Bolusvs. continuous hepatic arterial infusion of cisplatin plus intravenous 5-fluorouracil chemotherapy for unresectable colorectal metastases

A multicenter, randomized Phase 2 study that compared patients, affected by colorectal liver metastases, who received intrahepatic arterial infusion with two different schedules of cisplatin, bolusvs. continuous infusion, and systemic 5-fluorouracil. PURPOSE: The aim of this study was to validate results of a previous Phase 2 trial on bolus cisplatin intrahepatic arterial infusion, which reported a 47 percent response rate and a 32 percent 4-year survival rate for Gennari's Stage 2 patients, with a high rate of neurologic, gastrointestinal, and hematologic toxicity. METHODS: One hundred nine patients were randomized in a Phase 2 study to receive cisplatin intrahepatic arterial infusion (24 mg/m²/day, 15, bolusvs. continuous infusion) and systemic intravenous 5-fluorouracil (250, 375, or 500 mg/m²/day, 15; escalating doses, respectively, at cycles I, II, III, and VI). To avoid neurotoxicity a maximum of six cycles was administered. RESULTS: Preliminary results for the 78 evaluable patients are similar to those of the previous study: response rate 46 percent and at a median follow-up of 16.5 months, the overall survival was 16.5 months, with 45 percent of the patients who received more than 3 cycles alive at 3 years. Toxicity, evaluable in 99 patients, showed a decreased incidence of neurotoxicity and a tolerable gastrointestinal and hematologic toxicity, lower in the cisplatin continuous infusion arm. CONCLUSION: This study clearly shows that cisplatin intrahepatic arterial infusion is able to provide a good palliative effect with a tolerable toxicity.This study was supported in part by Pharmacia-Deltec, Italy.     

Improved long-term survival for unresectable hepatocellular carcinoma (HCC) with a combination of surgery and intrahepatic arterial infusion of 131I-anti-HCC mAb. Phase I/II clinical trials

Resectional therapy has been accepted as the only curative therapy for hepatocellular carcinoma (HCC). Unfortunately, it is estimated that only 10% of HCC are resectable at the time of diagnosis. Cytoreduction and sequential resection offer a new hope for patients with unresectable HCC. Radioimmunotherapy (RIT) is an attractive approach for cytoreduction. We have previously shown that intrahepatic arterial ¹³¹I-labelled anti-HCC monoclonal antibody (¹³¹I-Hepama-1 mAb) could be used safely in combination with hepatic artery ligation for treatment of unresectable HCC, and encouraging results have been achieved. In this paper, the long-term survival and the prognostic factors in HCC patients treated with radioimmunotherapy will be analysed. Sixty-five patients with surgically verified unresectable HCC were treated with hepatic artery ligation plus hepatic artery cannulation and infusion from 1990 to 1992. Thirty-two patients were enrolled in a phase I–II clinical trial with infusion of ¹³¹I-radiolabelled anti-HCC monoclonal antibody (Hepama-1 mAb) via the hepatic artery (the RIT group). Another 33 patients formed the group treated with intrahepatic-arterial chemotherapy (the non-RIT group). T cell subsets were measured in 24 patients and human anti-(murine Ig) antibody (HAMA) were monitored in the RIT group. The 5-year survival rate was significantly higher in the RIT group than in the chemotherapy group, being 28.1% compared to 9.1% (P < 0.05); this was mainly a result of better cytoreduction and a higher sequential resection rate (53.1% compared to 9.1%). Significant prognostic factors in the RIT group included tumour capsule status and the number of tumour nodules. HAMA incidence and CD₄ ⁺ T lymphocytes influenced short-term, but not long-term survival. It is suggested that intrahepatic-arterial RIT, using ¹³¹I-Hepama-1 mAb, combined with hepatic artery ligation might be an effective approach to improve long-term survival in some patients with unresectable HCC, which may successfully be made resectable by intra-arterial infusion of ¹³¹I-Hepama-1 mAb. Received: 21 April 1997 / Accepted: 14 January 1998     

