Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histamine H2-receptor antagonists are widely used in the treatment of gastrointestinal diseases related to gastric acid hypersecretion. Cimetidine was introduced into medical practice in 1976 and ranitidine, famotidine and nizatidine in 1981, 1985 and 1987, respectively. Haematological adverse effects are relatively uncommon and most have been reported in cases of cimetidine administration. These adverse effects are reviewed under 4 main headings: (a) blood cytopenias and leucocytosis; (b) coagulation disorders related to drug interactions with oral anticoagulants; (c) reduction of dietary iron absorption; and (d) reduction of dietary cobalamin absorption. 85 reported cases of blood cytopenias attributed to these drugs are reviewed, of which 75 (88%) were associated with cimetidine therapy. In postmarketing surveillance studies, the incidence of cimetidine-associated blood cytopenia has been evaluated at about 2.3 per 100,000 patients. Neutropenia and agranulocytosis are by far the most frequently encountered. Whatever the drug or the type of cytopenia, this adverse effect is almost always rapidly reversible when treatment is stopped. Moreover, in several cases other factors such as underlying diseases or additional drugs could have been responsible, at least partly, for the cytopenia. The pathophysiological basis of these adverse effects remains poorly explained. Various mechanisms have been proposed, which in some cases are probably associated: (a) direct toxicity for haemopoietic stem cells; (b) drug-induced immune reactions leading to blood or bone marrow cell damage, and (c) drug interactions, with increased and prolonged action of potentially haematotoxic drugs. Mechanisms (a) and (c) appear to be of particular clinical importance in cases of impaired renal elimination of H2-receptor antagonists. Cimetidine and probably to a lesser extent ranitidine potentiate the action of oral anticoagulants of both coumarin and indanedione structure. This may result in haemorrhagic complications. Such action is a consequence of the reduced hepatic metabolism of oral anticoagulants through a dose-dependent, reversible inhibition of cytochrome P450. Malabsorption of dietary iron and cobalamin appears to result from inhibition of gastric secretion by the H2-receptor antagonists. This is of no clinical importance in short term treatment, but long term use of H2-receptor antagonists may theoretically contribute to the occurrence of iron or cobalamin deficiency anaemia.
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PMID:Haematological adverse effects of histamine H2-receptor antagonists. 290 59

The effect of repeated parenteral administration of aluminum (Al) was investigated to determine if a relationship exists between the severity of anemia and increase in hepatic heme oxygenase activity. Female Swiss Webster mice were dosed for 11 d with 50 mg Al/kg, as Al lactate, and sodium lactate was given to control mice. On d 12, hematocrit, hemoglobin, blood smears, hepatic heme oxygenase activity, and cytochrome P450 levels were assessed. Significant decreases in hematocrit (39.1 +/- 0.7 vs 43.1 +/- 0.3% in controls) and hemoglobin (13.1 +/- 0.4 vs 14.2 +/- 0.2 g/dL in controls) were produced by Al administration. Blood smears from Al-treated mice consistently showed smaller, more irregular red cells. Cytochrome P450 content was significantly decreased (0.443 +/- 0.043 vs 0.665 +/- 0.055 nmol/mg) whereas hepatic heme oxygenase activity was significantly increased (2.75 +/- 0.34 vs 1.66 +/- 0.20 nmol/mg/h) in Al-treated animals. The production of mild anemia by parenteral aluminum correlated significantly with the increase in heme oxygenase activity, which, although only 66% greater than in control, preceded a significant loss of cytochrome P450. The increased heme oxygenase activity, with subsequent increased destruction of heme and/or heme proteins is discussed as a possible mechanism for the microcytic, hypochromic anemia associated with Al overload.
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PMID:Heme oxygenase induction. A possible factor in aluminum-associated anemia. 751 25

Benzene, an important industrial solvent, is also present in unleaded gasoline and cigarette smoke. The hematotoxic effects of benzene are well documented and include aplastic anemia and pancytopenia. Some individuals exposed repeatedly to cytotoxic concentrations of benzene develop acute myeloblastic anemia. It has been hypothesized that metabolism of benzene is required for its toxicity, although administration of no single benzene metabolite duplicates the toxicity of benzene. Several investigators have demonstrated that a combination of metabolites (hydroquinone and phenol, for example) is necessary to duplicate the hematotoxic effect of benzene. Enzymes implicated in the metabolic activation of benzene and its metabolites include the cytochrome P450 monooxygenases and myeloperoxidase. Since benzene and its hydroxylated metabolites (phenol, hydroquinone, and catechol) are substrates for the same cytochrome P450 enzymes, competitive interactions among the metabolites are possible. In vivo data on metabolite formation by mice exposed to various benzene concentrations are consistent with competitive inhibition of phenol oxidation by benzene. Other organic molecules that are substrates for cytochrome P450 can inhibit the metabolism of benzene. For example, toluene has been shown to inhibit the oxidation of benzene in a noncompetitive manner. Enzyme inducers, such as ethanol, can alter the target tissue dosimetry of benzene metabolites by inducing enzymes responsible for oxidation reactions involved in benzene metabolism. The dosimetry of benzene and its metabolites in the target tissue, bone marrow, depends on the balance of activation processes, such as enzymatic oxidation, and deactivation processes, like conjugation and excretion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Critical issues in benzene toxicity and metabolism: the effect of interactions with other organic chemicals on risk assessment. 769 73

