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)

Twenty selected patients suffering from severe, long-standing rhumatoid arthritis (RA) not controlled by anti-inflammatory drugs (19 cases) and from disseminated lupus erythematosis (DLE) (1 case) were treated with levamisole. The subjects were divided into 2 groups: Group I comprised fourteen patients (13 RA and 1 DLE) treated continuously by levamisole 150 mg/day for 3 or 6 months then on an intermittent regime (150 mg/day-3 days per week). Group II comprised 6 RA patients treated on the intermittent regime from the beginning. In Group I, following average treatment of 9 months (5-12 months), clinical results assessed according to precise clinical criteria were favorable in 9 out of eleven cases. In the other 2 cases no change was noted. Side effects included reversible agranulocytosis in 9 cases, on 3 occasions this necessitated the discontinuation of treatment. A signifcant reduction in sedimentation rate was noticed in 5 cases out of eleven and in 3 patients the Rose-Waller test turned negative. A monoclonal disglobulinemia of IgG lambda appeared under treatment in 1 patient who was deficient in IgA. Skin tests carried out periodically showed a significant augmentation of the response to candida. Lymphocyte culture in the presence of mitogens gave highly variable results from one control to the other in the same subject, as well as in the treated subjects as in the group of RA not receiving levamisole. These results are compared with those previously published; the mechanism of action and possible indications for levamisole in RA are discussed.
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PMID:[Treatment of rheumatoid arthritis by levamisole. First results]. 32 47

An unexpected precipitous fall in peripheral leucocyte count may occur during treatment of certain sensitised individuals with drugs usually well tolerated by most people. Three basic mechanisms for drug sensitivity have been found. One is characterised by sudden destruction of large numbers of leucocytes in peripheral blood by antibodies elicited in response to drug sensitivity. A prototype for this type of reaction is aminopyrine. A second mechanism involves the production of a lupus-like syndrome followed by leucopenia in response to sensitisation to drugs such as procainamide. A third type involves development of agranulocytosis following a latent period during which a sensitive patient is treated with large amounts of chlorpromazine. This type of reaction is associated with production of bone marrow insufficiency in a patient who is believed to have a limited proliferative potential of bone marrow cells, which limit compensatory bone marrow response during treatment with a drug (e.g. chlorpromazine) that has limited bone marrow toxicity.
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PMID:Drug-induced agranulocytosis. 34 30

A 73-year-old woman was found to have clinically significant pancytopenia in association with procainamide hydrochloride ingestion. The syndrome, resembling systemic lupus erythematosus, which has been reported to develop in patients treated with this agent, is characterized by mild to moderate anemia and mild to moderate granulocytopenia. Severe granulocytopenia in patients taking procainamide and unrelated to a lupus syndrome has not previously been reported in association with significant thrombocytopenia. The clinical severity of this patient's presentation, suggesting an aleukemic leukemia, and its complete remission after cessation of procainamide administration occasional this report.
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PMID:Severe transient pancytopenia associated with procainamide ingestion. 103 16

Activated neutrophils and monocytes were found to metabolize procainamide to a reactive hydroxylamine. In contrast, there was little or no metabolism by lymphocytes or platelets. Therefore, it appears that only leukocytes that contain myeloperoxidase can metabolize procainamide to a significant degree. There was no difference in the degree to which neutrophils from males or females metabolized procainamide; however, monocytes from males formed significantly more hydroxylamine than did monocytes from females. By use of radiolabeled procainamide, covalent binding of procainamide to leukocytes was detected, and the degree of binding correlated with the cells' ability to oxidize procainamide. These findings suggest that myeloperoxidase is the major enzyme involved in the formation of reactive metabolites by leukocytes, a pathway that we propose may be responsible for procainamide-induced lupus and agranulocytosis.
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PMID:Comparative metabolism and covalent binding of procainamide by human leukocytes. 134 86

