Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002878 (hemolytic anemia)
 7,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A confirmatory familiarization study of the Combined Repeat Dose and Reproductive/Developmental Toxicity Screening (ReproTox) test protocol proposed by the Organization for Economic Cooperation and Development (OECD) was performed using nitrobenzene, a testicular toxicant. The agent was given daily by gavage to groups of 10 male and 10 female Sprague-Dawley rats at doses of 100, 60, 20 and 0 mg/kg body weight. Some of the high dose animals exhibited neurological signs, and two males and 9 females died. Hemolytic anemia due to methemoglobin formation was evident in treated males. Histopathologically, treated males showed atrophy of seminiferous tubules of the testis, reactive changes secondary to hemolytic anemia in the hematopoietic organs, and hepatocellular swelling. Cerebral gliosis was observed in middle and high dose males. Male fertility was not affected. The body weights of pups from treated dams were lowered, and their postnatal loss was increased. Most of the known toxicological properties of this chemical was demonstrated in the present study, with the exception of reduced fertility. Therefore, the ReproTox protocol was concluded as being useful as a screening test of existing high production volume chemicals. It should be noted that while the reproductive toxicity test alone is insensitive for detection of male fertility disturbances associated with testicular toxicity, the latter easily be distinguished on morphological grounds.
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PMID:Confirmation study, using nitrobenzene, of the Combined Repeat Dose and Reproductive/Developmental Toxicity Test protocol proposed by the Organization for Economic Cooperation and Development (OECD). 796 51

Malaria is a major cause of health problems in a large portion of the world. The 8-aminoquinoline compound, primaquine, is one of the only compounds useful for relapses of Plasmodium vivax and Plasmodium ovale malaria. Primaquine has several toxicities that include methemoglobinemia and hemolytic anemia. The induction of methemoglobinemia is a treatment for cyanide poisoning. We studied the pharmacokinetics and pharmacodynamics (percentage methemoglobin) for WR242511, an 8-aminoquinoline primaquine replacement and potential anticyanide compound. The drug's pharmacokinetics and pharmacodynamics are described for oral and intravenous dosing, and two kinetic-pharmacodynamic models are shown to describe the single dose data. A significant lag occurs between the onset of appearance of drug in the plasma and the onset of methemoglobinemia. Peak drug concentrations occurred within 4 hr for oral dosing, and peak effect (percentage methemoglobin) did not occur for 72-96 hrs for both the oral and intravenous routes. Elimination half-life for the drug was 30 +/- 14 hr. Two kinetic-dynamic models, one with an effect compartment relating drug concentration to effect and one with metabolite causing a first-order conversion of hemoglobin to methemoglobin, are compared as to their ability to predict multiple dose pharmacokinetics and pharmacodynamics. Both models were useful in predicting drug concentrations and methemoglobin levels for multiple-dose experiments.
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PMID:Pharmacokinetics and kinetic-dynamic modeling of an 8-aminoquinoline candidate anticyanide and antimalarial drug (WR242511). 807 Mar 11

DQ-2511, a new anti-ulcer drug, was administered to beagle dogs for 4 weeks to investigate the mechanism whereby this drug induced hemolytic anemia and its reversibility in comparison with beta-acetylphenylhydrazine. Hemolytic anemia accompanied by an increase in the number of cells containing Heinz bodies that was preceded by a marked decrease in blood-reduced glutathione concentration was observed in dogs receiving 600 mg/kg of DQ-2511, but only a slight increase in the methemoglobin level was noted. beta-Acetylphenylhydrazine, however, caused hemolytic anemia accompanied by marked increases in both Heinz body-containing cells and methemoglobin concentration, but the blood-reduced glutathione concentration was not decreased consistently with the formation of Heinz bodies. Hemolytic anemia disappeared after a 4-week recovery period in the dogs that received DQ-2511. These results suggest that decreases in reduced glutathione in erythrocytes play an important role in the anemia and Heinz body formation induced by DQ-2511, but not by beta-acetylphenylhydrazine.
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PMID:Heinz body hemolytic anemia induced by DQ-2511, a new anti-ulcer drug, in dogs. 844 84

Hemoglobinopathies responsible for hemolytic anemias may be divided into two groups. The first one corresponds to thalassemias and the second to the presence of a structurally abnormal hemoglobin (Hb). In thalassemia, the primary biochemical abnormality is a quantitative defect in the biosynthesis of one type of Hb chain. This defect leads to an overall deficit of Hb accumulation in the erythrocyte (hypochromia) together with the presence of an excess of the normally synthesized chains. The unpaired subunits which are less soluble than HbA precipitate, bind to the membrane and ultimately lead to hemolysis. In the second group, the hemolytic anemia is a direct consequence of the physicochemical properties of the structurally abnormal Hb. This molecule may polymerize, precipitate or crystallize within the red blood cell (RBC) leading to membrane alterations and to the destruction of the cell. This chapter will emphasize several examples of structurally abnormal Hbs, such as sickle cell disease and congenital Heinz body hemolytic anemia (CHBHA).
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PMID:Hemolytic anemias due to hemoglobinopathies. 881 15

