Kazutomo Saito

Anti-Allergic Drugs Tranilast and Ketotifen Dose-Dependently Exert Mast Cell- Stabilizing Properties

Background: Anti-allergic drugs, such as tranilast and ketotifen, inhibit the release of chemokines from mast cells. However, we know little about their direct effects on the exocytotic process of mast cells. Since exocytosis in mast cells can be monitored electrophysiologically by changes in the whole-cell membrane capacitance (Cm), the absence of such changes by these drugs indicates their mast cell-stabilizing properties. Methods: Employing the standard patch-clamp whole-cell recording technique in rat peritoneal mast cells, we examined the effects of tranilast and ketotifen on the Cm during exocytosis. Using confocal imaging of a water-soluble fluorescent dye, lucifer yellow, we also examined their effects on the deformation of the plasma membrane. Results: Relatively lower concentrations of tranilast (100, 250 µM) and ketotifen (1, 10 µM) did not significantly affect the GTP-γ-S-induced increase in the Cm. However, higher concentrations of tranilast (500 µM, 1 mM) and ketotifen (50, 100 µM) almost totally suppressed the increase in the Cm, and washed out the trapping of the dye on the surface of the mast cells. Compared to tranilast, ketotifen required much lower doses to similarly inhibit the degranulation of mast cells or the increase in the Cm. Conclusions: This study provides electrophysiological evidence for the first time that tranilast and ketotifen dose-dependently inhibit the process of exocytosis, and that ketotifen is more potent than tranilast in stabilizing mast cells. The mast cell-stabilizing properties of these drugs may be attributed to their ability to counteract the plasma membrane deformation in degranulating mast cells.

Anticoagulant Managements of Left Ventricular Assist Device Implantation inTwo Patients with Heparin-Induced Thrombocytopenia (HIT): Use ofArgatroban as an Anticoagulant for Cardiopulmonary Bypass

Heparin-induced thrombocytopenia (HIT) can cause fatal arterial or venous thrombosis/thromboembolism. In high-risk cases, heparin should be immediately discontinued and an alternative administered; the only alternative permitted in Japan is argatroban, a direct thrombin inhibitor. Anticoagulation in patients with recent HIT requiring cardiopulmonary bypass (CPB) surgery is challenging, because it is sometimes difficult to find out appropriate dosage of argatroban using ACT based monitoring calculation. Two dilated cardiomyopathy patients with HIT were administered argatroban as the anticoagulant for the CPB in left ventricular assist device (LVAD) implantation. After discontinuing argatroban, blood coagulopathy persisted beyond its expected half-life, leading to abnormal haemostasis. Because of severe intraoperative and postoperative bleeding, both patients required massive transfusion support, despite the case 2 performed plasmapheresis to eliminate argatroban at the weaning from CPB. However, blood loss in case 2 (18,159 ml) was significantly lower than that in case 1 (31,292 ml), which might be contributed by the smaller dosage of argatroban (242 mg in case 2 vs. 489 mg in case 1) and plasmapheresis. Prolongation of ACT is multifactorial and affected by platelet count, fibrinogen concentration and, particularly total dose of argatroban. Furthermore, literatures and our experienses revealed that the recovery time to baseline ACT after stopping argatroban was significantly correlated with the total dose of argatroban (r=0.927). But, we could not authenticate the potency of plasmapheresis to eliminate argatroban and HIT antibodies. Because no specific antidotes are available for argatroban, surgical teams should carefully monitor timing of argatroban administration and the total dosage.

Less contribution of mast cells to the progression of renal fibrosis in Rat kidneys with chronic renal failure.

Chronic renal failure (CRF) is histopathologically characterized by tubulointerstitial fibrosis in addition to glomerulosclerosis. Although mast cells are known to infiltrate into the kidneys with chronic inflammation, we know little about their contribution to the pathogenesis of renal fibrosis associated with CRF. The aim of this study was to reveal the involvement of mast cells in the progression of renal fibrosis in CRF.

