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Biomedical subjects

P D Hall

Publications and source records attributed to P D Hall.

52 records · Page 3Linked to original sources
PubMed1988

Effects of treatment with phenobarbitone or isoniazid on hepatotoxicity due to prolonged subanaesthetic halothane inhalation.

Rats were exposed to halothane vapour, 50 p.p.m., or air for a period of four weeks. Within each exposure group, some animals drank plain water, some received water plus phenobarbitone, while some received water plus isoniazid. Halothane exposure resulted in increased serum bromide concentrations and liver injury evidenced by increased serum alanine aminotransferase activity, focal hepatocellular necrosis and fatty change. Administration of isoniazid reduced halothane metabolism by 33% as assessed by serum bromide concentrations, and completely blocked the injurious effects of halothane on the liver, suggesting that halothane metabolism plays a role in halothane hepatotoxicity under these conditions. Administration of phenobarbitone partially prevented the increase in serum alanine aminotransferase activity and hepatocellular necrosis due to halothane. In contrast to isoniazid, phenobarbitone led to a slight increase in halothane metabolism. However, phenobarbitone also caused an increase in liver size, such that the amount of halothane metabolised per gram of liver was reduced by phenobarbitone treatment. These results suggest that metabolism of halothane is an important factor in liver injury due to prolonged, subanaesthetic halothane exposure.

Animals↗
PubMed1987

Hepatic effects of repeated halothane anesthetics in the hypoxic rat model.

The hepatic effects of repeated anesthesia of phenobarbital-induced Fischer 344 rats with 1% halothane/14% oxygen were investigated, after anesthetics were administered at either 1-day or 5-day intervals. Urinary excretion of fluoride, a product of reductive halothane metabolism, was increased in the 24-h period following anesthesia, but was the same after the first, second, and third anesthetics. Rats killed 24 h after a single anesthetic all had centrilobular hepatocellular necrosis. All animals killed 24 h after the second or third anesthetic also had centrilobular necrosis, but, in most animals, this was no more extensive than that following a single anesthetic, regardless of whether the interval between anesthetics was one or five days.

Anesthesia, Inhalation↗
PubMed1987

Immunohistochemical localization and quantitation of NADPH-cytochrome P-450 reductase in human liver.

An antibody raised in a goat against the human liver NADPH-cytochrome P-450 reductase (EC 1.6.2.4.) enzyme has been used to: 1) immunoquantify the level of this enzyme in human liver microsomes, and 2) study the distribution of the reductase across the human liver acinus. Employing the Western blot procedure, anti-human reductase IgG recognized a single band in human liver microsomes which corresponded in molecular weight to the purified reductase. The content of the NADPH-cytochrome P-450 reductase in six normal human livers varied from 87 to 121 pmol/mg of microsomal protein. NADPH-cytochrome P-450 reductase activity of the same microsomes ranged from 107 to 222 nmol of cytochrome c reduced per min per mg of protein. The correlation between reductase content and activity (r = 0.54) was not statistically significant (p greater than 0.1). The total cytochrome P-450 content (cytochrome P-450 and P-420) of the same microsomes varied from 423 to 1413 pmol/mg of microsomal protein. The average ratio of cytochrome P-450 to NADPH-cytochrome P-450 reductase was 7.1:1 +/- 3.1 (mean +/- SD) in the human liver microsomal preparations studied. The reductase was found to be nonuniformly distributed across the human liver acinus. Although all hepatocytes stained positively for NADPH-cytochrome P-450 reductase, the staining intensity was highest in zone 3 and in some cases also in zone 1 hepatocytes. These results show that human liver contains a gross excess of cytochrome P-450 molecules to NADPH-cytochrome P-450 reductase molecules. Furthermore, the differential distribution of the reductase within the human liver acinus may lead to a better understanding of the mechanism underlining site-specific drug hepatotoxicity.

Cytochrome P-450 Enzyme System↗
PubMed1987

A randomized prospective controlled study of the metabolism and hepatotoxicity of halothane in humans.