The Fanconi anemia (FA) genes play an important role in maintaining chromosomal stability and the defense of mammalian cells against cross-linking agents, such as cisplatin and mitomycin C (MMC). Cells derived from FA patients display a characteristic hypersensitivity toward cross-linking agents. Despite great progression in our understanding of the mechanisms that protect cells against these potent anti-cancer drugs, the specific roles of FA gene products in these processes have not been delineated. Recent studies have shown that the FA group C gene product, FANCC, can bind to and regulate the activity of cytochrome P450-reductase (P450R), an enzyme involved in the bioactivation of MMC. In this mini-review, this finding is placed in the context of complex mechanisms involved in the bioreductive activation of MMC and the hypersensitivity of FA cells to MMC. Although it would be premature to attribute the FA phenotype wholly to an abnormal activation of MMC, the regulation of P450R by FANCC suggests a novel link between one or more FA gene products, the cellular oxidative state, and the response to chemotherapeutic agents. Copyright 2000 Harcourt Publishers Ltd.
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PMID:Do Fanconi anemia genes control cell response to cross-linking agents by modulating cytochrome P-450 reductase activity? 1149 88

Bosentan, a dual endothelin receptor antagonist, is indicated for the treatment of patients with pulmonary arterial hypertension (PAH). Following oral administration, bosentan attains peak plasma concentrations after approximately 3 hours. The absolute bioavailability is about 50%. Food does not exert a clinically relevant effect on absorption at the recommended dose of 125 mg. Bosentan is approximately 98% bound to albumin and, during multiple-dose administration, has a volume of distribution of 30 L and a clearance of 17 L/h. The terminal half-life after oral administration is 5.4 hours and is unchanged at steady state. Steady-state concentrations are achieved within 3-5 days after multiple-dose administration, when plasma concentrations are decreased by about 50% because of a 2-fold increase in clearance, probably due to induction of metabolising enzymes. Bosentan is mainly eliminated from the body by hepatic metabolism and subsequent biliary excretion of the metabolites. Three metabolites have been identified, formed by cytochrome P450 (CYP) 2C9 and 3A4. The metabolite Ro 48-5033 may contribute 20% to the total response following administration of bosentan. The pharmacokinetics of bosentan are dose-proportional up to 600 mg (single dose) and 500 mg/day (multiple doses). The pharmacokinetics of bosentan in paediatric PAH patients are comparable to those in healthy subjects, whereas adult PAH patients show a 2-fold increased exposure. Severe renal impairment (creatinine clearance 15-30 mL/min) and mild hepatic impairment (Child-Pugh class A) do not have a clinically relevant influence on the pharmacokinetics of bosentan. No dosage adjustment in adults is required based on sex, age, ethnic origin and bodyweight. Bosentan should generally be avoided in patients with moderate or severe hepatic impairment and/or elevated liver aminotransferases. Ketoconazole approximately doubles the exposure to bosentan because of inhibition of CYP3A4. Bosentan decreases exposure to ciclosporin, glibenclamide, simvastatin (and beta-hydroxyacid simvastatin) and (R)- and (S)-warfarin by up to 50% because of induction of CYP3A4 and/or CYP2C9. Coadministration of ciclosporin and bosentan markedly increases initial bosentan trough concentrations. Concomitant treatment with glibenclamide and bosentan leads to an increase in the incidence of aminotransferase elevations. Therefore, combined use with ciclosporin and glibenclamide is contraindicated and not recommended, respectively. The possibility of reduced efficacy of CYP2C9 and 3A4 substrates should be considered when coadministered with bosentan. No clinically relevant interaction was detected with the P-glycoprotein substrate digoxin. In healthy subjects, bosentan doses >300 mg increase plasma levels of endothelin-1. The drug moderately reduces blood pressure, and its main adverse effects are headache, flushing, increased liver aminotransferases, leg oedema and anaemia. In a pharmacokinetic-pharmacodynamic study in PAH patients, the haemodynamic effects lagged the plasma concentrations of bosentan.
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PMID:Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. 1556 89