Congenital hemolytic anemias resulting from PK, PFK, and G6PD enzyme deficiencies have been reported in domestic animals. Dogs with PFK deficiency may have episodes of intravascular hemolysis with hemoglobinuria in addition to a persistent compensated hemolytic anemia. Patients with mild G6PD deficiency are not anemic but may show increased susceptibility to oxidant-induced erythrocyte injury. Persistent methemoglobinemia has been reported in dogs and cats with methemoglobin reductase enzyme deficiency. Affected animals have cyanotic-appearing mucous membranes but show no or only mild clinical signs attributable to hypoxemia. Enzyme assays are usually done after acquired causes of hemolytic anemia and methemoglobinemia have been ruled out.
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PMID:Congenital erythrocyte enzyme deficiencies. 886 87

A previous study revealed that DQ-2511, a new gastroprokinetic drug, induced hemolytic anemia together with increased Heinz body formation, preceded by a marked decrease in erythrocyte reduced glutathione (GSH) content, after 2 weeks of dosing onward in dogs. In this study, the effect of DQ-2511 on erythrocytes in the early period of dosing, in comparison with that of beta-acetylphenylhydrazine (APHZ), was investigated to confirm the difference between this drug and APHZ in the mechanism of increased Heinz body formation. DQ-2511 and APHZ were administered orally to beagle dogs for 1 week at dose levels of 600 and 4 mg/ kg, respectively. Dogs receiving APHZ showed anemia after dosing for 7 days, together with an increase in methemoglobin and Heinz body formation after 3 days of dosing. In contrast, blood GSH, glutathione reductase, and gamma-glutamylcysteine synthetase were only slightly decreased after dosing for 7 days. In dogs treated with DQ-2511, erythrocyte GSH began to decrease after 1 day of treatment and was about 25% of the control value after 7 days; however, no changes were seen in blood glutathione reductase, GSH peroxidase, or gamma-glutamylcysteine synthetase level. Hepatic GSH was decreased slightly. In another experiment, SD rats were administered DQ-2511 and APHZ orally for 1 week at dose levels of 1600 and 15 mg/kg, respectively. Rats receiving DQ-2511 showed no anemia or any changes in erythrocyte GSH and Heinz body formation. In contrast, rats treated with APHZ showed a marked anemia and increases in Heinz body formation and erythrocyte GSH. These results demonstrate that DQ-2511 causes a marked decrease in GSH in dogs, resulting in Heinz body anemia, whereas APHZ induces Heinz body formation after a significant increase in methemoglobin, and suggest that impairment of the GSH redox cycle and synthetases of GSH are not involved in the decreased GSH after DQ-2511 treatment. This difference in effects on GSH content may indicate the existence of a species difference in the anemia induced by DQ-2511.
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PMID:A possible mechanism of heinz body hemolytic anemia induced by DQ-2511, a new gastroprokinetic drug, in dogs. 892 30

Hb Auckland is a newly described unstable hemoglobin with a mutation of alpha 97(F8)His-->Asn. This substitution, involving the proximal histidine, does not lead to methemoglobinemia, but to instability and accelerated heme loss. The clinical picture is of a mild compensated hemolytic anemia. The presence of an abnormal hemoglobin was first demonstrated by the isopropanol stability test and confirmed by electrospray ionization mass spectrometry of total lysate. This showed that 14% of the alpha chains had a mass of 15,103.4 Da, i.e. 23 Da less than normal. Examination of tryptic digests showed an identical decrease in mass for peptide alpha T-9 (from 2,997.4 to 2,974.5 Da). Subdigestion with endoproteinase Asp-N located the 23 Da loss to residues alpha 85-90, and further digestion with thermolysin identified the mutation as His-->Asn at position 87 of the alpha chain. This was confirmed by sequence analysis of the peptide alpha 85-90.
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PMID:Hb Auckland [alpha 87(F8) His-->Asn]: a new mutation of the proximal histidine identified by electrospray mass spectrometry. 932 75

