Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Soft tissue infections were seen in 25 patients with underlying malignancy and immunosuppressive disease. The primary disease included leukemia, lupus, aplastic anemia, lymphoma, carcinoma and myeloma. Infectious sites included the perianal area, gluteal, chest wall, extremity and the vulva. Eighty per cent of the infectious episodes occurred in patients who were granulocytopenic. Initial presentation was of local tenderness and redness. Fluctuation and discoloration were present in nine patients who were also hypotensive. Local drainage in five patients resulted in the death of two (20%). Overall, the mortality was 3/25 (12%). Wide debridement and drainage and appropriate antibiotic therapy resulted in the death of 1/20 (5%) patients. Hypotension, discoloration and fluctuation were found to be late signs in these patients. Soft tissue infections in the compromised host present subtly and progress to death if treatment is delayed. Temperature elevation and localized tenderness and erythema are indications for broad spectrum antibiotics and extensive intraoperative drainage and debridement.
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PMID:Soft tissue infections in the compromised host. 338 98

Over a period of nine years we observed 52 children with acute neurological symptoms which were caused by a cerebrovascular disease. Fourteen patients had congenital vascular malformations, most frequently AV-angiomas (9 patients). A Sturge-Weber-Syndrome and a venous angioma were found in two cases and one patient had an aneurysm of the middle cerebral artery. Thirty-eight patients had acquired cerebrovascular diseases such as ischaemic infarctions (22), intracranial haemorrhages without vascular malformations (14) and thromboses of the dural sinus (2). The cerebral infraction was a complication of a congenital heart disease in 8 children, two others suffered from chronic renal insufficiency and were on haemodialysis. Two children had a trauma of the internal carotid artery and in one patient a large haemorrhagic infarct was caused by hypernatremic dehydration. In 9 patients (6 females, 3 males) no obvious aetiology of the infarct could be found. However, in most of these cases a nonspecific febrile illness preceded the neurological manifestations. The thrombosis of the dural sinus occurred in a 6-week old previously healthy infant and in a 3-year old boy as a complication of a nephrotic syndrome. Intracranial haemorrhages (without cerebrovascular malformations) occurred in 14 patients, mainly as a complication of haematological diseases (acute lymphatic leukaemia, severe aplastic anaemia, haemophilia A, lupus erythematodes). Four children had spontaneous intracerebral haemorrhages without obvious causes. The prognosis for survival was good in children with infarcts, but persisting neurological deficits were more severe than in children with haemorrhages. At the acute stage the lethality was higher in children with intracranial haemorrhages.
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PMID:[Cerebrovascular diseases in childhood--etiology, clinical aspects and prognosis]. 395 16

Aplastic anaemia is rare as a primary feature of systemic lupus erythematosus and is more commonly a complication of treatment with cytotoxic drugs. Three years after starting treatment for systemic lupus erythematosus a 22-year-old woman developed bone-marrow depression. Azathioprine was thought to be responsible and was withdrawn. The aplastic anaemia worsened despite treatment with prednisolone. In view of clinical and serological evidence of lupus disease activity the patient was given high-dose intravenous cyclophosphamide and the aplastic anaemia responded in a sustained manner.In such cases of continued disease activity high-dose immunosuppressive agents may prove effective.
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PMID:Reversal of aplastic anaemia secondary to systemic lupus erythematosus by high-dose intravenous cyclophosphamide. 681 Sep 92

A retrospective study of 26 quinacrine-treated lupus erythematosus patients failed to show evidence of drug-induced ocular changes. Although quinacrine commonly produces minor side effects, such as yellow discoloration of the skin, and may rarely produce very serious side effects, such as aplastic anemia, it appears to produce much less oculotoxicity than does chloroquine.
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PMID:Antimalarial therapy for lupus erythematosus: an apparent advantage of quinacrine. 720 69

A modification of the microcytotoxicity assay of Terasaki & McClelland was used to screen for serum inhibitors of myeloid progenitor cells (CFU-C). Sera from 104 patients with neutropenia or bone marrow failure and from 104 controls, including 30 normal subjects and 74 patients with various disorders or multiple transfusions, were studied. Inhibitors of CFU-C were found in 19 of the 104 patients with neutropenia or marrow failure: three with acquited neutropenia and 16 with aplastic anaemia. In 17 of the 19 patients the inhibitor was either complement dependent or chavincingly associated with clinical remission of disease in one patient. In another patient, the inhibitor was an IgG antibody directed against non-HL1 antigens present on CFU-C of all 50 normal target marrows tested; however, it was not clearly autoreactive. Inhibitors were also found in one of nine patients with lupus erythematosus, one with breast carcinoma, one patient with renal transplant rejection, and six of 46 multiply transfused patients without marrow failure. Our findings indicate that most serum inhibitors are associated with multiple transfusion: convincing evidence of pathogenetically important autoreactive antibody was present in only one of 19 patients with inhibitors.
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PMID:Serum inhibitors of myelopoiesis. 737 94

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

Thyroid hormone preparations, especially thyroxine, are widely used either at replacement doses to correct hypothyroidism or at suppressive doses to abolish thyrotropin (thyroid-stimulating hormone) secretion in patients with differentiated thyroid carcinoma after total thyroidectomy or with diffuse/ nodular nontoxic goitre. In order to suppress thyrotropin secretion, it is necessary to administer slightly supraphysiological doses of thyroxine. Possible adverse effects of this therapy include cardiovascular changes (shortening of systolic time intervals, increased frequency of atrial premature beats and, possibly, left ventricular hypertrophy) and bone changes (reduced bone density and bone mass), but the risk of these adverse effects can be minimised by carefully monitoring serum free thyroxine and free liothyronine (triiodothyronine) measurements and adjusting the dosage accordingly. Thionamides [thiamazole (methimazole), carbimazole, propylthiouracil] are the most widely used antithyroid drugs. They are given for long periods of time and cause adverse effects in 3 to 5% of patients. In most cases, adverse effects are minor and transient (e.g. skin rash, itching, mild leucopenia). The most dangerous effect is agranulocytosis, which occurs in 0.1 to 0.5% of patients. This life-threatening condition can now be effectively treated by granulocyte colony-stimulating factor administration. Other major adverse effects (aplastic anaemia, thrombocytopenia, lupus erythematosus-like syndrome, vasculitis) are exceedingly rare.
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PMID:Adverse effects of thyroid hormone preparations and antithyroid drugs. 886 63