This retrospective study evaluated treatment with sulfasalazine (SAS) in a mean dosage of 2.1 g/day in 95 patients with rheumatoid arthritis (RA) who were followed-up for 3 months to 4 years. Mean disease duration was 7 years; 79 patients had previously received at least one disease-modifying drug. Four per cent of patients were lost to follow-up. Mean duration of treatment was 15 months (3 weeks-50 months). Treatment continuation rates were 57% at one year, 40% at two years, and 26% at three years. Reasons for discontinuation of SAS included adverse effects (n = 24), inefficacy (n = 33), and death unrelated to SAS therapy (n = 2). In four patients, SAS was discontinued within three months of the first dose because of a severe adverse effect (diffuse erythematous rash, diffuse bullous rash, hepatitis with jaundice, agranulocytosis). SAS-induced biologic markers for lupus were seen in one patient. Furthermore, 12% of evaluable patients developed antinuclear antibodies during SAS therapy. The SAS treatment continuation rate was higher (p = 0.05) among patients under 40 years of age (n = 18) than among older patients. This difference was due to a correlation between age and tolerance with less SAS-induced side effects in patients under 40 years of age (p = 0.03). The SAS treatment continuation rate was unrelated to the duration of rheumatoid arthritis or number of previous maintenance treatments. This study suggests that rheumatoid arthritis patients under 40 years of age exhibit better tolerance to SAS therapy.
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PMID:[Therapeutic maintenance and tolerance of sulfasalazine in rheumatoid polyarthritis. Retrospective study of 95 patients]. 136

We present a non-controlled prospective study of 10 hypertensive patients with systemic erythematous lupus and nephropathy, treated with captopril exclusively or combined with other drugs, in order to assess its effectivity and potential side effects. Four of these 10 patients had mild hypertension; 3, moderate hypertension and 3, severe hypertension. In 5 of them, arterial pressures was controlled with just captopril; in other 3, we added furosemide and in one patient, we added furosemide and nifedipine. In one case, hypertension was not controlled. Renal function remained stable and proteinuria improved in six patients. Three patients presented reversible agranulocytosis, during or immediately after treatment. One of them was treated two years after with enalapril, without observing hematologic recurrence. We conclude that captopril is useful in treating arterial hypertension associated to lupous nephropathy, but frequent leukocyte counting controls must be done during the first months.
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PMID:[Treatment of arterial hypertension with captopril in lupus nephropathy]. 821 76

The authors report a case of lupus showed in labour by the presence of generalised convulsions and coma after the crisis. This was followed by labile transitory hypertension, by massive proteinuria which cleared in 15 days, by major hyperthermia (higher than 39.5 degrees) and transitory agranulocytosis. The infant had a purely biological neonatal lupus. Pregnancy in a lupus patient has two risks: the mother's relapses of lupus, it is usual that renal failure is the worst of the prognostic features, but in this patient cerebral complications were much more serious. In the fetus there is a risk of spontaneous abortion linked to the anticardiolipin antibody level, and the risk of disease in the heart due to the anti-SSA (or anti-Ro) factor giving rise to congenital auriculo-ventricular blocks. The therapeutic possibilities are classically treated with immunosuppressants, mainly corticoids, which is added to low doses of aspirin. Plasmaphoresis and immunoglobulin treatments are being tried out.
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PMID:[Disseminated lupus erythematosus discovered during delivery: a difficult diagnosis]. 162 23