Clarithromycin Dose-Dependently Stabilizes Rat Peritoneal Mast Cells

Background: Macrolides, such as clarithromycin, have antiallergic properties. Since exocytosis in mast cells is detected electrophysiologically via changes in membrane capacitance (Cm), the absence of such changes due to the drug indicates its mast cell-stabilizing effect. Methods: Employing the whole-cell patch clamp technique in rat peritoneal mast cells, we examined the effects of clarithromycin on Cm during exocytosis. Using a water-soluble fluorescent dye, we also examined its effect on deformation of the plasma membrane. Results: Clarithromycin (10 and 100 μM) significantly inhibited degranulation from mast cells and almost totally suppressed the GTP-γ-S-induced increase in Cm. It washed out the trapping of the dye on the surface of mast cells. Conclusions: This study provides for the first time electrophysiological evidence that clarithromycin dose-dependently inhibits the process of exocytosis. The mast cell-stabilizing action of clarithromycin may be attributable to its counteractive effect on plasma membrane deformation induced by exocytosis.

Implantation of ventricular assist device for systemic right ventricular failure in a patient with transposition of the great arteries and post-Mustard procedure: a case report

BackgroundVentricular assist device (VAD) is usually attached by an inflow cannula to the apex of the systemic left ventricle (LV), but very few cases with implantation of the VAD in the morphologic right ventricle (RV) have been described.Case presentationWe describe the case of a 41-year-old male who developed severe systemic RV failure related to a Mustard procedure he had as an infant for treatment of TGA. His heart failure was refractory and irreversible, and therefore, he underwent VAD implantation for systemic RV support. Although the patient developed pulmonary congestion on postoperative day (POD) 5, he was discharged on POD 60. He is now looking forward to receiving heart transplantation.ConclusionsPlacement of a VAD for systemic RV failure could be a life-saving treatment in adult patients with heart failure due to congenital heart disease.

Management of three cardiogenic pulmonary edemas occurring in a patient scheduled for left ventricular assist device implantation: indicators for determining left ventricular assist device pump speed

A male patient with Marfan syndrome underwent aortic root replacement and developed left ventricular (LV) failure. Four years later, he underwent aortic arch and aortic valve replacement. Thereafter, his LV failure progressed, and cardiogenic pulmonary edema (CPE) appeared, which we treated with extracorporeal LV assist device (LVAD) placement. Three months later, the patient developed aspiration pneumonia, which caused hyperdynamic right ventricle (RV) and CPE. We treated by changing his pneumatic LVAD to a high-flow centrifugal pump. A month later, he underwent thoracoabdominal aortic replacement. After four weeks, he developed septic thrombosis and LVAD failure, which caused CPE. We treated with LVAD circuit replacement and an additional membrane oxygenator. Four months later, he underwent DuraHeart® implantation. During this course, pulmonary artery wedge pressure (PAWP) varied markedly. Additionally, systolic pulmonary artery pressure (sPAP), left atrial diameter (LAD), RV end-diastolic diameter (RVEDD) and estimated RV systolic pressure (esRVP) changed with PAWP changes. In this patient, LV failure and hyperdynamic RV caused the CPEs, which we treated by adjusting the LVAD output to the RV output. Determining LVAD output, RV function and LV end-diastolic diameter are typically referred, and PAWP, LAD, RVEDD, and sPAP could be also referred.

Preoperative Assessment of the Impact of Positive Pressure Ventilation With Noninvasive Positive Pressure Ventilation in a Patient With Eisenmenger Syndrome: A Case Study.

In Eisenmenger syndrome (ES), positive pressure ventilation (PPV) during general anesthesia may lead to an increase in pulmonary vascular resistance and potentially to hypoxemia. In an attempt to predict the patients hemodynamic response to intraoperative ventilation, we tested preoperatively the hemodynamic effects of noninvasive PPV with continuous positive pressure in a woman with ES scheduled for oophorectomy. The surgery was performed without complications, and the patient was discharged on postoperative day 8.