Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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
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PMID:Adrenergic modulation of hepatotoxicity. 918 24

From 1984 through 1992, staff at The Marine Mammal Center (TMMC, Sausalito, California, USA) examined 207 northern elephant seals (Mirounga angustirostris) with a condition of unknown etiology called northern elephant seal skin disease (NESSD). The skin lesions were characterized by patchy to extensive alopecia and hyperpigmentation, punctate or coalescing epidermal ulceration, and occasionally, massive skin necrosis. Microscopic lesions included ulcerative dermatitis with hyperkeratosis, squamous metaplasia and atrophy of sebaceous glands. All diseased seals were less than 2 years of age and suffered from emaciation, depression, and dehydration. Mortality from septicemia increased significantly with severity of skin ulceration. Compared to 14 apparently unaffected seals, diseased seals had depressed levels of circulating thyroxine, triiodothyronine, retinol, serum iron, albumin, calcium, and cholesterol. Levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, gamma glutamyl transpeptidase, blood urea nitrogen, and uric acid were elevated. Morphometrically, diseased animals were approximately 15% smaller than normal seals of the same sage. Serum and blubber concentrations of 36 polychlorinated biphenyl congeners (sigma PCB) and dichloro-diphenyl-dichloroethylene (p,p'-DDE) were negatively correlated with body mass. Mean concentrations of sigma PCB and p,p'-DDE in serum in diseased seals were elevated as compared to apparently normal seals. Etiology of this syndrome remains unknown, but the possibility of PCB toxicosis cannot be ruled out.
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PMID:Clinical and pathological characterization of northern elephant seal skin disease. 924 88

Although studies have shown that hepatocellular function is depressed during the early, hyperdynamic stage of sepsis, the mechanism responsible for this remains unknown. To determine whether neutrophils play any role in producing this depression, hepatocellular function was measured in neutrophil-competent and neutropenic animals subjected to sepsis. Neutropenia was induced by tail vein injection of an immunoglobulin directly against rat neutrophils (anti-neutrophil Ig) at 16 and 2 h prior to the initiation of cecal ligation and puncture (CLP, i.e., a model of polymicrobial sepsis). Neutropenia was confirmed by peripheral blood smears. Neutrophil-competent controls were given nonimmunized Ig before the onset of sepsis. Sham-operated animals received anti-neutrophil Ig or control Ig. Hepatocellular function [i.e., the maximal velocity of indocyanine green clearance (Vmax) and efficiency of the clearance (Km)] was determined by a fiber-optic catheter and in vivo hemoreflectometer at 5 h after CLP (i.e., early, hyperdynamic sepsis) or sham operation. Serum alanine aminotransferase (ALT) levels were also determined. The results indicate that although circulating levels of ALT were not elevated, hepatocellular function was significantly depressed during early sepsis. The depression in Vmax and Km was, however, prevented by neutrophil depletion, suggesting an integral role of the neutrophils in depressing hepatocellular function under such conditions. The results suggest that the prudent modulation of neutrophil function during the early stage of polymicrobial sepsis may be beneficial for preventing or delaying the occurrence of hepatocellular dysfunction.
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PMID:The role of neutrophils in producing hepatocellular dysfunction during the hyperdynamic stage of sepsis in rats. 944 4

Three red kangaroos (Megaleira rufus), an adult male, an adult female, and a yearling, were exposed in bedding and food to coastal bermuda hay that contained the toxic plant Lantana camara. The adult male exhibited signs of anorexia, depression, lethargy, and jaundice. The adult female was presented dead. After 1 wk, following exposure to sunlight, the adult male and a yearling joey developed exudative dermatitis of the ear margins, eyelids, muzzle, and scrotum and opacity of the corneas. The adult male had a leucocytosis, anemia, bilirubinemia, bilirubinuria, hyperproteinemia, and elevated alanine aminotransferase, gamma glutamyl transpeptidase, alkaline phosphatase, and bile acid serum levels. Postmortem examination of the adult male revealed jaundice, and the liver was swollen, mottled, and pale yellow to reddish yellow. The gall bladder was markedly distended. Histopathologically, there was hepatocellular enlargement with vesiculation of the nuclei and sporadic feathery degeneration of the cytoplasm. The yearling joey survived and was treated symptomatically with i.v. fluids and antibiotics. The history, clinical signs, diagnostic findings, necropsy findings, and exposure to the toxic plant Lantana camara support the diagnosis of secondary photosensitization and hepatoxicity.
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PMID:Hepatotoxicity and secondary photosensitization in a red kangaroo (Megaleia rufus) due to ingestion of Lantana camara. 973 38

