Teruji Tanaka

Therapeutic and diagnostic potential of a vasopressin‐2 antagonist for impaired water handling in cirrhosis

Progressive cirrhosis is associated with increasing difficulty to handle free water. We examined the therapeutic potential of an orally active nonpeptide vasopressin‐2 receptor antagonist (OPC‐31260) in the management of edema and ascites in patients with cirrhosis. By means of its chemical blockade of the vasopressin‐2 receptor in the kidney, we also assessed the ability of renal water handling in the early stage of cirrhosis.

Comparison of the pharmacokinetics of E2020, a new compound for Alzheimer's disease, in healthy young and elderly subjects

E2020, a central‐acting cholinesterase inhibitor, is now under clinical development as a potential therapeutic agent for senile dementia of Alzheimer type. In the current study, the authors compared the pharmacokinetics of this drug after single oral administration in 12 healthy young volunteers (20–27 years of age) and 6 elderly volunteers (65–82 years of age). The subjects received a single 2‐mg oral dose of E2020 after a meal. Blood samples for determination of the drug level were collected over 168 hours after drug administration and were measured by specific high‐pressure liquid chromatography methods with ultraviolet detection. E2020 was generally well tolerated by all subjects of both groups. The plasma elimination half‐life of the β‐phase (t1/2β) and time to maximum peak plasma concentration (tmax) were significantly longer in the elderly than in the young: t1/2β, 103.8 ± 40.6 versus 59.7 ± 16.1 hours; and tmax, 5.2 ± 2.8 versus 3.4 ± 1.5 hours, respectively. There were no statistically significant differences in maximum peak plasma concentration and area under the curve between the two groups. The mean (± standard deviation) oral clearance (Cl/F) in the elderly (9.1 ± 2.4 L/h) was similar to that in the young (10.6 ± 2.7 L/h). The volume of distribution in the steady state (Vdss/F) was significantly larger in the elderly than that in the young: 1217.2 ± 223.2 versus 852.5 ± 147.7 L, respectively. These results suggested that the drug was absorbed more slowly and distributed more widely and thoroughly, but that its clearance from the body is essentially unaffected by age. It is concluded that a modification of the dose of E2020 in the elderly is unnecessary.

Kinetics and dynamics of enalapril in patients with liver cirrhosis

The pharmacokinetics and pharmacodynamics (blood pressure, heart rate, serum angiotensin‐converting enzyme, and plasma renin activity) of enalapril and enalaprilat were studied after oral administration of enalapril maleate (10 mg) to seven biopsy‐proven cirrhotic patients and to seven healthy subjects. The mean Cmax, AUC, and urinary excretion of enalapril and enalaprilat were greater and less (p < 0.01), respectively, and mean oral clearance of enalapril was less (p < 0.01) in the cirrhotic group than in the healthy group. However, there was no significant difference in the mean total drug (enalapril plus enalaprilat) excretion between the two groups. Blood pressure fell (p < 0.05) only at 3 or 4 hours postdose, with no change in heart rate in the two groups. Serum angiotensin‐convering enzyme (ACE) decreased (p < 0.001) and plasma renin activity (PRA) increased (p < 0.05) in the two groups. The magnitude of the percentage of inhibition of ACE activity was comparable between the two groups. Serum enalaprilat concentration correlated (p < 0.001) with the percentage of inhibition of ACE activity. The results suggest that the bioactivation of enalapril to enalaprilat is considerably impaired in patients with cirrhosis but that the pharmacodynamic effects do not appear to be blunted in those patients. The mechanism and clinical implications remained unclear.

Expression of insulin receptor substrate-1 in hepatocytes : an investigation using monoclonal antibodies

To investigate the expression and subcellular distribution of insulin receptor substrate-1 in hepatocytes, which are major targets of insulin along with muscle and adipose tissue, we obtained monoclonal antibodies by immunizing mice with a fusion protein consisting of the C-terminal portion of the human insulin receptor substrate-1 and glutathione-S-transferase. Two of the monoclonal antibodies (designated as 7B3 and 6G5) were found to be useful for immunohistochemical studies. Using 6G5 we demonstrate a high level of expression of insulin receptor substrate-1 in liver cirrhosis hepatocytes and variable expression in hepatocellular carcinoma cells. These results suggest that insulin receptor substrate-1 may play a role in liver regeneration during cirrhosis and that an insulin signaling cascade may be involved in hepatocarcinogenesis.

