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Biomedical subjects

R C James

Publications and source records attributed to R C James.

At least 55 records · Page 3Linked to original sources
PubMed1984

Paradoxical effects of perturbation of intracellular levels of glutathione on halothane-induced hepatotoxicity in hyperthyroid rats.

Exposure of hyperthyroid rats to halothane results in a centrilobular necrosis of the liver and an 11-fold increase in serum glutamate-pyruvate transaminase (SGPT) levels. These effects are not seen in euthyroid animals. Paradoxically, administration of diethylmaleate to hyperthyroid rats significantly decreased the levels of hepatic glutathione and blocked the halothane-induced hepatic necrosis as well as decreased the elevation of SGPT. In contrast, pretreatment of animals with N-acetylcysteine, an intracellular sulfhydryl repletor , significantly increased the severity of the halothane-induced hepatic necrosis and increased the elevation of SGPT. Similarly, cysteamine, another intracellular sulfhydryl repletor , also exacerbated halothane-induced liver injury. Halothane-induced hepatotoxicity is at least in part apparently regulated by cellular glutathione levels. Paradoxically, glutathione seems to be involved in the bioactivation rather than the detoxification of halothane.

Acetylcysteine↗
PubMed1984

L-alpha-acetylmethadol-induced tissue alterations in mice.

Single oral dosages of the synthetic narcotic analgesic, L-alpha-acetylmethadol (LAAM) increased serum glutamic-pyruvic transaminase (SGPT) levels throughout a two-day observation period and produced a persistent depletion of hepatic and renal glutathione (GSH) levels. These LAAM-induced changes demonstrated dose- and time-dependence within that dosage range producing mortality. Histological evaluation of livers from LAAM-treated mice revealed cytoplasmic and nuclear changes in centrilobular hepatocytes. Interestingly, neither the LAAM-induced histopathological changes nor the depression of hepatic GSH were altered by the induction of hepatic metabolism following pretreatment with either phenobarbital or 3-methylcholanthrene; however, the induction of hepatic drug metabolism did abate the four-day mortality and SGPT elevations.

Alanine Transaminase↗
PubMed1983

Characterization of hyperthyroidism enhancement of halothane-induced hepatotoxicity.

Administration of anesthetic doses of halothane to hyperthyroid male rats results in the development of hepatic necrosis. The severity of the hepatic lesion was dependent on the dose of triiodothyronine (T3) and the length of time it was administered. Pretreatment of rats with iodinated metabolites of thyroxin which do not induce hyperthyroidism did not result in any signs of hepatotoxicity after halothane exposure. The administration of halothane to hyperthyroid female rats or mice of either sex did not result in the development of any overt hepatotoxicity. Likewise, hyperthyroidism did not enhance the hepatotoxicity of another hepatotoxin bromobenzene. The in vitro enzymatic activities associated with cytochrome P-450-dependent metabolism and glutathione S-transferase conjugation activity were markedly altered in hyperthyroid rats. Cytochrome P-450 levels, aminopyrine N-demethylase activity, glutathione levels and glutathione S-transferase activity were all significantly lower in hyperthyroid rats. However, other enzyme activities were stimulated by T3 pretreatment; aniline hydroxylase activity was increased by 45% and cytochrome c reductase activity was increased by 54% in hyperthyroid rats. Glutathione levels were also reduced significantly in hyperthyroid male rats. Maximal changes in both the cytochrome P-450 system and in the glutathione detoxification system were required before halothane demonstrated its hepatotoxic effects. Thus, a new balance between cytochrome P-450-dependent bioactivation and glutathione conjugation of halothane may be necessary for the exaggerated hepatotoxicity of halothane seen in hyperthyroid male rats.

Alanine Transaminase↗
PubMed1982

Hepatic glutathione and hepatotoxicity: effects of cytochrome P-450 complexing compounds SKF 525-A, L-alpha acetylmethadol (LAAM), norLAAM, and piperonyl butoxide.

Four compounds forming metabolic intermediate complexes with cytochrome P-450 in vitro were studied for their effects on hepatic glutathione in the mouse. All four compounds depleted glutathione within 1-3 hr after administration. The effect was transient for piperonyl butoxide while lasting at least 24 hr for other compounds. Induction of the mixed-function oxidase system by phenobarbital had no effect on the glutathione-depleting actions of the compounds, but induction with 3-methylcholanthrene abolished the depletion seen with piperonyl butoxide and SKF 525-A. For SKF 525-A, L-alpha-acetylmethadol (LAAM) and norLAAM, the persistent lowering of glutathione was paralleled by elevations in serum glutamic-pyruvic transaminase (SGPT) activity. This depletion of glutathione and subsequent elevations in SGPT were found to be strain and species dependent for SKF 525-A, LAAM and norLAAM. Compounds which complex with cytochrome P-450 in vitro may increase drug toxicities in vivo by mechanisms other than inhibition of oxidative drug metabolism.