1. Thonningia sanguinea, a plant used prophylactically against bronchial asthma in Ghana was recently found to have antioxidative and hepatoprotective actions in our laboratory. 2. In this study, the effect of T. sanguinea extract on certain biochemical indices in serum and liver of Fischer 344 rats given a single intraperitoneal (i.p.) dose (1 mg/kg) of aflatoxin B1 (AFB1) was investigated. 3. Administration of AFB1 resulted in significant increases in serum alanine aminotransferase (ALT) and glutathione S-transferase (GST) levels and a significant decrease in aniline hydroxylase activity in liver microsomes. When T. sanguinea (5 ml/kg) was intraperitoneally administered to rats 12 h and 1 h before AFB1, liver injury was significantly reduced as seen in the decreased levels of serum ALT and serum GST. However, the decrease in aniline hydroxylase activity by AFB1 was not recovered but enhanced by T. sanguinea pre-treatment. 4. Kinetic analysis of cytochrome P450 activity of rat liver microsomes in vitro demonstrated that T. sanguinea inhibited aniline hydroxylase non-competitively suggesting depression of biotransformation of AFB1 to toxic metabolites. 5. The data indicate a hepatoprotective action of T. sanguinea against AFB1-induced liver injury.
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PMID:Medicinal herb, Thonningia sanguinea protects against aflatoxin B1 acute hepatotoxicity in Fischer 344 rats. 975 33

The effect of Kupffer cell depression on concanavalin A (Con A)-induced cytokine mRNA expression in the liver was studied. Gadolinium chloride (GdCl3) is a commonly used Kupffer cell inhibitor. GdCl3 (40 mg/kg, i.p.) was injected into each mouse, and 24 hr later, Con A (0.2 mg/mouse) was administered. Plasma was obtained at 24 hr after Con A treatment for alanine aminotransferase (ALT) measurement. GdCl3 treatment inhibited Con A-induced elevation of ALT. However, it did not inhibit Con A-induced interleukin-2 or tumor necrosis factor-alpha mRNA expression. The present results suggest that Kupffer cells are not responsible for Con A-induced cytokine expression in the liver.
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PMID:Effect of gadolinium chloride treatment on concanavalin A-induced cytokine mRNA expression in mouse liver. 980 71

Cholestatic jaundice is the major complication of total parenteral nutrition (TPN) in infancy. We have previously shown that the TPN solution is directly toxic to the liver, and that this toxicity appears to be mediated by one or more amino acids. Elevated serum methionine levels, without corresponding increases in its metabolites, suggest that accumulation of this toxic amino acid may cause TPN cholestasis. Nine-week-old rabbits (n = 28) were divided into three groups. The FED group was fed standard rabbit chow ad libitum. The TPN group was not fed and received only i.v. TPN (including methionine 121 mg.kg-1.d-1), and lipids. The EXP group was fed chow ad libitum and received i.v. methionine (121 mg.kg-1.d-1). After 14 d, we evaluated bile flow, bromosulfophthalein excretion, serum liver enzymes, liver histology, and serum amino acid levels. Bile flow was significantly depressed in the TPN and EXP groups compared with FED controls (32.9 +/- 9.4 and 45.7 +/- 14.4 versus 82.9 +/- 13.8). Excretion of the bilirubin analog bromosulfophthalein tended to be delayed by methionine infusion (p = 0.15). Serum liver enzymes (aspartate transaminase, alanine aminotransferase, gamma-glutamyltransferase, and alkaline phosphatase) were normal in all groups. Histologic liver injury in the EXP group was similar to that caused by TPN. Balloon degeneration, and portal inflammation were seen in both groups. Homocysteine, an early metabolite of methionine, was elevated in the TPN and EXP groups compared with FED controls. Intravenous methionine is hepatotoxic. Despite full oral feeding, it produces a depression of bile flow and histologic liver injury similar to that seen with TPN. Elevated homocysteine levels suggests an enzymatic block early in the pathway of methionine metabolism. We believe that methionine may be an important factor in the pathogenesis of TPN cholestasis.
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PMID:Methionine infusion reproduces liver injury of parenteral nutrition cholestasis. 1023 61

