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Featured researches published by Y. Israel.


Gastroenterology | 1979

Effect of Short-Term Therapy with Propylthiouracil in Patients with Alcoholic Liver Disease

Hector Orrego; H. Kalant; Y. Israel; Joan E. Blake; Alan Medline; J.G. Rankin; A. Armstrong; B. Kapur

The effect of propylthiouracil (PTU; 300 mg/day) on alcoholic liver disease was evaluated in 133 patients in a short-term randomized double-blind trial. Severity of the disease was assessed by a composite clinical and laboratory index (CCLI). A normalization rate (NR) representing the rate of improvement in CCLI was calculated. Patients with alcoholic hepatitis, with and without cirrhosis, showed a significantly higher NR on PTU (43.6 +/- 4.6) than on placebo (19.8 +/- 3.3; P less than 0.001). A similar effect was observed in patients with abnormal prothrombin (no biopsy): NR was 32.9 +/- 6.9 on PTU and 2.6 +/- 3.7 on placebo (P less than 0.005). The effect of PTU on each clinical and laboratory component of the CCLI was also compared in these two groups. In 38 patients with alcoholic hepatitis and in 25 with abnormal prothrombin, those on PTU showed a greater improvement in 15 of 15 items (P less than 0.001) and 14 of 15 (P less than 0.01), respectively. When patients were divided according to the severity of the disease into those in the lower and upper halves of the CCLI range (81 and 52 patients, respectively), PTU was shown to have a significant effect only in the latter: The NR was 41.4 +/- 3.8 on PTU and 22.5 +/- 4.2 on placebo (P less than 0.005). PTU was ineffective in patients with inactive cirrhosis.


Gastroenterology | 1979

Thyroid hormones in alcoholic liver disease. Effect of treatment with 6-n-propylthiouracil.

Y. Israel; P.G. Walfish; Hector Orrego; Joan E. Blake; H. Kalant

The relationship between alcoholic liver disease and circulating thyroid hormones was investigated in 124 hospitalized patients treated with placebo or propylthiouracil (PTU) for a maximum of 46 days in a double-blind study. Serum triiodothyronine (T3) levels on admission were significantly (P less than 10(-6) and inversely correlated with the severity of alcoholic liver disease. After hospitalization, changes in T3-levels in patients with low admission T3 significantly correlated (P less than 0.001) with the degree of spontaneous improvement of liver function (placebo group). Treatment with 300 mg of PTU daily (Orrego et al. Gastroenterology 76:105--115, 1979) markedly increased the rate of improvement in severely ill patients with low T3 on admission. In this group, serum T3-levels were also increased after PTU, but this increase did not correlate with the change in the patients condition. It is suggested that the known inhibitory effect of PTU on peripheral deiodination of T4 to T3 is marked by a more marked improvement in liver function in this group. PTU treatment in this group reduced the free T4-index and increased TSH levels markedly (16%; P less than 0.02) toward levels found in hypothyroidism. PTU did not improve the condition of mildly ill patients with normal admission T3-levels, nor did it alter free T4-index or serum TSH levels in these patients. Serum T3-levels provide a sensitive indicator of the severity of alcoholic liver disease and of its response to conventional treatment. Serum T3-levels also distinguish between a group of patients, in whom low-dose PTU administration results in a beneficial effect, and another group, in whom no therapeutic effect of PTU is observed.


European Journal of Clinical Investigation | 1971

Hepatic vein oxygenation, liver blood flow, and the rate of ethanol metabolism in recently abstinent alcoholic patients

Hernán Iturriaga; G. Ugarte; Y. Israel

Abstract. To determine whether hepatic hypoxia is associated with hepatocellular necrosis in alcoholics, oxygen tension in the hepatic vein and hepatic blood flow were determined in thirteen patients without overt clinical liver disease. Ethanol metabolic rate was also assayed as an index of liver metabolism. Hepatic blood flow and ethanol metabolic rate were also determined in six normal volunteers. According to liver histology patients were separated into two groups, with and without hepatocellular necrosis. Alcoholics with necrosis showed a higher (P < 0–002) ethanol metabolic rate (405±0–23 mmol/kg/h) than those without necrosis (2–46±0–34). Hepatic blood flow in the total group of alcoholics was not significantly different from controls; in the group with necrosis it was lower (651‐7±44‐6 ml/min/m2) than in the group without necrosis (878‐3±81‐6; P < 0025). Hepatic vein pO2 was lower (P < 001) in patients with hepatocellular necrosis (31‐7±0–68 mmHg) than in patients without necrosis (35‐7±0–99). In the whole group, a significant negative correlation (r= ‐0 76, P < 0–003) was observed between hepatic vein pO2 and ethanol metabolic rate. Acute administration of ethanol (21‐7 mmol/kg) did not alter hepatic blood flow in six normal individuals nor in five alcoholic patients, although an increase in hepatic vein pO2 was observed in the latter. The changes observed in hepatic vein pO2, functional hepatic blood flow, and ethanol metabolic rate which correlate with hepatocellular necrosis, may be of pathogenic importance in alcoholic liver disease.


