Hematological abnormalities

Neither the mechanism by which benzene damages bone marrow nor its role in the leukemia process are well understood. It is generally beheved that the toxic factor(s) is a metaboHte of benzene (107). Benzene is oxidized in the fiver to phenol [108-95-2] as the primary metabolite with hydroquinone [123-31-9] catechol [120-80-9] muconic acid [505-70-4] and 1,2,4-trihydroxybenzene [533-73-3] as significant secondary metabolites (108). Although the identity of the actual toxic metabolite or combination of metabolites responsible for the hematological abnormalities is not known, evidence suggests that benzene oxide, hydroquinone, benzoquinone, or muconic acid derivatives are possibly the ultimate carcinogenic species (96,103,107—112). 

Some rare toxic effects that may result from tocainide therapy are a lupus-fike syndrome, skin rash, pulmonary complications, and hematologic abnormalities, eg, agranulocytosis (1,2,24). 

Rare Neuroleptic malignant syndrome, hematologic abnormalities... 

Adverse Effects Adverse effects due to oxcarbazepine include drowsiness, dizziness, gastrointestinal upset, and hyponatremia, the latter two of which may be more likely than with carbamazepine. It is less likely than carbamazepine to cause hematologic abnormalities.34... 

K6. Kawamura, M Kitayoshi, T Terashita, Z., Fujiwara, S Takatani, M and Nishikawa, K Effects of TCV, a novel PAF antagonist, on circulatory shock and hematological abnormality induced by endotoxin in dogs. / Lipid Medial. Cell Signal. 9,255-265 (1994). 

Anemias in children are often due to a primary hematologic abnormality. The risk of iron-deficiency anemia is increased by rapid growth spurts and dietary deficiency. 

In a group of uranium mill workers, there was an excess of deaths from malignant disease of lymphatic and hematopoietic tissue data from animal experiments suggested that this excess may have resulted from irradiation of lymph nodes by thorium-230, a disintegration product of uranium. Some absorbed uranium is deposited in bone. A potential risk of radiation effects on bone marrow has been postulated, but extensive clinical studies on exposed workers have disclosed no hematologic abnormalities. ... 

Adverse effects occurring in at least 3% of patients include diarrhea, nausea, flatulence, hematologic abnormalities, rash, and increases in ALT, AST, and creatine kinase. 

Hematologic events Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving infliximab. The causal relationship to infliximab therapy remains unclear. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (eg, persistent fever) while on infliximab. Consider discontinuation of infliximab therapy in patients who develop significant hematologic abnormalities. 

Mild to moderate side effects, including nausea, vomiting, abdominal pain, diarrhea, anorexia, and headache, occur in up to 33% of patients taking this drug. Skin rash and discoloration, fever, reversible male infertility, and liver enzyme elevation occur less frequently. Rare hematological abnormalities, such as agranulocytosis, aplastic anemia, hemolytic anemia, neutropenia, or other blood dyscrasias, can be fatal. Hypersensitivity reactions occur rarely. 

Etanercept therapy should not be initiated in patients with active infection. If an infection develops in a person taking etanercept, he or she should be closely monitored. If a serious infection or sepsis occurs, the drug should be discontinued. Etanercept should be used with caution in individuals who have conditions predisposing them to serious infection (e.g., uncontrolled diabetes, hematological abnormalities). Data on drug interactions are limited. Live virus vaccines are contraindicated because of the potential for secondary transmission of the infection by the vaccine. Myelo-suppressive antirheumatic agents have been associated with pancytopenia in some patients treated with etanercept. 

Mild proteinuria is fairly common and does not always require discontinuance of therapy however, severe proteinuria may indicate a toxic nephritis. The proteinuria is usually reversible when gold administration is stopped. Hepatotoxicity has also been reported. Fatahties from gold therapy have been reported, usually a consequence of a blood dyscrasia. The most common hematological abnormality is eosinophilia. Serious blood dyscrasias, such as thrombocytopenia, agranulocytosis, and hypoplastic or aplastic anemia, are rare. 

The cephalosporins have good safety profiles. The overall incidence of adverse events attributed to cephalosporins is between 1 and 10%. The most common adverse drug reactions are rashes (1-5%), eosinophilia (3-10%), gastrointestinal symptoms (3%), hematological abnormalities (1-2%), phlebitis (2%), and fever (<1%). Anaphylactic reactions to cephalosporins are rare (<0.02%). 

Hematologic abnormalities, including myelosupression, unusual bleeding, drug fever, renal complications, and lupus erythematous-like reaction including fever, arthralgia, and lymphadenopathy rarely occur. 