A 38-year-old female was admitted to our hospital because of pancytopenia in April 1992. She was diagnosed as aplastic anemia by bone marrow biopsy and other examinations. Then she was treated with methyl-prednisolone pulse therapy followed by administration of cyclosporin in out-patient clinic. Though the modest improvement of peripheral blood count was observed, the worsening of pancytopenia was developed in association with tapering of cyclosporin. Anabolic steroid was given from June 1994 and gradual improvement of peripheral blood count was observed. On June 1995, she developed sudden onset of swelling and discoloration of a lower extremity, and thrombosis in the femoral vein was detected by Doppler ultrasonography. She was positive for lupus anticoagulant and anticardiolipin antibody, thus a diagnosis of antiphospholipid syndrome was made. Aplastic anemia associated with antiphospholipid syndrome has never been reported as far as we know. This case will be of importance for analyzing the cause of thrombosis in aplastic anemia.
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PMID:[Development of deep vein thrombosis in an aplastic anemia patient with antiphospholipid antibodies]. 896 Jun 62

With donor and recipient matched at the major histocompatibility complex (MHC) locus, peripheral lymphoid tissue transplantation can be carried out without producing a graft-versus-host reaction or graft-versus-host disease (GVHD), thus correcting profound T cell immunodeficiencies of neonatally thymectomized mice. This analysis set the stage for clinical application of bone marrow transplantation (BMT) to provide for the first time cure of a human disease. With successful BMT, we cured immunologic deficiencies of a patient with XL severe combined immunodeficiency; thereafter we were the first to employ BMT to cure aplastic anemia. BMT regularly corrects immune and hematologic deficiencies caused by fatal irradiation without producing GVHD if the bone marrow (BM) used for the transplants has been purged of postthymic T cells. Over two decades in conjunction with Ikehara et al., we have shown that lethal total body irradiation (TBI) plus allogeneic BMT prevents or cures many organ-specific and systemic experimental autoimmune diseases. Animal models successfully treated by BMT include type I diabetes in nonobese diabetes (NOD) mice, type II diabetes in insulin-insensitive, glucose intolerant, diabetes mellitus (KK/Ay) mice, and autoimmune lupus erythematosus (LE) and glomerulonephritis in New Zealand Black x New Zealand White first generation hybrid (NZB x NZW)F1 females. El-Badri extended Ildstad's original research showing a high frequency of survival with a normal functioning immune system after stable mixed chimerism is produced by mixed BMT in C57BL/6 (normal long-lived black strain) mice transplanted with T cell-depleted marrow (TCDM) from BALB/c ("normal" long-lived strain) allogeneic donors and C57BL/6 syngeneic donors. We showed that osteoblasts act as facilitator cells for allogeneic BMT and promote engraftment of allogeneic hematopoietic stem cells. Wang et al. then showed that the autoimmunities and fulminating renal disease of BXSB (C57BL x SB cross and selective lupus-like systemic autoimmunity) male mice was prevented and could be cured by transplantation using TCDM from both BALB/c (resistant) and BXSB (susceptible) strains given to BXSB recipients after lethal TBI. This treatment produced mixed BMT and a stable mixed chimerism, increased longevity, corrected all manifestations of autoimmunity, and cured fulminant glomerulonephritis in these recipients. These studies generated a new perspective on the potential usefulness of BM and stem cell transplants to cure major diseases that can possibly be treated by BMT. Mixed BMT from TCD BALB/c and BXSB mice cured autoimmunities and fulminant glomerulonephritis in BXSB mice. LE disease plus coronary vascular disease that occurs in (NZW x BXSB)F1 mice, along with idiopathic thrombocytopenic purpura, is also cured in lethally irradiated (NZW x BXSB)F1 mice by BMT from C57BL/6 donors. Furthermore, hemolytic anemia, autoimmune phenomena, and hyalinizing glomerular renal disease of New Zealand Black (NZB) mice were prevented or cured by stem cell transplants using purified stem cells from MHC-matched DBA/2 donors or NZB donors. Consequently, we reasoned that autoimmunities reside in stem cells. More recently, we found that transplants of both BM cells and bones can completely and permanently prevent otherwise highly resistant autoimmune diseases of MRL/lpr lpr mice and an autoimmune polyarthritis of NZB/Kn mice. Ildstad concluded that lethal preparative measures would not be acceptable for preparations to treat autoimmune diseases, so we now employ a gentle method for producing stable mixed chimerism described by Sharabi and Sachs to achieve mixed marrow transplantation and mixed hematopoietic chimerism. Other diseases we are approaching using this gentle manipulation include two forms of diabetes: insulin-dependent diabetes mellitus (IDDM) type I in NOD mice and non-insulin-dependent diabetes mellitus (NIDDM) type II in KK/Ay mice, atherosclerosis of apolipoprotein-E + kno
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PMID:Progress toward production of immunologic tolerance with no or minimal toxic immunosuppression for prevention of immunodeficiency and autoimmune diseases. 1083 46


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