Drug and Alcohol Dependence | 1979

Studies on metabolic tolerance to alcohol, hepatomegaly and alcoholic liver disease

Y. Israel; J.M. Khanna; Hector Orrego; Gloria Rachamin; Samina Wahid; R. Britton; A. Macdonald; H. Kalant

Abstract We previously reported that chronic ethanol administration to Wistar rats results in an increased rate of ethanol metabolism (EMR) and an increased rate of liver oxygen consumption. These increases, expressed per gram of liver, are obtained in conditions in which little or no hepatomegaly occurs. We have confirmed data showing that when hepatomegaly occurs, it is produced by an increased cell volume rather than by an increase in the number of cells. Intracellular water accounts for 60% of the increase in liver weight while a marked reduction in DNA g of tissue is seen. When the EMR and oxygen consumption following chronic ethanol treatment are expressed per total liver, marked increases are obtained in both parameters, independent of the production of hepatomegaly. In Wistar-derived male SH rats chronic ethanol treatment produces increases in EMR of the order of 100%. In young naive males of this strain, EMR and liver alcohol dehydrogenase (ADH) are high, but both are markedly reduced at the time of sexual maturity (6–10 weeks of age). In male SH rats chronic ethanol administration results in higher EMR and ADH which increase in a parallel fashion. Castration prevents the drop in EMR and ADH in naive animals fed chow or sucrose diet and abolishes the increase in EMR and ADH produced by chronic alcohol administration. It is suggested that, in mature male SH rats, ADH under control of testosterone constitutes the primary rate-limiting step in ethanol metabolism, and that chronic ethanol administration acts as a chemical castration. These studies indicate that, at least in laboratory animals, the mechanisms of metabolic tolerance can vary, and are genetically determined. This may explain some discrepancies found in the literature. We have previously shown that propylthiouracil (PTU) administration reduces liver oxygen consumption and protects animals fed alcohol chronically against hypoxic liver damage. A recently concluded double-blind clinical study in three Toronto hospitals indicates that (PTU) administration (300 mg/day) doubles (p


Gastroenterology | 1976

Protection by Propylthiouracil Against Carbon Tetrachloride-Induced Liver Damage

Hector Orrego; F.J. Carmichael; M.J. Phillips; H. Kalant; J. Khanna; Y. Israel

Rats given a single intragastric dose of carbon tetrachloride (CCl4), 0.25, 0.50, or 1.0 ml per kg) showed a dose-dependent increase in SGOT, serum ornithine carbamyltransferase, and liver necrosis (graded histologically as 0 to 4+) 24 hr after the treatment. Daily intubation with propylthiouracil (PTU) for 10 days in doses of 5 to 50 mg per kg significantly reduced the elevation of SGOT activity, completely suppressed the serum ornithine carbamyltransferase changes, and reduced the degree of necrosis found 24 hr after the intragastric administration of CCl4. Similar protection was found when CCl4 was given intraperitoneally. When PTU was given in liguid diets for 6 days, protection against CCl4 was increased. PTU did not affect the absorption or covalent binding of 14CCl4 to lipids or proteins. Also, control and PTU-treated rats did not differ with respect to glucose-6-phosphatase activity and conjugated diene production after CCl4. Thus, it has been observed that PTU affords partial protection against some end-stage consequences of CCl4 liver injury such as cell necrosis and release of intracellular enzymes. However, PTU afforded no protection against early chemical effects such as covalent binding of CCl4 carbon, lipid peroxidation, or loss of glucose-6-phosphatase. Therefore, it is concluded that the mechanism of the PTU effect comes into play after the initial effects of CCl4 are exerted and in some unknown manner modulates the expression of these early effects.


Archive | 1977

Alcohol Induced Susceptibility to Hypoxic Liver Damage: Possible Role in the Pathogenesis of Alcoholic Liver Disease?

