Various forms of chemically induced liver injury and their detection by diagnostic procedures.
A large number of chemical agents, administered for therapeutic or diagnostic purposes, can produce various types of hepatic injury by several mechanisms. Some agents are intrinsically hepatotoxic, and others produce hepatic injury only in the rare, uniquely susceptible individual. Idiosyncrasy of the host is the mechanism for most types of drug-induced hepatic injury. It may reflect allergy to the drug or a metabolic aberation of the host permitting the accumulation of hepatotoxic metabolites. The syndromes of hepatic disease produced by drugs have been classified hepatocellular, hepatocanalicular, mixed and canalicular. Measurement of serum enzyme activities has provided a powerful tool for studies of hepatotoxicity. Their measurement requires awareness of relative specificity, knowledge of the mechanisms involved, and knowledge of the relationship between known hepatotoxic states and elevated enzyme activities. (+info)
Glomerular, tubular and interstitial nephritis associated with non-steroidal antiinflammatory drugs. Evidence of a common mechanism.
AIMS: To study the mechanisms behind NSAID-associated nephropathy. METHODS: Analysis of published case reports satisfying strict criteria for NSAID nephropathy. RESULTS: Ninety-seven cases with acute nephritis (AN; 19 patients), minimal change nephropathy (MC; 38 patients), membranous glomerulonephritis (MGN; 19 patients), focal sclerosis (FS; 13 patients) and other glomerulonephritis subgroups (8 patients) were identified. Hypersensitivity reactions were seen in all groups, most often in AN. Proteinuria was more severe in MC and FS than in MGN and unrelated to amount of glomerular deposits. The mean NSAID treatment time was 1.7 months in AN, 8.2 months in MC and 39 months in MGN and associated with amount of glomerular deposits, fusion of podocytes and proteinuria, and inversely associated with hypersensitivity, interstitial damage and renal failure. Rheumatic diseases were common in MGN. At follow-up 68 of 72 patients who had discontinued NSAID treatment had improved, 57 with normal renal function. CONCLUSIONS: NSAID nephropathy may be caused by hypersensitivity. The reaction is milder than in drug-induced acute tubulointerstitial nephritis, probably because the offending drug inhibits the inflammatory reaction it has started itself. Heavy proteinuria is probably due to lymphokines produced as a result of the immunological response. If the allergic reaction is strong, AN is produced rapidly with severe renal failure but little proteinuria; if it is less violent, immunocompetent cells may develop to produce lymphokines and proteinuria. Immune complexes may be formed eventually, secondary to the increased glomerular permeability, more easily in patients with a hyperactive immune system and with little consequence for renal function. (+info)
Cellular disposition of sulphamethoxazole and its metabolites: implications for hypersensitivity.
1. Bioactivation of sulphamethoxazole (SMX) to chemically-reactive metabolites and subsequent protein conjugation is thought to be involved in SMX hypersensitivity. We have therefore examined the cellular metabolism, disposition and conjugation of SMX and its metabolites in vitro. 2. Flow cytometry revealed binding of N-hydroxy (SMX-NHOH) and nitroso (SMX-NO) metabolites of SMX, but not of SMX itself, to the surface of viable white blood cells. Cellular haptenation by SMX-NO was reduced by exogenous glutathione (GSH). 3. SMX-NHOH and SMX-NO were rapidly reduced back to the parent compound by cysteine (CYS), GSH, human peripheral blood cells and plasma, suggesting that this is an important and ubiquitous bioinactivation mechanism. 4. Fluorescence HPLC showed that SMX-NHOH and SMX-NO depleted CYS and GSH in buffer, and to a lesser extent, in cells and plasma. 5. Neutrophil apoptosis and inhibition of neutrophil function were induced at lower concentrations of SMX-NHOH and SMX-NO than those inducing loss of membrane viability, with SMX having no effect. Lymphocytes were significantly (P<0.05) more sensitive to the direct cytotoxic effects of SMX-NO than neutrophils. 6. Partitioning of SMX-NHOH into red blood cells was significantly (P<0.05) lower than with the hydroxylamine of dapsone. 7. Our results suggest that the balance between oxidation of SMX to its toxic metabolites and their reduction is an important protective cellular mechanism. If an imbalance exists, haptenation of the toxic metabolites to bodily proteins including the surface of viable cells can occur, and may result in drug hypersensitivity. (+info)
Evidence of anaphylaxy after alteplase infusion.
BACKGROUND AND PURPOSE: Although alteplase, a recombinant tissue plasminogen activator (tPA), is structurally identical to endogenous tPA and therefore should not induce allergy, single cases of acute hypersensitivity reactions have been reported. Until now, specific antibodies against alteplase were not detected in blood samples obtained in these patients. CASE DESCRIPTION: We report an anaphylactic reaction in a 70-year-old white female who was treated with intravenous alteplase for thrombolysis of acute ischemic stroke 160 minutes after onset of a right-sided hemiparesis. Thirty minutes after infusion of alteplase had been started, the patient suffered acute severe sinus tachycardia and hypotension, followed by cyanosis and loss of consciousness. The alteplase infusion was stopped, and following antiallergic therapy, tachycardia and hypotension resolved within 1 hour. The hemiparesis remained unaltered, but additional harm resulting from the hemodynamic complication was not observed. Serum samples analyzed with a radioimmunoprecipitation assay were negative for total antibodies to alteplase, but in a subsequent ELISA, both samples were positive for IgE antibodies to alteplase. CONCLUSIONS: The detection of specific IgE antibodies reactive with alteplase in this patient could provide the first evidence of an anaphylactic-type reaction to alteplase in man. Because previous exposure to alteplase can be excluded, the results suggest that this patient had preexisting antibodies that were cross-reactive with one or more epitopes of alteplase and therefore precipitated the anaphylactic-type reaction. (+info)
Successful treatment with gabapentin in the presence of hypersensitivity syndrome to phenytoin and carbamazepine: a report of three cases.