In a randomized prospective controlled study in humans, the metabolism and hepatic effects of a single administration of halothane were compared with enflurane and meperidine. Pre- and postoperative antipyrine pharmacokinetics, intraoperative indocyanine green clearance, liver histology, and postoperative liver function tests were determined in 24 patients undergoing abdominal surgery who were randomly allocated to receive either halothane (0.5%, group I), enflurane (0.8%, group II), or meperidine (group III) as a supplement to a common basal anesthetic regimen consisting of thiopental, nitrous oxide/oxygen/muscle relaxant. In addition, end-tidal concentrations of the volatile reductive metabolites of halothane, chlorodifluoroethylene (CDF), and chlorotrifluoroethane (CTF) were determined in group I patients and serum and urinary inorganic fluoride were determined in both group I and II patients. Indocyanine green clearance was measured before anesthesia (stage I), during basal anesthesia (stage II), in the presence of surgical stimuli (stage III), and after introduction of the selected anesthetic agent (stage IV). CDF and CTF were detectable within 20 min of the start of halothane anesthesia in every patient receiving halothane. Peak serum fluoride concentrations occurred at 2 and 24 hr in the enflurane and halothane groups, respectively, whereas urinary fluoride excretion was elevated postanesthesia in the enflurane group only. There was no difference between the pre- and postoperative disposition of antipyrine in group II or III, but after anesthesia, antipyrine clearance was significantly decreased (P less than 0.02) and plasma half-life increased (P less than 0.05) in group I patients (halothane). Concentrations of serum alanine aminotransferase (ALT) and bilirubin were significantly elevated (P less than 0.5) postoperatively in groups I and II but unchanged from preoperative values in group III patients. Three of the 24 liver biopsies taken at the end of stage IV showed several foci of acute liver cell necrosis; of these, two patients were from group I and one from group II. There were no significant differences in liver cell morphology (P greater than 0.5) in biopsies taken at the end of stage IV compared with biopsies at the end of stage III, from groups I and II. The results of this study show that reductive metabolism of halothane occurs routinely in patients undergoing halothane anesthesia under conditions of normoxia. This may be the cause of the changes in antipyrine clearance after halothane anesthesia.

Antipyrine↗
PubMed1987

Halothane hepatitis in an animal model: time course of hepatic damage.

The present study extends previous reports of hepatic damage 24 h after halothane anaesthesia in the phenobarbitone pretreated hypoxic rat model by fully characterizing the lesion during the time course of its onset and recovery. Phenobarbitone treated animals exposed to halothane (1% for 2 h in 14% inspired oxygen) were killed 1, 2, 4, 6, 12 and 24 h and 2, 3, 5, 10, 15 and 30 days after commencement of the anaesthetic period. Blood was collected 1 day before the administration of halothane and at the time of killing for determination of serum alanine aminotransferase (ALT), a biochemical index of hepatic damage. Liver tissue was obtained immediately at post-mortem for histological examination. Serum ALT was increased at the end of the anaesthetic period, i.e. 2 h, with peak levels occurring at 12-24 h and remaining elevated for 3 days after exposure. Minor changes in liver histology were evident at 2 h in 50% of the animals and by 6 h all animals had mild hepatic injury. The extent of the necrosis was maximal at 24 h and this was sustained until 3 days. By 5 days after exposure minimal evidence of liver damage was observed and animals killed at 30 days had morphologically normal livers. Elevation of serum ALT or changes in liver histology were not observed in other treatment groups. The early onset of damage at 2-6 h is in keeping with direct hepatotoxicity associated with the biotransformation of halothane.

Alanine Transaminase↗
PubMed1985

Hepatic and renal effects of prolonged exposure of rats to 50 p.p.m. methoxyflurane.

Male Fischer 344 rats were exposed to air or to 50 p.p.m. methoxyflurane vapour for a period of 14 weeks. At the end of this period, half of the rats in each group were killed; the remainder breathed air only for a further four weeks (recovery period) before being killed. During the exposure period, growth of the methoxyflurane-exposed rats was markedly depressed, though food consumption was similar in the two groups. Both water consumption and urine volume were increased by methoxyflurane, possibly due to the nephrotoxic effect of fluoride, the concentration of which exceeded 50 micromolar in the sera of all exposed rats. At the end of the exposure period, livers of all exposed rats, but no controls, showed focal hepatocellular degeneration and necrosis, and evidence of liver cell regeneration. Fatty change was prominent. During the recovery period, water consumption and urine volumes returned to near-normal levels. At the end of the recovery period, focal necrosis was still observed in the livers, although fatty change was no longer present. No histological abnormalities were observed in the kidneys of any rats.

