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)

Hydralazine and isoniazid reduce the covalent binding capacity of C4. Since these two drugs are known to induce a systemic lupus erythematosus (SLE)-like syndrome, it has been suggested that this reduced binding could lead to the abnormal processing of immune complexes in vivo. Complement mediated solubilization and inhibition of immune precipitation were tested in vitro in normal human serum exposed to various concentrations of the two drugs. The formation of soluble immune complexes in the assays was reduced. The concentrations needed to induce a significant decrease were (a) for solubilization: 50 mM hydralazine and 25 mM isoniazid, and (b) for inhibition of immune precipitation: 50 mM of both. Such concentrations are unlikely to be present in vivo, so that the induction of SLE by these two drugs cannot be explained exclusively by reduced formation of soluble complexes by complement.
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PMID:Hydralazine and isoniazid reduce the formation of soluble immune complexes by complement. 399 5

The acetylation pathway of drug metabolism is the pathway by which aromatic amines and hydrazines are metabolized. Hydralazine and procainamide are aromatic amines or hydrazines that are metabolized by this pathway. Persons who are genetically slow acetylators are predisposed to development of lupus from these two drugs, suggesting that the free amine or hydrazine moiety is the inciting agent. When acetylprocainamide was given as an antiarrhythmic drug to patients with procainamide-induced lupus, the disease went into remission, indicating that the free amine group on procainamide had induced the disease. The genetic acetylator phenotypes of persons with idiopathic lupus were studied, and an excess of genetic slow acetylators was observed. This suggests amines or hydrazines induce some cases of this disease. One patient was identified with a lupus-like illness due to occupational exposure to hydrazine itself.
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PMID:Aromatic amines and the pathogenesis of lupus erythematosus. 619 68

The true incidence of the lupus syndrome induced by hydralazine was determined in a longitudinal study of 281 patients consecutively starting hydralazine for hypertension over a 51 month period. Data on the duration of treatment and the maximum dose achieved were examined using life table analysis. After three years' treatment with hydralazine the incidence of the lupus syndrome was 6.7% (95% confidence limits 3.2-10.2%). The incidence was dose dependent, with no cases recorded in patients taking 50 mg daily and incidences of 5.4% with 100 mg daily and of 10.4% with 200 mg daily. The incidence was higher in women (11.6%) than in men (2.8%). In women taking 200 mg daily the three year incidence was 19.4%. Hydralazine is an effective antihypertensive drug that has come to be used in restricted dosage (not more than 200 mg daily) because of its risk of inducing the lupus syndrome. This study shows that the true incidence of the syndrome is still unacceptably high even when the drug is prescribed according to current recommendations.
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PMID:The lupus syndrome induced by hydralazine: a common complication with low dose treatment. 643 20

Relapsing polychondritis is a rare disease of uncertain etiology, characterized by inflammation of cartilage. Cartilage of the respiratory tract is engaged in more than half of all cases. Hydralazine-induced systemic lupus erythematosis (SLE) is a well known disease. Females who are slow acetylators and are HLA-DR4 positive when treated with hydralazine are at serious risk of contracting SLE syndrome. We describe here a woman, treated for 10 years with hydralazine, who was a slow acetylator and was HLA-DR4 positive and who presented with a relapsing polychondritis and ultimately required a permanent tracheostoma. To our knowledge, this is the first published case of relapsing polychondritis induced by hydralazine.
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PMID:Hydralazine-induced relapsing polychondritis-like syndrome. Report of a case with severe chronic laryngeal complications. 660 52

Twenty-seven hypertensive patients (23 of whom were black) were treated with hydralazine as their major antihypertensive drug and were followed for evidence of autoimmunity and clinical systemic lupus erythematosus (SLE). Only one patient developed SLE but many, although asymptomatic, had serologic evidence of autoimmunity: antibodies to single- and double-stranded ribonucleic acid (RNA), single-stranded deoxyribonucleic acid (DNA), histones, and lymphocytes. Acetylation phenotype profoundly influenced this response; slow acetylators had a higher incidence and larger amounts of autoantibodies. Antibodies to both types of RNA were a more sensitive index of autoimmunity than antinuclear antibodies. Hydralazine treatment did not alter cell-mediated immune responses. The hydralazine SLE patient had large amounts of autoantibodies that were predominantly IgG, while in the others IgM autoantibodies were predominant. No antibodies, but positive lymphoproliferative responses to hydralazine, were found in half the patients tested.
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PMID:Prospective study of immunologic effects of hydralazine in hypertensive patients. 697 Jun 46

Twenty-seven hypertensive patients (23 blacks, 4 whites) treated with hydralazine had frequent serologic evidence of autoimmunity. However, only 1 patient developed a lupus syndrome. Acetylator phenotype influenced the autoimmune response; slow acetylators had a higher incidence and titers of autoantibodies. The lupus patient not only had high titers of autoantibodies but they were predominantly IgG in contrast to the predominant IgM antibodies found in other slow acetylators. Hydralazine treatment did not alter cell-mediated immune responses and hydralazine antibodies were not detected. However, half the patients tested who received hydralazine had positive lymphoproliferative responses to the drug.
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PMID:Immunologic effects of hydralazine in hypertensive patients. 697 54

