 mg of tofacitinib twice daily, 156 patients randomized to 10 mg of tofacitinib twice daily, and 152 patients randomized to placebo) who were included in this meta-analysis. The American College of Rheumatology 20% response rate was significantly higher in the tofacitinib 5- and 10-mg groups than in the control group (relative risk [RR], 2.445; 95% confidence interval [CI], 1.229 to 4.861; p = 0.011; and RR, 2.597; 95% CI, 1.514 to 4.455; p = 0.001, respectively). The safety outcomes did not differ between the tofacitinib 5- and 10-mg groups and placebo groups with the exception of infection in the tofacitinib 10-mg group (RR, 2.133; 95% CI, 1.268 to 3.590; p = 0.004). The results of two phase-III trials (1,123 patients) confirmed the findings in the phase-II studies. CONCLUSIONS: Tofacitinib at dosages of 5 and 10 mg twice daily was found to be effective in patients with active RA that inadequately responded to methotrexate or disease-modifying antirheumatic drugs, and showed a manageable safety profile.
Antirheumatic Agents/administration & dosage/adverse effects/*therapeutic use ; Arthritis, Rheumatoid/*drug therapy ; Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Humans ; Janus Kinases/antagonists & inhibitors ; Methotrexate/therapeutic use ; Piperidines/administration & dosage/adverse effects/*therapeutic use ; Protein Kinase Inhibitors/administration & dosage/adverse effects/therapeutic use ; Pyrimidines/administration & dosage/adverse effects/*therapeutic use ; Pyrroles/administration & dosage/adverse effects/*therapeutic use ; Randomized Controlled Trials as Topic ; Treatment Outcome

INTRODUCTIONWe aimed to assess the efficacy of fixed dose combination of atorvastatin plus ezetimibe in Indian patients with dyslipidaemia.

METHODSA double-blind study was conducted to assess the effect of fixed dose combination of ezetimibe 10 mg plus atorvastatin 10 mg on lipid profile, oxidised low-density lipoprotein (ox-LDL), high-sensitivity C-reactive protein (hsCRP) and soluble intercellular cell adhesion molecule (sICAM) in dyslipidaemic patients with or at high risk of coronary artery disease, and compare it with atorvastatin 10 mg monotherapy. 30 patients were randomised to receive ezetimibe plus atorvastatin or atorvastatin once daily for four weeks.

RESULTSOf the 30 patients, 10 men and 5 women (mean age 54.3 ± 1.6 years) received ezetimibe plus atorvastatin, while 13 men and 2 women (mean age 53.7 ± 2.8 years) received only atorvastatin. The combination treatment significantly reduced total cholesterol (percentage treatment difference -14.4 ± 6.5, 95% confidence interval [CI] -1.0 to -27.7; p = 0.041) and LDL cholesterol (LDL-C; percentage treatment difference -19.9 ± 6.1, 95% CI -7.4 to -32.4; p = 0.003) compared to atorvastatin monotherapy. 13 patients on combination treament achieved the National Cholesterol Education Program target for LDL-C as compared to 9 patients on atorvastatin monotherapy (p = 0.032). Significant reductions in very low-density lipoprotein cholesterol, triglyceride, ox-LDL and sICAM were observed with combination treatment compared to atorvastatin monotherapy. However, no significant change was seen in high-density lipoprotein cholesterol or hsCRP levels between the two groups.

CONCLUSIONCombination treatment with atorvastatin and ezetimibe had relatively better lipid-lowering and anti-inflammatory efficacy than atorvastatin monotherapy.

Anti-Inflammatory Agents ; therapeutic use ; Anticholesteremic Agents ; administration & dosage ; Atorvastatin Calcium ; Azetidines ; administration & dosage ; C-Reactive Protein ; metabolism ; Double-Blind Method ; Drug Therapy, Combination ; methods ; Dyslipidemias ; drug therapy ; Ezetimibe ; Female ; Heptanoic Acids ; administration & dosage ; Humans ; Hypolipidemic Agents ; therapeutic use ; India ; Intercellular Adhesion Molecule-1 ; metabolism ; Lipoproteins, LDL ; metabolism ; Male ; Middle Aged ; Pyrroles ; administration & dosage ; Treatment Outcome

No abstract available.
Colitis, Ulcerative/*drug therapy ; Female ; Humans ; Janus Kinases/*antagonists & inhibitors ; Male ; Protein Kinase Inhibitors/*administration & dosage ; Pyrimidines/*administration & dosage ; Pyrroles/*administration & dosage

Sunitinib as a multitarget tyrosine kinase inhibitor is one of the anti-tumor agents, approved by the United States Food and Drug Administration to use treat gastrointestinal stromal tumor and metastatic renal cell carcinoma. The agent is known to commonly induce adverse reactions such as fatigue, nausea, diarrhea, stomatitis, esophagitis, hypertension, skin toxicity, reduciton in cardiac output of left ventricle, and hypothyroidism. However, it has been reported to rarely induce adverse reactions such as nephrotic syndrome and irreversible reduction in renal functions, and cases of intestinal perforation or pneumatosis interstinalis as such reactions have been consistently reported. In this report, a 66-year old man showing abdominal pain had renal cell carcinoma and history of sunitinib at a dosage of 50 mg/day on a 4-weeks-on, 2-weeks-off schedule. Seven days after the third cycle he was referred to the hospital because of abdominal pain. Computed tomography showed pneumoperitoneum with linear pneumatosis intestinalis in his small bowel. The patient underwent surgical exploration that confirmed the pneumatosis intestinalis at 100 cm distal to Treitz's ligament. We report a rare case of intestinal perforation with pneumatosis intestinalis after administration of sunitinib to a patient with metastatic renal cell carcinoma.
Aged ; Antineoplastic Agents/adverse effects/*therapeutic use ; Carcinoma, Renal Cell/*drug therapy ; Drug Administration Schedule ; Humans ; Indoles/adverse effects/*therapeutic use ; Intestinal Perforation/*diagnosis/etiology/surgery ; Kidney Neoplasms/*drug therapy ; Lung/radiography ; Male ; Pneumatosis Cystoides Intestinalis/*diagnosis/etiology ; Positron-Emission Tomography ; Pyrroles/adverse effects/*therapeutic use ; Tomography, X-Ray Computed