Evidence strongly suggests that many adverse drug reactions, including idiosyncratic drug reactions, involve reactive metabolites. Furthermore, certain functional groups, which are readily oxidized to reactive metabolites, are associated with a high incidence of adverse reactions. Most drugs can probably form reactive metabolites, but a simple comparison of covalent binding in vitro is unlikely to provide an accurate indication of the relative risk of a drug causing an idiosyncratic reaction because it does not provide an indication of how efficiently the metabolite is detoxified in vivo. In addition, the incidence and nature of adverse reactions associated with a given drug is probably determined in large measure by the location of reactive metabolite formation, as well as the chemical reactivity of the reactive metabolite. Such factors will determine which macromolecules the metabolites will bind to, and it is known that covalent binding to some proteins, such as those in the leukocyte membrane, is much more likely to lead to an immune-mediated reaction or other type of toxicity. Some reactive metabolites, such as acyl glucuronides, circulate freely and could lead to adverse reactions in almost any organ; however, most reactive metabolites have a short biological half-life, and although small amounts may escape the organ where they are formed, these metabolites are unlikely to reach sufficient concentrations to cause toxicity in other organs. Many idiosyncratic drug reactions involve leukocytes, especially agranulocytosis and drug-induced lupus. We and others have demonstrated that drugs can be metabolized by activated neutrophils and monocytes to reactive metabolites. The major reaction appears to be reaction with leukocyte-generated hypochlorous acid. Hypochlorous acid is quite reactive, and therefore it is likely that many other drugs will be found that are metabolized by activated leukocytes. Some neutrophil precursors contain myeloperoxidase and the NADPH oxidase system, and it is likely that these cells can also oxidize drugs. Therefore, although there is no direct evidence, it is reasonable to speculate that reactive metabolites generated by activated leukocytes, or neutrophil precursors in the bone marrow, could be responsible for drug-induced agranulocytosis and aplastic anemia. This could involve direct toxicity or an immune-mediated reaction. These mechanisms are not mutually exclusive, and it may be that both mechanisms contribute to the toxicity, even in the same patient. In the case of drug-induced lupus, a prevalent hypothesis for lupus involves modification of class II MHC antigens.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of leukocyte-generated reactive metabolites in the pathogenesis of idiosyncratic drug reactions. 162 36

In previous studies we had shown that procainamide is metabolized to reactive metabolites by activated leukocytes, and evidence pointed to involvement of myeloperoxidase (MPO). In this study we examine the metabolism of procainamide by MPO/H2O2, in the presence and absence of chloride ion. In the absence of chloride ion, the metabolism was very similar to that seen with activated leukocytes. The major metabolite was formed by oxidation of the arylamine group to a hydroxylamine. In the presence of chloride ion, a much greater degree of metabolism occurred, and the major product (40% of the starting procainamide) was a reactive species that could not be isolated. This metabolite spontaneously rearranged to 3-chloroprocainamide, and from its mass spectrum and chemical reactions, we deduce its structure to be N-chloroprocainamide. The N-chloroprocainamide metabolite reacted very rapidly with reducing agents, such as ascorbate, and also reacted with protein such as albumin, the major product in both cases being procainamide. This metabolite also chlorinated phenylbutazone. When radiolabeled procainamide was oxidized by MPO/H2O2 in the presence of albumin, covalent binding of the radiolabel to albumin occurred, and binding was greater under conditions in which N-chloroprocainamide was formed. It is probable that the failure to observe N-chloroprocainamide, when procainamide is oxidized by activated leukocytes, is due to its rapid reaction with the cells. We propose that modification of neutrophils (or neutrophil precursors in the bone marrow) by these reactive metabolites is responsible for procainamide-induced agranulocytosis. In a similar manner, procainamide-induced lupus could be due to modification of monocytes by monocyte-generated reactive metabolites.
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PMID:N-Chlorination and oxidation of procainamide by myeloperoxidase: toxicological implications. 166 58

Despite their importance, little is known about the mechanism of idiosyncratic reactions, many such reactions have characteristics that suggest an immune-mediated mechanism. This is particularly true of drug-induced lupus which is an autoimmune syndrome. Certain functional groups are associated with a high incidence of idiosyncratic reactions, probably reflecting the ease with which they are metabolized to reactive metabolites. Although the liver is the principal organ of drug metabolism, most reactive metabolites generated in the liver would not reach other organs in significant concentrations. Because of the function of leukocytes, especially monocytes, in the induction of an immune response, the generation of reactive metabolites by monocytes would seem likely to lead to an immune-mediated adverse reaction. We have found that drugs that are associated with drug-induced lupus are oxidized to reactive metabolites by the myeloperoxidase system of monocytes. The initial step in drug-induced lupus could be haptenization of a protein on the surface of monocytes by these reactive metabolites. Other types of idiosyncratic drug reactions may involve a similar mechanism and the same drugs that induce lupus are usually associated with a high incidence of other types of idiosyncratic reactions. for example, procainamide, which causes the highest incidence of drug-induced lupus, also causes a relatively high incidence of agranulocytosis. Even some of the therapeutic effects of drugs may involve the production of reactive metabolites by myeloperoxidase or thyroid peroxidase.
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PMID:Metabolism of drugs by activated leukocytes: implications for drug-induced lupus and other drug hypersensitivity reactions. 206 78


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