Biomedical subjects

P D Hall

Publications and source records attributed to P D Hall.

At least 37 records · Page 2Linked to original sources

PubMed1995

The influence of serum tumor necrosis factor-alpha and interleukin-6 concentrations on nonhematologic toxicity and hematologic recovery in patients with acute myelogenous leukemia.

To confirm the reported correlation of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) serum concentrations with nonhematologic toxicity after cytotoxic chemotherapy and to examine their possible effects on hematopoiesis, we evaluated serum TNF-alpha and IL-6 concentrations every 3 days during 21 chemotherapy cycles in 11 patients with acute myelogenous leukemia (AML) and one patient with chronic myelogenous leukemia in blast crisis (CML-BC). All patients developed grade IV hematologic toxicity. In 13 patient cycles, grade III-IV nonhematologic toxicity developed: hepatic (nine), pulmonary (six), and stomatitis (five). In these patient cycles, IL-6 concentrations increased from 10.1 pg/mL (4.6-15.6, 95% CI) before nonhematologic toxicity to 64.8 (5.3-124.2, 95% CI) at the onset of toxicity (p = 0.02). TNF-alpha concentrations were not detectable before nonhematologic toxicity but increased to 20.4 pg/mL (not detectable [ND]-45.5, 95% CI) at the onset of grade III-IV toxicity. In six patient cycles, grade II nonhematologic toxicity developed: hepatic (five), pulmonary (one), and stomatitis (two). In these six, IL-6 concentrations increased from 12.1 pg/mL (6.8-17.4, 95% CI) before toxicity to 21.4 (11-31.8, 95% CI) at the onset of toxicity (p = 0.03). TNF-alpha concentrations were detectable in one patient cycle before toxicity and detectable in only two patient cycles at the onset of toxicity. The peak IL-6 and TNF-alpha concentrations did not correlate with the onset of nonhematologic toxicity in 87% of patient cycles. In patient cycles with a cumulative IL-6 area-under-the-serum concentration vs. time curve (AUC) > 1000 pg/mL.d, platelet recovery (> 30 x 10(9)/L and platelet transfusion-independent) occurred earlier at 21.9 days (18.7-25.1, 95% CI) compared to the 30.6 days (23.6-37.5, 95% CI, p = 0.02) in patient cycles with an IL-6 AUC < 1000 pg/mL.d. Patient cycles with a cumulative TNF-alpha AUC > 150 pg/mL.d required a mean of 17.5 units of red blood cells (RBCs) (9.3-25.7, 95% CI) compared to patient cycles with an AUC < 150 pg/mL.d, which required only 8.9 units of RBCs (6.2-11.7, 95% CI, p = 0.03). The peak concentration and AUC for IL-6 and TNF-alpha were not significantly different between those receiving growth factors (G-CSF, six; GM-CSF, one) and those not receiving growth factors (14). Endogenous IL-6 and TNF-alpha serum concentrations increase in patients who experience nonhematologic toxicity and correlate with hematologic recovery after chemotherapy.

Antineoplastic Agents↗

PubMed1994

Cirrhosis in patients with rheumatoid arthritis receiving low dose methotrexate.

We describe three patients with RA who developed cirrhosis while taking low dose methotrexate (MTX). This report includes a review of the risk factors for cirrhosis occurring in association with MTX. Two of these patients were part of a prospective study to quantify changes in pericellular and total collagen in 76 patients with RA receiving low dose pulse MTX, giving a point prevalence of cirrhosis of 2.63%.

Aged↗

PubMed1994

Alcohol/"low-dose" carbon tetrachloride-induced cirrhosis in rats using different methods of alcohol feeding.

Cirrhosis may be reliably produced in rats by exposing them to low levels of carbon tetrachloride vapor while feeding alcohol in the Lieber-DeCarli liquid diet. This study aimed to determine whether alternative cheaper and more convenient ways of feeding alcohol would also allow the production of cirrhosis. Animals were fed alcohol in the Lieber-DeCarli diet, in a gel diet, or by addition of alcohol + sucrose to their drinking water, and were exposed to carbon tetrachloride vapor 6 hr/night, 5 nights/week. After 12 weeks of treatment, all animals (4 of 4) receiving alcohol in the Lieber-DeCarli diet, but only two in each of the gel and drinking water groups, were cirrhotic. The variable results with the gel diet may be due to loss of alcohol by evaporation from the gel. Alcohol intake in the group receiving alcohol in drinking water was greater than in those receiving Lieber-DeCarli diet. We suggest that the increased carbohydrate intake due to addition to sucrose to the water exerted a protective effect on the liver.