Pharmacokinetics and pharmacodynamics of intravenous OPC-18790 in humans : a novel nonglycosidic inotropic agent

OPC‐18790, a nonglycosidic intropic agent, is now under clinical development for treatment of congestive heart failure. Two separate studies (one placebo‐controlled) were conducted to evaluate its pharmacokinetics and pharmacodynamics after intravenous administration to a total of 36 healthy male subjects. The drug was administered both rapidly as a .05‐, .1‐, .2‐, or .4‐mg/kg intravenous dose, and as a 1‐hour infusion of .5, 1.0, 2.5, 5.0,10.0, or 15.0 μg/kg/minute. Echocardiograms (ECHO) were evaluated before and immediately and 4 hours after the rapid administrations. Blood pressure (BP), heart rate (HR), and QTc in the electrocardiogram also were monitored in the rapid administration study. OPC‐18790 was generally well tolerated by all subjects. Maximum peak plasma concentration and area under the curve increased linearly with dose in both studies. The t1/2, total body clearance of drug from plasma (CL), and the dose fraction excreted unchanged in the urine (fe) were comparable and dose‐independent at the doses tested in both studies. The overall mean values of t1/2α, t1/2β, CL, and fe were .08 ± .01 hours, 3.64 ± .22 hours, .46 ± .01 L/kg, and 43.5 ± 1.0%, respectively. Echocardiograms showed that, immediately after rapid administration of up to .4 mg/kg, OPC‐18790 increased left cardiac function dose‐proportionally (P < .05 to .01): the ejection fraction by 21.1% and fractional shortening by 26.5% compared with the predose values, blood pressure, heart rate, and QTc did not differ between subjects given OPC‐18790 and these receiving placebo. Intravenous OPC‐18790 at the dose ranges used is considered to be safe and tolerable and exerts positive inotropic effects in a dose‐proportional manner. This drug is potentially useful in the treatment of severe congestive heart failure.

Effects of a sustained thromboxane synthase inhibition on exercise-induced changes in eicosanoid formation, catecholamine concentration, and platelet aggregation in humans

In an effort to characterize an interaction between the eicosanoids and sympathoadrenal system on platelet aggregation, we tried to determine if a sustained thromboxane A2 (TXA2) synthase inhibition would modulate changes in eicosanoid formation, catecholamine concentration, and platelet aggregation induced by a physical stress. We measured thromboxane B2 (TXB2), ll‐dehydro‐TXB2, 6‐ketoprostaglandin F1α (6‐keto‐PGF1α), norepinephrine, and epinephrine in vivo and platelet aggregation ex vivo before and after a treadmill exercise with and without the oral doses (400 mg twice daily for 7 days) of a new selective TXA2 synthase inhibitor (DP‐1904) in nine healthy male subjects. The exercise tests performed on the pretreatment day (day 0) and posttreatment day (day 7) gave a similar result. DP‐1904 caused a decrease in serum and urinary TXB2 and urinary ll‐dehydro‐TXB2 (p < 0.001 to p < 0.01) and an increase in serum 6‐keto‐PGF1α (p < 0.001 to p < 0.05) throughout the dosing interval on days 4 and 7. Despite the drug effect on eicosanoid formation at rest and after exercise, the exercise‐induced plasma norepinephrine and epinephrine concentrations did not differ between days 0 and 7. The 7‐day treatment decreased (p < 0.01) platelet aggregation induced both by adenosine diphosphate and by collagen at rest. However, the exercise increased (p < 0.01) platelet aggregation by the two aggregators, resulting in the disappearance of the drug‐induced antiaggregatory effects observed at rest. The treatment with a TXA2 synthase inhibitor does not appear to attain the antithrombotic action during an exercise despite the occurrence of a sustained endoperoxide shunting.