Animals↗
PubMed1985

Guinea-pig model of halothane-associated hepatotoxicity in the absence of enzyme induction and hypoxia.

Halothane anesthesia (1%) administered in 21% oxygen for 4 hr to an outbred strain of guinea pig in the absence of enzyme induction resulted in liver damage in 40 of the 65 animals studied. Necrosis was either confluent around the central veins or in scattered foci throughout the lobules. Damage was present on the second and third days after anesthesia. By day 7 the livers had recovered, evidenced by lack of histological changes and normal serum alanine aminotransferase activity. Administration of halothane in 14 or 80% inspired oxygen did not alter the extent or incidence of liver damage. Major end-metabolites of halothane biotransformation (2-chloro-1,1-difluoroethylene, 2-chloro-1,1,1-trifluoroethane, inorganic fluoride and trifluoroacetic acid) were identified at each oxygen concentration. The metabolic inhibitor SKF-525A significantly decreased the amounts of the volatile metabolites 2-chloro-1,1,1-trifluoroethane and 2-chloro-1,1-difluoroethylene. SKF-525A also decreased the incidence and severity of hepatic damage. Both halothane (1%) and isoflurane (1.1%) anesthesia caused similar reductions in mean arterial blood pressure. However, in contrast to halothane, isoflurane was not hepatotoxic. The results indicate that liver necrosis is unlikely to be caused by anesthesia per se, but rather by hepatotoxic metabolites of halothane. This model offers the opportunity to study the pathogenesis of halothane hepatotoxicity after the administration of halothane alone.

Animals↗
PubMed1983

Hepatic injury in rats due to prolonged sub-anaesthetic halothane exposure.

Fischer-344 rats of both sexes were exposed to halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) at a concentration of 50 p.p.m. for twelve weeks. During the course of the experiment, weight gain of both sexes was depressed and serum alanine aminotransferase activities were elevated, compared to control animals. The temporal pattern of alanine aminotransferase elevation differed between the sexes. After 12 weeks of exposure, liver/body weight ratio was increased in both sexes, and pathological changes were observed in their livers. Livers of all halothane-exposed animals showed focal liver cell necrosis, considerable lobular disarray and occasional mitoses. Many liver cells showed fatty change. None of these changes were observed in any control animals. These results indicate that prolonged exposure to a low concentration of halothane caused mild liver damage with regeneration. This finding may be of significance to humans occupationally exposed to halothane.

Aerosols↗
PubMedDate not supplied

Cell-specific modulation of drug resistance in acute myeloid leukemic blasts by diphtheria fusion toxin, DT388-GMCSF.

Radiochemotherapy-resistant blasts commonly cause treatment failure in acute myeloid leukemia (AML), and their resistance is due, in part, to overexpression of multidrug resistance (mdr) proteins. We reasoned that targeted delivery of protein synthesis inactivating toxins to leukemic blasts would reduce the cellular concentrations of relatively short half-life resistance proteins and sensitize the cells to cytotoxic drugs. To test this hypothesis, we employed human granulocyte-macrophage colony-stimulating factor fused to truncated diphtheria toxin (DT388-GMCSF). The human AML cell line HL60 and its vincristine-resistant sublines, HL60Vinc and HL60VCR, were incubated in vitro for 24 h with varying concentrations of toxin. Doxorubicin was added for an additional 24 h, and cell cytotoxicity was assayed by thymidine incorporation and colony formation in semisolid medium. DT388-GMCSF sensitized HL60Vinc and HL60VCR but not HL60 to doxorubicin. Combination indices for three log cell kill varied from 0.2 to 0.3. In contrast, pretreatment with doxorubicin followed by toxins failed to show synergy. At least in the case of the vincristine-resistant cell lines, modulation of drug resistance correlated with reduction in membrane P-glycoprotein concentrations based on immunoblots with C219 antibody, flow cytometry with MRK16 antibody, and cell uptake of doxorubicin. These observations suggest clinical trials of combination therapy may be warranted in patients with refractory AML. Further, targeted toxins may represent a novel class of cell-specific modulators of drug resistance for a number of malignancies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Effects of cimetidine and ranitidine on halothane metabolism and hepatotoxicity in an animal model.