Alcohol Drinking↗

PubMed1994

Dose-response relationships in hepatic injury produced by alcohol and carbon tetrachloride.

Dose-response relationships were examined for the production of hepatic fibrosis and cirrhosis by combined exposure of male Porton rats to alcohol and carbon tetrachloride. Alcohol was administered orally in Lieber-DeCarli liquid diet at levels of 75, 150, or 300 kcal/liter, giving mean daily intakes of 2.29, 4.61, and 8.16 g/kg/day, respectively. Carbon tetrachloride was administered by inhalation at concentrations of 10, 20, or 40 ppm, 6 hr/night, 5 nights/week. Liver biopsies were taken at intervals up to a maximum treatment period of 20 weeks. All four rats that received the high dose of both agents, and 1 of 4 that received the medium alcohol and high carbon tetrachloride treatments, were cirrhotic by 10 weeks. Two of the 4 rats that received the low alcohol and high carbon tetrachloride dose were cirrhotic at 20 weeks. Cirrhosis was not observed in rats that received the low or medium carbon tetrachloride dose, but some degree of hepatic fibrosis was observed in all treatment groups. Severity of fibrosis was significantly associated with both dose of alcohol and dose of carbon tetrachloride received. It is concluded that, in the alcohol-carbon tetrachloride rat model for chronic liver injury, both alcohol and carbon tetrachloride contribute to the response in a dose-related manner. Hepatic injury was observed even when relatively low doses of these agents are administered together.

Alcohol Drinking↗

PubMed1994

Pathological spectrum of alcoholic liver disease.

Alcoholic liver disease encompasses three main forms of liver injury: fatty change, alcoholic hepatitis and cirrhosis. However, there are many other types of injury, including perivenular fibrosis, venous occlusive lesions, microscopic cholangitis and chronic active hepatitis. The pathological spectrum is reviewed in this paper, and the contribution of other injurious agents to the pathological features is identified. Alcoholic liver disease can be mimicked by a variety of non-alcoholic liver diseases. However, features such as fatty liver with perivenular fibrosis, giant mitochondria, spotty hepatocyte necrosis, Mallory bodies, a micronodular pattern of cirrhosis, and iron deposition are strongly suggestive of an alcoholic aetiology. Correlation of clinical findings, and especially the alcohol history, and histopathological factors is necessary for the definitive diagnosis.

Fatty Liver, Alcoholic↗

PubMed1993

Immunohistochemical detection of the NS4 antigen of hepatitis C virus and its relation to histopathology.

The immunohistochemical localization of the hepatitis C virus (HCV) nonstructural antigen 4 (NS4) was investigated in formalin-fixed human liver biopsy samples taken from 10 patients who were anti-HCV positive. NS4 was detected within the cytoplasm of hepatocytes in all HCV-positive patients studied, but not in the mononuclear cell infiltrates, bile duct epithelium, or endothelial cells. A high proportion of hepatocytes appeared positive, but the staining intensity was variable. After a coded histological evaluation of the liver tissue, the pattern of liver injury was shown to have no significant correlation with antigen-positive hepatocytes, and no direct relationship was observed between the distribution of antigen-positive hepatocytes and areas of hepatocyte necrosis. The staining pattern was considered to be specific because liver samples from patients chronically infected with hepatitis B virus or from uninfected individuals were negative. Furthermore, no staining was noted when either preimmune rabbit serum or anti-NS4 adsorbed against the specific synthetic peptide was substituted for the primary antibody.

Adult↗

PubMed1992

Subanesthetic halothane is hepatotoxic in the guinea pig.

Subanesthetic concentrations of halothane were examined for their hepatotoxic potential in the guinea pig. Outbred male, Hartley guinea pigs (600-700 g) were exposed to either 1.0%, 0.25%, or 0.10% (vol/vol) halothane, 40% O2, for 4 h. Plasma isocitrate dehydrogenase (ICDH) activity was compared to plasma alanine aminotransferase (ALT) for sensitivity as an indicator of hepatic injury. As previously seen, exposure to the anesthetic concentration of 1.0% halothane produced limited to confluent centrilobular necrosis in 50% (4/8) of the guinea pigs. The subanesthetic concentrations of 0.25% and 0.1% halothane were also hepatotoxic. After exposure to 0.25%, confluent centrilobular necrosis developed in 2 of 8 animals, whereas 0.10% halothane produced limited centrilobular necrosis in 3 of 8. Plasma ICDH activity was a more sensitive indicator of halothane-induced hepatic injury than ALT. Mean plasma ALT activity increased significantly after 1.0% halothane exposure only. However, ICDH activity was significantly increased after exposure to all three concentrations of halothane. Comparison of peak plasma enzyme activities demonstrated significantly larger increases in ICDH than in ALT when centrilobular necrosis was present. Use of subanesthetic concentrations of halothane should help overcome the many transient effect that high concentrations of halothane have on whole liver and hepatocyte functions. By being able to isolate and titrate the bioactivation of halothane, the mechanisms through which halothane biotransformation produces acute hepatotoxicity should be more easily elucidated.

