Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Frentizole is a benzimidazoleurea that has immunosuppressive properties in mice. Eleven steroid-treated patients with active systemic lupus erythematosus received frentizole (150-350 mg/day) in combination with stable or decreasing doses of prednisone in an open label trial. Nine patients completed at least one 21- to 75-day course of therapy with this drug. Clinical parameters of disease improved in 8 of these 9 patients. Mean DNA binding decreased by 28%, mean CH50 increased by 20%, and mean absolute lymphocyte and T cell counts decreased by 25-26%. Granulocytopenia was not observed. Three patients developed reversible hepatic toxicity. Clinical and serologic improvement was noted in 3 patients who accepted a second 90-day course of frentizole therapy.
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PMID:Frentizole therapy of active systemic lupus erythematosus. 700 13

In summary, procainamide is a useful agent for suppressing premature depolarization frequency. Its short half-life of elimination requires a dosing frequency of every 3 hours with regular dosage forms or every 6-8 hours with a sustained action dosage. Because of the extreme unpredictability of plasma concentration, the dosage must be titrated in each patient with electrocardiographic monitoring serving as the most useful method of evaluating efficacy. Maximum and minimum plasma concentrations are helpful in monitoring the achievement of therapeutic plasma levels and adjusting the frequency of dosing, especially in the presence of impaired renal function or low cardiac output. Adverse effects of procainamide include anorexia, nausea, vomiting, fatigue, insomnia, visual hallucinations, and disorientation; these are minor and cease with discontinuation of the drug. Agranulocytosis has rarely been reported. Long-term treatment has resulted in the occurrence of a lupus-like syndrome that is reversible when the drug is stopped. Procainamide is excreted in breast milk and infants of mothers receiving procainamide should not be nursed.
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PMID:Pharmacokinetics of a sustained release procainamide preparation. 703 27

Carbamazepine, a widely used anticonvulsant, is associated with a wide range of adverse reactions including agranulocytosis, aplastic anemia and drug-induced lupus. It has also been reported to alter immune function in a variety of ways. We had previously demonstrated that carbamazepine is oxidized by activated neutrophils to several metabolites and this leads to covalent binding of the drug to the cells. It appears that the major metabolite responsible for this binding is 9-acridine carboxyaldehyde. In this study the effects on leukocyte function of carbamazepine and its leukocyte-generated metabolites were compared. Incubation of lymphocytes with 100 microM 9-acridine carboxaldehyde resulted in 40% cell death while carbamazepine at this concentration had no effect on viability. The effect on the immune cell function was investigated using the autologous mixed lymphocyte reaction (AMLR), allogeneic mixed lymphocyte reaction (MLR), lymphocyte transformation test (LTT) and mitogenesis assays. Alteration of immune cell function by the reactive metabolite, 9-acridine carboxyaldehyde, was demonstrated by an increased proliferation at low concentrations (0.08-1.0 microM) and inhibition at high concentrations (20-100 microM) in the allogeneic MLRs. Carbamazepine had no measurable effect. 9-Acridine appears to have more of an effect on B-cells since this augmentation-suppression phenomenon was also observed in mitogenesis assays with Staphylococcus aureus, a B-cell mitogen, in contrast to mostly inhibition observed in the mitogenesis assay with phytohemagglutinin, a T-cell mitogen. Again, carbamazepine had no measurable effects at comparable concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of carbamazepine and its reactive metabolite, 9-acridine carboxaldehyde, on immune cell function in vitro. 759 69

Invasive aspergillosis is seldomly described in systemic lupus erythematosus. We present two cases of aspergillosis and review 21 cases reported between 1957 and 1994. The typical clinical presentation is fever and cough in a hospitalized SLE patient previously treated with corticosteroids, immunosuppressors, and broad-spectrum antibiotics. Unlike aspergillosis in other conditions, granulocytopenia is uncommon. Chest radiographs show diffuse or patchy infiltration of lung fields. Diagnosis was suspected premortem in 2 patients. Aspergillus fumigatus was identified or isolated in sputum or parenchimal tissues in the majority of cases. Twenty-two patients died (95%). The finding of hyphae in the sputum of a systemic lupus erythematosus patient with a suggestive clinical picture should lead to bronchoscopy, bronchoalveolar lavage, and lung biopsy. Proof of diagnosis will come from the demonstration of hyphae in tissues and isolation of aspergillus from tissue cultures. Long-term therapy with amphotericin B alone or in combination with fluorocytosine or itraconazole may help improve survival.
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PMID:Invasive aspergillosis in systemic lupus erythematosus. 760 98

