Biomedical subjects
Publications and source records attributed to Y Ku.
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This study was undertaken to pharmacokinetically evaluate the efficacy of direct hemoperfusion under hepatic venous isolation (HVI-DHP) to cisplatin (CDDP) removal during hepatic arterial infusion. CDDP (2-4 mg/kg) was administered continuously to mongrel dogs through the hepatic artery for 10 min. Plasma levels and tissue concentrations were then compared between animals receiving CDDP alone (group 1, n = 4) and those treated with additional HVI-DHP for 20 min (group 2, n = 6). The peak CDDP levels in the right external jugular vein (systemic level) were 6.10 +/- 1.31 (mean +/- SD) and 1.41 +/- 0.12 micrograms/ml in groups 1 and 2 at a dosage of 2 mg/kg, respectively (P < 0.01). The estimated drug removal rates in group 2 animals at dosages of 2 and 4 mg/kg were 45.7 (mean, n = 5) and 46.9% (n = 1), respectively. The tissue concentrations of CDDP of the liver 30 min after the initiation of infusions were similar in both groups. The values of the liver, the heart, and the kidney were 1.90 +/- 0.55, 0.50 +/- 0.16, and 3.90 +/- 2.50 micrograms/g of wet tissue weight, respectively, in group 1. In contrast, tissue levels of the heart and the kidney in group 2 animals were significantly reduced, with the values at a dosage of 2 mg/kg being 0.21 +/- 0.03 micrograms/g (P < 0.01) and 0.86 +/- 0.53 micrograms/g (P < 0.05), respectively. This study demonstrated that the extrahepatic distribution of CDDP during hepatic arterial infusion can be reduced significantly by the concomitant use of HVI-DHP.
We have demonstrated a direct correlation between a high ATP level in a canine pancreas graft after preservation by the two-layer method and good posttransplant outcome. The purpose of this study was to examine the effect of fasting and exogenous adenosine on the ATP tissue level and viability of the canine pancreas graft during preservation by the two-layer method. Graft viability was judged by graft survival following autotransplantation. Maintenance of normoglycemia for 5 days post-transplant was considered graft survival. The pancreas was harvested from either 72-hr-fated (n = 3) or -fed dogs (n = 4) and preserved by the two-layer (Euro-Collins' solution [EC]/perfluorochemical [PFC]) method for 24 hr. Graft survival rates in fed and fasted groups were 4/4 (100%) and 3/3 (100%), respectively. There was no significant difference in ATP tissue concentrations between the two groups (7.48 +/- 0.55 vs. 7.03 +/- 0.74 mumol/g dry wt, NS). The pancreas was subjected to 60 min warm ischemia and then was preserved by the two-layer method using EC or EC containing 5 mM adenosine for 24 hr. Without adenosine, graft survival rate was 0/3 (0%) and ATP tissue levels were not changed during preservation (1.62 +/- 0.26 vs. 1.56 +/- 0.40 mumol/g dry wt, NS). However, provision of adenosine to the graft during preservation led to the restoration of ATP tissue levels (1.90 +/- 0.54 vs. 8.13 +/- 0.98 mumol/g dry wt, P < 0.01) in 4 of 5 grafts, and these grafts functioned immediately and maintained normoglycemia after transplantation. Graft survival rate was 4/5 (80%). One of 5 grafts, however, did not survive, and the ATP tissue level was not adequately recovered during preservation compared with viable grafts (3.67 vs. 8.13 +/- 0.98 mumol/g dry wt). This study clearly demonstrates that the nutritional state of the donor has no influence on the ATP tissue level and viability of the graft during 24-hr preservation by the two-layer method. On the other hand, provision of adenosine to the graft during preservation stimulates ATP synthesis and improves the viability of the ischemically damaged pancreas.