Alanine Transaminase↗

PubMed1991

Localization of CYP1A1 and CYP1A2 messenger RNA in normal human liver and in hepatocellular carcinoma by in situ hybridization.

To better characterize the precise cellular distribution of CYP1A gene products in man, we have undertaken Northern-blot and in situ hybridization analyses of CYP1A expression in human liver. Using riboprobes transcribed from both CYP1A1 and CYP1A2 complementary DNAs to probe a series of Northern blots of 23 human liver messenger RNA samples, CYP1A1 expression was demonstrated in 11 samples and CYP1A2 expression was evident in 22 samples. The level of expression of both CYP1A enzymes in these livers demonstrated marked variability. The CYP1A1 and CYP1A2 riboprobes were then used for in situ hybridization localization of CYP1A1/1A2 messenger RNA sequences on paraffin-embedded, formalin-fixed human liver sections. These studies demonstrated that both CYP1A1 and CYP1A2 messenger RNAs are distributed nonuniformly across the human liver acinus, with levels highest in hepatocytes surrounding terminal hepatic venules and intercalated veins. Immunohistochemistry with an anti-rabbit CYP1A1 serum demonstrated a corresponding distribution for the translated CYP1A proteins. In situ hybridization analysis was also performed on sections of hepatocellular carcinoma, demonstrating a significant down-regulation in CYP1A expression. Functional studies using the activation of the food-derived heterocyclic amine MeIQ (2-amino-3,4-dimethylimadazo [4,5-f] quinoline) to a mutagen in the Ames test as an indicator of CYP1A expression confirmed this down-regulation. These results demonstrate heterogeneity of hepatic CYP1A expression both between individuals and in different acinar zones. This variation in expression may be of significance in assessing cell specific toxicities of various drugs and carcinogens.

Carcinoma, Hepatocellular↗

PubMed1991

Hepatotoxicity in a rat model caused by orally administered methotrexate.

We undertook a dose-response study in Wistar rats to develop an animal model for methotrexate hepatotoxicity. Rats were given oral methotrexate in 300, 200, 150 and 100 micrograms/kg/day doses for variable lengths of time. The 300 micrograms/kg/day dose produced systemic toxicity; the animals needed to be killed early, and hepatotoxicity was not observed. The lower doses of methotrexate were tolerated for longer durations and were associated with hepatotoxicity in five of the five rats receiving 200 micrograms/kg/day, four of the five rats receiving 150 micrograms/kg/day and five of the five rats on 100 micrograms/kg/day. Within each treatment group the liver injury ranged in severity from focal necrosis of some zone 3 hepatocytes to confluent necrosis of zone 3. All five rats that received 100 micrograms/kg/day methotrexate for 6 wk showed continuing liver injury in the form of focal necrosis, cell lysis and enlarged Kupffer cells. In addition, three of the rats showed evidence of early hepatic fibrosis. We believe that this is the first experimental model in which oral methotrexate administration has been associated with hepatotoxicity. Further development of this model should provide valuable insights into the pathogenesis of methotrexate hepatotoxicity.

Administration, Oral↗

PubMed1991

Hepatic fibrosis and cirrhosis after chronic administration of alcohol and "low-dose" carbon tetrachloride vapor in the rat.

Rats were exposed to carbon tetrachloride vapor, 5 days/wk, 6 hr/day, for periods of 5 or 10 wk at a concentration that by itself caused only fatty change with minimal liver cell necrosis and no fibrosis. The same carbon tetrachloride exposure when given in association with chronic alcohol feeding resulted in extensive hepatic fibrosis at 5 wk and established micronodular cirrhosis at 10 wk. The periodicity of the exposure profile was chosen to simulate that of human exposure to environmental toxins, albeit at a higher dose than would be permitted in the workplace. The development of significant liver injury in this animal model raises the possibility that some chronic liver injury in humans may be due to alcohol potentiation of other hepatotoxins present in the environment at subtoxic levels.

Alanine Transaminase↗

PubMed1991

Two methods of assessment of methotrexate hepatotoxicity in patients with rheumatoid arthritis.

