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Biomedical subjects

J Alderman

Publications and source records attributed to J Alderman.

At least 37 records · Page 2Linked to original sources
PubMed1995

The use of ultrasound in the non-invasive detection of changes in the renal circulation in response to blood loss using an animal model.

Using a continuous haemorrhage model, 8 anaesthetised swine were bled 1 ml/kg per min for 30 min. The resistance index (RI) of the main renal artery, interlobar and arcuate vessels all significantly increased. Cortical Doppler signals were lost in 4 animals at a mean arterial pressure of 26 mmHg. After reinfusion of blood and normal saline only the RI of the interlobar vessels was significantly different from baseline readings. Ultrasound demonstrated non-invasively changes in regional blood flow within the kidney in response to hypovolaemic shock.

Animals↗
PubMed1994

Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine.

The pharmacokinetic interactions of sertraline and fluoxetine with the tricyclic antidepressant desipramine were studied in 18 healthy male volunteers phenotyped as extensive metabolizers of dextromethorphan. Concentrations in plasma were determined after 7 days of desipramine (50 mg/day) dosing alone, during the 21 days of desipramine and selective serotonin reuptake inhibitor (SSRI) coadministration (fluoxetine, 20 mg/day; sertraline, 50 mg/day), and for 21 days of continued desipramine administration after SSRI discontinuation. Desipramine Cmax was increased 4.0-fold versus 31% and AUC0-24 was increased 4.8-fold versus 23% for fluoxetine versus sertraline, respectively, relative to baseline after 3 weeks of coadministration. Desipramine trough concentrations approached baseline within 1 week of sertraline discontinuation but remained elevated for the 3-week follow-up period after fluoxetine discontinuation. Concentrations of SSRIs and their metabolites correlated significantly with desipramine concentration changes (for fluoxetine/norfluoxetine, r = 0.94 to 0.96; p < 0.001; for sertraline/desmethylsertraline, r = 0.63; p < 0.01). Thus, sertraline had less pharmacokinetic interaction with desipramine than did fluoxetine at their respective, minimum, usually effective doses.

1-Naphthylamine↗
PubMed1994

Radioprotection of hematopoietic stem cells by interleukin-1.

Radioprotective agents such as interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha), when given prior to irradiation, protect animals from radiation damage. However, in vivo administration of these cytokines does not allow one to determine whether the protective effects act directly on the hematopoietic system. In the present study, we subjected male bone marrow cells to in vitro treatment with IL-1 prior to irradiation and bone marrow transplantation. We found that male bone marrow cells pretreated with IL-1 prior to irradiation increased the survival of irradiated female recipient mice when compared with nontreated irradiated marrow cells. In addition, irradiated female recipients that received IL-1-pretreated male donor bone marrow cells displayed an increased presence of male donor cells in their bone marrow, spleen, and thymus for up to 3 months posttransplant. Furthermore, serial transplantation studies revealed that male cells could only be detected in tertiary female recipients who received bone marrow from mice transplanted with IL-1-treated cells. These results indicate that IL-1 pretreatment protects both short-term and long-term repopulating stem cells from an irradiation insult and that these cells are capable of reconstituting the myeloid and lymphoid organs of recipient mice.

Animals↗
PubMed1990

Role of xanthine oxidase in ethanol-induced lipid peroxidation in rats.