BACKGROUNDSunitinib has been proved an effective new option for treatment of metastatic renal cell carcinoma (mRCC). Analysis of clinical data of 22 patients, who were exposed to sunitinib for at least 1 year, was conducted to evaluate the long-term efficacy and safety of sunitinib for the treatment of mRCC.

METHODSA total of 54 patients with mRCC were treated with sunitinib malate, 50 mg/d orally, on a 4-weeks-on and 2-weeks-off dosing schedule in Peking University First Hospital. Treatment continued until disease progression, unacceptable adverse events (AEs), or death. Among them, 22 patients continued treatment for at least 1 year. The clinical data of these 22 patients were prospectively collected for analysis. AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0. Tumor response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors.

RESULTSMedian progression-free survival was 19.5 months until last follow-up. The best efficacy results achieved were complete response, partial response, and stable disease for 2, 9, and 11 patients, respectively. Objective response rate was 50%. The most common AEs were hand-foot syndrome (95%) and hypertension (91%). Other common AEs were thyroid-stimulating hormone elevation (82%), platelet decrease (77%), and loss of appetite (77%). Only one patient withdrew from treatment for cardiac infarction. Another nine patients experienced dose modifications or short-term suspensions.

CONCLUSIONLong-term exposure to sunitinib malate showed encouraging efficacy in the treatment of mRCC. At the same time, the tolerability was good.

Adult ; Aged ; Antineoplastic Agents ; administration & dosage ; Carcinoma, Renal Cell ; drug therapy ; pathology ; Drug Administration Schedule ; Female ; Follow-Up Studies ; Humans ; Indoles ; administration & dosage ; Kidney Neoplasms ; drug therapy ; pathology ; Male ; Middle Aged ; Neoplasm Metastasis ; Pyrroles ; administration & dosage ; Young Adult

OBJECTIVETo observe the effect of atorvastatin on eNOS synthesis in the vital organs of aging rats and explore its mechanism for protection against myocardial ischemia-reperfusion injury.

METHODSTwenty-month-old Wistar rats were given daily atorvastatin lavage for 4 months. Myocardial ischemia-reperfusion model was established by ligating the coronary artery. The rats were randomized into normal control group, untreated model group, medication without surgery group, and atorvastatin-treated surgical group. The content of eNOS in the heart, liver and kidneys was detected by Western blotting, and eNOS mRNA expression by RT-PCR. The effects of different doses of atorvastatin on eNOS expressions were also evaluated.

RESULTSAtorvastatin significantly promoted eNOS synthesis in the heart, liver and kidney of the rats (P<0.05) regardless of myocardial ischemia-reperfusion. A higher dose of atorvastatin caused a more obvious increase of eNOS protein and mRNA expression in the vital organs of the aging rats (P<0.05).

CONCLUSIONAtorvastatin can increase eNOS synthesis in the vital organs of aging rats, which partially explains the organ-protective effect of atorvastatin against myocardial ischemia- reperfusion.

Animals ; Atorvastatin Calcium ; Female ; Heptanoic Acids ; administration & dosage ; pharmacology ; Kidney ; metabolism ; Liver ; metabolism ; Male ; Myocardial Reperfusion Injury ; drug therapy ; metabolism ; Myocardium ; metabolism ; Nitric Oxide Synthase Type III ; genetics ; metabolism ; Pyrroles ; administration & dosage ; pharmacology ; Rats ; Rats, Wistar

OBJECTIVETo evaluate the efficacy of atorvastatin in preventing contrast agent-induced nephropathy (CIN) in patients undergoing coronary angiography and explore the mechanism.

METHODSA total of 180 patients undergoing coronary angiography or percutaneous coronary interventions (PCI) were randomized into regular dose and high dose atorvastatin groups (n=90). Serum creatinine (Scr), glomerular filtration rate (GFR), cystatin, peripheral blood levels of myeloperoxidase (MPO), malondialdehyde (MDA), and superoxide dismutase (SOD) before and after the procedure were compared between the two groups.

RESULTSThe incidence of CIN was significantly lower in high-dose atorvastatin group than in the regular dose group. At 48-72 h after the surgery, serum Scr and cystatin levels were significantly lower and eGFR was significantly higher in the high-dose group. At 24 h after the surgery, MPO and MDA levels were significantly lower, and SOD activity was significantly higher in high-dose group than in the regular dose group.

CONCLUSIONHigh-dose atorvastatin used before angiography is more effective than the regular dose in attenuating contrast agent-induced renal dysfunction, and its mechanism is related with the inhibition of oxidative stress.

Aged ; Atorvastatin Calcium ; Contrast Media ; adverse effects ; Coronary Angiography ; adverse effects ; Female ; Heptanoic Acids ; administration & dosage ; pharmacology ; therapeutic use ; Humans ; Kidney Diseases ; chemically induced ; prevention & control ; Male ; Middle Aged ; Oxidative Stress ; drug effects ; Pyrroles ; administration & dosage ; pharmacology ; therapeutic use