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)

The existence of iatrogenic lupus is now well-established and seems to be on the increase. A number of drugs must take the blame for these outbreaks: Hydrazine derivatives (Hydralazine, I.N.H.), anticonvulsants, Procainamide, psychotropics, antibiotics, antalgics, contraceptives. Clinically, these drugs can: --either mimic L.E. without showing any visceral or biological signs; --or aggravate a chronic L.E., or a systemic L.E. during a remission with biological symptoms appearing; --or trigger a true L.E.: all the various clinical symptoms of idiopathic L.E. may be encountered, certain articular, cutaneous symptoms predominating, renal symptoms rarely appearing. The discovery of HARGRAVES cells is the only certain biological sign to confirm systemic lupus, the existence of antinuclear antibodies or antinuclear factors merely serving as a guide to the collecting of a whole gamut of clinical and biological symptoms.
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PMID:[Iatrogenic lupus-like syndromes]. 13 11

The immunological side-effects under treatment with antihypertensive drugs are mainly limited to autoimmunity and autoimmune disease caused by alpha-methyldopa and hydralazine. Autoimmune hemolytic anemia is more common during treatment with alpha-methyldopa. Hydralazine may induce antinuclear antibodies. Some patients develop a SLE-like syndrome. Its clinical picture is less severe and its prognosis is more favourable than that of spontaneous SLE. During treatment with low doses the disease develops exclusively in patients who are slow acetylators. It may appear also in rapid acetylators during the high dose treatment. The symptoms are usually reversible after withdrawal of the drug.
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PMID:Immunological side-effects of antihypertensive drugs. 28 3

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease affecting a variety of tissues and organs. The diagnosis of SLE can be made only after several related illnesses are considered and ruled out. The etiology of SLE is unclear, but hormonal factors, environmental toxins, infectious viruses, genetic predisposition, and certain medications have all been considered risk factors. Idiopathic SLE is seen predominantly in young women, with a female:male ratio of approximately 10:1. Each patient is unique and may suffer from a variety of signs and symptoms. The disease is highly unpredictable, and most patients experience flare-ups or fluctuations. The epidemiologic characteristics of medication-induced SLE (MI-SLE) are different from those of idiopathic SLE. Musculoskeletal symptoms predominate the clinical presentation of MI-SLE, while renal and central nervous system involvement is rare or absent. Moreover, a greater percentage of caucasian patients with no female predominance is evidenced in MI-SLE. Several medications can produce positive results on an antinuclear antibody test with or without evidence of clinical lupus. Hydralazine and procainamide are the most commonly recognized medications for inducing SLE. The onset of procainamide- and hydralazine-induced SLE occurs after 50 years of age, which is directly related to the age of the population using these medications. Estrogen-containing oral contraceptives and ibuprofen can exacerbate the symptoms of idiopathic SLE. Clinical judgment dictates the importance of careful patient monitoring and selection of therapy.
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PMID:Medication-induced systemic lupus erythematosus. 135 74

Hydralazine is associated with a lupus-like syndrome. There is evidence that many drug hypersensitivity reactions are due to reactive metabolites. Incubation of hydralazine with activated neutrophils or monocytes led to the production of phthalazinone, phthalazine and 3 unidentified metabolites. Formation of the metabolites, with the exception of phthalazine, required activation of the leukocytes. Using radiolabelled hydralazine, covalent binding to activated neutrophils was observed. Oxidation of hydralazine catalyzed by myeloperoxidase (MPO) produced the same metabolites and covalent binding to protein. We conclude that hydralazine is metabolized by activated leukocytes to a reactive metabolite which may be associated with hydralazine induced lupus.
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PMID:Metabolism of hydralazine by activated leukocytes: implications for hydralazine induced lupus. 166 57

Hydralazine caused site-specific DNA damage in the presence of Cu(II), Co(II), Fe(III), or peroxidase/H2O2. The order of inducing effect of metal ions on hydralazine-dependent DNA damage [Cu(II) greater than Co(II) greater than Fe(III)] was related to that of accelerating effect on the O2 consumption rate of hydralazine autoxidation. Catalase completely inhibited DNA damage by hydralazine plus Cu(II), but hydroxyl radical (.OH) scavengers and superoxide dismutase did not. On the other hand, DNA damage by hydralazine plus Fe(III) was inhibited by catalase and .OH scavengers. Hydralazine plus Cu(II) induced piperidine-labile sites predominantly at guanine and some adenine residues, whereas hydralazine plus Fe(III) caused cleavages at every nucleotide. Activation of hydralazine by peroxidase/H2O2 caused guanine-specific modification in DNA. ESR-spin trapping experiment showed that .OH and superoxide are generated during the Fe(III)- or Cu(II)-catalysed autoxidation of hydralazine, respectively, and that nitrogen-centered radical is generated during the Cu(II)- or peroxidase-catalysed oxidation. The generation of nitrogen-centered radical was also supported by HPLC-mass spectrometry. The results suggest that the guanine-specific modification by the enzymatic activation of hydralazine is due to the nitrogen-centered hydralazyl radical or derived active species, whereas .OH participates in DNA damage by hydralazine plus Fe(III). The mechanism of hydralazine plus Cu(II)-induced DNA damage is complex. The possible role of the DNA damage induced by hydralazine in the presence of Cu(II) or peroxidase/H2O2 is discussed in relation to hydralazine-induced lupus, mutation, and cancer.
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PMID:Free radical production and site-specific DNA damage induced by hydralazine in the presence of metal ions or peroxidase/hydrogen peroxide. 184 78