To investigate a possible role of free radical production by xanthine oxidase in the pathogenesis of ethanol-induced hepatic lipid peroxidation, chow-fed rats were given ethanol (5 g/kg) and placed at 32 degrees C for 6 h, which resulted in increased hepatic malondialdehyde levels. Pretreatment with allopurinol in amounts that effectively inhibited xanthine metabolism also significantly decreased ethanol-induced lipid peroxidation, suggesting participation of free radicals produced by xanthine oxidase in the peroxidative process. Both acetaldehyde and purine can serve as substrates for xanthine oxidase. Pretreatment with cyanamide increased hepatic acetaldehyde levels 5-fold, yet this was associated with a decrease in lipid peroxidation, indicating that acetaldehyde is not the xanthine oxidase substrate involved. By contrast, ethanol increased hepatic contents of hypoxanthine and xanthine and enhanced urinary output of allantoin (a final product of xanthine metabolism), incriminating increased metabolism of purines. Ethanol administration also enhanced hepatic nicotinamide adenine dinucleotide (reduced form). A corresponding rise of nicotinamide adenine dinucleotide (reduced form) in vitro inhibited xanthine dehydrogenase activity by 60%-76%. Increased purine degradation, possibly associated with a shift from the dehydrogenase to the xanthine oxidase pathway (secondary to nicotinamide adenine dinucleotide [reduced form]-mediated inhibition of xanthine dehydrogenase activity) is proposed as a possible mechanism for ethanol-stimulated free radical production. Because allopurinol attenuates the associated lipid peroxidation, this agent might be considered for possible therapeutic use in alcohol-induced liver damage.

Allopurinol↗
PubMed1989

The microsomal ethanol oxidizing system mediates metabolic tolerance to ethanol in deermice lacking alcohol dehydrogenase.

Metabolic tolerance to ethanol has been attributed to enhanced mitochondrial reoxidation of reducing equivalents produced in the alcohol dehydrogenase (ADH) pathway or to non-ADH mechanisms. To resolve this issue, deermice lacking low Km hepatic ADH were fed for 2 weeks a liquid diet containing ethanol or isocaloric carbohydrate and hepatocytes were isolated. Ethanol (50 mM) oxidation increased (9.8 vs 4.5 nmol/min/10(6) cells in controls). To differentiate which of two non-ADH pathways (the microsomal ethanol oxidizing system (MEOS) or catalase) was responsible for the induction, four approaches were used. First, MEOS was assayed in hepatic microsomes and found to be increased (24.4 vs 6.8 nmol/min/mg protein in controls). Second, hepatocyte ethanol metabolism was measured after addition of the catalase inhibitor azide (0.1 mM) and found to be unchanged. By contrast, the competitive MEOS inhibitor, 1-butanol, depressed metabolism in a concentration-dependent manner. A third approach relied on measurement of isotope effects known to be different for MEOS and catalase. From the isotope effect values, MEOS was calculated to contribute 85% or more of total ethanol oxidation by cells from both ethanol-fed and control animals. A fourth approach involved in vivo pretreatment with pyrazole (300 mg/kg/day for 2 days), which reduced peroxidation by catalase to 13% of control values in liver homogenates while inducing MEOS activity to 152% of controls. Hepatocytes from pyrazole-treated deermice showed a 47% increase in ethanol metabolism, paralleling the MEOS induction and contrasting with the catalase suppression. These results indicate that since metabolic tolerance occurs in the absence of ADH, it is not necessarily ADH mediated, and further, that MEOS rather than catalase accounts for basal ethanol metabolism and its increase after chronic ethanol treatment.

1-Butanol↗
PubMed1987

Ethanol-metabolizing pathways in deermice. Estimation of flux calculated from isotope effects.

The apparent deuterium isotope effects on Vmax/Km (D(V/K] of ethanol oxidation in two deermouse strains (one having and one lacking hepatic alcohol dehydrogenase (ADH] were used to calculate flux through the ADH, microsomal ethanol-oxidizing system (MEOS), and catalase pathways. In vitro, D(V/K) values were 3.22 for ADH, 1.13 for MEOS, and 1.83 for catalase under physiological conditions of pH, temperature, and ionic strength. In vivo, in deermice lacking ADH (ADH-), D(V/K) was 1.20 +/- 0.09 (mean +/- S.E.) at 7.0 +/- 0.5 mM blood ethanol and 1.08 +/- 0.10 at 57.8 +/- 10.2 mM blood ethanol, consistent with ethanol oxidation principally by MEOS. Pretreatment of ADH- animals with the catalase inhibitor 3-amino-1,2,4-triazole did not significantly change D(V/K). ADH+ deermice exhibited D(V/K) values of 1.87 +/- 0.06 (untreated), 1.71 +/- 0.13 (pretreated with 3-amino-1,2,4-triazole), and 1.24 +/- 0.13 (after the ADH inhibitor, 4-methylpyrazole) at 5-7 mM blood ethanol levels. At elevated blood ethanol concentrations (58.1 +/- 2.4 mM), a D(V/K) of 1.37 +/- 0.21 was measured in the ADH+ strain. For measured D(V/K) values to accurately reflect pathway contributions, initial reaction conditions are essential. These were shown to exist by the following criteria: negligible fractional conversion of substrate to product and no measurable back reaction in deermice having a reversible enzyme (ADH). Thus, calculations from D(V/K) indicate that, even when ADH is present, non-ADH pathways (mostly MEOS) participate significantly in ethanol metabolism at all concentrations tested and play a major role at high levels.