Liver and muscle insulin sensitivity,glycogen concentration and glycogen synthase activity in a rat model of non-insulin-dependent diabetes

Summary Mild diabetes was induced in adult rats with streptozotocin (45 mg/kg body weight), and insulin sensitivity, glycogen deposition and glycogen synthase activity assessed in liver and muscle 5 weeks later. Diabetic rats had significantly elevated fasting blood glucose concentrations (5.6±0.1 versus 3.6±0.1 mmol/l, p<0.001), and blood glucose concentrations 2 h after a 1 g/kg glucose load (12.0±0.6 versus 3.7±0.2 mmol/l, p<0.001). After a 20-h fast hepatic glucose output was significantly elevated (58±3 versus 47±3 mol·min^–1·kg^–1, p<0.05), and failed to suppress at high insulin concentrations during a euglycaemic clamp (hepatic glucose output 21±4 versus 2±4 mol·min^–1·kg^–1, p<0.02). Liver glycogen was lower in the diabetic rats by the end of the clamp (16±3 versus 38±6 mol/g wet wt, p<0.05). At the end of the clamp total glucose turnover was lower in the diabetic rats (107±4 versus 161±17 mol·min^–1· kg^–1, p<0.01), as was skeletal muscle glycogen synthase activity (0.46±0.04 versus 0.67±0.05 U/g wet wt, p<0.01) and glycogen concentration (22±2 versus 33±3 mol/g wet wt, p<0.05). Blood lactate and pyruvate responses suggested that glycolytic pathways were similarly affected. Thus, insulin insensitivity develops in both liver and skeletal muscle after 5 weeks of mild streptozotocin-induced diabetes.     

Radioimmunotherapy for unresectable hepatocellular carcinoma using131I-Hepama-1 mAb: preliminary results

Twenty-three patients with surgically verified unresectable hepatocellular carcinoma (HCC) have been treated by intrahepatic arterial administration of¹³¹I-labeled anti-HCC monoclonal antibody (Hepama-1) combined with hepatic artery ligation. Radioimmunoimaging demonstrated that the median tumor/liver ratio was 2.1 (1.1–3.6) at day 5. A decline in -fetoprotein level and shrinkage of tumor were observed in 75% (12/16) and 78% (18/23) of patients respectively. Sequential resection was done in 11 patients (48%) after treatment. The surgical specimens revealed massive necrosis of tumor, but residual cancer cells were found at the edge of the specimens. Anti-antibody was determined in 43% (10/23) of patients 2–4 weeks after the administration of¹³¹I-Hepama-1 mAb. No marked toxic effects were noted. It is suggested that¹³¹I-Hepama-1 mAb might be of value as one of the multimodality treatments for unresectable HCC.     

Serum ferritin and binding of serum ferritin to concanavalin A as a tumor marker in patients with primary liver cell cancer and chronic liver disease

Total ferritin concentration was measured in sera of 30 patients with primary liver cell cancer (PLCC) and 33 patients with cirrhosis and compared with serum alpha-fetoprotein levels as a diagnostic marker of PLCC. Serum ferritin concentration was raised in 19 patients (63%) with PLCC and 11 patients (33%) with cirrhosis. The median level was significantly higher (P<0.001) in the PLCC group (560 g/liter) than in the cirrhotic group (137 g/liter), although there was considerable overlap. Serum ferritin was posititively correlated with serum aminotransferase levels in the cirrhotic patients (r=0.53,P<0.001), reflecting hepatic necrosis, but not in the PLCC patients. The concentration of ferritin binding to concanavalin A was measured in the sera of patients with elevated total serum ferritin. Although the proportion of bound ferritin was decreased in the majority of PLCC sera compared to controls (P<0.001), there was overlap with the cirrhotic group, making it unlikely that this assay is useful in distinguishing a tumor-specific isoferritin. Serum alpha-fetoprotein levels were elevated in 21 patients (70%) with PLCC and proved to be a highly sensitive and specific test for PLCC. There was no relationship between the alpha-fetoprotein and serum ferritin concentrations. Serum ferritin is inferior to alpha-fetoprotein as an initial screening test for PLCC, but in alpha-fetoprotein-negative patients serum ferritin may have a role in monitoring therapy. Patients with cirrhosis with normal serum alpha-fetoprotein and ferritin concentrations are very unlikely to have PLCC.     