Drug-induced systemic lupus erythematosus arises from toxic side-effects of administration of hydralazine, isoniazid, procainamide and practolol. Hydralazine and isoniazid are nucleophilic drugs and inhibit the covalent binding reaction of complement components, C3 and C4, an effect likely to lead to deposition of immune complexes (a feature of systemic lupus erythematosus). Procainamide and practolol do not themselves inhibit C3 and C4. A range of metabolites and putative metabolites of procainamide and practolol were synthesized, and tested for their ability to inhibit the covalent binding reactions of C3 and C4. The highly nucleophilic hydroxylamine metabolite of procainamide was strongly inhibitory in both tests, as was a putative hydroxylamine metabolite of practolol. These studies indicate a potential role for the hydroxylamine metabolites in mediating the toxic side-effects of procainamide and practolol, and emphasize the need for adequate measurements of hydroxylamine metabolites in human tissue.
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PMID:Metabolites of procainamide and practolol inhibit complement components C3 and C4. 245 55

A range of drugs including hydralazine, isoniazid, procainamide and penicillamine cause toxic side effects which resemble systemic lupus erythematosus (SLE). Deficiencies of C1, C4 and C2 are associated with idiopathic SLE, and these defects may compromise the ability of the patient to deal with immune complexes. Immune complexes with protein as antigen, such as has been reported to be diagnostic of procainamide-induced SLE, interact more with the C4A isotype of C4 than the C4B isotype. It is shown that hydralazine, isoniazid and penicillamine inhibit the covalent binding of C4 to a complement-activating surface and that the drugs themselves become covalently bound to C4. For each of these drugs, C4A is inhibited more than C4B, and it is suggested that this is an important contributory factor in the development of the toxic side effects to these drugs involving immune-complex deposition. For procainamide, it is shown that the hydroxylamine metabolite rather than the drug itself inhibits the covalent binding reaction of C4. Hydralazine, isoniazid and procainamide are metabolised by the polymorphic N-acetyltransferase, and slow acetylators are at increased risk of drug-induced lupus. For procainamide, oxidation to the hydroxylamine form is an alternative metabolic route of increased importance in slow acetylators, and it is suggested that investigation of C4 type in susceptible patients could provide a means of identifying those at greatest risk of immunotoxicity.
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PMID:Drug-induced immune-complex disease. 252 48

Systemic lupus erythematosus (SLE) induced by drugs, primarily hydralazine and procainamide, is reviewed and compared with idiopathic SLE, and the use of these drugs in patients with idiopathic SLE is discussed. The etiology of SLE is unclear, but genetic predisposition is an important factor. Although more than 25 drugs have been suggested as causes of SLE, the majority of confirmed cases of drug-induced SLE involve hydralazine or procainamide. Parts of these chemical compounds apparently interact with nucleoproteins, causing stimulation of antinuclear antibody (ANA) production. The average age of patients with drug-induced SLE is nearly twice that of patients with idiopathic SLE. Approximately half the patients with drug-induced SLE are women, compared with 92% of patients with idiopathic SLE. For SLE induced by hydralazine or procainamide, musculoskeletal symptoms (especially arthritis in the hands and wrists) are the most common clinical manifestation. In patients with SLE induced by these drugs, ANAs and LE cells are present, erythrocyte sedimentation rate is often elevated, and a false-positive serologic test for syphilis is seen more frequently than in idiopathic SLE. Baseline ANA status should be determined before therapy with these drugs, and patients should be observed carefully for signs and symptoms of SLE. Hydralazine-induced SLE may be dose related; limiting the daily dose to 200 mg is recommended. Some drugs have been shown to exacerbate idiopathic SLE; these include estrogen-containing oral contraceptives and ibuprofen. Hydralazine and procainamide are probably safe for use in patients with idiopathic SLE, but alternative therapy should be considered. The clinical and laboratory manifestations of drug-induced SLE are similar to those of idiopathic SLE, but central nervous system and renal involvement are rare in drug-induced SLE.
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PMID:Drug-induced systemic lupus erythematosus. 286 63

The clinical features, autoantibody changes, acetylator and HLA-DR phenotype of 20 patients with hydralazine-induced systemic lupus erythematosus are described. Four cases of particular interest are discussed in greater detail. Hydralazine sensitivity is more common in women, slow acetylators and the HLA-DR4 phenotype. Symptoms can occur even after many years of treatment and clinical awareness must be maintained for all patients to detect sensitivity at an early stage; there is no timely safe dose even in rapid acetylators. Joint symptoms predominate and full resolution is usual on discontinuing hydralazine. Failure of resolution should raise the suspicion of an underlying cause for the arthritis.
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PMID:Hydralazine sensitivity: clinical features, autoantibody changes and HLA-DR phenotype. 332 39

Long-term treatment with hydralazine is sometimes associated with deposition of immune complexes and development of systemic lupus erythematosus (SLE) as an adverse side-effect. Hydralazine inhibits the covalent binding reaction of the complement protein C4. We show that when hydralazine inhibits C4, it becomes covalently bound to the polypeptide chain containing the active site thiol ester. C4 is encoded at 2 adjacent polymorphic loci, C4A and C4B, within the major histocompatibility complex. We show that hydralazine binds more efficiently to the C4A than to the C4B gene product and suggest that C4 type may predispose patients to hydralazine-induced SLE.
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PMID:Hydralazine binds covalently to complement component C4. Different reactivity of C4A and C4B gene products. 387 56


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