Acetates↗
PubMed1987

Respective roles of the microsomal ethanol oxidizing system and catalase in ethanol metabolism by deermice lacking alcohol dehydrogenase.

To evaluate the roles of MEOS (microsomal ethanol oxidizing system) and catalase in non-alcohol dehydrogenase (ADH) ethanol metabolism, MEOS and catalase activities in vitro and ethanol oxidation rates in hepatocytes from ADH-negative deermice were measured after treatment with catalase inhibitors and/or a stimulator of H2O2 generation. Inhibition of ethanol peroxidation by 3-amino-1,2,4-triazole (aminotriazole) was found to be greater than 85% up to 3 h and 80% at 6 h in liver homogenates. Urate (1 mM) which stimulates H2O2 production in living systems, increased ethanol oxidation fourfold in control but not in cells from aminotriazole-treated animals, documenting effective inhibition of catalase-mediated ethanol peroxidation by aminotriazole. While aminotriazole slightly depressed (15%) basal ethanol oxidation in hepatocytes, in vitro experiments showed a similar decrease in MEOS activity after aminotriazole pretreatment. Azide (0.1 mM), a potent inhibitor of catalase in vitro, also did not affect ethanol oxidation in control cells. By contrast, 1-butanol, a competitive inhibitor of MEOS, but neither a substrate nor an inhibitor of catalase, decreased ethanol oxidation rates in a dose-dependent manner. These results show that, in deermice lacking ADH, catalase plays little if any role in hepatic ethanol oxidation, and that MEOS mediates non-ADH metabolism.

1-Butanol↗
PubMed1987

The microsomal ethanol oxidizing system and its interaction with other drugs, carcinogens, and vitamins.

The interaction of ethanol with the oxidative drug-metabolizing enzymes present in liver microsomes results in a number of clinically significant side effects in the alcoholic. Following chronic ethanol consumption, the activity of the microsomal ethanol oxidizing system (MEOS) increases. This enhancement of MEOS activity is primarily due to the induction of a unique microsomal cytochrome P-450 isozyme, which has a high capacity for ethanol oxidation, as shown in reconstituted systems. Normally present in liver microsomes at low levels, this form of cytochrome P-450 increases dramatically after chronic ethanol intake in many species, including baboons. The in-vivo role of cytochrome P-450 in hepatic ethanol oxidation, especially following chronic ethanol consumption, has been conclusively demonstrated in deer-mice lacking liver ADH. Induction of microsomal cytochrome P-450 by ethanol is associated with the enhanced oxidation of other drugs as well, resulting in metabolic tolerance to these agents. There is also increased cytochrome P-450-dependent activation of known hepatotoxins such as carbon tetrachloride and acetaminophen, which may explain the greater susceptibility of alcoholics to the toxicity of industrial solvents and commonplace analgesics. In addition, the ethanol-inducible form of cytochrome P-450 has the highest capacity of all known P-450 isozymes for the activation of dimethylnitrosamine, a potent (and ubiquitous) carcinogen. Moreover, cytochrome P-450-catalyzed oxidation of retinol is accelerated in liver microsomes, which may contribute to the hepatic vitamin A depletion seen in alcoholics. In contrast to chronic ethanol consumption, acute ethanol intake inhibits the metabolism of other drugs via competition for shared microsomal oxidation pathways. Thus, the interplay between ethanol and liver microsomes has a profound impact on the way heavy drinkers respond to drugs, solvents, vitamins, and carcinogens.