Effect of phenformin on hepatic balances of gluconeogenic substrates in man

Summary The effect of a five day pretreatment with phenformin (3 x 50 mg daily) on hepatic metabolism was studied in six healthy volunteers. Arterial and hepatic venous concentrations of substrates and hepatic blood flow were estimated during a basal period and during a low-dose lactate infusion (0,03 mmol · kg^–1· min^–1). The results have been compared with those obtained from untreated normal subjects in a previous study (16). During the baseline period arterial concentration of alanine and the hepatic venous concentration ratios of alanine: pyruvate and-hydroxybutyrate: acetoacetate were significantly increased with phenformin treatment, while the balances of carbon dioxide and glucose and the fractional extraction of alanine were decreased compared to the values obtained in untreated subjects. During lactate infusion mean arterial lactate concentration was significantly increased and hepatic lactate extraction was decreased compared to untreated persons under the same conditions. In the phenformin-treated group lactate infusion resulted in hepatic output of pyruvate and the hepatic glucose balance remained unchanged compared to baseline. Since the rate of hepatic blood flow was not increased during lactate infusion a significantly smaller glucose output and lactate uptake was obtained with phenformin. These findings support the present view that the hypoglycaemic effect of biguanides is due, at least in part, to inhibition of hepatic gluconeogenesis.     

Antibody-targeted lymphokine-activated killer cells inhibit liver micrometastases in severe combined immunodeficient mice

Animal models for hepatic metastases can facilitate the investigation of lymphokine-activated killer (LAK) cell-based immunotherapy. The aim of this study was to investigate the efficacy of ccM4 antibody-targeted LAK cells in inhibiting hepatic micrometastases. Hepatic micrometastases were generated after the intrasplenic injection of HM7 colon carcinoma cells. TAG72 expression was detected in these hepatic micrometastases using ccM4 antibody. The ccM4 antibody was conjugated onto LAK cells by treatment with 17.5% polyethylene glycol 8000. After the intrasplenic injection of HM7 cells, severe combined immunodeficient mice were randomized into five groups (i–v) and received either 10⁷ ccM4-LAK cells plus 1000 U interleukin 2 (IL-2; group i), LAK cells plus 50 μg ccM4 and IL-2 (group ii), LAK cells plus IL-2 (group iii), IL-2 alone (group iv), or only phosphate-buffered saline (group v). The ccM4-LAK cells retained cytolytic activity and acquired TAG72-binding reactivity. The results showed that group i had significantly fewer hepatic metastases compared with group ii or group iii (P < 0.05) and even fewer hepatic metastases compared with group iv or group v (P < 0.001). These results show that ccM4 antibody-targeted LAK cells significantly inhibited tumor growth in vivo; thus, they can be potentially useful in treatment of hepatic micrometastases.     