Hydralazine, the prototypic drug that induces systemic lupus erythematosus, reacts with thymidine and deoxycytidine. Analysis of a reaction mixture of therapeutic concentrations of hydralazine with labeled thymidine reveals at least four labeled products. At higher concentrations, hydralazine reacts with labeled deoxycytidine to form at least three labeled products. Formation of these products is markedly enhanced by exposure to ultraviolet light. The reaction of hydralazine with thymidine and deoxycytidine may be in part responsible for initiating drug-induced systemic lupus erythematosus.
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PMID:Hydralazine-pyrimidine interactions may explain hydralazine-induced lupus erythematosus. 736 66

1-Hydrazinophthalazine [hydralazine (HDZ)] is a hydrazine derivative that is a direct acting vasodilator effective in the treatment of essential hypertension. HDZ is biotransformed by the phase II conjugation enzyme N-acetyltransferase (NAT) forming acetyl HDZ, which spontaneously cyclized to the stable product 3-methyl-s-triazolo- [3,4-alpha]-phthalazine (MTP). Therapeutic use of HDZ has resulted in adverse side effects, specifically a drug-induced systemic lupus erythematosus. Slow acetylators are more likely than rapid acetylators to develop this toxicity. Bacteria expressing different levels of NAT were used to test the hypothesis that acetylation of HDZ decreases its mutagenic potential. The variation in NAT activities was confirmed by incubating bacterial cultures with HDZ, and the formation of MTP was monitored by HPLC. At 1.0 mg/ml HDZ, YG1029 (NAT overexpresser) produced 5.3 times the amount of MTP as TA100 (normal NAT expresser), and this production was linear for 20 hr. In the Salmonella mutagenesis assay, HDZ produced a dose- and strain-dependent increase in the number of revertants observed. Exposure to 4 mg HDZ/plate resulted in 1000 revertants in the overexpressing strain, YG1029, whereas both TA100 and TA100/1,8DNP6, which express normal levels and lack the NAT protein respectively, produced 1600 revertants. Colony hybridization analysis using probes for each of the six possible TA100 reverting mutations was performed to determine the nature of the mutations. The G:C to T:A transversion was the only mutation whose frequency was increased significantly by HDZ. Fifty-four percent of the induced vs. 25% of the spontaneous mutations were C to A transversions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acetylation and its role in the mutagenicity of the antihypertensive agent hydralazine. 758 31

A 58 year old woman developed systemic symptoms, interstitial lung disease, splenomegaly, leukopenia and anti-histone and anti-nuclear antibodies (ANA), while treated with hydralazine for hypertension. Five months after presentation she was admitted with high fever, skin rash and atypical lymphocytosis due to acute cytomegalovirus (CMV) infection. Worsening leukopenia and increased ANA were found, and high titres of anti-DNA antibodies, anti-cardiolipin antibodies and rheumatoid factors appeared. Hydralazine was stopped and the patient gradually became asymptomatic. All autoantibodies spontaneously disappeared (over 16 weeks), and the white cell count and spleen size became normal. The patient was found to be a slow acetylator and to have both HLA-DR4 and selective IgA deficiency. Thus, a multifactorial genetic susceptibility to develop drug-induced lupus was brought out in stages first by hydralazine and then by CMV, yet all manifestations and autoantibodies resolved spontaneously, demonstrating the complex interplay of varied environmental factors with a genetic predisposition in the pathogenesis of autoimmunity.
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PMID:Effect of acute cytomegalovirus infection on drug-induced SLE. 783 Nov 73

Autoantibodies directed against myeloperoxidase and elastase have been found in patients developing hydralazine-induced lupus and hydralazine-induced isolated glomerulonephritis. The aim of this study was to investigate influence of hydralazine and dihydralazine upon myeloperoxidase and elastase enzyme activity. Using a 4-aminoantipyrin in vitro system, dihydralazine was 2.5 times as potent in inhibiting myeloperoxidase activity as compared to hydralazine. The corresponding Ki-values were 4 microns M for dihydralazine and 25 microM for hydralazine. When using 2.2'-azino-bis-3-ethyl-benzothiazoline-6-sulphonic acid system inhibition was found at lower concentrations. Furthermore, the difference between the compounds was not so pronounced as seen for 4-aminoantipyrin. The Ki-values for hydralazine and dihydralazine were 1.2 and 1.4 microM respectively. Complete inhibition was seen for both compounds at concentrations above 7.5 microM. Hydralazine binds to elastase, but neither hydralazine nor dihydralazine inhibited elastase enzyme activity.
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PMID:Interaction of myeloperoxidase and elastase enzyme activity with the antihypertensive agents hydralazine and dihydralazine. 824 10


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