Alcohol Dehydrogenase↗
PubMed1987

Evidence against the involvement of opiate neurons in mediating the effect of clomiphene citrate on gonadotropin-releasing hormone neurons.

This study was designed to assess whether the hypothalamic action of clomiphene citrate (CC) on gonadotropin-releasing hormone (GnRH) neurons required activity of opiate neurons. Ten women were studied in two successive cycles. In the first cycle they received infusion of saline or naloxone (2 mg intravenous bolus followed by 1.6 mg/hour) for 9 hours, in random order on days 5 and 6 of the cycle. In the second cycle each woman was treated with CC (100 mg) for 5 days before study on day 6. In each study, blood samples were collected at 15-minute intervals for 9 hours; during the last hour 10 micrograms GnRH was given to test the pituitary response. After CC, luteinizing hormone (LH) pulse frequency was accelerated, and mean serum LH, serum follicle-stimulating hormone, and estradiol increased, but the pituitary response to GnRH was unchanged. These changes are best explained by an increase in activity of GnRH neurons. Conversely, naloxone had no effect on LH pulsatility or the pituitary response to GnRH. This indicates that the action of CC at least during the early follicular phase is exerted primarily at the levels of the hypothalamic GnRH pulse generator and does not depend on the activity of opiate neurons.

Clomiphene↗
PubMed1987

Ethanol metabolism in alcohol dehydrogenase deficient deermice is mediated by the microsomal ethanol oxidizing system, not by catalase.

The participation of the microsomal ethanol oxidizing system (MEOS) and catalase in total ethanol metabolism is reviewed. Non-alcohol dehydrogenase (ADH) dependent pathways contribute to in vivo ethanol metabolism, but the respective role of each has long been debated. The principal data supporting a role for catalase is an occasionally reported moderate depression of ethanol metabolism after aminotriazole. In deermice lacking ADH, we observed a slight (though not statistically significant) decrease in basal ethanol metabolism of hepatocytes after aminotriazole. However, this decrease was found to parallel a similar inhibition of MEOS by aminotriazole, and thus may not reflect catalase mediated peroxidation in this animal. 1-butanol, a competitive inhibitor of ethanol oxidation by MEOS and not a substrate for catalase, decreased ethanol metabolism by hepatocytes in a concentration dependent manner. These results, as well as those from other investigators, indicate that MEOS mediates virtually all of non-ADH ethanol metabolism in vivo.

1-Butanol↗
PubMed1986

Assessment of the role of non-ADH ethanol oxidation in vivo and in hepatocytes from deermice.

Deermice genetically lacking alcohol dehydrogenase (ADH-) were used to quantitate the effect of 4-methylpyrazole (4-MP) on non-ADH pathways in hepatocytes and in vivo. Although primarily an inhibitor of ADH, 4-methylpyrazole was also found to inhibit competitively the activity of the microsomal ethanol-oxidizing system (MEOS) in deermouse liver microsomes. The degree of 4-MP inhibition in ADH- deermice then served to correct for the effect of 4-MP on non-ADH pathways in deermice having ADH (ADH+). In ADH+ hepatocytes, the percent contributions of non-ADH pathways were calculated to be 28% at 10 mM and 52% at 50 mM ethanol. When a similar correction was applied to in vivo ethanol clearance rates in ADH+ deermice, non-ADH pathways were found to contribute 42% below 10 mM and 63% at 40-70 mM blood ethanol. The catalase inhibitor 3-amino-1,2,4-triazole, while reducing catalase-mediated peroxidation of ethanol by 83-94%, had only a slight effect on blood ethanol clearance at ethanol concentrations below 10 mM, and no effect at all at 40-70 mM ethanol. These results indicate that non-ADH pathways (primarily MEOS) play a significant role in ethanol oxidation in vivo and in hepatocytes in vitro.

