Nobuya Kusunoki

Inhibitory effects of a cyclosporin derivative, SDZ PSC 833, on transport of doxorubicin and vinblastine via human P-glycoprotein

The inhibitory effects of SDZ PSC 833 (PSC833), a non‐immunosuppressive cyclosporin derivative, on the P‐glycoprotein (P‐gp)‐mediated transport of doxorubicin and vinblastine were compared with those of cyclosporin A (Cs‐A). The transcellular transport of the anticancer drugs and PSC833 across a monolayer of LLC‐GA5‐COL150 cells, which overexpress human P‐gp, was measured. Both PSC833 and Cs‐A inhibited P‐gp‐mediated transport of doxorubicin and vinblastine in a concentration‐dependent manner and increased the intracellular accumulation of doxorubicin and vinblastine in LLC‐GA5‐COL150 cells. The values of the 50%‐inhibitory concentration (IC50) of PSC833 and Cs‐A for doxorubicin transport were 0.29 and 3.66 μM, respectively, and those for vinblastine transport were 1.06 and 5.10 μM, respectively. The IC50 of PSC833 for doxorubicin transport was about 4‐fold less than that for vinblastine transport, suggesting that the combination of PSC833 and doxorubicin might be effective. PSC833 itself was not transported by P‐gp and had higher lipophilicity than Cs‐A. These results indicated that the inhibitory effect of PSC833 on P‐gp‐mediated transport was 5‐ to 10‐fold more potent than that of Cs‐A, and this higher inhibitory effect of PSC833 may be related to the absence of PSC833 transport by P‐gp and to the higher lipophilicity of PSC833.

Stimulation of Haematogenous Liver Metastases by Ischaemia-Reperfusion in Rats

OBJECTIVE To find out whether hepatic ischaemia-reperfusion stimulates hepatic tumour metastases using a cell line of rat ascitic hepatoma (AH130). DESIGN Prospective experimental study. SETTING University laboratories, Japan. MATERIALS 118 male Donryu rats. INTERVENTION After laparotomy alone (group 1, n = 35) or laparotomy and 20-minutes ischaemia (group 2, n = 34) or laparotomy and 30-minutes ischaemia (group 3, n = 34) of the median and left hepatic lobes, the animals were given either an intraportal injection of 1 x 10(5) or an intravenous injection of 1 x 10(6) viable AH130 cells. MAIN OUTCOME MEASURES 10 days after inoculation of tumour cells the number of nodules on the surface of the right lobe and of the median plus left lobes were separately counted for each liver. RESULTS Irrespective of the route of tumour inoculation in group 1, there was no significant difference in the number of tumours/g liver between the right and the median plus left lobes. However, in groups 2 and 3, the number of tumours/g liver in the median plus left lobes was significantly higher than in the right lobe (p < 0.05). Furthermore, in the median plus left lobes, animals who had had 30 minutes of ischaemia had significantly more tumours than those in the other two groups (p < 0.01). CONCLUSION Hepatic ischaemia-reperfusion may increase the risk of development of haematogenous liver metastases, by stimulating tumour cell-endothelial cell interactions.

Induction of long-term remission in advanced hepatocellular carcinoma with percutaneous isolated liver chemoperfusion.