Alanine Transaminase↗
PubMed1982

Placental toxicology.

A review is presented of the literature concerning the placenta as a target organ for chemical- and drug-induced injuries that can ultimately lead to teratogenesis or reproductive defects. Such defects can result from the effects of xenobiotics on placental transport, blood flow or pathology, from the metabolism by the placenta of xenobiotics to harmful substances, or from the alteration by xenobiotics of placental endocrine function. Although it is clear that drug- or chemical-induced placental toxicity should be considered as a possible mechanism of teratogenicity, it is an area of research that has been comparatively neglected and is in need of extensive investigation.

Amino Acids↗
PubMed1982

Hepatic glutathione and hepatotoxicity: changes induced by selected narcotics.

Propoxyphene and morphine lowered hepatic glutathione and increased serum glutamic-pyruvic transaminase (SGPT) activity when administered to male mice. Maximal changes were seen at 3 to 6 hr after administration, but the effects lasted for as long as 18 hr. Morphine-induced hepatic changes potentiated both acetaminophen and cocaine-induced hepatotoxicity. Naltrexone, a narcotic antagonist, abolished the glutathione depletion produced by both propoxyphene and morphine, but did not alter the propoxyphene-induced elevations of SGPT. Naltrexone also was tested against other narcotic agonists we have previously demonstrated to be hepatotoxic. Naltrexone pretreatment of antagonized L-alpha-acetylmethadol (LAAM)-induced depletion of glutathione and elevations of SGPT. Similarly, naltrexone antagonized norLAAM-induced depletion of glutathione and elevations of SGPT, but only lessened the magnitude of the changes induced by SKF525-A. The narcotic agonists morphine, LAAM, norLAAM and propoxyphene lower hepatic glutathione and induce hepatocellular damage, but these two effects appear to be unrelated.

Acetaminophen↗
PubMed1980

The determination of meperidine, noremeperidine and deuterated analogs in blood and plasma by gas chromatography mass spectrometry selected ion monitoring.

A gas chromatographic mass spectrometric assay using selected ion monitoring for meperidine and normeperidine in blood and plasma is described. Both unlabeled and [3H]-phenyl ring labeled drugs may be determined simultaneously using [2H10] analogs as internal standards. Calibration curves are linear over the range 5--100 ng ml-1, the results reproducible (coefficient of variation < 5%), the sensitivity limit is about 5 ng using a 1 ml sample and no interference is present in blank blood or plasma, or by isotope inpurity. The method is shown to be applicable to measuring the concentration of meperidine and its metabolite, normeperidine, in blood, following simultaneous administration by the intravenous and oral routes of 25 mg each of unlabeled and [2H5] labeled drug, respectively.

Gas Chromatography-Mass Spectrometry↗
PubMedDate not supplied

The perturbation of hepatic glutathione by alpha 2-adrenergic agonists.

Single injections of epinephrine significantly lowered the hepatocellular levels of reduced glutathione (GSH) while producing small but significant elevations in serum glutamic-pyruvic transaminase (SGPT) activity. Hormones, i.e. glucagon and the corticosteroids, were also found to depress significantly hepatic glutathione. Based upon the agonist-antagonist studies performed, the hepatic GSH lowering effects of epinephrine appear to be mediated solely by alpha 2 receptors. Adrenergic antagonists with alpha 2 receptor blocking properties, phenotolamine and yohimbine, prevented the epinephrine-induced lowering of GSH while agonists with alpha 2 activity, clonidine and guanabenz, mimicked epinephrine's response. Antagonists with either alpha 1 or beta activity, i.e. prazosin, phenoxybenzamine and propranolol, did not prevent the epinephrine-induced lowering of hepatic GSH. Contrary to these findings antagonists with either alpha or beta receptor blocking activity significantly reduced the epinephrine-induced elevations in SGPT activity. Thus, there was no apparent relationship between the elevation of SGPT activity and the reduction in hepatic glutathione levels. It is concluded that the therapeutic administration of these compounds, or physiologic responses to stress or pain, may exacerbate the hepatotoxicity of compounds detoxified by GSH or alter important glutathione-mediated hepatocellullar processes.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Adrenergic modulation of hepatotoxicity.