Alcohol Dehydrogenase↗
PubMed1986

Interaction between ethanol metabolism and mixed-function oxidation in alcohol dehydrogenase positive and negative deermice.

To assess the effect of non alcohol dehydrogenase (ADH) ethanol metabolism on mixed-function oxidation, aminopyrine demethylation was studied in vivo and in vitro in deermice having normal liver ADH (ADH+) or lacking it (ADH-), in the presence and absence of ethanol. When injected 15 min prior to administration of [14C]aminopyrine, ethanol reduced the 14CO2 exhalation rate in both ADH- and ADH+ deermice. The inhibitory effect of ethanol was dose dependent in both strains, and there was no significant difference between strains. Chronic ethanol feeding increased 14CO2 production from [14C]aminopyrine in both animal strains (ADH- alcohol 5.9 +/- 1.3 vs ADH- control 2.9 +/- 0.03, P less than 0.025; ADH+ alcohol 5.9 +/- 0.3 vs ADH+ control 2.7 +/- 1.3 nmoles aminopyrine/100 g body wt/min, P less than 0.001). Alcohol feeding also induced aminopyrine N-demethylase activity measured in vitro. This induction was more pronounced in ADH- deermice. Ethanol also inhibited aminopyrine demethylation in liver homogenates from ADH- and ADH+ animals in a dose-dependent manner and to a comparable degree in both strains. The kinetics of aminopyrine N-demethylase inhibition by ethanol was competitive in the microsomal fraction from ADH- as well as ADH+ animals. These results suggest that inhibition of mixed-function oxidation by ethanol may be due to an effect of ethanol on the hepatic microsomes rather than to redox changes produced by ADH-mediated ethanol oxidation. Further, chronic ethanol feeding increased microsomal aminopyrine demethylation independently of the presence of ADH.

Alcohol Dehydrogenase↗
PubMed1982

Partial characterization of hepatic aldehyde dehydrogenase from the baboon.

The activities, isozymic forms, response to disulfiram and some physical and kinetic properties of hepatic aldehyde dehydrogenase (A1DH, [EC.1.2.1.3]) from baboons were investigated. A1DH specific activity was greater in mitochondria than in cytosol but cytosolic A1DH was more sensitive to disulfiram than mitochondrial A1DH. Gel isoelectric focusing revealed three major isozyme groups focusing between pH 4 and 7, two in mitochondria and one in cytosol. Isozyme profile differences between control and ethanol-fed baboons appeared chiefly in the cytosol. Cytosolic A1DH from a control baboon was purified 42 fold with a 21% yield by ammonium sulfate fractionation, ion exchange chromatography, and affinity chromatography. The enriched enzyme displayed non-linear kinetics with 10% of the total activity having a Km of 0.3 microM and 90% having a Km of 160 microM. pH for optimum activity was 9.0, molecular weight 290,000 and, between pH 6.8 and 8.0, Mg++ ions inhibited the A1DH activity in the cytosol.

Aldehyde Dehydrogenase↗
PubMed1980

Suppressive effects of thiopental and halothane on specific arms of the immune response.

The effect of thiopental, halothane and surgery on specific arms of the immune response of normal mice was studied. These experiments represent the first step in localizing a potentially correctable anesthesia/surgery-induced defect in immune reactivity which may be involved with postoperative increases in tumor growth. The delayed-type hypersensitivity (DTH) response of mice to 2,4-dinitrochlorobenzene (DNCB) was studied. Combinations of induction and inhalation anesthesia and surgery were administered at various phases of the immune response to DNCB. Thiopental impaired the afferent response while halothane impaired the efferent response. When the agents were combined, both arms of the immune response were suppressed. A surgical procedure, in most experiments, did not produce a greater immunosuppression than thiopental and halothane. The administration of an immunorestorative agent, thiabendazole, returned reactivity to normal levels. Thiopental and halothane either affect different immune cell populations or they affect different functions of a cell population active in both arms of the DTH response. In relation to tumor growth, the degree of suppression may not be as significant as the cell population impaired.

Anesthesia↗