Miscellaneous other reactions include hematologic abnormalities, provocation of pyridoxine deficiency anemia, tinnitus, and gastrointestinal discomfort. Isoniazid can reduce the metabolism of phenytoin, increasing its blood level and toxicity. 

Carbamazepine. The anticonvulsant carbamazepine was actually the first to be shown to be effective in the manic phase of bipolar disorder, but it has not been approved for this use by regulatory authorities such as the U.S. Food and Drug Administration (FDA). Its mechanism of action may be to enhance GABA function, perhaps in part by actions on sodium and/or potassium channels (Fig. 7—24). Because its efficacy is less well documented and its side effects can include sedation and hematological abnormalities, it is not as well accepted for first-line use in the treatment of mood disorders as either lithium or valproic acid. 

Adverse Effects. Gastrointestinal disturbances including nausea, vomiting, diarrhea, stomach pain, and an unpleasant taste in the mouth are relatively common with metronidazole. Other adverse effects such as hypersensitivity reactions, peripheral neuropathy, hematologic abnormalities, and genitourinary problems have been reported, but their incidence is relatively low. 

It is generally well tolerated side effects are vomiting, diarrhea, abdominal pains, dizziness, and headache. Prolonged use may cause hypersensitive reactions such as fever, arthralgia, muscle pains, and CNS effects like headache, insomnia, dizziness, and convulsions. Hematologic abnormalities such as granulocytosis, leukopenia, and thrombocytopenia may occur. 

No hematological abnormalities were found in rats fed diets providing 1,806 mg chromium(III)/kg/day as chromium oxide 5 days/week for 90 days (Ivankovic and Preussmann 1975), or in rats exposed to 3.6 mg chromium(III)/kg/day as chromium trichloride in the drinking water for 1 year (MacKenzie et al. 1958). 

Deficiencies of vitamin B12 can result from either low dietary levels or, more commonly, from poor absorption of the vitamin due to the failure of gastric parietal cells to produce intrinsic factor (as in pernicious anemia) or to a loss of activity of the receptor needed for intestinal uptake of the vitamin.5 Nonspecific malabsorption syndromes or gastric resection can also cause vitamin B12 deficiency. The vitamin may be administered orally (for dietary deficiencies), or intramuscularly or deep subcutaneously (for pernicious anemia). [Note Folic acid administration alone reverses the hematologic abnormality and thus masks the B12 deficiency, which can then proceed to severe neurologic dysfunction and disease. Therefore, megaloblastic anemia should not be treated with folic acid alone, but rather with a combination of folate and vitamin B12.] Therapy must be continued for the remainder of the life of a patient suffering from pernicious anemia. There are no known adverse effects of this vitamin. 

Indirect indicators of vitamin B12 deficiency include measurements of the metabolites homocysteine and methylmalonic acid (MMA) in serum and MMA in urine (see the Biochemical Perspectives section). Whereas the serum homocysteine concentration increases during folate or vitamin B12 deficiencies, the serum and urine MMA concentrations increase only in vitamin B12 deficiency. Therefore, MMA determinations can be used to differentiate vitamin B12 deficiency from folate deficiency. The normal concentration of MMA in serum ranges from 0.08 to 0.28 pmol/L. MMA is quantified using gas-liquid chromatography and mass spectrometry. Elevated concentrations of MMA and homocysteine in serum may precede the development of hematological abnormalities and reductions in serum vitamin B12 concentrations. One should be aware that other conditions, including renal in sufficiency and inborn errors of metabolism, can also result in elevated serum levels of MMA. 

Vitamin B12 is required by only two enzymes in human metabolism methionine synthetase and L-methylmalonyl-CoA mutase. Methionine synthetase has an absolute requirement for methylcobalamin and catalyzes the conversion of homocysteine to methionine (Fig. 28-5). 5-Methyltetrahydrofolate is converted to tetrahydrofolate (THF) in this reaction. This vitamin B12-catalyzed reaction is the only means by which THF can be regenerated from 5-methyltetrahydrofolate in humans. Therefore, in vitamin B12 deficiency, folic acid can become trapped in the 5-methyltetrahydrofolate form, and THF is then unavailable for conversion to other coenzyme forms required for purine, pyrimidine, and amino acid synthesis (Fig. 28-6). All folate-dependent reactions are impaired in vitamin B12 deficiency, resulting in indistinguishable hematological abnormalities in both folate and vitamin B12 deficiencies. 

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