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Query: UMLS:C0002878 (hemolytic anemia)
 7,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hemolytic anemia and methemoglobinemia induced by exposure to certain arylamines, such as aniline and dapsone, are known to be mediated by their N-hydroxylamine metabolites. The arylamide propanil (3,4-dichloropropionanilide), a herbicide used extensively in rice fields, is also thought to induce methemoglobinemia through the action of metabolites. However, the hemolytic potential of this compound has not previously been reported. The present studies were undertaken to determine the hemolytic potential of propanil, and, if positive, the role of metabolites in this hemotoxicity. The survival of previously administered 51Cr-labeled erythrocytes in rats was reduced in a dose-dependent manner by ip administration of both propanil and its deacylated metabolite, 3,4-dichloroaniline (ED50 for both ca. 1.8 mmol/kg). When labeled erythrocytes were exposed in vitro to propanil or 3,4-dichloroaniline and then readministered to rats, no decrease in erythrocyte survival was observed, which indicated that these compounds were not direct-acting hemolytic agents. In contrast, erythrocyte survival was markedly reduced by ip administration or in vitro exposure to N-hydroxy-3,4-dichloroaniline. In addition, N-hydroxy-3,4-dichloroaniline was detected in the blood of propanil-treated rats in amounts sufficient to account for the hemolytic activity of the parent compound. These data indicate that N-hydroxy-3,4-dichloroaniline mediates propanil-induced hemolytic anemia, and that occupational exposure to propanil may result in an increased risk of hemolytic episodes.
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PMID:Role of metabolites in propanil-induced hemolytic anemia. 187 73

Phenacetin is well known to cause hemolytic anemia and methemoglobinemia in humans. Early mechanistic studies clearly established a causal role for active/reactive drug metabolites in the process but did not unequivocally identify these metabolite(s) or resolve the question of whether these two hemotoxicities are mechanistically linked. As part of ongoing studies on the mechanism underlying arylamine-induced hemotoxicities, we have recently shown that the arylhydroxylamine metabolites of aniline and dapsone mediate the hemolytic activity of aniline and dapsone, respectively. The present study was undertaken to determine if N-hydroxyphenetidine (PNOH), the known arylhydroxylamine metabolite of phenacetin, is responsible for phenacetin-induced hemolytic anemia. As measured by decreased survival of 51Cr-labeled erythrocytes in rats, phenacetin, p-phenetidine, and PNOH were all hemolytic in vivo, with PNOH being significantly the most potent of the three. In vitro exposure of 51Cr-tagged erythrocytes to PNOH, followed by transfusion into isologous rats, resulted in a concentration-dependent reduction in erythrocyte survival, indicating that PNOH is a direct-acting hemolytic agent. Phenacetin and p-phenetidine were inactive. Phenacetin, p-phenetidine, and PNOH all produced dose-dependent methemoglobinemia in rats. In parallel in vitro studies, PNOH elevated methemoglobin levels, p-phenetidine and phenacetin did not. However, attempts to identify PNOH in the blood of phenacetin- and p-phenetidine-treated rats were unsuccessful, despite the use of a highly sensitive analytical method. Hemotoxic concentrations of PNOH were found to be highly unstable in the presence of red cells, though relatively stable in the buffer vehicle alone. Inhibitors of acetylation (p-aminobenzoic acid [PABA]) and deacetylation (bis-[p-nitrophenyl]phosphate [BNPP]), used to alter the cyclic interconversion of phenacetin and p-phenetidine, caused changes in phenacetin hemotoxicity that indicated the hemotoxin was a deacetylated metabolite distal to p-phenetidine. These data are consistent with the hypothesis that PNOH, formed during the metabolic clearance of phenacetin, mediates phenacetin-induced hemolytic anemia and methemoglobinemia through direct toxic actions in the erythrocyte.
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PMID:The role of N-hydroxyphenetidine in phenacetin-induced hemolytic anemia. 194 26