It is known that activation of neutrophils or monocytes leads to the formation of hydrogen peroxide and the release of myeloperoxidase (MPO). We found that sulfamethoxazole was chlorinated by the combination of MPO, hydrogen peroxide, and chloride. The product, N-chlorosulfamethoxazole, is reasonably stable but reacts rapidly with a variety of compounds. The same product was formed by the reaction between sulfamethoxazole and hypochlorous acid, and dapsone was also N-chlorinated by the MPO system or hypochlorous acid. Although N-chlorination was not observed when sulfamethoxazole or dapsone was incubated with activated neutrophils, this is presumably because the chloramine products react rapidly with the cells. When radiolabeled sulfamethoxazole was incubated with activated neutrophils, covalent binding was observed. When radiolabeled sulfamethoxazole was incubated with MPO and hydrogen peroxide in the presence of albumin, covalent binding to the albumin occurred. Although binding to albumin occurred in the absence of chloride, it was increased by the presence of chloride. This suggests that N-chlorosulfamethoxazole may be one of several reactive metabolites of sulfamethoxazole that covalently bind to neutrophils. We suspect that covalent binding of arylamine drugs, such as sulfamethoxazole, to activated leukocytes is responsible for some of the adverse reactions associated with these drugs, especially adverse reactions that involve leukocytes such as agranulocytosis or drug-induced lupus.
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PMID:N-chlorination of sulfamethoxazole and dapsone by the myeloperoxidase system. 790 44

Peripheral blood leukocytes contain a variety of enzymes that are capable of metabolising xenobiotics. The enzyme myeloperoxidase (MPO) appears to be the most important for drug metabolism. MPO is a peroxidase/oxidase and generates the powerful oxidant hypochlorous acid. MPO- or MPO-generated oxidants are capable of oxidizing a wide variety of compounds and a broad range of functional groups, especially those that contain nitrogen and sulfur. Leukocytes have a role in immune response; therefore, reactive intermediates generated by leukocyte metabolism of xenobiotics may have a role in idiosyncratic drug reactions, particularly those that are immune-mediated such as drug-induced lupus or agranulocytosis.
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PMID:Myeloperoxidase-mediated activation of xenobiotics by human leukocytes. 823 77

Carbamazepine is an anticonvulsant which is associated with a significant incidence of hypersensitivity reactions including agranulocytosis. We have postulated that many drug hypersensitivity reactions, especially agranulocytosis and lupus, are due to reactive metabolites generated by the myeloperoxidase (MPO) (EC 1.11.1.7) system of neutrophils and monocytes. This led to a study of the metabolism and covalent binding of carbamazepine with MPO/H2O2/Cl- and neutrophils. Metabolism and covalent binding were observed in both systems and the same pathway appeared to be involved; however, the metabolism observed with the MPO system was approximately 500-fold greater than that observed with neutrophils. The metabolites identified were an intermediate aldehyde, 9-acridine carboxaldehyde, acridine, acridone, choloroacridone, and dichloroacridone. We postulate that the first intermediate in the metabolism of carbamazepine is a carbonium ion formed by reaction of hypochlorous acid (HOCl) with the 10,11 double bond. Although we have no direct proof for the proposed carbonium ion, it provides the most likely mechanism for the observed ring contraction. Iminostilbene, a known metabolite of carbamazepine, was also metabolized by a similar pathway leading to ring contraction; however, the rate was much faster and the first step may involve N-chlorination and a nitrenium ion intermediate. These data confirm that carbamazepine is metabolized to reactive intermediates by activated leukocytes. Such metabolites could be responsible for some of the adverse reactions associated with carbamazepine, especially reactions such as agranulocytosis and lupus which involve leukocytes.
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PMID:Carbamazepine metabolism to a reactive intermediate by the myeloperoxidase system of activated neutrophils. 838 60

