Biomedical subjects

L Zieve

Publications and source records attributed to L Zieve.

At least 37 records · Page 2Linked to original sources

PubMed1986

Ammonia toxicity: comparative protective effect of various arginine and ornithine derivatives, aspartate, benzoate, and carbamyl glutamate.

Ornithine and arginine compounds were highly effective in preventing an increase in blood ammonia and in preventing or minimizing encephalopathy after acute subcoma, coma-inducing, or lethal doses of NH4+. Similar protection was seen after subacute loading with glycine. Ornithine ketoacid derivatives were no more effective than ornithine alone or ornithine glutamate. Ornithine appeared to be a little more effective than arginine, but the differences were slight. Aspartate and glutamate alone were ineffective. Carbamyl glutamate was much less effective than either ornithine glutamate or arginine glutamate. Orotic acid excretion was markedly increased in the presence of excess NH4+. This increment was eliminated with ornithine or arginine, although the reduction with arginine was unpredictably erratic. Aspartate increased the orotic acid excretion and the amount of urea formed. Sodium benzoate was borderline in its effect on the blood ammonia and on orotic acid excretion.

Ammonia↗

PubMed1986

Hepatic regenerative enzyme activity after pericentral and periportal lobular toxic injury.

Pericentral and periportal liver injuries involving less than 50% of the parenchyma were produced with acetaminophen and allyl alcohol, respectively. Doses were selected to produce comparable peak serum malate dehydrogenase, sorbitol dehydrogenase, and SGPT activities. The regenerative response was assessed by serial measurements of hepatic thymidine kinase (TK) activity and ornithine decarboxylase (ODC) activity. The initial responses reflected in ODC activity were more or less similar. However, the ultimate regenerative response reflected by TK activity was almost three times as great after periportal injury as after pericentral injury, after allowing for differences in the extent of necrosis. Histologic examination also showed greater mitotic and tissue reparative responses after periportal injury. These results suggest that the concept of hepatocellular heterogeneity applies to the regenerative response of liver cells as well as the metabolic functions previously identified.

Acetaminophen↗

PubMed1986

Conditional deficiencies of ornithine or arginine.

Relative deficiencies of ornithine or arginine occur in the presence of excessive ammonia, excessive lysine, growth, pregnancy, trauma, or protein deficiency and malnutrition. Ammonia excess may occur in the presence of a normal liver when amino acid mixtures lacking ornithine, arginine, or citrulline are infused; when specific amino acids such as glycine are injected; when ammonium salts, urea, or urease are injected; or when the gastrointestinal tract contains an excess of protein, urea, or NH4+, as occurs after a gastrointestinal hemorrhage. In these states, ornithine is often rate-limiting for urea cycle function. Ornithine is also rate-limiting when ammonia excess occurs in the presence of hepatic failure. In three of the inherited urea cycle disorders, ornithine insufficiency and ammonia excess also occur. These disorders are citrullinemia, argininosuccinic aciduria, and argininemia. In the presence of excessive lysine the availability of arginine is reduced and the formation of ornithine is decreased in the liver; urea synthesis is reduced, but orotic acid synthesis is increased, and orotic aciduria results as carbamyl phosphate is directed toward the pyrimidine pathway. Hereditary lysinuric protein intolerance results in ornithine depletion, hyperammonemia, and orotic acid uria. Optimal growth in several species of animals requires 0.4-1.0% arginine in the diet. Diets deficient in arginine are associated with poor wound healing as well as stunted growth. The measurement of orotic acid excretion has been a convenient indicator of insufficiency of ornithine or arginine during growth or pregnancy in animals and should prove useful in assessing the requirement for arginine after trauma. Normal human pregnancy is associated with low-grade orotic aciduria. Protein deficiency and malnutrition increase the vulnerability of the animal or child to ammonia toxicity. This is presumably due to insufficient ornithine for normal urea cycle responsiveness.

Amino Acids↗

PubMed1985

Carbamoyl-phosphate synthetase I activity and ureagenesis in regenerating liver of the normal rat.