Absidiosis was produced experimentally in 18 buffalo calves by intravenous inoculation of spores of Absidia corymbifera. Infected animals exhibited dullness, depression, partial anorexia and an initial pyrexia and coughing during the first week and two animals died on each of 9, 13 and 16 days post infection (DPI). The haemoglobin concentration and total erythrocyte count showed no appreciable change from their basal values at any stage of the experiment. However, the erythrocyte sedimentation rate and total leukocyte count increased significantly in the infected animals. The differential leukocyte count revealed a relative neutrophilia from 5 to 20 DPI. There was a significant increase in the serum total proteins, blood urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, serum alkaline phosphatase, total immunoglobulins and circulating immune complexes in the infected animals as compared to the controls. In the sera of the infected animals, specific Absidia corymbifera IgM and IgG antibodies were detected from 3 DPI to 6 DPI respectively by Dot-EIA. Type I and type III skin hypersensitivity were detected from 10 DPI and type IV hypersensitivity from 15 DPI onwards. The gross and microscopic pathological lesions were seen mainly in the lungs, in all except one of the affected animals. This animal died 9 DPI and mycotic granulomas were also seen in its heart and kidneys. The microscopic lesions in the lung took the form of well-developed granulomas.
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PMID:Sequential clinical, haematological, biochemical, immunopathological and histopathological alterations in buffalo calves (Bubalus bubalis) intravenously infected with Absidia corymbifera. 1044 50

Due to the limited efficacy of alpha-interferon for chronic hepatitis C amantadine has been proposed as a possible alternative method of treatment. However, few studies about efficacy of amantadine in chronic hepatitis C are available with controversial results. Stimulated by recent data in the literature, we studied the effect of 100 mg of amantadine HCL (alone) PO bid, for a four month period on alanine aminotransferase serum levels and viral load in a cohort of 18 patients (14 males and 4 females) with chronic hepatitis C, non-responders to alpha-interferon. Inclusion criteria were: detectable serum HCV-RNA, alanine aminotransferase above the upper limit of normal, chronic inflammation on liver biopsy, no other associated chronic liver disease and written informed consent. Available biopsies showed initially four cases of cirrhosis, six of chronic persistent hepatitis and eight of chronic active hepatitis. The most prevalent HCV genotypes were 3a (n = 9, 52.94%) and 1b (n = 6, 32.29%). Viral load (Amplicor HCV Monitor, Roche, USA) and alanine aminotransferase levels were obtained at baseline and after four months of treatment. All patients enrolled into the study but one completed the treatment. One patient discontinued amantadine due to severe depression. No significant reduction was observed between baseline and final values of alanine aminotransferase (139.118 +/- 79.789 vs. 99.588 +/- 62.583 U/L, P = 0.059) and viral load (7.154 +/- 1.596 vs. 6.574 +/- 1.584 log copies/mL, P = 0.147). Amantadine alone was not effective neither eradicating viremia nor normalizing alanine aminotransferase levels in chronic hepatitis C non-responders to alpha-interferon patients. It is suggested that only a study with amantadine alone in-patients without previous treatments could determine its efficacy in comparison with alpha-interferon.
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PMID:[Amantadine-HCL in the treatment of chronic hepatitis C in non-responders to alpha-interferon. Effect on ALT serum levels and viral load]. 1051 83

Some haematological and biochemical parameters were studied in guinea-pigs infected intraperitoneally with Salmonella dublin 493 at 1 x 10(6) viable cells per animal. The infected animals showed a rise in temperature within 24 h, followed by depression and loss of body weight. On the 15th day post infection, haematological studies revealed a significant increase in the total leukocyte count due to both lymphocytosis and neutrophilia, and a decrease in the total erythrocyte count and haemoglobin concentration. There was also a significantly higher mean corpuscular volume and lower mean corpuscular haemoglobin concentration, indicating a macrocytic hypochromic anaemia. The infection caused a significant increase in alanine aminotransferase activity and creatinine, blood urea nitrogen and globulin concentrations, and a decrease in albumin and triiodothyronine. There was no significant effect on serum total protein or on thyroxine, or in the activity of aspartate aminotransferase in the serum.
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PMID:Experimental salmonellosis in guinea-pigs: haematological and biochemical studies. 1059 73


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