Preventive Effect of FK 506 (Tacrolimus Hydrate) on Experimentally Induced Acute Liver Injury in Rats

The aim of the study was to investigate the effect of the immunosuppressant FK 506 (tacrolimus hydrate) on acute liver injury induced by Propionibacterium acnes and lipopolysaccharide (LPS). Acute liver injury was induced in male Wistar rats by injecting the animals with P. acnes (10 mg/rat), and administering LPS (10 g/rat) seven days later. One group was given FK 506 (1 mg/kg) 24 and 2 hr before administration of LPS, and the other group was given the same dose of saline. The 24-hr survival rate, serum alanine aminotransferase (ALT) concentration, and tumor necrosis factor (TNF) - mRNA and protein concentrations in the liver and spleen were then compared. Hepatic macrophages were also isolated from rats seven days after P. acnes injection, LPS, and FK 506 or saline were added to the culture supernatant, and TNF- production was studied. The 24-hr survival rate was 100% in the FK 506-treated group, in contrast with 16.6% in the saline group. Four hours after LPS injection, the serum ALT concentration was 755 ± 401 in the saline group versus 119 ± 42 units/ml (P < 0.01) in the FK 506-treated group. The serum TNF- concentration was lower in the FK 506-treated group (1419 ± 957 pg/ml) than in the saline group (9205 ± 2215) (P < 0.01). The mRNA and protein concentrations in the liver and spleen in the two groups did not differ significantly 1 hr after LPS injection but were significantly lower in the FK 506-treated group after 4 hr. FK 506 did not directly inhibit TNF- production by isolated cultured hepatic macrophages. FK 506 is unable to inhibit initial TNF- production by hepatic macrophages (or probably that by splenic macrophages either) stimulated by injection of LPS in P. acnes + LPS-induced acute liver injury. However, the immunosuppressant does limit hepatic damage by inhibiting subsequent aggravation of inflammation by the cytokine network.     

Comparative pharmacokinetics of sisomicin after intravenous injection, intravenous infusion and intramuscular injection in man

The parmacokinetics of sisomicin were determined in ten subjects after intravenous injection, intravenous infusion over a 35 to 45 minute period and after intramuscular injection of a single dose of 1 mg/kg respectively. The plasma elimination curve of sisomicin after i.v. administration revealed a bi-exponential decrease. The -phase T/2 averaged approximately ten minutes after intravenous injection of sisomicin. The postdistributive plasma elimination halflives were 129 min after i. v. injection, 145 min after i. v. infusion and 161 min after i. m. injection. The apparent distribution volume after i. v. injection averaged 147 ml/kg. Urinary recovery rates were 57–80% after four hours and 75–100% after 24 hours.     

Graft loss and the antiphospholipid syndrome following liver transplantation

Background/Aims: The antiphospholipid syndrome is characterised by arterial and venous thromboses affecting small and large vessels, together with the presence of lupus anticoagulant and anticardiolipin antibodies.Methods: We report two cases of the antiphospholipid syndrome following liver transplantation which resulted in hepatic vessel thrombosis and subsequent graft loss, and we discuss the value of anticoagulation in prevention of further thrombotic episodes. Identification of these cases prompted a retrospective analysis for the presence of IgG anticardiolipin antibody, the most useful laboratory marker of vascular thrombosis in the antiphospholipid syndrome. Serum taken at 2 to 4 weeks following transplantation (when thrombotic events might be anticipated) was analysed further in 132 patients undergoing liver transplantation.Results: Hepatic vessel thrombosis occurred in (16%) post transplantation. Anticardiolipin IgG was present in (8.8%) recipients who developed a hepatic vessel thrombosis following liver transplantation, compared to (6.3%) (p=0.59) in whom transplantation was not complicated by hepatic vessel thrombosis.Conclusions: The presence of IgG anticardiolipin antibody was uncommon in recipients following liver transplantation and was not associated with an increased risk of hepatic vessel thrombosis. In contrast, the antiphospholipid syndrome which is rare may result in hepatic artery occlusion and graft loss, and so prompt recognition of the clinical syndrome is critical. Although screening for the antibody is not warranted in liver transplant recipients, it is important to be aware of the syndrome as optimal management of such cases may prevent graft loss.     