Agranulocytosis is a well recognized but uncommon complication of procainamide (PA) therapy, whereas a lupus-like syndrome occurs in approximately 20% of patients treated chronically with PA. In order to gain insight into the immunopathogenic relationships among these conditions, we compared the humoral immune abnormalities in these patient groups as well as in asymptomatic PA-treated patients. A relatively uniform profile of IgM but not IgG autoantibody reactivity with a set of chromatin-related antigens was observed in eight elderly men who developed agranulocytosis after treatment with PA. In contrast PA-induced lupus patients had predominant reactivity with [(H2A-H2B)-DNA] in both IgM and IgG classes. Five of eight patients with agranulocytosis had elevated levels of neutrophil-reactive IgG which appeared to be due to immune complexes based on Fc gamma receptor blocking studies. However, 12 of 15 patients with PA-induced lupus, none of whom had neutropenia, had similar levels of neutrophil-reactive IgG, suggesting that this reactivity was not causally related to agranulocytosis. Agranulocytosis developed after less than 3 months treatment with PA in six of eight patients. This time course was similar to that seen in 77 PA-induced agranulocytosis patients reported in the literature plus 127 patients reported to the U.S. Food and Drug Administration in whom 90% developed agranulocytosis within 3 months of starting PA. In contrast, the mode duration of treatment with PA before lupus-like symptoms develop is 10-12 months. These findings, together with the different profiles of autoantibodies and clinical presentations, suggest that agranulocytosis arises from a different mechanism than that underlying PA-induced lupus.
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PMID:Procainamide-induced agranulocytosis differs serologically and clinically from procainamide-induced lupus. 862 53

Reactive metabolites are believed to be responsible for many types of toxicity, including idiosyncratic drug reactions. Bone marrow is a frequent target of idiosyncratic reactions, and, since these reactions have characteristics that suggest involvement of the immune system, the formation of reactive metabolites by leucocytes could also play a role in the aetiology of idiosyncratic drug reactions. The major oxidation system in neutrophils and monocytes is a combination of NADPH oxidase and myeloperoxidase. This system oxidizes primary arylamines, such as sulphonamides, to reactive metabolites and these drugs are also associated with a high incidence of agranulocytosis, generalized idiosyncratic reactions and/ or drug-induced lupus. Clozapine is oxidized by this system to a relatively stable nitrenium ion; clozapine is also associated with a high incidence of agranulocytosis. Arylamines that have an oxygen or nitrogen in the para position, such as amodiaquine, vesnarinone and 5-aminosalicylic acid, are oxidized to quinone-like reactive intermediates. Aminopyrine is oxidized to a very reactive dication. Such reactive metabolites could also inhibit neutrophil function and mediate some of the therapeutic effects of these drugs: for example, the use of dapsone for dermatitis herpetiformis and the use of 5-aminosalicylic acid for inflammatory bowel disease.
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PMID:Myeloperoxidase as a generator of drug free radicals. 866 Mar 93

Infection is the major cause of morbidity and mortality in systemic lupus erythematosus (SLE). Although various fungi account for a substantial number of these lethal infections, aspergillosis, an important opportunistic infection in immunosuppressed patients, is described rarely. Only 23 cases have been reported in the English-language medical literature. Risk factors for acquiring aspergillosis in these patients were high grade disease activity, granulocytopenia, use of steroids and other immunosuppressive treatment and presence of bacterial infection. The diagnosis in most patients was delayed and they died. Here, we describe three SLE patients with invasive aspergillosis. Features of our patients' diseases were similar to those reported previously. Aspergillosis appeared while they had active SLE treated with high dose corticosteroids. In 2 patients the fungal infection was systemic and diagnosed post mortem. Both were leukopenic and had concurrent bacterial infection and one received amphotericin B prior to death. In the third, the infection was localized to a transplanted kidney and was cured by nephrectomy. Aspergillosis should be suspected in patients with active SLE, who are immunocompromised and sustain concomitant bacterial infections. The currently poor prognosis may be improved with more aggressive diagnostic investigation and treatment.
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PMID:Aspergillosis in systemic lupus erythematosus. 898 8


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