Serial liver biopsy specimens from 18 patients with rheumatoid arthritis receiving a weekly dose of methotrexate 7.5-20 mg for a minimum of 12 months were assessed semiquantitatively and by a microcomputer image analysis system. The semiquantitative histological method showed a significant increase in pericellular collagen and in overall disease while morphometry showed a significant increase in pericellular, perivenular, and portal tract collagen. There was a significant correlation between the two methods, but morphometry had the advantage of objectivity and efficiency. There was no correlation between the increase in collagen and the accumulated dose of methotrexate, which suggests that other factors in addition to methotrexate may contribute to liver injury.

Adult↗

PubMed1991

Hepatic methotrexate content and progression of hepatic fibrosis: preliminary findings.

Liver tissue from 16 patients with rheumatoid arthritis was studied. The patients had received low dose methotrexate weekly for a minimum of 12 months between two liver biopsies. The progression of pericellular fibrosis was measured by computerised image analysis. Extracts of these liver biopsy specimens were pooled into five samples according to the progression of hepatic fibrosis and analysed by high performance liquid chromatography. The concentrations of methotrexate, 2,4 diamino-N(10)-methylpteroic acid, and methotrexate polyglutamate were markedly increased in the samples obtained from the three patients who recorded the greatest increase in fibrosis. These preliminary data suggest that progression of hepatic fibrosis is related to the retention of methotrexate and metabolites in the liver.

Adult↗

PubMed1991

Direct evidence for cytotoxicity associated with expression of hepatitis delta virus antigen.

It has been postulated that hepatocyte injury resulting from infection with hepatitis D virus may be caused by a direct virus cytotoxicity in contrast to immune-mediated injury associated with hepatitis B virus. We have transfected HeLa and HepG2 continuous cell lines with a recombinant plasmid containing the hepatitis D antigen gene under the inducible control of the human metallothionein promoter. The addition of zinc to the cell culture medium then led to the expression of hepatitis D antigen associated with, in the short term, a significant reduction in the rate of RNA but not DNA synthesis and, in the longer term, cell death. The necrotic cells had pyknotic nuclei and shrunken eosinophilic cytoplasm; these necrotic cells resembled the apoptotic bodies seen in hepatitis D virus-related hepatitis. The level of hepatitis D antigen in individual cells that produced these changes was similar to the level of hepatitis D antigen in hepatocytes from a chimpanzee with acute hepatitis D virus infection. We conclude that the expression of hepatitis D antigen resulted in significant cytotoxic changes in these cells, providing strong support for the view that hepatitis D antigen may be specifically cytotoxic to infected hepatocytes in vivo.

Animals↗

PubMed1990

Covalent binding of oxidative biotransformation intermediates is associated with halothane hepatotoxicity in guinea pigs.

In vivo covalent binding of halothane biotransformation-reactive intermediates to hepatic protein and lipid was examined in association with the subsequent development of hepatic necrosis in the guinea pig. Oxidative halothane biotransformation was inhibited by the use of deuterated halothane, whereas reductive metabolism was enhanced by low inspired oxygen concentrations. Male outbred Hartley guinea pigs (n = 8) were exposed to either 1% (v/v) halothane or deuterated halothane--with a fractional inspired O2 concentration (FIO2) of 0.40 or 0.10--for 4 h. Livers removed from half of the animals immediately after anesthesia were evaluated for organic fluorine bound to protein and lipid. The remaining animals were evaluated for a hepatotoxic response up to 96 h after exposure. Only guinea pigs that received 1% halothane at an FIO2 of 0.40 had centrilobular necrosis develop with significantly increased plasma alanine aminotransferase activities. All other treatment conditions significantly reduced oxidative halothane biotransformation, as indicated by decreased plasma trifluoroacetic acid concentrations. These reductions were associated with a significant decrease in organic fluorine bound to hepatic proteins. An FIO2 of 0.10 during halothane anesthesia significantly enhanced reductive biotransformation, as indicated by plasma fluoride ion concentrations. This was associated with a significant increase in organic fluoride bound to hepatic lipids. Centrilobular necrosis did not develop under these conditions. Thus, covalent binding to subcellular proteins by the trifluoroacetyl acid chloride intermediate generated by oxidative halothane biotransformation is implicated as a mechanism of centrilobular necrosis in guinea pigs. Binding to lipids by reductive pathway generated free radicals does not appear to be involved in production of the lesion.

Animals↗

PubMed1989

The effect of everyday exercise on steady state digoxin concentrations.