OBJECTIVE The aim of this study was to report the long-term results of percutaneous isolated liver chemoperfusion with hepatic venous isolation and charcoal hemoperfusion (HVI-CHP) in patients with multiple advanced hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA The results of conventional chemotherapy including regional and systemic chemotherapy in patients with HCC remain dismal, and long-term survivors after treatment are rare among patients with multiple advanced HCC. In an effort to improve this situation, we previously developed a novel system of percutaneous isolated liver chemoperfusion with HVI-CHP. METHODS Doxorubicin (60 to 150 mg/m2) was administered via the hepatic artery, under conditions of extracorporeal drug elimination by HVI-CHP in 28 consecutive patients with advanced HCC (39 total treatments). Hepatic venous isolation and charcoal hemoperfusion was accomplished mainly by the single catheter technique using a newly developed 4-lumen-balloon catheter, which was used to isolate and capture total hepatic venous outflow and, at the same time, to direct the filtered blood to the right atrium. RESULTS Complete remission was achieved in five patients, of which four received repeated treatments (two or three times). Although 1 of 5 patients with complete remission died of pulmonary metastases at 8 months, the other 4 remain healthy and free of disease at 20, 24, 27, and 42 months after the first treatment. Partial responses were observed in 12 patients. Duration of response in responders (complete and partial) with repeated treatments was significantly longer than that with a single treatment (p = 0.01). The overall survival rate by the Kaplan-Meier method was 39.7% at 5 years. The treatments were well-tolerated, and the primary side effects were mild to moderate chemical hepatitis and reversible myelosuppression. CONCLUSIONS The results suggest that percutaneous isolated liver chemoperfusion with HVI-CHP is an effective palliative treatment in the majority of patients and yields long-term complete remission in some patients with multiple advanced HCC.

Single catheter technique of hepatic venous isolation and extracorporeal charcoal hemoperfusion for malignant liver tumors.

BACKGROUND A single catheter technique of hepatic venous isolation and charcoal hemoperfusion (HVI-CHP) using a 4-lumen/2-balloon (4L-2B) catheter was developed to perform high-dose intra-arterial chemotherapy of the liver. Herein we report the technique, safety, and pharmacokinetics of this system in comparison with the original double-balloon technique. PATIENTS AND METHODS Sixteen patients with malignant liver tumors were treated by hepatic arterial infusion (HAI) with adriamycin at a dose of 100 mg/m2 under HVI-CHP. Seven patients underwent HVI-CHP by the double-balloon technique (group A), in which filtered hepatic effluent and the rest of the inferior vena caval blood were separately drawn and returned to the left axillary vein. The other nine patients were treated by the single catheter technique (group B). In group B, hepatic effluent was isolated by balloon inflations and directed to filters through fenestrations of one major lumen of a 4L-2B catheter. The filtered blood was returned straight to the right atrium through the other major lumen of the catheter. RESULTS All patients in group A had a smooth stepwise induction of HVI-CHP, whereas one of nine patients in group B developed severe hypotension requiring interruption of HVI. The hepatic venous flow rate in group B during HVI-CHP was significantly higher than that in group A (P < 0.05). Systemic adriamycin exposure, as assessed by the area under the time concentration curve in systemic serum, was significantly higher in group A compared to that in group B (P < 0.01). CONCLUSIONS The single catheter technique is hemodynamically tolerable and feasible in the majority of patients with malignant liver tumors. In view of systemic drug exposure, the single catheter technique is superior to the original double-balloon technique.

Percutaneous isolated liver chemoperfusion for treatment of unresectable malignant liver tumors: technique, pharmacokinetics, clinical results.

We have developed a single-catheter technique for percutaneous isolated liver chemoperfusion (PILP) with hepatic venous isolation and charcoal hemoperfusion (HVI-CHP) for the treatment of malignant liver tumors. We report here the surgical technique, pharmacokinetics, and effectiveness of PILP in multiple advanced liver tumors. Twenty-eight patients with hepatocellular carcinoma (HCC) and 18 with metastatic liver tumors underwent a total of 61 PILPs with HVI-CHP. HVI-CHP was accomplished mainly by the single-catheter technique using a novel four-lumen, two-balloon catheter; it was used to isolate and capture total hepatic venous outflow and, at the same time, to direct the filtered blood to the right atrium. Under HVI-CHP, either doxorubicin 960-150 mg/m2) or cisplatin (150-200 mg/m2) was infused via the hepatic artery. The PILP was completed successfully in all 61 trials. Two of forty-six patients died early; one of necrotizing pancreatitis and the other of hepatic arterial thrombosis. Both deaths were related directly to the hepatic arterial catheter. Excluding these two deaths, the treatments were well tolerated. The major side effects were mild to moderate chemical hepatitis and reversible myelosuppression. Of the 27 evaluable HCC patients, 17 (63%) had an objective tumor response (5 complete and 12 partial responses). In 15 patients with colorectal hepatic metastases (CHM), 7 had a sharp decrease in serum carcinoembryonic antigen (CEA) levels (to < 50% of their pretreatment levels) after treatment. However, a single PILP had limited efficacy in terms of the durability of remission (< or = 6 months in most CHM patients, as assessed by CEA levels). These results indicate that PILP with HVI-CHP has high efficacy in most patients with multiple advanced liver tumors. In addition, the results suggest a role of multiple treatment courses of PILP in the induction of long-term remission, especially for patients responsive to the first treatment.