Y. Israel; Hector Orrego; J.M. Khanna; D. J. Stewart; M. J. Phillips; H. Kalant

Previous studies in our laboratory (1–3), have indicated that the major rate limiting factor in ethanol metabolism in the intact liver cell is the rate of mitochondrial reoxidation to NAD+ of NADH produced in the oxidation of ethanol. This has now been confirmed in several laboratories (4–8). In this process oxygen is utilized and water is formed. The capacity of mitochondria to oxidize reducing equivalents is related to the relative availability of phosphate acceptor (ADP), or more generally to the phosphorylation potential (ATP/ADP × Pi) (9–12). Mitochondrial uncouplers such as dinitrophenol (DNP), carbonyl cyanide p-trifluoromethoxyphenyl-hydrazone (FCCP) and arsenate allow the mitochondria to oxidize reducing equivalents independently of phosphate acceptor availability and thus they increase the rate of oxygen consumption (13). Accordingly, the rate of ethanol metabolism has been shown to be increased by uncoupling agents both in vivo (2,4) and in vitro in liver slices (1, 14), perfused liver (3,5) and isolated hepatocytes (8). Figure 1 shows the effect of DNP on the rate of ethanol metabolism by perfused rat liver.


Alcohol and Aldehyde Metabolizing Systems#R##N#Intermediary Metabolism and Neurochemistry | 1977

IN VIVO METABOLISM OF ETHANOL AT HIGH AND LOW CONCENTRATIONS

J.M. Khanna; K.O. Lindros; Y. Israel; Hector Orrego

Recent studies with liver slices, perfused liver and hepatocytes have shown that the rate of ethanol metabolism is dependent on the concentrations of ethanol. In order to study whether this occurs in vivo, we studied the rate of ethanol elimination in four groups of animals given four different doses of ethanol (0.5, 1.0, 2.0 & 4.0 g/kg i.p.). Regardless of the dose given, ethanol metabolism (mg/kg/hr) was virtually identical in all four groups. Furthermore, administration of 4-methylpyrazole (2 mmol/kg b. wt) produced an inhibition ranging from 82–92% in all groups. Both at a low dose of ethanol (0.5 g/kg) and a high dose (2. 5 g/kg), blood ethanol disappearance was significantly faster in chronically alcohol-fed rats than in pair-fed sucrose controls. The increase in rate was identical at the low and high doses. The results are interpreted as evidence against any quantitatively important function of a non-ADH mediated pathway in ethanol elimination that would operate preferentially at the high dose in vivo. Chronic ethanol treatment did not appear to induce such a pathway.


Cellular and Molecular Life Sciences | 1979

Does an excess in liver proline increase the accumulation of collagen induced by carbon tetrachloride

R. Devenyi; H. Tiefenbach; Hector Orrego; George Varghese; Y. Israel

A 20-fold, diet-induced increase in liver proline does not result in an increased accumulation of hydroxyproline following chronic carbon tetrachloride administration.


Alcohol | 1984

The inhibitory effect of testosterone on the development of metabolic tolerance to ethanol

Gloria Rachamin; Robert S. Britton; J.A. Macdonald; Y. Israel

We have investigated the mechanism(s) of metabolic tolerance to ethanol in a rat strain (spontaneously hypertensive or SH) in which liver alcohol dehydrogenase (ADH) levels are very low due to a marked inhibitory effect of testosterone on ADH. Chronic ethanol administration resulted in marked increases in the rate of ethanol metabolism and in ADH activity (+65 to 90%). Oxygen consumption measured in the perfused livers of the ethanol-fed rats was also elevated (+40%). The administration of 6-n-propyl-2-thiouracil (PTU), which was previously found to reduce hepatic oxygen consumption and to increase ADH activity, resulted in no change in the rate of ethanol metabolism in the ethanol-fed rats and an increase in the sucrose-fed controls, suggesting that increased ADH activity is more important for the development of metabolic tolerance to ethanol, in the male SH rat, than increased oxygen consumption. The activity of the microsomal ethanol-oxidizing system (MEOS) in vitro was induced by chronic ethanol treatment (+95%), but it may only account for a small part (32%) of the increase in ethanol metabolism in vivo. Serum testosterone concentrations were lower in the ethanol-fed rats at peak blood ethanol levels, relative to those found in controls. Concurrent chronic administration of ethanol and testosterone abolished about one-third of the absolute increases in ethanol metabolism and in ADH activity in the ethanol-fed rats. In conclusion, most of the metabolic tolerance to ethanol, in the male SH rat, appears to occur mainly due to a testosterone-independent increase in ADH activity and to a lesser degree to an increase in ADH activity produced by a reduction in testosterone levels in the ethanol-fed rats.


Drug and Alcohol Dependence | 1979

Effect of alpha- and beta-blockers on ethanol metabolism

J.M. Khanna; Joel M. Mayer; Hector Orrego; Y. Israel

The acute administration of propranolol or phentolamine resulted in a small (16-19%) but significant reduction in the rate of ethanol disappearance in vivo in the naive Wistar rat. A reduction of essentially similar magnitude was also observed in ethanol-treated rats and pair-fed (sucrose) control animals, following the administration of these blockers.

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H. Kalant

University of Toronto

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