A randomised trial to compare the results of injection sclerotherapy with a bulk laxative alone in the treatment of bleeding haemorrhoids

In a prospective randomised trial, 43 patients with bleeding haemorrhoids were allocated to receive either a bulk laxative with injection of phenol (5%) in arachis oil (20 patients) (Group 1), or a bulk laxative alone (23 patients) (Group 2). Treatment was given by one author and patients were assessed blind by the other at 6 weeks, 3 months and finally at 6 months. At 6 weeks 12 (48%) in Group 1 and 12 (57%) in Group 2 were still bleeding (NS; ²= 0.54). At 3 months 10 (40%) in group 1 and 6 (35%) in group 2 (NS; ²=0.10), and at 6 months 10 (43%) in group 1 and 7 (47%) in group 2 were still bleeding (NS; ²=0.04). No significant difference in bleeding at 6 months after either injection sclerotherapy with bulk laxative or bulk laxatives alone was found.     

Arterial,portal or combined arterio-portal regional chemotherapy in experimental liver tumours?

Summary The most appropriate route for regional administration of chemotherapeutic drugs to liver tumours was studied in a standardized rodent model: cells of Novikoff hepatoma were transplanted into the central liver lobe of Sprague-Dawley rats. From day 5 to day 12 after transplantation, the liver was continuously perfused with 420 mg/kg 5-fluoro-2-deoxyuridine by subcutaneous osmotic micropumps via the hepatic artery (n=20), the portal vein (n=20) or both vessels together (n=12). The tumour multiplication factor (TMF) and the vascularization of the tumour were evaluated. Arterial and combined infusion led to a highly significant reduction in TMF, but combined infusion was not more effective than arterial alone. Portal infusion had no significant effect. There was no correlation between vascularization and tumour response in arterial infusion, but a strong correlation in portal infusion. Thus chemotherapy via the portal route may be effective in selected tumours with considerable portal vascularisation.     

Combination treatment of CC531-lac-Z rat liver metastases by chemoembolization with pemetrexed disodium and gemcitabine

Purpose: The aim of this study was to evaluate the combination effect of pemetrexed disodium (MTA; Alimta; LY 231514) and gemcitabine (GEM) administered by hepatic artery and portal vein chemoembolization (HACE and PVCE) in a colorectal cancer rat liver metastasis model.Materials and methods: Proliferation studies on CC531-lac-Z rat colon cancer cells were performed using the MTT assay to obtain the optimal combination schedule of the two antineoplastic agents. To generate diffuse liver metastasis, 4×10⁶ tumor cells were implanted into the portal vein of male WAG/Rij rats. MTA (30 mg/kg, 60 mg/kg, and 90 mg/kg) was administered locoregionally by portal vein chemoembolization (PVCE) and compared with repeated systemic intravenous injection. GEM (50 mg/kg) was also given locoregionally by hepatic artery chemoembolization (HACE) as well as systemically. All routes of administration were examined alone as well as in combination. Efficacy of treatment in terms of liver metastases burden was determined at the end of the experiment by measuring the -galactosidase activity of CC531-lac-Z cells with a chemoluminescence assay.Results: Combination experiments in vitro showed a more than additive tumor cell reduction after sequential exposure to MTA preceding GEM (observed/expected ratio [O/E] =0.73). Experiments with the reverse sequence (GEMMTA) resulted only in additive combination effects (O/E ratio =1.08). Simultaneous drug exposure showed less than additive combination effects (O/E ratios 1.25). In vivo, locoregional administration by HACE with GEM was significantly more effective than systemic intravenous bolus treatment (P=0.03). Portal vein chemoembolization with MTA performed immediately after tumor cell inoculation was ineffective. Repeated systemic treatment with MTA yielded a slight reduction in tumor cell load that was significant versus control at the medium and high doses (60 mg/kg, P=0.009; 90 mg/kg, P=0.046) but not versus intraportal chemoembolization. The combination treatment of systemic (60 and 90 mg/kg) or locoregional (60 mg/kg) MTA with HACE using GEM (50 mg/kg) resulted in more than 80% tumor growth inhibition; this antineoplastic combination effect was maximally additive.Conclusion: A regimen-dependent synergistic combination effect of both drugs was found in vitro. In animals, hepatic artery chemoembolization with GEM was superior to systemic intravenous bolus treatment. Portal vein chemoembolization with MTA was ineffective. The optimal in vitro regimen of MTA (intravenous or PVCE) preceding GEM (HACE) resulted in a maximally additive tumor growth inhibition. The results indicate that MTA and GEM can successfully be combined and favor further evaluation in patients.     