We have demonstrated that a two-layer (University of Wisconsin solution [UW]/perfluorochemical [PFC]) cold storage method restores the function of ischemically damaged pancreas during 24-hr preservation in canine autotransplantation model. The purpose of this study was to examine the possibility of a long-term preservation of the ischemically damaged pancreas by the two-layer (UW/PFC) method. After 60 or 90 min of warm ischemic time, pancreas grafts were preserved by the two-layer (UW/PFC) method or a simple cold storage in UW alone for up to 96 hr. A K value of i.v. glucose tolerance test more than 1.0 2 weeks after autotransplantation was considered successful preservation. After 60 min warm ischemia, limitation of preservation time by the simple cold storage in UW was 24 hr (5/5 100% and 0/5 0%; 24- and 48-hr preservation, respectively). However, the two-layer method made it possible to extend the preservation time up to 48 hr (5/5 100%, 5/5 100%, 2/5 40%, and 0/5 0%; 24-, 48-, 72-, and 96-hr preservation, respectively). After 90 min warm ischemia, the simple cold storage in UW was not effective even for 24-hr preservation (0/5 0%). However, 48-hr preservation was successful by the two-layer (UW/PFC) method (5/5 100%, 5/5 100%, and 0/5 0%; 24-, 48-, and 72-hr-preservation, respectively). After preservation by the two-layer (UW/PFC) method, ATP tissue concentrations of viable grafts were significantly higher compared with nonviable grafts (9.11 +/- 3.05 (n = 22) versus 5.22 +/- 1.02 (n = 13) mumol/g dry wt, P < 0.001). Based on analysis of individual ATP for each graft, if an ATP concentration of 6.0 mumol/g dry weight was determined as a critical value for doing the transplant, sensitivity, specificity, positive predictive value, and negative predictive value were 100%, 84.6%, 91.7%, and 94.3%, respectively. This study clearly demonstrated that 48-hr preservation of the canine pancreas subjected to either 60 or 90 min warm ischemia was successfully achieved by the two-layer (UW/PFC) cold storage method, and ATP tissue concentration at the end of preservation by this method would predict the post-transplant outcome of the ischemically damaged pancreas just prior to transplantation.
We investigated the effect of hypothermic aerobic perfusion of the rat liver using perfluoro-N-methyl-decahydroisoquinoline (FMIQ) on the cell viabilities of hepatic parenchyma and nonparenchyma in comparison with University of Wisconsin (UW) solution. Rat liver were perfused at 4 degrees C up to 24hr at a flow rate of 0.2 ml/g liver tissue/min with either UW or a perfusate (m-FMIQ) containing 20% FMIQ with or without oxygen saturation. After storage, livers were perfused with Krebs-Henseleit buffer containing trypan blue (200 microM). Nuclear dye uptake was measured as an indicator of cell death. Dye uptake of parenchymal cells remained less than 2% for up to 24hr, regardless of perfusate or O2-saturation. In UW perfused livers, nonparenchymal cells showed time related increases of dye positive nuclei, which were not affected by O2-saturation (39.9 +/- 4.7% and 36.5 +/- 4.2% at 24hr in O2-saturated and nonsaturated groups, respectively). In contrast, we found excellent protective effects of oxygen supply with m-EMIQ on the nonparenchymal cell viability, the dye uptake values being 16.9 +/- 5.7% and 39.4 +/- 9.1% at 24hr in O2-saturated and nonsaturated groups, respectively (p < 0.001). In conclusion, oxygen supply during hypothermic perfusion may be useful in preventing nonparenchymal cell injury of the liver, thereby leading to dramatic improvement of the hepatic microcirculation.
