Biomedical subjects
Publications and source records attributed to F Kanai.
Vanoxonin, a new inhibitor of thymidylate synthetase, was found in cultured broths of the strain MG245-CF2 classified as Saccharopolyspora hirsuta. Vanoxonin, C18H25N3O9, was obtained as colorless powder. Vanoxonin forms a vanadium complex which exhibits a strong inhibition against thymidylate synthetase. The concentration for 50% inhibition of the enzyme (IC50) was 0.7 micrograms/ml.
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A new biodegradable tracheal prosthesis was developed using hydroxyapatite rings as the artificial tracheal cartilage, a carbon fiber tube as the tracheal tube; it was then implanted into the cervical trachea in dogs. Morphologic examination revealed that the hydroxyapatite ring was anchored firmly to the tracheal cartilage by ingrowth of cartilaginous tissue into the macropores of the hydroxyapatite.
A multicomparative study to establish adequate anticoagulation therapy for left ventricular assist devices was undertaken by administrating various anticoagulants: heparin, a prostacyclin analogue combined with a protease inhibitor; thromboxane A2 synthetase inhibitor; or a protease inhibitor alone. Our investigation suggested that combined administration of prostacyclin analogue and protease inhibitor (FUT-175) is ideal anticoagulation therapy from the point of blood coagulation and fibrinolysis. Currently, however, sole administration of FUT-175 is adequate anticoagulation therapy during clinical use of left ventricular assist devices.
FUT, a new synthetic protease inhibitor, has been used recently in hemodialysis as an anticoagulant in patients with bleeding tendencies. As some new adsorbents require alternatives to heparin because of their strong adsorbing capacity for heparin, plasma perfusion with FUT anticoagulation was pharmacodynamically investigated. Blood was pumped from a dog (QB = 50-70 ml/min) into a plasma separator. The separated plasma (QP = 10-20 ml/min) passed through an adsorbent column and was reinfused into the blood that had passed through the plasma separator. FUT was continuously infused, at a flow rate of 50 mg/hr, into the blood as it left the dog and entered the extracorporeal circuit. Blood and plasma samples were taken as it exited the dog (S1), before and after the adsorbent column (S2, S3), and before reinfusion into the dog (S4). Except for that done with a charcoal-column, adsorbent plasma perfusion went well and the dog tolerated the procedure. FUT levels in S2, S3, and S4 provided anticoagulation. However, as the FUT levels in S1 remained negligible, the dog's coagulation time was within normal limits. In conclusion, FUT was pharmacodynamically proven to be a safe and reasonable anticoagulant for adsorbents that adsorb large amounts of heparin and for patients with bleeding tendencies.
To establish ideal anticoagulation therapy for use with a left ventricular assist device, a study was done administering various anticoagulants: heparin, argatroban, a prostacyclin analogue combined with a protease inhibitor, or a protease inhibitor alone. Cardiac asisting by LVAD without any anticoagulants results in marked activation of blood coagulation or fibrinolysis. Administration of argatroban, as well as heparin, produces a bleeding tendency. Administration of a protease inhibitor (nafamostat mesilate, FUT-175) as a sole anticoagulant induces activation of the blood coagulation system to some extent, but it is within acceptable limits. Combined administration of a prostacyclin analogue (PG) and FUT-175 is most effective in maintaining balanced blood coagulation and fibrinolysis.
The sole administration of urokinase causes no initial prolongation of activated partial thromboplastin time (A-PTT), but thereafter produces serious progressive prolongation of A-PTT; it also causes a progressive, severe decrease in fibrinogen levels and alpha 2-plasmin inhibitor activity by depletion. The antithrombogenicity of urokinase is not caused by prevention of blood coagulation system activation by antithrombin effect, but by secondary fibrinolysis by plasmin. Consequently, the administration of urokinase as a sole anticoagulant results in activation of coagulation and fibrinolysis, and, as a result, induces disseminated intravascular coagulation. Therefore, it is concluded that administration of urokinase is an inadequate anticoagulation therapy unless it is combined with other antithrombin agents.