Renal and hormonal responses to repeated treatment with enalapril in non-azotemic cirrhosis with ascites

Since a single dose of the angiotensin-converting enzyme inhibitor enalapril was shown to cause natriuresis in cirrhosis in a previous study, we investigated whether repeated doses of this substance would sustain a favorable renal effect in cirrhosis. Ten milligrams of enalapril maleate were administered once a day for 8 days to ten patients with non-azotemic cirrhosis and ascites. Enalapril reduced blood pressure significantly at 4 to 12 h (systolic blood pressure) and 2, 6, and 8 h (diastolic blood pressure) on day 2, compared to pretreatment (day 0) values, but this depressor effect decreased on day 8. No change in heart rate could be detected. Enalapril significantly suppressed serum angiotensin-converting enzyme activity and plasma aldosterone concentration (p < 0.001 to 0.01), which were elevated prior to treatment, with pretreatment values of 25.8 +/- 1.8 IU/l for serum angiotensin-converting enzyme activity and 241 +/- 67 pg/ml for plasma aldosterone concentration. This drug caused a 12 to 24% increase (p < 0.05 to 0.01) in mean daily urinary volume and a 40 to 54% increase (p < 0.001 to 0.01) in mean daily urinary sodium excretion from the respective pretreatment baselines during the 8-day period. Creatinine clearance was improved (p < 0.05) by the treatment, with mean improvement values from 24 to 34% above the pretreatment value of 47.4 +/- 4.3 ml/min.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of prednisone and prednisolone in human serum by high-performance liquid chromatography —especially on impaired conversion of corticosteroids in patients with chronic liver disease

A reliable and rapid method is described for the determination of prednisone and prednisolone in human serum by high-performance liquid chromatography, using a Zorbax-SIL column with dichloromethane-ethanol (92.5:7.5) as eluent, with UV detection at 254 nm. Metabolites and endogenous hydrocortisone did not interfere with the determination of prednisone and prednisolone. The alteration of corticosteroid concentrations in serum from patients with chronic liver diseases was studied following a single oral administration of prednisone or prednisolone (30 mg). The proposed method showed good separation of several corticosteroids and was time-saving, suitable and reliable for the routine analysis of corticosteroids in human serum.

Prostaglandin production in cirrhosis and portal hypertension—Experimental and clinical study

Abstract Disease-related changes in prostaglandin (PG) levels may contribute to a bleeding tendency and local vasodilation in the portal circulation in patients with liver cirrhosis. We measured the plasma and tissue PG metabolite levels (6-keto PGF1 α and thromboxane TXB 2 ) in the systemic and portal circulation in 12 rats with CCl 4 -induced liver cirrhosis (LC rats) and ten with portal hypertension induced by 2 weeks of partial portal ligation (PH rats) and compared them with normal control rats ( n =10). We also compared the plasma PG metabolite levels in the systemic and portal circulations in 11 cirrhotic patients with hepatocellular carcinoma (HCC) and five patient controls without liver disease. In the animal study, LC rats had significantly higher portal blood 6-keto PGF1 α ( P 2 ( P 2 level than PH rats ( P P α levels were not significantly different among the three groups. PH and LC rats had significantly higher portal vein tissue 6-keto PGF1 α levels than the control rats ( P P P 2 level than control rats ( P α /TXB 2 ratios in the portal circulation ( P P P P P P

Hepatic denervation ameliorates sodium and water retention in experimental cirrhosis in rats.

Increased activity in the hepatic sympatheticnervous system may exacerbate salt and water retentionin patients with liver cirrhosis. The aim of this studywas to evaluate sodium and water homeostasis in rats with cirrhosis induced bydiethylnitrosamine and to investigate the influence ofhepatic denervation in this model. Animals wererandomized into three groups: diethylnitrosamine-treatedrats with (N = 13) and without (N = 8) hepaticdenervation and control rats (N = 8). Rats were fed anormal salt diet (0.23% sodium ad libitum). The 24-hrmeasurements for sodium balance, water balance, andcreatinine clearance were performed every two weeks for 12weeks after surgery. Diethylnitrosamine-inducedcirrhosis was confirmed histologically. The cumulativechange in sodium balance in the innervateddiethylnitrosamine-treated rat increased progressively and wassignificantly higher than the control during the lastfour weeks of the study. Meanwhile, rats with hepaticdenervation showed significantly smaller changes incumulative sodium balance at week 12 than those in theinnervated group. The cumulative changes in waterbalance in the innervated group were significantlygreater at weeks 10 and 12 than those of the denervatedand control group, which remained unchangedthroughout the study. Creatinine clearance in theinnervated group decreased at weeks 10 and 12 byapproximately 70% from baseline (P < 0.05); incontrast, it did not change significantly in the denervatedgroup and control group throughout the study. Theseresults demonstrated that hepatic denervationameliorates sodium and water retention as well asglomerular function in cirrhosis model in rats.