Urea excretion per gram of liver was increased 219% 2-5 h post-partial hepatectomy (Hx) and 45% 24-27 h post-Hx. Mitochondrial carbamoyl-phosphate synthetase was also increased 5 h post-Hx but was not increased at 27 h. An NH4+ load did not increase urea excretion per gram liver or the enzyme activity noticeably in the 2- to 5-h period but did increase them 24-27 h post-Hx. These results suggest that the enzyme activity and urea formation per unit weight of liver were nearly maximal early during regeneration. Orotic acid excretion per gram of liver in rats that received NH4+ was increased more than 30-fold 2-5 h post-Hx and was similar in this respect to nonhepatectomized rats. Ornithine prevented the increase in both normal and hepatectomized rats, suggesting that ornithine was rate limiting for the ornithine carbamoyltransferase (OCT) reaction. The orotic acid excretion response to NH4+ was much less 24-27 h post-Hx, indicating that ornithine availability for the OCT reaction may be increased at this time.

Ammonia↗

PubMed1985

Course of hepatic regeneration after 80% to 90% resection of normal rat liver. Comparison with two-lobe and one-lobe hepatectomy.

After subtotal (80% to 90%) hepatectomy of the normal rat liver, thymidine kinase activity began to increase after 24 hours and reached a maximum at 36 hours. This persisted for another 60 hours before it declined to reach the baseline by 7 to 8 days. The maximal increase was 30- to 50-fold. After two-lobe (67% to 78%) hepatectomy, the maximal increase was similar, but the onset and the maximum each occurred 12 hours earlier, and the maximum only persisted for another 24 hours. The important first peak of ornithine decarboxylase activity occurred earlier and rose higher after 67% to 78% hepatectomy. The distributions with time of histologic mitosis counts were similar to the distributions of thymidine kinase activity (reflects DNA synthesis) at each of the three levels of hepatectomy, 80% to 90%, 67% to 78% and 37% +/- 0.5%. Thus the initiation of regeneration was delayed after subtotal resection, but the regenerative response as reflected by DNA synthesis and cell multiplication was prolonged.

Alanine Transaminase↗

PubMed1985

Acetaminophen liver injury: sequential changes in two biochemical indices of regeneration and their relationship to histologic alterations.

Massive liver injury was produced in fasting male Sprague-Dawley rats weighing 200 +/- 25 gm each by gastric administration of 1400 mg/kg acetaminophen. The time sequence of changes in liver ornithine decarboxylase (ODC) activity, which reflects the earliest phases of cell multiplication, liver thymidine kinase (TK) activity, which reflects DNA synthesis, and liver histology (necrosis, mitosis, and repair processes) was recorded. ODC showed the usual biphasic response. By 12 hours, it reached its first peak, a six- to eightfold increase. At this time there was no histologic evidence of necrosis, and serum malate dehydrogenase (MDH), sorbitol dehydrogenase (SDH), and alanine aminotransferase (SGPT) were normal. During the next 12 hours ODC decreased by 60% to 70% and cellular necrosis became evident, and reached a peak at 24 to 36 hours, as did serum MDH, SDH, and SGPT. The serum enzymes fell precipitously at 48 hours, but the histologic evidence of necrosis subsided gradually over 60 hours. The secondary ODC peak, a fourfold increase, coincided with rising activity of TK, which increased 25- to 35-fold over 54 to 72 hours, and then subsided. At 54 hours, when DNA synthesis had already peaked, there was no histologic evidence of repair other than mitoses. However, within the next 6 hours, evidences of repair became prominent, and remained so for another 36 hours before subsiding. Thus, with acetaminophen injury, the initial phases in preparation for cell multiplication occurred before histologic evidence of injury was apparent, and DNA synthesis peaked before other evidence of tissue repair became evident.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗

PubMed1985

Effect of hepatic failure toxins on liver thymidine kinase activity and ornithine decarboxylase activity after massive necrosis with acetaminophen in the rat.

After massive liver injury with acetaminophen, subcoma doses of hepatic failure toxins (NH+4, dimethyl disulfide [----methanethiol], octanoic acid) depressed liver thymidine kinase (TK) activity by 78%, 85%, and 90%, respectively, and ornithine decarboxylase (ODC) activity by 40%, 83%, and 78%, respectively. Twenty-four hours after the last dose of the toxins the depressant effects were still evident. The doses of dimethyl disulfide and octanoic acid required for these depressant effects on TK activity were less than half those required for similar effects previously reported after two-lobe hepatectomy of normal rat liver. The dose of NH+4 required was not reduced. None of the toxins depressed ODC activity after the hepatectomy, in contrast to their depressant effects after acetaminophen. Thus doses of the hepatic failure toxins that were about one fourth to one half those needed to induce coma in normal rats inhibited activity of regenerative enzymes after acute massive liver injury with acetaminophen. The effects were persistent for at least 24 hours. These observations may have relevance to the lack of regeneration observed commonly after fulminant hepatic failure in humans.

