Objectives: To assess the effects of tocilizumab on pregnancy outcomes in Japanese patients with rheumatic disease. Methods: Data from Chugai’s tocilizumab safety database (April 2005 to October 2014) were retrospectively analyzed to identify pregnancy outcomes in patients exposed to tocilizumab. Results: Data were available for 61 pregnancies exposed to tocilizumab, and outcomes were reported for 50 of those pregnancies. In 36 births, no congenital anomalies were identified; however, six neonatal abnormalities were reported: five cases of low birth weight (<2500 g) and one case of neonatal asphyxia. Of 36 births, tocilizumab was resumed during lactation in two patients, with no subsequent adverse events reported in newborns. The spontaneous abortion rate was 18.0% (9 of 50 pregnancies), which is comparable to the rate in the general population. The five terminated pregnancies included one case of caudal regression syndrome. Conclusions: The present retrospective study of 61 pregnancies exposed to tocilizumab at conception indicated no increased rates of spontaneous abortion or congenital abnormalities in patients with rheumatic disease. However, further study is necessary to confirm the benefit-risk profile of tocilizumab treatment during pregnancy.
BackgroundNicorandil, an anti-angina agent, reportedly improves outcomes even in angina patients with diabetes. However, the precise mechanism underlying the beneficial effect of nicorandil on diabetic patients has not been examined. We investigated the protective effect of nicorandil on endothelial function in diabetic rats because endothelial dysfunction is a major risk factor for cardiovascular disease in diabetes.MethodsMale Sprague-Dawley rats (6 weeks old) were intraperitoneally injected with streptozotocin (STZ, 40 mg/kg, once a day for 3 days) to induce diabetes. Nicorandil (15 mg/kg/day) and tempol (20 mg/kg/day, superoxide dismutase mimetic) were administered in drinking water for one week, starting 3 weeks after STZ injection. Endothelial function was evaluated by measuring flow-mediated dilation (FMD) in the femoral arteries of anaesthetised rats. Cultured human coronary artery endothelial cells (HCAECs) were treated with high glucose (35.6 mM, 24 h) and reactive oxygen species (ROS) production with or without L-NAME (300 μM), apocynin (100 μM) or nicorandil (100 μM) was measured using fluorescent probes.ResultsEndothelial function as evaluated by FMD was significantly reduced in diabetic as compared with normal rats (diabetes, 9.7 ± 1.4%; normal, 19.5 ± 1.7%; n = 6-7). There was a 2.4-fold increase in p47phox expression, a subunit of NADPH oxidase, and a 1.8-fold increase in total eNOS expression in diabetic rat femoral arteries. Nicorandil and tempol significantly improved FMD in diabetic rats (nicorandil, 17.7 ± 2.6%; tempol, 13.3 ± 1.4%; n = 6). Nicorandil significantly inhibited the increased expressions of p47phox and total eNOS in diabetic rat femoral arteries. Furthermore, nicorandil significantly inhibited the decreased expression of GTP cyclohydrolase I and the decreased dimer/monomer ratio of eNOS. ROS production in HCAECs was increased by high-glucose treatment, which was prevented by L-NAME and nicorandil suggesting that eNOS itself might serve as a superoxide source under high-glucose conditions and that nicorandil might prevent ROS production from eNOS.ConclusionsThese results suggest that nicorandil improved diabetes-induced endothelial dysfunction through antioxidative effects by inhibiting NADPH oxidase and eNOS uncoupling.
Sirolimus (SRL) is widely used to prevent restenosis after percutaneous coronary intervention. However, its beneficial effect is hampered by complications of thrombosis. Several studies imply that reactive oxygen species (ROS) play a critical role in endothelial dysfunction and thrombus formation. The present study investigated the protective effect of nicorandil (NIC), an anti-angina agent, on SRL-associated thrombosis. In human coronary artery endothelial cells (HCAECs), SRL stimulated ROS production, which was prevented by co-treatment with NIC. The preventive effect of NIC on ROS was abolished by 5-hydroxydecanoate but not by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. NIC also inhibited SRL-induced up-regulation of NADPH oxidase subunit p22(phox) mRNA. Co-treatment with NIC and SRL significantly up-regulated superoxide dismutase 2. NIC treatment significantly improved SRL-induced decrease in viability of HCAECs. The functional relevance of the preventive effects of NIC on SRL-induced ROS production and impairment of endothelial viability was investigated in a mouse model of thrombosis. Pretreatment with NIC inhibited the SRL-induced acceleration of FeCl3-initiated thrombus formation and ROS production in the testicular arteries of mice. In conclusion, NIC prevented SRL-induced thrombus formation, presumably due to the reduction of ROS and to endothelial protection. The therapeutic efficacy of NIC could represent an additional option in the prevention of SRL-related thrombosis.
The present study was undertaken to identify functional isoforms of the Na,K-ATPase in single rat cardiac myocytes. Na,K-ATPase activity was measured as ouabain-sensitive, extracellular K-activated outward current (Na pump current) in ventricular myocytes voltage-clamped with single low-resistance (0.5- 1 M omega) patch electrodes at 36 degrees C. Solutions to block contaminating currents allowed Na pump current to be measured without significant contamination in 140 mM Na-containing superfusion solutions. The current-voltage relationship had a positive slope at potentials from -125 to 0 mV but became almost voltage-independent at positive potentials. The apparent Km for activation of this current at -40 mV by extracellular K was 2.7 +/- 0.3 mM (mean +/- SEM, n = 3) and increasing electrode Na increased the amplitude of the current to a maximum density of 4.11 +/- 0.17 pA/pF (n = 34). Intracellular vanadate (100 microM) produced an extracellular K-dependent inhibition of Na pump current that was rapidly reversed in K-free superfusion solution. Dose-dependent inhibition of Na pump current by ouabain was best described as the sum of two Michaelis-Menten binding sites: one with higher affinity (K1/2 = 1.0 +/- 0.7 microM) comprising 33 +/- 9% (n = 5-6) of the total current and the second with a K1/2 of 43 +/- 14 microM. Changing electrode [Na] from 15 to 100 mM had no effect on the dose-dependent inhibition of the current by ouabain. Thus, the properties of high and low affinity components of Na pump current are consistent with the presence of different Na,K-ATPases isoforms that have a similar ion dependence for transport activity.
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