This study was undertaken to determine the effects of two H2-receptor antagonists, cimetidine and ranitidine, on halothane metabolism and hepatotoxicity in the hypoxic Fisher 344 rat model for halothane hepatitis. In this model, liver injury is caused by toxic intermediates formed during metabolism of halothane by a reductive pathway. Administration of cimetidine (120 mg/kg ip) 20 min prior to anesthesia led to inhibition of the reductive pathway, as assessed by measurement of the exhaled metabolites, 2-chloro-1,1,1-trifluoroethane and 2-chloro-1,1-difluoroethylene, during anesthesia, and urinary fluoride excretion in the 22-hr postanesthesia period. Oxidative metabolism of halothane, assessed by serum bromide concentrations 22 hr postanesthesia, was unaffected. Cimetidine administration provided partial protection against the hepatotoxic effect of halothane, as indicated by serum alanine aminotransferase activities 22 hr postanesthesia. When ranitidine HCl (120 mg/kg ip) was administered prior to anesthesia, reductive metabolism of halothane was unaffected, but the oxidative pathway was slightly inhibited. Ranitidine did not provide protection against halothane-induced liver injury. These results provide additional evidence that halothane hepatotoxicity in the hypoxic rat model is due to toxic intermediates formed during the reductive metabolism of halothane.

Animals↗
PubMedDate not supplied

Immunomodulation with intravenous immunoglobulin.

Since its introduction over a decade ago for the treatment of primary immunodeficiencies, intravenous immunoglobulin (IVIG) has demonstrated activity in a variety of autoimmune disorders. An understanding of IVIG's immunomodulatory effects provides the rationale for its potential application in the management of autoimmune disorders. The agent has exhibited the ability to block fragment crystallizable receptors on phagocytes, interact with the idiotype-anti-idiotype network, and modulate T lymphocyte, B lymphocyte, and natural killer cell populations, as well as complement activity. Its immunomodulatory effects have been demonstrated in a variety of disorders such as idiopathic thrombocytopenic purpura, Guillain-Barré syndrome, Kawasaki disease. Numerous case reports and small studies revealed IVIG's activity in a variety of other autoimmune disorders, but controlled clinical trials are necessary to clarify these initial observations.

Antibodies, Anti-Idiotypic↗
PubMedDate not supplied

The interaction of maintenance interferon with cytolytic cells in patients with multiple myeloma who responded to cytotoxic chemotherapy.

STUDY OBJECTIVE: To determine the long-term effects of maintenance interferon on CD56+ and CD3+ cell activity. DESIGN: Prospective phase II trial. SETTING: Tertiary medical center and level 2 Veterans Administration hospital. PATIENTS: Seven patients (age 45-74 yrs) with multiple myeloma who had reached the plateau phase from cytotoxic chemotherapy, and seven age- and sex-matched controls. INTERVENTIONS: All patients were given interferon-alpha 2b 3 x 10(6) U/m2 3 times/week. MEASUREMENTS AND MAIN RESULTS: The CD56+, CD3+, and CD16+ counts were determined by flow cytometry in both peripheral blood and bone marrow. Natural killer (NK) cell functional activity was determined by a 51chromium release assay. Monocyte cell numbers were determined from the white blood cell count with differential. Interleukin-6 (IL-6) concentrations were determined by a commercially available enzyme-linked immunosorbent assay. During the 24-week study, the peripheral blood CD3+ and monocyte counts in patients with myeloma remained constant (p > or = 0.39) but their absolute CD56+ counts decreased significantly (p = 0.05). In peripheral blood, CD56+, CD16-, CD3- was the predominant phenotype in patients. The predominant phenotype in bone marrow was CD56+, CD16-, CD3+ at baseline but changed to CD56+, CD16-, CD3- by week 24. The cytolytic activity of NK cells significantly increased in bone marrow (p = 0.05) whereas it remained stable in the peripheral blood (p = 0.55), but only half that of the controls. Concentrations of IL-6 did not increase significantly during the study. CONCLUSION: In peripheral blood, NK cell activity remained stable in patients but was significantly lower than that in controls, probably secondary to the predominance of the CD56+, CD16-, CD3- phenotype in the patients. In contrast, NK cell activity increased significantly in bone marrow despite the predominance of the CD56+, CD16-, CD3- phenotype by week 24.

Aged↗