(1) When multiple myeloma relapses more than one year after initial treatment, the median survival time is only 12 to 15 months. (2) Bortezomib is a cytotoxic agent that inhibits the 26S proteasome, a complex involved in intracellular protein breakdown in mammals. Bortezomib was initially licensed for the treatment of myeloma after multiple treatment failure; its indications were subsequently modified to include second-line treatment. (3) Second-line bortezomib therapy has not been compared with haematopoietic stem cell grafting, a treatment with documented efficacy. (4) An unblinded comparative trial involving 54 patients requiring second-line treatment showed that bortezomib at a dose of 1.3 mg/m to the 2nd power (twice a week for two weeks, followed by a 10 day rest period) was significantly more effective than a dose of 1 mg/m to the 2nd power in terms of the median survival time (not determined in the 1.3 mg group, versus 26.7 months in the 1 mg group) and the median time to disease progression (11.7 versus 4.2 months). (5) Among 251 patients in whom first-line treatment had failed, bortezomib was significantly more effective than dexamethasone: the one-year survival rate was 80% versus 66% on dexamethasone, and the progression-free survival time was 6.2 months versus 3.5 months. (6) Adverse effects occurred in 30% to 60% of patients enrolled in clinical trials, and were severe in about 10% to 20% of patients. They mainly included fatigue, nausea and vomiting, diarrhoea, anaemia, thrombocytopenia, and peripheral neuropathy. Animal studies indicated a possible risk of cardiotoxicity, and cases of cardiac arrhythmias and conduction disorders were observed in clinical trials. (7) Bortezomib is metabolised by the cytochrome P450 isoenzyme CYP3A4, with a high risk of interactions. (8) The vials contain an excessive amount of this costly drug, creating a risk of inadvertent overdose and leading to unnecessary waste. (9) In practice, bortezomib is an alternative to steroid therapy for patients with multiple myeloma in whom first-line treatment has failed and who do not qualify for stem cell grafting. The choice of treatment must be discussed with the patient, after providing thorough information on the likely benefits and risks
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PMID:Bortezomib: new indication. Second-line treatment of myeloma: limited efficacy, major risks. 1676 98

This study was aimed at delineating molecular pathways essential in gender-different pathogenesis of chronic kidney diseases (CKD). Renal transcripts of nuclear receptors and metabolic enzymes in male and female kidneys from 5/6 nephrectomized (Nx) rats 7 weeks post-Nx were examined using branched DNA signal amplification assay. Nx-males had marked kidney injury coupled with anemia and malnutrition. Nx-females had moderate renal injury, and were free of albuminuria, anemia, and malnutrition. Nx-males had systemic and renal inflammation, which were largely absent in Nx-females. Blood 17beta-estradiol, testosterone, and corticosterone did not change, whereas urinary testosterone decreased in both genders. Compared to males, female kidneys had higher androgen receptor (AR) and aryl hydrocarbon receptor (AhR) but lower estrogen receptor alpha (ERalpha). Compared to Nx-males, female remnant kidneys had less decreases in ERalpha and peroxisome proliferator-activated receptor alpha (PPARalpha), had no induction of AR and decrease of acyl-CoA oxidase, whereas had induction of cytochrome P450 4a1 (Cyp4a1) but decrease of AhR. Renal protein expression of a 52-kDa isoform of Wilm's tumor 1 (WT1), transcription factor critical in nephrogenesis, decreased dramatically in Nx-males but largely preserved in Nx-females. In conclusion, gender divergences in basal expression and alteration of ERalpha, AR, AhR, WT1, and PPARalpha/Cyp4a1 during CKD may explain gender differences in CKD progression and outcome of renal transplantation.
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PMID:Gender differences in renal nuclear receptors and aryl hydrocarbon receptor in 5/6 nephrectomized rats. 1713 Aug 19