Effect of physiological elevation of plasma growth hormone levels on ketone body kinetics and lipolysis in normal and acutely insulin-deficient man

Summary The effect of physiological elevation of growth hormone levels on ketone body kinetics was determined using a ¹⁴C-ketone body tracer technique in normal and acutely insulin-deficient man. Changes of ketone body production and metabolic clearance rates during growth hormone infusion (plasma levels of approximately 25 g/l) were measured during basal conditions and during heparin-induced elevation of non-esterified fatty acid levels. Growth hormone administration to six subjects fasted overnight resulted in an increase in ketone body production which exceeded that observed in nine control subjects (5.5±0.5 versus 3.1±0.1mol·kg^-1·min^-1, p<0.025) after elevation of plasma non-esterified fatty acids. Growth hormone infusion increased glycerol and non-esterified fatty acid concentrations indicating enhanced lipolysis. During somatostatin-induced acute insulin deficiency (n=7), growth hormone enhanced the increase in total ketone body production observed in six subjects receiving somatostatin alone (8.4±0.8 versus 4.1±0.7mol·kg^-1·min^-1, p<0.01). Total ketone body metabolic clearance decreased by 50% during somatostatin and remained uninfluenced by growth hormone. Non-esterified fatty acids and glycerol levels increased during somatostatin, and growth hormone failed to alter nonesterified fatty acid levels significantly. The results demonstrate a stimulatory effect of high physiological growth hormone levels on ketogenesis which is largely explained by an enhancement of lipolysis and thus increase in substrate supply for ketogenesis. Growth hormone administration during acute insulin deficiency enhanced ketogenesis in the absence of alterations in plasma non-esterified fatty acid levels, suggesting a direct hepatic ketogenic effect.     

Modulation of hepatic glucose production by non-esterified fatty acids in Type 2 (non-insulin-dependent) diabetes mellitus

Summary To study the effect of changes in plasma non-esterified fatty acid concentration on suppression of hepatic glucose production by insulin eight Type 2 (non-insulin-dependent) diabetic patients participated in three euglycaemic, hyperinsulinaemic (108pmol · m^2–1 · min^–1) clamp studies combined with indirect calorimetry and infusion of [3-³H]-glucose and [1-¹⁴C]palmitate; (1) a control experiment with infusion of NaCl 154 mmol/l, (2) heparin was infused together with insulin, and (3) an antilipolytic agent, Acipimox, was administered at the beginning of the experiment. Six healthy volunteers participated in the control experiment. Plasma non-esterified fatty acid concentrations during the insulin clamp were in diabetic patients: (1) 151±36 mol/1, (2) 949±178 mol/l, and (3) 65±9 mol/l; in healthy control subjects 93±13 mol/l. Non-esterified fatty acid transport rate, oxidation and non-oxidative metabolism were significantly higher during the heparin than during the Acipimox experiment (p<0.001). Suppression of hepatic glucose production by insulin was impaired in the diabetic compared to control subjects (255±42 vs 51±29 mol/min, p<0.01). Infusion of heparin did not affect the suppression of hepatic glucose production by insulin (231±49 mol/min), whereas Acipimox significantly enhanced the suppression (21±53 mol/min, p<0.001 vs 154 mmol/l NaCl experiment). We conclude that insulin-mediated suppression of hepatic glucose production is not affected by increased non-esterified fatty acid availability. In contrast, decreased non-esterified fatty acid availability enhances the suppression of hepatic glucose production by insulin.     