Thirty-six mongrel dogs underwent 24hr left ventricular assist. The VAD was placed between the left atrium and the descending aorta, and the dogs were divided into four groups according to type of anticoagulation: no anticoagulation, argatroban, nafamostat mesylate, and nafamostat mesylate + prostacyclin analog. Results of this animal experiment revealed that a newly developed synthetic thrombin inhibitor argatroban can prevent activation of the intrinsic coagulation pathway. Argatroban is efficient under any blood coagulative condition, even lack of anti-thrombin III, because of its direct inhibitory effect on thrombin, making argatroban more useful than heparin as an anticoagulant for LVAD. Argatroban, as well as heparin, provides marked and significant prolongation of the prothrombin time from early assisted circulation, but produces a bleeding tendency. Nafamostat mesylate can maintain blood coagulation parameters within the acceptable range. Combined administration of nafamostat mesylate and a prostacyclin analog cause the least decrease in fibrinogen and alpha2-plasmin inhibitor among the four groups and causes no significant prolongation of prothrombin time.
A new ventricular assist device (VAD) pneumatic driver with a servomatic left atrial pressure (LAP) control mechanism was developed for easy and safe control of left ventricular assist devices. The negative driving pressure (NP) can be automatically varied to control the assisted circulatory flow (AF), comparing the patient's LAP with prescheduled LAP (s-LAP). Animal experiments revealed this servomatic control system to be useful.
To establish ideal anticoagulant therapy for left ventricular assist devices (LVADs), a comparative study was made of a thromboxane A2 synthetase inhibitor, a protease inhibitor, and combined administration of the two. Results of the investigation indicate that combined administration of a thromboxane A2 synthetase inhibitor (OKY-046) and a protease inhibitor (nafamostat mesilate, FUT-175) provides ideal anticoagulant therapy during cardiac support using LVADs from the point of blood coagulation and fibrinolysis. Artificial hearts have come into practical use as left ventricular assist devices, and have contributed to the saving of many patients with severe postoperative low cardiac output syndrome, but they sometimes encounter severe complications, i.e. cerebrovascular bleeding, thromboembolism, infection, or multiple organ failure. It is very important, therefore, to control coagulation and fibrinolysis adequately during cardiac support by an LVAD.
Recently, adoptive immunotherapy for cancer with lymphokine activated killer (LAK) cells has been widely used experimentally. The therapy has several problems, including difficulty in handling, sterilization, and time consumption. To solve these problems, new materials able to induce antitumor immune cells were investigated. Pokeweed mitogen (PWM) and PWM-conjugated materials (CMC-1) could induce strong killer cells by short-term stimulation of human peripheral blood lymphocytes (PBL). The induced killer cells showed a wide killing spectrum in vitro against human tumor cell lines (MKK-1, PRMI4788, NBT-2, ZR-7530, H-1, Hela, KB, HMV-1, PC-10, C-1). Human PBL stimulated for a short time by CMC-1 also showed a tumoricidal effect on tumor bearing (MKN-1, MKN-45) nude mice. These results suggest that CMC-1 may solve the problems with currently used LAK therapy and may provide easily applicable extracorporeal immunotherapy for cancer.
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A combination of plasma exchange and dialysis, the procedure of which is easily and safely performed by our hepatic assist system, composed of a membrane plasma separator, blood and plasma pumps, hemodialyzer and controller. This may be a practical and reliable method for hepatic support at the present time, however, the results are not so satisfactory. In order to improve our system, a surfactant-free polyolefine membrane plasma separator has been developed and evaluated to be better than conventional ones in both efficiency and biocompatibility. And also, a new module of IONEX, completely saturated with heparin, has been developed as a safe and an efficient adsorbent, which selectively adsorb bilirubin and bile acids.
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