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This study was undertaken to evaluate the efficacy of a new technique of regional liver hyperthermia using the femoro-hepatic arterial (FA.HA) thermal bypass. With mongrel dogs (n = 5), an 8 F catheter was placed in the hepatic artery (HA) through the gastroduodenal artery. A 12 F catheter was introduced into the abdominal aorta through the right femoral artery (FA). These catheters were connected to a system containing a centrifugal pump and a heat exchanger. The heat exchanger consists of warmer coils and a water bath kept at a temperature of 47 degrees C. The bypass was run at an average blood flow rate of 160 +/- 20 (mean +/- SD) ml/min. The temperature was continuously monitored at four measuring points of water bath, inflow blood of HA, liver parenchyma and rectum. The temperature of liver parenchyma promptly reached 42.1 +/- 1.1 and 42.8 +/- 0.8 degrees C 20, 30 minutes after the start of hyperthermia, respectively. The rectal temperature remained 39.3 +/- 1.2 degrees C at 30 minutes. These results indicate that our method is simple and highly effective to perform regional liver hyperthermia.
We have developed a new system consisting of direct hemoperfusion (DHP) under the infrahepatic vena caval isolation for high-dose intraarterial chemotherapy of pelvic tumor. In a patient with unresectable retroperitoneal liposarcoma, a catheter (16 F) was introduced into the left common iliac vein via the left greater saphenous vein. In addition, a balloon catheter (16F) was introduced into the intrahepatic inferior vena cava through the right greater saphenous vein. Adriamycin (100 mg/body) was administered through the internal iliac artery for 15 min. During drug infusion, the infrahepatic vena caval blood was isolated by balloon occlusion, and filtered by DHP cartridges. Then, the blood was re-directed to the patient through the central lumen of the balloon catheter. The patient showed good hemodynamic tolerance during this treatment. Adriamycin toxicities including leucopenia, gastrointestinal problems and alopecia were not observed throughout the follow-up period. Based on these results, it was concluded that this method allows high-dose intraarterial chemotherapy of the kidney and pelvis without increased systemic toxicities.
We investigated the characteristics of tumor responses of hepatocellular carcinoma (HCC, n = 14) and colorectal hepatic metastasis (CHM, n = 10) to high dose hepatic arterial chemotherapy using direct hemoperfusion under hepatic venous isolation. Adriamycin was given at doses ranging from 100 to 150 mg/m2. During drug infusion, two patients with HCC and three with CHM were treated by balloon-occluded arterial infusion (BOAI). Computerized tomographic findings after treatment were compared between the two diseases. In addition, response characteristics in each disease were investigated in relation to tumor factors such as size, capsule formation, vascularity and macroscopic type. Eight (57%) out of 14 patients with HCC showed either size reduction (n = 5) or liquefaction (n = 3), while the remaining six patients showed no apparent changes. On the other hand, seven (70%) of 10 patients with CHM showed liquefaction without any evidence of tumor size reduction. Regardless of the disease, all patients treated with BOAI had liquefaction as a sign of tumor responses. Based on these observations, it is concluded that response characteristics may differ depending on tumor factors such as vascularity and the nature of the treatment as represented by BOAI.
A 67-year-old man with an extensive hepatocellular carcinoma (HCC) was treated successfully with intraarterial infusion of high-dose adriamycin (ADR), 150 mg/m2, five minutes continuous infusion using an extra-corporeal system consisting of direct hemoperfusion (DHP) under hepatic venous isolation (HVI). During drug infusion, hepatic effluent was isolated and adsorbed by the DHP for 30 mins. Plasma ADR levels in the radial artery reached a peak of 2.00 micrograms/ml at five mins after the initiation of drug infusion. Peak values at the inlet and outlet of the DHP were 19.71 micrograms/ml and 1.75 micrograms/ml, respectively, indicating substantial drug adsorption by the DHP. The estimated drug removal rate was 31.1%. This treatment led to a marked regression of tumors with tolerable systemic toxicities. Although the patient subsequently died 9 months after treatment of progression of disease, this treatment resulted in a remission of significant duration.