Ingestion of strong oxidant substances may result in acquired methemoglobinemia, a clinical condition in which the oxidized blood hemoglobin is incapable of delivering oxygen to the tissues, and the patient becomes cyanotic. Traditional first-line therapy consists of infusion of methylene blue, whose action depends on the availability of reduced nicotinamide adenine nucleotide phosphate (NADPH) within the red blood cell (RBC). Some patients, particularly those who are deficient in glucose-6-phosphate dehydrogenase (G6PD), will not benefit from methylene blue. In these patients, and in some patients who have ingested very strong oxidants, methylene blue may also precipitate Heinz body hemolytic anemia. We present a case of severe, acquired methemoglobinemia in a 26-month-old, 9.8-kg boy with G6PD deficiency. He was cyanotic, in respiratory failure, intubated in a pediatric intensive care unit. In typical fashion, he did not respond to methylene blue. Manual exchange of two whole blood volumes, performed over 4 1/2 hr, also failed to resolve his severe methemoglobinemia. An automated RBC exchange (1.3 RBC volume), lowered his methemoglobin content from 31.8% to 7% in a single 40-min procedure. Thereafter his methemoglobin level continued to decrease rapidly and spontaneously. He was discharged home 2 days later, with 0.4% methemoglobin. To our knowledge, this is the first report to demonstrate the (potentially superior) effectiveness of automated RBC exchange for treatment of patients with high-risk acquired methemoglobinemia, that is, those with G6PD deficiency or who have ingested strong oxidants.
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PMID:Treatment of high-risk, refractory acquired methemoglobinemia with automated red blood cell exchange. 959 Apr 95

Hemoglobin (Hb) S-Oman has two mutations in the beta-chains. In addition to the classic betaS mutation (beta6 Glu --> Val), it contains a second mutation in the same chain (beta121 Glu --> Lys) identical to that of HbOARAB. We have studied a pedigree of heterozygous carriers of HbS-Oman that segregates into two types of patients: those expressing about 20% HbS-Oman and concomitant -/ thalassemia and those with about 14% of HbS-Oman and concomitant -/- thalassemia. The higher expressors of S-Oman have a sickle cell anemia (SS) clinical syndrome of moderate intensity, while the lower expressors have no clinical syndrome, and are comparable to the solitary case first described in Oman. In addition, the higher expressors exhibit a unique form of irreversibly sickled cell reminiscent of a "yarn and knitting needle" shape, in addition to folded and target cells. The CSAT of S-Oman is identical to that of S-Antilles, another supersickling hemoglobin, whose carriers express the abnormal hemoglobin at 40% to 50%, with a very similar clinical picture to HbS-Oman. Because the level of expression is so different and the clinical picture so similar, and based on the hemolysates CSAT's, we conclude that HbS-Oman produces pathology beyond its sickling tendencies. A clue for this additional pathogenesis is found in the fact that homozygous HbOARAB, which has the same second substitution as S-Oman, has a moderately severe hemolytic anemia; when HbOARAB is combined with HbS, it makes the phenotype of this double heterozygote as severe as SS. Properties of HbS-Oman red blood cells (RBCs) include reticulocytes that are much denser than normal (similar to those of SC and CC disease), a decrease in the Km for Ca2+ needed to activate the Gardos' channel (making this transporter more sensitive to Ca2+), increased association of HbS-Oman with the RBC membrane, the presence of dense cells by isopycnic gradient, the presence of folded cells, and abundant nidus of polymerization under the membrane. Other properties include a clear increase in volume and N-ethylmaleimide-stimulated K:Cl cotransport in RBCs expressing more than 20% HbS-Oman. We conclude that the pathology of heterozygous S-Oman is the product of the sickling properties of the beta6 Val mutation which are enhanced by the second mutation at beta121. In addition, the syndrome is further enhanced by a hemolytic anemia induced by the mutation at beta121. We speculate that this pathology results from the abnormal association of the highly positively charged HbS-Oman (3 charges different from normal hemoglobin) with the RBC membrane.
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PMID:HbS-oman heterozygote: a new dominant sickle syndrome. 983 44

The unstable Hb Khartoum with a Pro-->Arg replacement at position beta124 was identified by isoelectrofocusing, high performance liquid chromatography, and peptide mapping in a mother and two male children of a Sudanese family. All three were heterozygous for the abnormal hemoglobin; the father and a third male child did not carry the mutation. The mother was also homozygous for two putative gamma+-thalassemia point mutations, one affecting both Agamma and Ggamma genes at IVS-II-115 (A-->G), and one affecting the Ggamma gene at the 3' untranslated region (-A) at position -6 from the polyadenylation site. The father had normal gamma genes. All three children were heterozygous for both the gamma+-thalassemia mutations. The two older children, who were compound heterozygotes for Hb Khartoum/gamma+-thalassemia, presented at birth with severe neonatal jaundice which necessitated exchange blood transfusions. Other causes of neonatal jaundice were excluded. The third male child, who did not carry the Hb Khartoum anomaly but was heterozygous for gamma+-thalassemia, did not develop neonatal jaundice. It is concluded that the instability of Hb Khartoum in combination with gamma+-thalassemia is responsible for neonatal hemolytic anemia in this family.
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PMID:The association of Hb Khartoum [beta124(H2)Pro-->Arg] with gamma+-thalassemia is responsible for hemolytic disease in the newborn of a Sudanese family. 1008 84


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