Abnormal vitamin D metabolism in patients with cirrhosis

To assess the role of hepatic function and alcohol on vitamin D metabolism, serum 25-hydroxyvitamin D (25-OHD) levels were measured in 20 healthy nonalcoholic control subjects, 31 inactive cirrhotics whose alcoholism was in remission, 8 alcoholic cirrhotics, and 15 alcoholics with normal liver function. Cirrhosis, but not alcoholism, was associated with low serum 25-OHD levels. The aminopyrine breath test (ABT) was performed because aminopyrine, like vitamin D₃, is metabolized by hepatic microsomes; the ABT correlated highly (r-0.74,P<0.01) with serum 25-OHD in the inactive cirrhotics. After an intravenous injection of 120 g vitamin D₃, serum 25-OHD rose significantly within 24 hr in 6 healthy controls and 2 patients with celiac disease but not in 6 inactive cirrhotics. The data suggest impaired 25-hydroxylation of vitamin-D impaired in patients with cirrhosis, related predominantly to the degree of hepatic dysfunction.This work was supported in part by Grant AM 17303 from the National Institutes of Health.     

Relationship between vascular adrenergic receptors and prostaglandin biosyntheses in canine diabetic coronary arteries

Summary Before the onset of histologically detectable alterations of diabetic arteries, a considerable decrease of vasodilation ability develops. The role of an altered prostaglandin biosynthesis in this phenomenon was investigated in connection to the altered vascular adrenergic mechanisms. The effect of phenylephrine on prostacyclin production of isolated coronary arterial rings (100 mol/l) as well as on conductivity of the coronary arterial bed (7.5-15-30-60 pmol·kg^–1·min^–1) were compared in 12 metabolically healthy and 12 alloxan-diabetic (560 mol/kg) dogs. Furthermore, the effect of phentolamine (5 mol/l) on the prostacyclin and thromboxane productions of the isolated vessels (coronary, femoral and basilar arteries) was investigated by radioimmunoassay. Although the basal prostacyclin amounts synthesized by healthy and diabetic coronary vessels were not different (5.1±1.6 and 4.9±1.4pg/mg vessel/30 min), similarly to femoral and basilar arteries, the diabetic arterial rings produced significantly (p<0.05) more thromboxane than the control rings. The -adrenergic blockade by phentolamine did not influence the prostacyclin production in the healthy arteries, but considerably (p<0.05) increased it in the diabetic coronary arteries. Phentolamine normalised the thromboxane synthesis in the diabetic group (p<0.01) and enhanced (p<0.05) it in the metabolically healthy group. Phenylephrine was ineffective (98±6%) on the prostacyclin production in vitro versus the stimulated (150±22%) prostacyclin synthesis detected in the metabolically healthy group; and in vivo induced a more significant (p<0.05) decrease in the coronary conductivity in diabetic than in control groups. These results refer to the supposition that altered adrenergic mechanisms are involved in the imbalamce of the vasoactive prostaglandins contributing to the high incidence of ischaemic heart disease in diabetes mellitus.     

Influence of somatostatin and octreotide on liver microcirculation in an experimental mouse model of cirrhosis studied by intravital fluorescence microscopy