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Hepatic extraction rates (ER) of anticancer drugs during hepatic arterial infusion were investigated with the aid of direct hemoperfusion (DHP) under hepatic venous isolation (HVI). Using mongrel dogs (n = 6), adriamycin (ADR), mitomycin C (MMC) and cisplatin (CDDP) were simultaneously administered to the hepatic artery at each dosage of 1 mg/kg in 10 minutes under HVI.DHP. Hepatic venous flow and plasma concentrations of each drug at the carotid artery, the inlet and outlet sides of DHP were periodically determined during HVI.DHP. Based on these data, drug adsorption and removal rates were estimated. In addition, hepatic tissue uptakes of each drug were calculated from the amounts of drug administered and leaked in the hepatic effluent. Subsequently, the percentage of tissue uptake of each drug to the amount of drug administered was determined as ER of each drug. Drug adsorption rates during the first 10 minutes after infusion showed no significant difference among three drugs. Drug removal rate of CDDP tended to be higher than those of other two drugs. ER of CDDP (54.8 +/- 18.3%) were significantly lower (p < 0.01) as compared to ADR (84.4 +/- 16.2%) and MMC (83.1 +/- 15.7%). These results indicate that ER of each drug should be taken into consideration to determine appropriate drug for hepatic arterial chemotherapy.
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We tested the preservation of the pancreas for 96 h by a modified two-layer (UW solution/perfluorochemical) cold storage method (group 1) in the canine model of pancreas autotransplantation and compared this with an original two-layer (Euro-Collins' solution/perfluorochemical) cold storage method (group 2) and simple cold storage method with UW solution (group 3). A graft was considered functioning if the dog had a normal blood glucose for at least 5 days after transplantation. The functional success rates after preservation for 72 h were 100%, 100% and 80% for groups 1, 2 and 3 respectively. On the other hand, the functional success rates for groups 1, 2 and 3 after preservation for 96 h were 75%, 0% and 0% respectively. The mean K value of 96-hour preserved grafts for group 1 at 2 weeks after transplantation was 1.52 +/- 0.30 compared with 1.98 +/- 0.48 before preservation. Biopsies of grafts from group 1 showed almost normal pancreatic architecture even after preservation for 96 h. In addition, biopsies of grafts preserved for 96 h in group 1 at 4 weeks after transplantation showed almost normal endocrine tissue with mild fibrosis of the exocrine tissue. This study demonstrated the possibility of preserving the pancreas for 96 h prior to transplantation.
To clarify the mechanism of action of a two-layer [Euro-Collins' solution (EC)/perfluorochemical (PFC)] cold storage method in the preservation of the pancreas, pancreatic viability and tissue concentrations of adenosine triphosphate (ATP) were examined in the canine model of pancreatic autotransplantation after preservation for 24 and 48 h by simple cold storage in EC (group 1), the two-layer, EC/PFC, method (group 2) and the two-layer, EC+2, 4 dinitrophenol (DNP)/PFC, method (group 3). DNP is an uncoupler of oxidative phosphorylation. Maintenance of normoglycemia for at least 5 days after transplantation was considered a successful preservation. After preservation for 24 h, the functional success rates of groups 1, 2 and 3 were 100% (4/4), 100% (5/5) and 80% (4/5) respectively. One of five dogs in group 3 died of a cause unrelated to the pancreas. ATP tissue concentrations in group 2 were significantly higher than in group 1 (7.47 +/- 0.47 micromol/g dry weight vs 1.41 +/- 0.53 micromol/g dry weight, P < 0.01) and ATP tissue concentrations in group 3 were significantly lower than in group 2 (1.25 +/- 0.37 micromol/g dry weight vs 7.47 +/- 0.47 micromol/g dry weight, P < 0.01). It was apparent that ATP was not an essential factor for successful 24-hour preservation of the canine pancreas in EC because all the pancreatic grafts except one of five grafts in group 3 remained viable after preservation for 24 h, regardless of ATP tissue concentrations. On the other hand, after preservation for 48 h, the functional success rates for groups 1, 2 and 3 were 0% (0/4), 100% (4/4) and 0% (0/3) respectively. ATP tissue concentrations in group 2 were significantly higher than in group 1 (7.91 +/- 1.21 micromol/g dry weight vs 1.21 +/- 0.31 micromol/g dry weight, P < 0.01) and ATP tissue concentrations in group 3 were significantly lower than in group 2 (0.61 +/- 0.07 micromol/g dry weight vs 7.91 +/- 1.21 micromol/g dry weight, P < 0.01). It was clear that preservation of the pancreas for 48 h was unsuccessful by simple cold storage in EC (group 1) and the two-layer method (group 2) made preservation for 48 h possible by increasing ATP tissue concentrations. However, DNP (group 3) inhibited the synthesis of ATP and the effectiveness of the two-layer method for 48-hour preservation of the pancreas. It was clear that maintenance of high ATP tissue concentrations during preservation was essential for the successful preservation of the canine pancreas in EC by the two-layer method for more than 48 h. We concluded that an adequate supply of oxygen to the pancreas during preservation by the two-layer method led to sufficient production of ATP to maintain cellular integrity and permitted the improvement of pancreatic preservation.