Hemolytic anemia after aniline and aniline-related drugs such as dapsone and primaquine is thought to be mediated by active/reactive metabolite(s) formed during the hepatic clearance of the parent compounds. To determine whether any of the known metabolites of aniline contribute to the hemolytic response seen in rats given aniline, rats were infused with isologous 51Cr-labeled erythrocytes 24 hr before administration of aniline or aniline metabolites. The time course of blood radioactivity was followed in individual rats by serial sampling from the orbital sinus and the time required for blood radioactivity to fall by 50% (T50Cr) was used as a measure of in vivo erythrocyte survival. Aniline HCl produced a dose-dependent reduction in the T50Cr. Acetanilide also reduced the T50Cr, but was less potent than aniline. Aminophenols (2-, 3- and 4-) in similar doses did not significantly alter the T50Cr. In contrast, phenylhydroxylamine produced a dose-dependent decrease in the T50Cr with approximately 10 times the potency of aniline. The T50Cr was also decreased in a concentration-dependent manner for labeled erythrocytes incubated in vitro with phenylhydroxylamine, then readministered to rats, indicating a direct toxic effect of phenylhydroxylamine on erythrocytes. In addition, the area under the blood time course curve for phenylhydroxylamine plus nitrosobenzene was equivalent in rats administered equitoxic doses of aniline or phenylhydroxylamine, indicating that sufficient phenylhydroxylamine is formed in vivo during aniline clearance to account for aniline's toxicity. These results suggest that phenylhydroxylamine is the active metabolite that mediates aniline-induced hemolytic anemia.
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PMID:Role of aniline metabolites in aniline-induced hemolytic anemia. 374 58

Two patients developed symptomatic methemoglobinemia and hemolytic anemia after treatment with phenazopyridine. Methemoglobinemia appears to be a rare occurrence after commonly used doses of phenazopyridine; phenazopyridine-associated hemolytic anemia has been reported both after overdose and after usual doses. The presentation of methemoglobinemia in the first patient and the response to treatment with methylene blue in the second patient were unusual, suggesting that the patients had a red cell defect or were exposed to other oxidizing substances. One of the major metabolites of phenazopyridine is aniline, a known cause of methemoglobinemia. Aniline-induced methemoglobinemia is less responsive to treatment with methylene blue than nitrate- or nitrite-induced methemoglobinemia. This may explain, in part, the poor response to methylene blue by one of our patients.
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PMID:Acquired methemoglobinemia and hemolytic anemia after usual doses of phenazopyridine. 707 67

The acute oral toxicity of 3,7-bis-(4-trifluoromethylphenyl)-1,5,3,7-dioxadiazocane (4-TFMPD) was compared with its 3-substituted isomer, 3,7-bis-(3-trifluoromethylphenyl)-1,5,3,7-dioxadiazocane (3-TFMPD) and with N,N'-oxydimethylenebis(2-trifluoromethylaniline) (N,N'-oxy-DM-bis (2-TFMA)). 4-TFMPD, 3-TFMPD, N,N'-oxy-DM-bis (2-TFMA) and their precursors (4-trifluoromethylaniline (4-TFMA), 3-trifluoromethylaniline (3-TFMA) and 2-trifluoromethylaniline (2-TFMA), respectively) were administered intragastrically to male Wistar rats at a dose of 0.12 mmol/kg body weight/day for three consecutive days and the resulting effects on haematological variables were determined. 4-TFMPD induced the highest methaemoglobinemia as compared with 3-TFMPD and N,N'-oxy-DM-bis (2-TFMA). Haemolytic anaemia with Heinz bodies, neutrophilia, lymphocytosis, enlargement of the spleen and enhanced production of granulocytes/macrophages from multipotential bone marrow cells (as determined by CFU-C test) were observed in animals treated with 4-TFMPD and 4-TFMA, whereas no such effects were observed in the other treatment groups. In conclusion, 4-substituted aniline derivatives exert special haematotoxicity on the red blood cells and induce leucocytosis, which differs from the effects of their 2- and 3-substituted congeners.
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PMID:Acute oral toxicity in rats of 3,7-bis-(4-trifluoromethylphenyl)-1,5,3,7-dioxadiazocane compared with 3,7-bis-(3-trifluoromethylphenyl)-1,5,3,7-dioxadiazocane and N,N'-oxydimethylenebis(2-trifluoromethylaniline). 771 78

Methylene blue is utilized as the main treatment of methemoglobinemia conventionally, but it may be ineffective in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We report a G6PD-deficient patient who suffered from aniline-induced methemoglobinemia with initial good response Heinz body but hemolytic anemia appeared later 3 d after methylene blue therapy. G6PD deficiency was identified. He recovered uneventfully with hydration, packed blood transfusion and adjuvant luvela-N(dl-alpha-tocopheryl nicotinate) medication. Caution should be taken in using methylene blue as antidote of acute methemoglobinemia, especially when a history of G6PD deficiency is obscure.
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PMID:Hemolytic anemia after methylene blue therapy for aniline-induced methemoglobinemia. 1182 67