Relative adrenal insufficiency manifested with multiple organ dysfunction in a liver transplant patient

Relative adrenal insufficiency is now a well‐known clinical condition that occurs in critically ill patients particularly with septic complication. However, this pathology has long been unrecognized until recently in liver transplantation patients, for whom postoperative immunosuppressive therapies almost always comprise corticosteroids. We report an obvious case of relative adrenal insufficiency manifested by severe multiple organ dysfunction in a recipient after living donor liver transplantation (LDLT). A 38‐year‐old woman with multiple hepatocellular carcinoma developed refractory liver failure 2 months after the completion of the dual treatment; namely a cytoreductive right hepatectomy for bulky main tumors followed by 2 courses of percutaneous isolated hepatic perfusion for residual tumors in the remnant liver. She underwent a right‐lobe LDLT, and postoperative immunosuppression was initiated with a low‐dose tacrolimus monotherapy without corticosteroid because of a severe septic condition before transplantation. Postoperatively, she developed progressive hyperbilirubinemia, renal dysfunction, and coagulopathy. As the corticotropin stimulation test suggested the relative adrenal insufficiency, corticosteroid was commenced 40 days after LDLT. Thereafter, multiple organ dysfunction resolved dramatically and promptly. The patient is presently alive and well with completely normalized liver function 45 months after LDLT. Liver Transp 12:1896–1899, 2006.

Successful rescue of severe recurrent hepatitis C with interferon and ribavirin in a liver transplant patient

BACKGROUND Rapid graft dysfunction caused by hepatitis C virus (HCV) reinfection, although uncommon, is a disastrous complication in liver transplant patients. Finding an effective therapy for this subgroup of patients with severe recurrent HCV is a priority. METHOD We describe a successful rescue of a 46-year-old man with recurrent hepatitis C (HCV genotype 1b) using long-term interferon (IFN) and ribavirin. The patient had a very aggressive type of posttransplantation HCV infection, as judged by biochemical and histologic findings. RESULTS Despite high pretreatment values of serum alanine aminotransferase (ALT; peak value of 901 IU/L) and HCV-RNA (2.3 x 10(6) copies/ml), the combination therapy with IFN and ribavirin produced a rapid normalization of the serum ALT values, accompanied by the clearance of serum HCV-RNA. Although HCV-RNA reappeared in the serum at 3 months, the patient had continued ALT normalization and histological improvement with follow-up of over 26 months to date after the initiation of the combination therapy. CONCLUSION This observation suggests that IFN in combination with ribavirin may offer an effective therapeutic option for liver transplant patients with severe recurrent hepatitis C.

Effect of Sodium Thiosulfate on Cisplatin Removal With Complete Hepatic Venous Isolation and Extracorporeal Charcoal Hemoperfusion: A Pharmacokinetic Evaluation