Summaries of the interactions caused by altering adrenoreceptor activity in conjunction with the administration of selected hepatotoxicants are provided in Table 2 and Fig. 1. These hepatotoxicants can be divided into two groups, one whose toxicity is increased by adrenergic agonist drugs (group I) and the other whose toxicity is decreased by adrenergic antagonists (group II). Group I includes carbon tetrachloride, acetaminophen, and methylphenidate. Perhaps the most remarkable aspect these chemicals have in common is the striking potentiation that occurs with cotreatment with certain adrenergic agonist drugs. For each of these, cotreatment with the appropriate adrenergic agent can result in massive hepatocellular necrosis from an otherwise nontoxic dose. In terms of the specific adrenoreceptors involved and mechanisms of potentiation, however, they have little in common. Potentiation of carbon tetrachloride hepatotoxicity appears to be mediated by alpha(2)-adrenoceptor stimulation, acetaminophen is potentiated by alpha(1)-adrenoreceptor agonists, and methylphenidate responds to beta(2)-adrenoreceptor stimulation. Studies of the potentiation of carbon tetrachloride and acetaminophen agree that the timing of adrenergic stimulation relative to the hepatotoxicant dose is critically important to the interaction but markedly different for these two toxicants. Acetaminophen was potentiated only when the adrenergic drug was administered as a 3-h pretreatment. This is apparently a consequence of a mechanism of potentiation that involves adrenergic depression of hepatic glutathione content and a requirement that peak effects on glutathione of both the adrenergic agent and acetaminophen be coincident. The mechanism of potentiation of carbon tetrachloride hepatotoxicity is uncertain but clearly does not involve hepatic glutathione content. In contrast to acetaminophen, adrenergic effects must occur within a time window a few hours after the carbon tetrachloride dose for potentiation to occur. The importance of dose timing has not been evaluated for adrenergic potentiation of methylphenidate hepatotoxicity, but it is clear that this interaction is based on yet a third mechanism. While only three hepatotoxicants of the group I type have been examined in detail, the diversity of receptor types and mechanisms involved suggest that this phenomenon may be relevant for a wide variety of hepatotoxic drugs and chemicals. This interaction is also of interest because factors or events that lead to increased adrenergic stimulation are common in everyday life. Most over-the-counter cold and allergy preparations contain sympathomimetic drugs, and many prescription drugs produce adrenergic effects as either an extension of the intended therapeutic effect or as a side effect. Stress and some disease states can also lead to significant increases in peripheral adrenergic activity, creating the potential for increased susceptibility to hepatic injury from exposure to certain drugs or chemicals. Cocaine and bromobenzene represent group II, chemicals whose hepatotoxicity is diminished by cotreatment with adrenergic antagonist drugs. In the case of cocaine, adrenergic antagonist cotreatment was capable of reducing serum alanine aminotransferase activities by approximately 50%. For bromobenzene, the protection afforded by adrenergic antagonist cotreatment was more profound, with minimal hepatic lesions resulting from doses of bromobenzene that otherwise produced lethal hepatic necrosis. For the chemicals in group II, experimental observations are consistent with a phenomenon in which adrenergic potentiation of toxicity is supplied by the hepatotoxicant itself. Both cocaine and bromobenzene, in hepatotoxic doses increase endogenous catecholamine levels. When the effects of the elevated catecholamines are removed with the appropriate adrenergic antagonist, much lower toxicity (presumably due only to the direct hepatotoxic effects of the drug or chemical) is obse

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Excess costs of diabetes in the Aboriginal population of Manitoba, Canada.

OBJECTIVE: We developed a measure of the cost of diabetes for general and North American Indian populations of Manitoba and estimated the excess costs of diabetes which are attributable to diabetes prevalence rates and per person utilization of health services. RESEARCH DESIGN AND METHODS: We obtained data from the Manitoba Medicare database and the Manitoba Diabetes Database. We estimated costs for each service and cost per person for four populations: Indian and general population groups with and without diabetes. Excess cost formulas were estimated. RESULTS: Prevalence and utilization were considerably higher for the North American Indian population. As a first approximation, excess costs due to disease prevalence added 15.9% to total costs, while excess costs due to utilization add 14.6%. CONCLUSIONS: Disease prevalence indicates a need to focus on primary preventive measures. High utilization indicates complications, and suggests a need for secondary prevention.

Adolescent↗