Background and Aims: Chronic liver damage causes hepatic stellate cell (HSC) activation and contraction, leading to intrahepatic microvascular and structural changes. In vitro endothelin‐1 (ET‐1)‐induced contraction of HSCs can be reduced by somatostatin (SST); however, intrahepatic in vivo effects have never been studied. Methods: Sinusoidal diameter was measured by intravital fluorescence microscopy in carbon tetrachloride (CCl₄) and control mice before and after an intravenous (IV) bolus and after 0, 5, 10 and 15 min of an IV infusion of saline, 8 μg/kg/h SST or 8 μg/kg/h octreotide. Results: The baseline sinusoidal diameter in CCl₄ mice (3.01±0.05 μm) was significantly smaller than that in controls (4.37±0.06 μm). The sinusoidal diameter increased significantly in both groups after a bolus (27, 16% respectively) and following 5 min of SST IV infusion (28, 14% respectively). The percentage increase was significantly higher in CCl₄ mice as compared with controls. This dilatory effect continued for at least 15 min. SST did not influence the mean arterial blood pressure (MAP) and portal venous inflow. In none of the groups did octreotide or saline have any influence on sinusoidal diameters, MAP and portal venous inflow. Conclusions: Sinusoidal diameter in cirrhotic mice is significantly smaller than that in controls. SST causes significant sinusoidal dilation following a bolus and for at least 15 min of IV infusion. Octreotide does not have any influence on liver sinusoids. These results demonstrate for the first time the in vivo dilatory effect of SST on liver sinusoids.     

Efficacy of hepatic arterial infusion of prostaglandin E1 in the treatment of postoperative acute liver failure--report of a case

Prostaglandin E1 (PGE1) has received attention for its protective effects against various types of liver damage. However, it is known that approximately 70% of PGE1 is inactivated during a single passage through the lung. Therefore, direct infusion of PGE1 into the liver bloodstream is preferable to intravenous infusion. A 66-year-old man with hepatocellular carcinoma with liver cirrhosis developed postoperative acute liver failure following posterior segmentectomy under hepatic total vascular exclusion exceeding 1 hour. Because his liver function did not recover in spite of plasma exchange starting on postoperative day 8 and intravenous infusion of PGE1, hepatic arterial continuous infusion of PGE1 at a rate of 0.01 microgram/kg/min was carried out for 7 days from postoperative day 17. Immediately after the start of the arterial infusion, the bile flow significantly increased compared to before the arterial infusion, and the serum total bilirubin level decreased thereafter and finally recovered from the hepatic failure. In addition to its highly efficient drug delivery, the hepatic arterial infusion of PGE1 seems to be more advantageous in oxygen delivery to the liver compared with intravenous infusion. In conclusion, the hepatic arterial infusion of PGE1 may be useful in the treatment of acute liver failure.     

Studies on the insulin-antagonistic effect of catecholamines in normal man

Summary The insulin-antagonistic effect of adrenaline was studied in seven healthy subjects with the euglycaemic clamp technique using two insulin infusion rates (40 and 1200 mU (m²)^–1 min^–1). The adrenergic receptor mediating the adrenaline effect was characterized by concomitant infusion of propranolol ₁+ ₂-antagonist) or metoprolol ( ₁-antagonist). Each subject was studied four times (placebo, adrenaline, adrenaline + propranolol, adrenaline + metoprolol). Glucose turnover was measured with D(3-³H)-glucose. Similar plasma insulin levels were reached in all studies with the two insulin infusion rates (mean; placebo 51 ± 3 and 7421 ± 337 mU/l respectively). Glucose production was completely inhibited by the low insulin level during placebo infusion. Adrenaline antagonized this effect so that a significant glucose production was seen at the low but not at the high insulin level. Propranolol, but not metoprolol, reversed this insulin-antagonistic effeet of adrenaline. Glucose utilization increased from 2.53 ±0.17 to 7.28 ± 0.88 mg · kg^–1 · min^–1 during placebo when the insulin levels were increased from 4± 0.3 to 51 ± 3 mU/l. Increasing the insulin levels 150-fold to 7500 mU/l only doubled the glucose utilization (14.68 ±1.14 mg·kg^–1·min^–1). Adrenaline induced a pronounced inhibition of glucose utilization at both insulin levels (78% and 37% inhibition respectively). Propranolol, but not metoprolol, prevented this effect of adrenaline. Thus, physiological adrenaline levels exert a pronounced insulin-antagonistic effect which is mediated by ₂-receptor stimulation. The inhibitory effect on glucose uptake is maintained even at high insulin levels when hepatic glucose production is completely abolished.