We report three consecutive patients with hypersensitivity syndrome (HSS) due to phenytoin and carbamazepine and successful treatment with gabapentin. HSS is a rare but potentially fatal reaction to multiple drugs including several anticonvulsants. Cross-reactivity among drugs may occur. Immediate withdrawal of the offending drug is the most important step in treatment. Benzodiazepines acutely and, after resolution of the hepatitis, valproic acid have been successfully used for seizure control in patients with HSS. Our cases indicate that gabapentin is also a safe anticonvulsant in HSS. (+info)
Highly Th2-skewed cytokine profile of beta-lactam-specific T cells from nonatopic subjects with adverse drug reactions.
A positive lymphocyte transformation test to beta-lactams (beta-L) was found in 12 of 29 subjects with adverse drug reaction (ADR) to beta-L, irrespective of either the type of clinical manifestation or the presence of specific serum IgE. Short-term T cell lines specific for penicillin G, amoxicillin, and ampicillin could be generated only from subjects with ADR (eight with positive and one with negative lymphocyte transformation test), while streptokinase and Dermatophagoides pteronyssinus group 1 (Der p 1)-specific T cells were obtained from all these subjects, from 7 atopic Der p-sensitive donors without history of ADR and 17 healthy nonatopic donors. Streptokinase-specific T cells from all subjects showed intracellular expression of IFN-gamma with poor or no IL-4, whereas Der p 1-specific T cells exhibited IFN-gamma but low or no IL-4 expression in nonatopics, and remarkable IL-4 expression in atopic donors. By contrast, all penicillin G-, ampicillin-, and amoxicillin-specific short-term T cell lines showed high intracellular expression of IL-4, IL-5, and IL-13, but poor or no expression of IFN-gamma, thus exhibiting a clear-cut Th2 profile. Accordingly, most penicillin G-specific T cell clones derived from two subjects with ADR released high concentrations of IL-4 alone or IL-4 and IFN-gamma. These data suggest that cytokines produced by Th2 cells play an important role in all beta-L-induced ADR, even when late clinical manifestations occur and an IgE-mediated mechanism is apparently indemonstrable. (+info)
Prevention of occupational allergy caused by exposure to acid anhydrides.
This paper focuses on the prevention of IgE-mediated symptoms of the eyes and airways caused by exposure to acid anhydrides in the workplace. Acid anhydrides are widely used in the production of alkyd resins and as curing agents for epoxy resins. Heavy exposure to acid anhydrides causes severe irritation. However, reports of direct irritation of mucous membranes or skin are rare in recent years, since a package of multiple engineering controls has been introduced to reduce exposure. On the other hand, acid anhydrides are well-known industrial inhalant sensitizers and can cause occupational allergy even at very low exposure intensities. Therefore, safe use in industry demands both control of the level of exposure causing allergic diseases in the workshop and programmes for prevention of occupational allergy. (+info)
20 years of medical surveillance on exposure to allergenic and non-allergenic platinum compounds: the importance of chemical speciation.
OBJECTIVES: Chloroplatinates are potent allergens but other soluble platinum compounds such as tetraammine platinum dichloride (TPC) do not provoke reactions in subjects who are sensitive to chloroplatinates. TPC has been used in the manufacture of autocatalysts for 20 years. This study analyses 20 year data on exposure to soluble platinum compounds and medical surveillance to confirm that TPC is not allergenic. METHODS: Workers in three distinct operations were exposed to soluble platinum compounds as chloroplatinates, chloroplatinates with TPC, or to TPC alone. Results of personal air sampling for soluble platinum compounds were compared together with the results of medical surveillance. RESULTS: The levels of exposure to soluble platinum compounds in each operation were comparable but the incidence of allergy was significantly different. In a subgroup of workers consistently exposed to chemical processes in each operation, the cumulative chance of being sensitised after 5 years of exposure was estimated as 51% for chloroplatinate exposure, 33% for mixed exposure, and 0% for TPC alone. The differences in sensitisation rates could not be explained by age, sex, and atopy. Nor could they be explained by the increased frequency of smoking in the workers with chloroplatinate exposure, despite the markedly higher risk of sensitisation in smokers. The differences could only be explained by the chemical stability of TPC. CONCLUSIONS: This study shows that the soluble platinum compound TPC is not allergenic under normal industrial conditions. Characterisation of the chemical compound (speciation) is essential to prevent stringent exposure limits being imposed for all soluble compounds on a generic basis. (+info)