Acetaminophen↗

PubMed1984

Mechanism of arginine protection against ammonia intoxication in the rat.

To examine the beneficial effect of arginine on ammonia intoxication, rats were injected intraperitoneally with a single dose of NH4Cl (6.75 mmol/kg) with and without arginine (5.0 mmol/kg) or ornithine (5.0 mmol/kg). Arginine or ornithine reduced the blood ammonia nitrogen at 30 min after NH4Cl injection from 3,288 +/- 800 micrograms/dl (mean +/- SE) to 538 +/- 90 and 575 +/- 34 micrograms/dl, respectively. In rats administered this dose of NH4Cl, arginine or ornithine did not increase further the hepatic carbamoyl-phosphate synthetase (EC 6.3.4.16) activation by N-acetylglutamate beyond the effect of NH4Cl. However, arginine or ornithine did increase the hepatic citrulline and urea content as well as the plasma urea concentration in these NH4Cl-injected rats. In rats injected with four doses of NH4Cl (2.5 mmol/kg), arginine or ornithine pretreatment increased the urea excretion and normalized the orotic acid excretion. These results indicate that arginine mitigates ammonia intoxication in the rat by increasing ornithine carbamoyltransferase activity through increased ornithine availability and not via activation of N-acetylglutamate synthetase. By increasing ornithine carbamoyltransferase activity, ornithine enhances the conversion of ammonia to citrulline and urea.

Acetyltransferases↗

PubMed1984

Effects of methanethiol on erythrocyte membrane stabilization and on Na+,K+-adenosine triphosphatase: relevance to hepatic coma.

Methanethiol (CH3SH) has been implicated in the pathogenesis of hepatic coma. Studies are presented to identify the possible biochemical basis of anesthesia-like effects of methanethiol and those features which distinguish such effects from common anesthetics and may represent the basis of its toxicity. CH3SH was found to stabilize erythrocyte membranes against hypotonic hemolysis at relatively low concentrations. At 37 degrees C the AH25 value for human erythrocyte antihemolysis was observed at a concentration of 0.34 mumol of CH3SH bound per mg of erythrocyte protein. Similar results were obtained with rat erythrocytes. This property of CH3SH is in common with other anesthetic agents. Anesthetic agents also inhibit the membrane-associated Na+,K+-adenosine triphosphatase (ATPase); however, for effective and nontoxic agents of this type the inhibition of ATPase activity is elicited at concentrations which are at least an order of magnitude higher than those which influence the membrane stability characterized by the antihemolysis effect (P. Seeman, Pharmacol. Rev. 24: 583-655, 1972). CH3SH was also found to inhibit the membrane Na+,K+-ATPase activity. The I25 value for the inhibition of human erythrocyte ATPase activity was obtained at CH3SH concentration of 0.12 mM which corresponded to 0.3 mumol of CH3SH bound per mg of erythrocyte membrane protein. Rat erythrocyte membrane ATPase was somewhat more sensitive to CH3SH. In all cases the binding of CH3SH to erythrocytes occurred primarily on the membrane. These results indicate that no differential exists with respect to the dose-response of these two activities associated with human erythrocyte membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

The effect of lactulose on psychomotor performance tests in alcoholic cirrhotics without overt hepatic encephalopathy.

Thirty-two alcoholic cirrhotics without clinical evidence of encephalopathy were randomized to lactulose or sucrose treatment in order to evaluate the effects of chronic lactulose therapy on five psychomotor performance tests. Statistically significant improvement was seen in three of the five tests in the lactulose-treated group, while no significant improvement in any test was noted in the sucrose group. However, because of the limited extent of improvement in the lactulose treated group, problems with medication intolerance, and lack of improvement in complex psychosocial behavior, the impact of chronic lactulose therapy on mental function in cirrhotics without overt encephalopathy appears to be limited.