The purpose of this study was to evaluate the effect of 1 hour of everyday exercise (walking at patient's own pace) on serum digoxin concentrations. Nine white male subjects (ages 58-74) who had been taking the same digoxin dose for greater than 1 month participated. There were three continuous phases: 1 hour of rest, 1 hour of exercise, and a final hour of rest. Serum digoxin concentrations were drawn every 20 minutes. During the first rest period, serum digoxin concentrations rose 30% from the first concentration drawn in the study. After 1 hour of exercise, serum digoxin concentrations fell 26.8% from the last concentration of the first rest period. At the end of the second hour of rest, serum digoxin concentrations increased by 36.6% from the last concentration. Repeated measures analysis of variance demonstrated a significant (P less than .01) change in serum digoxin concentrations. Significant (P less than .01) differences were found between sampling times 0 and 60, 60 and 80, 60 and 100, 60 and 120 and 180 minutes using a paired t-test with Bonferroni correction. A weak correlation (r = 0.74, r2 = 0.55) between percent change in concentrations and age during the exercise phase was found, but there was no correlation between the percent change in concentrations and age during the two immobilization phases. Because significant changes in concentrations occurred during each phase of the study, we conclude that the influence of everyday exercise should be taken into account when interpreting serum digoxin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1989

The role of oxidative biotransformation of halothane in the guinea pig model of halothane-associated hepatotoxicity.

The role of the oxidative pathway of halothane biotransformation in mediating the hepatotoxicity of halothane in the guinea pig was examined by utilizing the deuterated form of halothane (d-halothane), which is resistant to oxidative metabolism. Male outbred Hartley guinea pigs were exposed to either 1% v/v halothane or d-halothane, FIO2 = 0.21, for 4 h. Significant reductions in both oxidative and overall halothane biotransformation were observed with the use of d-halothane as indicated by decreased plasma levels of trifluoroacetic acid and bromide ion, respectively, immediately following exposure. Plasma fluoride ion, indicative of the reductive metabolism of halothane, was significantly increased with the use of d-halothane. These changes in metabolism were accompanied by a reduced hepatotoxic response as indicated by significantly decreased plasma ALT levels 24-96 h following exposure and a significantly lesser incidence of centrilobular necrosis. Thus, the oxidative biotransformation of halothane is implicated as a mechanism of injury in guinea pigs.

Animals↗

PubMed1989

Age and gender influence halothane-associated hepatotoxicity in strain 13 guinea pigs.

The factors of age and gender, which have been linked to development of fulminant halothane hepatitis in humans, were evaluated in a guinea pig model of acute halothane-associated hepatotoxicity. Since nitrous oxide is commonly coadministered with halothane and has been shown to exacerbate halothane-associated liver injury in rats; this combination of anesthetics was also evaluated in guinea pigs. Male and female strain 13 guinea pigs (300-1000 g) were exposed to 1% v/v halothane and 39% O2 for 4 h with a balance of either 60% N2 or 60% N2O. Both animal age, as determined by body weight, and gender proved to be factors in the model with older (approximately 6.2 +/- 1.0 month) guinea pigs of both sexes, demonstrating significantly greater elevations in plasma ALT and a greater incidence of centilobular necrosis versus younger (approximately 3.1 +/- 0.6 month) animals. Older females showed a greater hepatotoxic response than older males. There were no significant differences in halothane plasma metabolite levels between older and younger animals of either gender. The addition of nitrous oxide affected neither plasma concentrations of halothane metabolites nor the degree of resultant hepatic injury. Older (approximately 5-6 month) male guinea pigs, from a strain (inbred Hartley) previously shown to be resistant to the halothane lesion, did not develop centrilobular necrosis following halothane exposure even though they generated plasma metabolite concentrations equivalent to those generated by strain 13 animals. The lack of differences in the biotransformation of halothane between groups indicates that other intrinsic factors must be involved in the observed variations in susceptibility to hepatic injury.

Aging↗

PubMed1989

Risk factors for halothane hepatitis.

Helothane hepatitis is a rare but sometimes fatal complication of halothane anaesthesia. Examination of case reports has pointed to a number of risk factors. Studies in animals and humans in the laboratory have provided evidence of a complex multifactorial basis for halothane hepatotoxicity, with the following factors playing a part: genetic predisposition; metabolism of halothane; repeated halothane anaesthetics; female sex; age of patient; intrahepatic hypoxia; and enzyme induction. Immunologic changes can be detected in a high percentage of cases of halothane hepatitis; however, studies establishing a cause-effect relationship are not available to determine if these changes cause, or result from, hepatic damage.

Anesthesia↗