The assessment of the carcinogenic properties of aniline is still controversial. Aniline has, if at all, genotoxic properties but is also acutely toxic and it has been proposed that the hematotoxic effects are responsible for the formation of hemangiosarcomas and fibrosarcomas in the spleen of male rats. As part of a bigger project in which the pathology of male Fischer F344 rats was studied after feeding 10, 30, or 100 mg/kg body weight aniline hydrochloride for 1 and 4 weeks in the diet, the aniline-hemoglobin (Hb) adducts were determined as a biochemical effect marker during those periods. An improved method for the work-up procedure and the adduct analysis was developed for this purpose. The Hb adduct levels increased proportionately with dose after 1 week, which indicates that metabolic activation was not saturated. After 4 weeks of feeding, the adduct levels increased less than proportionately, which suggests that a saturation process is involved. Since it is unlikely that metabolic activation was saturated, the results could be explained by a more rapid clearance of stressed erythrocytes at the carcinogenic dose level. The latter interpretation is supported by other observations which indicate that erythrocytes are damaged dose dependently. A no-observed-effect level (NOEL) has not been reached but could be close to the low dose of 10 mg/kg body weight per day. The Hb adduct formation at the low dose, however, indicates that this should not be considered a no-effect level (NEL). The results support the conclusion that hemolytic anemia is an essential prerequisite for aniline toxicity and tumor development, but they do not fully explain the tissue specificity.
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PMID:Biomonitoring of aromatic amines VI: determination of hemoglobin adducts after feeding aniline hydrochloride in the diet of rats for 4 weeks. 1455 19

Early indicators of aniline hydrochloride (AH) toxicity were investigated in male Fisher 344 rats for 1 or 4 weeks at dietary dose levels of 10, 30 or 100 mg/kg body weight (bw)/day (actual intake at least 6, 17 and 57 mg/kg). The doses were based on earlier studies that had shown spleen toxicity and carcinogenicity in male rats at 100 mg/kg/day but not at 10 mg/kg/day. In the present study a dose-related formation of haemoglobin adducts and Heinz bodies was found from 10 and 30 mg/kg bw/ day, respectively, onwards. Signs of anaemia (decreased red blood cell counts and increased reticulocytes) were recorded from 30 mg/kg onwards. At 100 mg/kg, an overt haemolytic anaemia was associated with increases in serum transferrin concentration and total iron binding capacity in the blood reflecting major perturbations in iron metabolism. At this dose there was an increase in peripheral neutrophil leucocytosis in the blood, indicating an inflammatory process in the spleen. Histopathologic evaluation showed a focal perisplenitis and haemosiderin deposition in sinusoidal Kupffer cells of the liver at 100 mg/kg. These results corroborate the contention that carcinogenic doses of aniline cause early effects on haematological parameters, inflammatory reaction in the spleen and perturbations in iron metabolism as a result of haemolytic anaemia. Accordingly, the carcinogenicity of aniline may be linked to definable threshold-related processes.
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PMID:Aniline: early indicators of toxicity in male rats and their relevance to spleen carcinogenicity. 1534 19

A 39-year-old woman intentionally ingested Amberes shoe dye containing both methanol and aniline. She subsequently developed life-threatening methanol poisoning, methemoglobinemia, hemolytic anemia, and sulfhemoglobinemia. Treatment involved methylene blue infusion, emergent hemodialysis, fomepizole therapy, and blood products. Multiple toxicities can occur after ingestion of shoe dyes.
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PMID:Aniline and methanol toxicity after shoe dye ingestion. 1549 17

Phenothiazine is an aromatic tricyclic compound that first emerged from the furtive chemical activity surrounding the aniline dye industry at the latter half of the 19th century. It contains both nitrogen and sulphur atoms and is the parent molecule of a multitude of drugs that have enjoyed varied and extensive use throughout medical and veterinary practice. The compound itself is not without biological activity and has been shown to possess insecticidal, antifungal, antibacterial and anthelmintic properties. It was this latter vermifugal application that has earned the molecule a place alongside penicillin and DDT for its colossal impact on mankind. Following its extensive usage over many years, unwanted reactions including neuromuscular incoordination, photosensitization and haemolytic anaemia have been reported and these have limited its use in the present climate. Investigations into the mode of action of phenothiazine and its underlying biochemical properties have been undertaken but the molecule has yet to reveal its secrets and still poses problems of understanding at the molecular level. This article reviews the literature, both established and current, and presents a contemporary view on phenothiazine and its interaction with biological systems.
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PMID:Phenothiazine: the parent molecule. 1701 93


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