Adult↗

PubMed1984

Brain methanethiol and ammonia concentrations in experimental hepatic coma and coma induced by injections of various combinations of these substances.

In normal rats in a coma induced by NH+4 alone or by methanethiol alone, the brain and blood levels of ammonia or methanethiol are much higher than those observed in rats in experimental hepatic coma. When various smaller dosage combinations of NH+4, methanethiol, and octanoic acid were injected simultaneously, coma occurred at lower brain and blood concentrations of ammonia and methanethiol. Brain ammonia and methanethiol concentrations in normal rats receiving 0.75 mmol NH+4 plus 0.15 mmol octanoic acid plus 18 mumol methanethiol were comparable with those observed in 24 rats in hepatic coma after fulminant hepatic failure caused by acute massive ischemic liver necrosis. The normal rats became comatose. In these rats and in the rats in hepatic coma, the ammonia level in the brain was increased threefold and the methanethiol level in the brain was increased fivefold. Because these levels of ammonia and methanethiol were sufficient to induce coma in normal rats, they should also have been sufficient to induce coma in rats with damaged livers. Therefore, the accumulation of ammonia and methanethiol in the central nervous system after the acute massive ischemic necrosis may have been sufficient to account for the coma that ensued, without the involvement of other factors.

Ammonia↗

PubMed1984

Urea excretion, galactose elimination, and aminopyrine disappearance during normal liver regeneration after partial hepatectomy. Comparison with other function tests reported.

After removal of 70% of normal rat liver, liver weight was 37% of control at 3 1/2 hours and 49% at 24 hours. Urea formation per gram liver after an NH4+ load and galactose elimination per gram liver were well-preserved during this early posthepatectomy period. At 46 hours after removal, galactose elimination was transiently less than would be expected from liver weight. The aminopyrine disappearance rate fell to 50% to 63% of control values until 72 hours, when it decreased further to 43%, disproportionately less than liver weight. The disappearance rate per gram liver at this time was 63% of control. Serum bile acid concentration increased 17-fold by 24 hours, and was five times that of control concentration at 72 hours. Comparisons of these four measures and six other in vivo measures of function previously reported permitted a segregation of the livers into two groups according to liver function after hepatectomy: those that were disproportionately preserved or were proportional to the amount of liver present, and those that were disproportionately reduced in relation to liver weight. Four additional measurements reported in isolated perfused livers after hepatectomy were similarly segregated. It appears that those liver functions that most closely reflect cellular growth or associated changes in liver blood flow are preserved, whereas those that are possibly more specialized and differentiated are depressed during regeneration.

Aminopyrine↗

PubMed1983

Toxicity of a fatty acid and ammonia: interactions with hypoglycemia and Krebs cycle inhibition.

In rats, hypoglycemia induced with insulin and Krebs cycle inhibition produced by fluoroacetate poisoning augmented the encephalopathic effects of octanoic acid and NH4Cl. Blood sugars in the range of 25 to 45 mg/dl resulted in a decrease of approximately 30% in the doses of NH+4 and of octanoate required to induce coma in otherwise normal rats. Mild fluoroacetate poisoning resulted in a corresponding decrease of 25% in the dose of NH+4 and 10% in the dose of octanoate. A single coma-inducing dose of octanoate or several subcoma doses resulted in blood sugar decrements of 50% or more within 1 to 3 hr. A combination of subcoma doses of octanoate and NH+4 had the same effect. Pretreatment with glucose prevented the hypoglycemia and blunted the encephalopathic response to octanoate. A single coma-inducing dose of NH+4 or several subcoma doses resulted in blood sugar increments of 50% or more within 1/2 to 5 hr.

Ammonium Chloride↗

PubMed1983

Encephalopathic effect of phenol in rats.