Tissue concentrations of adenosine triphosphate have been previously associated with successful pancreas preservation using the two-layer cold storage method in a canine autotransplantation model. To clarify the role of ATP vs. oxygenation per se, we used 2,4 dinitrophenol, an uncoupler of mitochondrial oxidative phosphorylation. DNP caused no toxicity in pancreas grafts preserved for 24 hr in Euro-Collins' solution or 48 hr in University of Wisconsin solution. Tissue concentration of ATP and viability of pancreas grafts, defined as maintenance of normoglycemia for 5 days following transplantation, were compared among six groups after a preservation interval of 24 or 48 hr. After 24 hr all grafts were viable, whether preserved using simple cold storage in EC (group 1a), two-layer (EC/perfluorochemical [PFC]) method (group 2a), or two-layer (EC+DNP/PFC) method (group 3a); respective graft survival was 4/4 (100%), 5/5 (100%), and 4/5 (80%); one of five dogs in group 3a died of a cause unrelated to the pancreas. ATP levels were higher in group 2a compared with group 1a (7.47 +/- 0.47 vs. 1.41 +/- 0.53 mumol/g dry weight, P less than 0.01) and lower in group 3a compared with group 2a (1.25 +/- 0.37 vs. 7.47 +/- 0.47, P less than 0.01). After 24 hr, we observed no difference in viability despite ATP concentration differences. However after 48 hr preservation, graft viability varied among the groups: 0/4 (0%), 4/4 (100%), and 0/3 (0%) in groups 1b, 2b, and 3b, respectively. ATP tissue concentration was again higher in group 2b after two-layer (EC/PFC) method preservation (7.91 +/- 1.21 vs. 1.21 +/- 0.31 mumol/g dry weight, P less than 0.01) compared with EC preservation (group 1b). DNP again caused a significant decrease in tissue ATP in group 3b (0.61 +/- 0.07 vs. 7.91 +/- 1.21, P less than 0.01). The two-layer (EC/PFC) method clearly protected pancreas viability, and inhibition of ATP production using DNP caused loss of viability in this model. We conclude that oxygenation of the pancreas during preservation by the two-layer method allows continued ATP production within the graft. Metabolic processes vital to cellular integrity can be maintained, which produces an extended period of preserved pancreatic viability.
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A revised method of the upper caval anastomosis in canine orthotopic liver transplantation is described. It uses the recipient retrohepatic inferior vena cava below the suprahepatic veins for vascular suturing. Ten consecutive operations were performed to assess the feasibility of this method, with special reference to the outflow obstruction at the level of the suprahepatic inferior vena cava. Seven of 10 dogs survived more than 6 days. The cause of death was not related to the outflow obstruction in any instance. Regardless of the duration of survival, free hepatic vein pressures as well as portal vein pressures of all dogs remained in the physiological range even after the skin closures. Based on these observations, we conclude that this approach is safe and reproducible in experimental transplantation of the canine liver.