Benzene is an important industrial chemical. At certain levels, benzene has been found to produce aplastic anemia, pancytopenia, myeloblastic anemia and genotoxic effects in humans. Metabolism by cytochrome P450 monooxygenases and myeloperoxidase to hydroquinone, phenol, and other metabolites contributes to benzene toxicity. Other xenobiotic substrates for cytochrome P450 can alter benzene metabolism. At high concentrations, toluene has been shown to inhibit benzene metabolism and benzene-induced toxicities. The present study investigated the genotoxicity of exposure to benzene and toluene at lower and intermittent co-exposures. Mice were exposed via whole-body inhalation for 6h/day for 8 days (over a 15-day time period) to air, 50 ppm benzene, 100 ppm toluene, 50 ppm benzene and 50 ppm toluene, or 50 ppm benzene and 100 ppm toluene. Mice exposed to 50 ppm benzene exhibited an increased frequency (2.4-fold) of micronucleated polychromatic erythrocytes (PCE) and increased levels of urinary metabolites (t,t-muconic acid, hydroquinone, and s-phenylmercapturic acid) vs. air-exposed controls. Benzene co-exposure with 100 ppm toluene resulted in similar urinary metabolite levels but a 3.7-fold increase in frequency of micronucleated PCE. Benzene co-exposure with 50 ppm toluene resulted in a similar elevation of micronuclei frequency as with 100 ppm toluene which did not differ significantly from 50 ppm benzene exposure alone. Both co-exposures - 50 ppm benzene with 50 or 100 ppm toluene - resulted in significantly elevated CYP2E1 activities that did not occur following benzene or toluene exposure alone. Whole blood glutathione (GSH) levels were similarly decreased following exposure to 50 ppm benzene and/or 100 ppm toluene, while co-exposure to 50 ppm benzene and 100 ppm toluene significantly decreased GSSG levels and increased the GSH/GSSG ratio. The higher frequency of micronucleated PCE following benzene and toluene co-exposure when compared with mice exposed to benzene or toluene alone suggests that, at the doses used in this study, toluene can enhance benzene-induced clastogenic or aneugenic bone marrow injury. These findings exemplify the importance of studying the effects of binary chemical interactions in animals exposed to lower exposure concentrations of benzene and toluene on benzene metabolism and clastogenicity. The relevance of these data on interactions for humans exposed at low benzene concentrations can be best assessed only when the mechanism of interaction is understood at a quantitative level and incorporated within a biologically based modeling framework.
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PMID:Genotoxicity of intermittent co-exposure to benzene and toluene in male CD-1 mice. 1845 11

This study was designed to analyze the effect of environmental oxidative stress on human placental monooxygenases, glutathione S-transferase (GST) activity and polycyclic aromatic hydrocarbon (PAH)-DNA adducts in human term placentas from radioactivity-contaminated and chemically-polluted areas of the Ukraine and Belarus, and to compare these biomarkers to the newborn's general health status. Placental PAH-DNA adduct formation, GST activity, 7-ethoxycoumarin O-deethylase (ECOD) activity, and thiobarbituric reactive substances (TBARS), an index of lipid peroxidation, were measured in groups of women exposed to different levels of radioactivity and PAH pollution. The in vitro metabolism data, obtained from 143 human placental samples at term, were compared to indices of maternal and newborn health. The highest ECOD activity was recorded in placentas obtained from chemically-polluted areas and a radioactivity-contaminated area; the ECOD activity was 7-fold and 2-fold higher compared to the region considered to be "clean". Newborns with the most compromised health status displayed the greatest down-regulation of GST activity (144-162mUmgprotein(-1) vs. 258-395mUmgprotein(-1)), enhanced ECOD activity and the highest level of PAH-DNA adduct formation. The highest level of TBARS was observed in women exposed to the highest levels of radiation. The efficiency of placental detoxification negatively correlated with maternal age and the health status of the newborn. Environmental oxidative stress was related to an increase in anemia, threatened abortions, toxemia, fetal hypoxia, spontaneous abortions and fetal hypotrophy. Our data suggest that chemically- or radioactivity-induced oxidative stress enhance cytochrome P450-mediated enzymatic activities potentially resulting in increased formation of reactive metabolites. The activity of GSH-transferase is not enhanced. This imbalance in detoxification capacity can be measured as increased production of PAH-DNA adducts, decreased lipid peroxidation and compromised fetal health.
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PMID:Human placental glutathione S-transferase activity and polycyclic aromatic hydrocarbon DNA adducts as biomarkers for environmental oxidative stress in placentas from pregnant women living in radioactivity- and chemically-polluted regions. 2038 Aug 73

Proton pump inhibitors (PPIs) are the drugs of choice in the therapy of acid-related disorders. PPIs are as a class remarkably safe. Serious adverse events such as acute interstitial nephritis are extremely rare. Some reports in recent years have placed some concern on the long-term use of PPIs. Long-term therapy with PPIs can cause hypochlorhydria, hypergastrinemia and has interactions on hepatic cytochrome P450 enzymes which might increase the risk of infectious complications, nutritional deficiencies and drug-drug interactions. The vast majority of data came from retrospective case-control or cohort studies which are prone to confounders. At the moment we cannot conclude that long-term PPI use causes anemia, osteoporosis and bone fractures, increases the risk for pulmonary or enteric infections, has an effect on GUT mucosa, polyp or tumor formation, or that PPI use increases the risk of cardiovascular events in patients on PPIs and clopidogrel. We need prospective randomized trials to be able to definitely answer the questions raised in epidemiologic studies. Maintenance therapy with PPIs should be started only if strict indications for that therapy are fulfilled.
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PMID:Long-term acid inhibition: benefits and harms. 2209 13


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