AbstractBackground: Complete hepatic venous isolation and extracorporeal charcoal hemoperfusion (HVI·CHP) can limit systemic exposure to high-dose chemotherapeutic agents when given by hepatic arterial infusion (HAI). The purpose of this study was to determine if the concomitant use of sodium thiosulfate (STS) could further expand the advantages of pharmacologic delivery of HVI·CHP for cisplatin (CDDP) during HAI chemotherapy. Methods: CDDP (4mg/kg) was administered over 20 minutes via HAI under conditions of HVI·CHP in 14 mongrel dogs. HVI·CHP was performed for 30 minutes after initiation of HAI. During CDDP infusion, 7 dogs each received 400 mg/kg STS (a 100-fold molar ratio to CDDP) over 20 minutes via the prefilter (STS group) circuit line, while the remaining 7 dogs (controls) received no STS. Blood samples were taken serially from the prefilter circuit line (hepatic venous blood), postfilter line, and the left carotid artery (systemic blood). The free and total CDDP concentrations in these samples were determined by flameless atomic absorption spectrophotometry. Results:During 20 minutes HAI of CDDP, the mean CDDP extraction ratios (ER) by CHP filter were always higher in the STS group than in the control group, regardless of the form (free or total) of CDDP. The differences between the STS and control groups in the extraction ratios of free and total CDDP were significant at all time points measured (P < .05). Consequently, systemic exposure to CDDP, as assessed by area under the time-concentration curve of total CDDP, was significantly lower in the STS group than in the control group (P < .05). Conclusions: These results indicated that concomitant STS infusion could further increase the effect of HVI·CHP on CDDP removal after HAI.

Pharmacokinetics of intravenous adriamycin for anhepatic chemotherapy during liver transplantation

Abstract  Frequent recurrence of hepatocellular carcinoma after liver transplantation indicates the necessity to eliminate patients with advanced disease and combine transplantation with some form of peri‐operative adjuvant chemotherapy. This study was undertaken to elucidate adriamycin pharmacokinetics for anhepatic chemotherapy during liver transplantation. Beagles of both sexes were allocated into two groups, controls (n= 4) and anhepatic animals with total hepatectomy under venovenous bypass (n= 5). In both groups, adriamycin was administered in 1 min at a dose of 1 mg/kg through the left antecubital vein and peripheral blood was obtained at intervals for up to 2 h to determine the plasma adriamycin levels. The animals were then sacrificed to determine tissue adriamycin levels in the liver, kidney, heart, lung, and skeletal muscle. Plasma adriamycin levels in anhepatic animals were significantly higher than those in controls at all measured time points after 10 min, resulting in a 50 % reduction of the mean total body clearance of adriamycin compared with controls (P < 0.01). However, there was no statistically significant difference in adriamycin levels between the two groups for all measured tissues except for the liver. Despite the complete lack of hepatic function, anhepatic animals showed only a 50 % reduction in total body clearance of adriamycin compared with normal controls, probably due to compensatory excretion from other organs such as the kidney. These results suggest that systemic chemotherapy with the standard dose of adriamycin may be tolerable during the anhepatic period of liver transplantation with enhanced tumoricidal effects on micrometastases.

Pharmacokinetics of Adriamycin and cisplatin for anhepatic chemotherapy during liver transplantation

Abstract We investigated the pharmacokinetics of cytotoxic anticancer agents administered under anhepatic conditions. Beagle dogs underwent either a sham operation consisting of laparotomy only (control group, n = 11) or a laparotomy and total hepatectomy under venovenous bypass (anhepatic group, n = 12). Each dog received a bolus intravenous injection of either Adriamycin (1 mg/kg) or cisplatin (1 mg/kg). The plasma and urine concentrations of each drug were measured at intervals for up to 2 h after drug injection. The dogs given Adriamycin were then sacrificed to determine tissue drug concentrations in the liver (controls only), spleen, kidney, heart, lung, skeletal muscle and small intestine. The control and anhepatic groups showed similar Adriamycin profiles during the initial 5 min after drug injection. However, subsequently, the plasma Adriamycin concentrations remained persistently higher in the anhepatic dogs than in the controls, yielding a two-fold elevation of the mean area under the concentration-time curve in the anhepatic group (P<0.01 vs controls). The renal clearance values did not significantly differ between the two groups. The tissue Adriamycin concentrations in all measured organs, excluding the liver, were higher in the anhepatic group than in the controls. In a second set of experiments with cisplatin, the plasma platinum concentrations did not significantly differ between the two groups throughout the time course. However, the renal clearance of platinum in the anhepatic dogs showed a fourfold increase compared with that in the controls (P<0.01). These pharmacokinetic data suggest that Adriamycin carries the risk of increased systemic toxicities, while cisplatin may be associated with increased renal toxicity when administered during the anhepatic period of liver transplantation.