The coma-inducing effect of phenol was studied in normal 300 +/- 50 gm Sprague-Dawley rats. Dose-response curves were developed which showed that one-half the animals became deeply comatose with 540 mumol of intraperitoneal phenol and 100% with 600 mumol. Five stages of encephalopathy were readily distinguished. In stage I, spontaneous activity was noticeably decreased, posture was upright, back-leg control normal, muscle tonus slightly increased, and response to stimuli normal. In Stage V, activity was gone, the rats were deeply unconscious, righting reflex and back-leg control were gone, muscles were completely relaxed, and there was no response to stimuli. With a coma-inducing dose of phenol, spontaneous activity decreased. After 1 min a body tremor developed interspersed with unpredictable jumping, and all four limbs began to shake. Leg control and then the righting reflex were lost by 2 min. Within 5 min rats were deeply unconscious and muscles completely relaxed while shaking of limbs continued until recovery 20 to 60 min later or death. With 480 mumol or less, none of the rats became comatose, but the shaking of limbs was present. The coma-inducing dose of phenol was reduced by 10% to 20% with simultaneous injection of subcoma doses of NH4+ or OA and by 20% to 30% with simultaneous DMDS leads to 2 methanethiol. Conversely, a subcoma dose of phenol reduced the coma-inducing doses of NH4+, OA, and DMDS by approximately 20% to 25%. Thus phenol, which accumulates in human hepatic failure, induces coma by itself in rats and acts synergistically with other hepatic failure toxins.

Animals↗

PubMed1982

Methanethiol and fatty acids depress urea synthesis by the isolated perfused rat liver.

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Animals↗

PubMed1981

Effect of sorbitol on psychomotor function: its use in alcoholic cirrhosis.

Sorbitol solution has been used to a control substance of evaluating the efficacy of lactulose therapy for hepatic encephalopathy (HE). However, recent in vitro studies suggested that sorbitol may be an inert placebo and may have therapeutic relevance. We evaluated in vivo metabolism of sorbitol in healthy volunteers and alcoholic cirrhotic patients and found that sorbitol was metabolized by gut bacteria in a similar manner to lactulose. We next evaluated the effect of sorbitol treatment on five psychomotor performances tests in cirrhotic patients. Patients receiving sorbitol demonstrated improvement in all psychomotor tests, whereas similar patients not receiving sorbitol showed no improvement. We conclude the following: sorbitol is metabolized by gut bacteria in man, sorbitol therapy improved psychomotor performance in cirrhotic patients, and previous studies using sorbitol as a control underestimated the beneficial effects of lactulose.

Humans↗

PubMed1980

Blood methanethiol in alcoholic liver disease with and without hepatic encephalopathy.

Blood methanethiol and ammonia concentrations were measured in 16 healty volunteers, 52 consecutive alcoholic cirrhotics without overt hepatic encephalopathy (HE), and 42 consecutive patients with alcoholic liver disease and overt HE. The mean concentration of blood methanethiol was significantly greater than normal in the cirrhotics without overt HE, and the means of both methanethiol and ammonia were significantly greater in the patients with than in those without overt HE. Only one patient with overt HE had both normal ammonia and methanethiol blood concentrations. Twenty of the patients with HE were followed serially. The directions of change in methanethiol and ammonia were consistent with the direction of change in mental status in 85% adn 60% respectively. All of the patients who deteriorated and died had changes in blood methanethiol that correlated with the change in mental status. We conclude that blood methanethiol is a valuable adjunct to the ammonia determination in the evaluation of the patient with possible HE. It is especially helpful in following the course of a patient with hepatic encephalopathy, both as to prognosis and as an indicator of response to therapy.

Adult↗

PubMed1980

Blood mercaptan and ammonia concentrations in cirrhotics after a protein load.

Measurements of blood ammonia and methanethiol were made in 17 moderate or severe alcoholic cirrhotics without overt hepatic encephalopathy under fasting conditions and 2, 3 1/2 and 5 hours after ingestion of a hamburger containing 80 gm. protein. At every time interval the average blood methanethiol in the cirrhotics was significantly higher than in 11 normal controls. The average blood ammonia in the cirrhotics was also higher than in the controls but only at five hours was the difference statistically significant. Fasting blood ammonia and methanethiol values were not strikingly effective in separating the normals and cirrhotics. After the protein load, however, the peak values of these measurements completely separated the cirrhotics from normals on a two-dimensional plot of methanethiol vs. ammonia. In our sample of patients, the peak postprotein load measurements were not effective in predicting which cirrhotics may develop overt encephalopathy. Utilization of the area under the curve of values obtained after the protein load did not appreciably improve on the results with the single peak value.

Adult↗