Dose-dependent anemia

Mostly chloramphenicol is well tolerated with only mild gastrointestinal disturbances. However this antibiotic inhibits mitochondrial protein synthesis in red blood cell precursors in the bone marrow and thus may cause dose-dependent anemia. This dose dependent reaction should not be confused with the idiosyncratic aplastic anemia which is dose-independent and usually fatal. The onset of this idiosyncrasy which has an incidence of about 1 20 000-1 50 000 may be during the treatment or weeks to months after therapy. 

To date, three pharmaceutical companies have entered clinical trials with PHD inhibitors for the treatment of anemia with the most advanced being FG-2216. In clinical studies, compound 2 (likely FG-2216) showed a dose- and time-dependent elevation of plasma erythropoietin after oral administration [66]. Healthy volunteers were orally administered various doses of compound 2 and serum erythropoietin (EPO) concentrations were measured at various times. Compound 2 increased serum EPO levels in a dose-dependent manner and, following administration of the 20 mg/kg dose, a 5-fold increase of EPO levels was observed after 12 h. In the same patent application, the effect of 2 on anemic predialysis patients with no previous rh-EPO exposure was also disclosed. Patients were treated with 2 three times/week for 4 weeks (no dose reported) and the hemoglobin levels were assessed on day 42. The patients who received treatment showed a mean increase in hemoglobin of 1.9 g/dL from baseline values, whereas subjects who received placebo showed a mean decrease of 0.35 g/dL from baseline levels. These data suggest for the first time that an oral PHD inhibitor could be effective for the treatment of anemia. 

Subsequent analysis of stored serum samples showed reduction of HCV RNA levels during treatment and durable eradication of virus in some cases [38]. These early results were confirmed by randomized controlled trials in patients with chronic hepatitis C [39-41]. Durable viral eradication (termed sustained virologic response, or SVR) was achieved in 6% to 15% of patients after six months of treatment with recombinant interferon at doses of 3 to 6 MU administered subcutaneously three times per week. SVR increased to 13% to 25% if treatment was extended to 12 months [41]. The combination of the oral nucleoside analogue ribavirin with recombinant interferon increased SVR to 41% [42-44]. Ribavirin, however, is potentially embryotoxic and induces a dose-dependent hemolytic anemia, a situation that calls for close monitoring during therapy. 

Thiamphenicol is a synthetic chloramphenicol analogue with a molecular structure that appears to preserve tlie antibacterial properties, decrease markedly the metabolism by the liver, enhance kidney excretion, and eliminate tlie occurrence of aplastic anemia, although it is probably more liable to cause dose-dependent reversible depression of the bone marrow (15). These properties make it preferable in certain cases to chloramphenicol (36, 37). 

Approximately 10-20% of patients experience a dose-dependent hemolytic anemia that may be dose-limiting. Other side effects are depression, fatigue, irritability, rash, cough, insomnia, nausea, and pruritus. Absolute contraindications to ribavirin therapy include anemia, end-stage renal failure, severe heart disease, and pregnancy. Ribavirin is both teratogenic in animals and mutagenic in mammalian cells. 

Adverse effects Side effects reported for oral or parenteral use of ribavirin have included dose-dependent transient anemia in Lassa fever victims. Elevated bilirubin has been reported. The aerosol may be safer, although respiratory function in infants can deteriorate quickly after initiation of aerosol treatment and therefore, monitoring is essential. Because of teratogenic effects in experimental animals, ribavirin is contraindicated in pregnancy. 

Some perturbation of the reticulocyte numbers was observed, but values at days 3 and 5 did not differ from controls. Absolute numbers of lymphocytes and neutrophils did not differ from controls (no data shown). A slight anemia was observed at 4 and 8 weeks of treatment with 300 and 900 ppm benzene. Results showed minor changes in the stem and progenitor cells. CFU-E depression after 4 days of exposure was significant. There was a dose-dependent depression of colony forming cell numbers present at 4 and 8 weeks of exposure with a maximal effect at the level of CFU-E. Decreased CFU-E and BFU-E were observed in a companion study in which hybrid mice were exposed to 300 or 900 ppm benzene for the same period of time (Plappert et al. 1994b). 

Myelosuppression, as evidenced by anemia, leukopenia, and thrombocytopenia, is common in patients taking efiornithine. The manufacturers quote respective incidence rates of 55, 37, and 14%. However, other reports have suggested that thrombocjdopenia is the most frequent problem it is dose-dependent and occurred in 90% of patients with cancer on a dose of 6-8 g/m with efiornithine concentrations over 400 mmol/1 (SED-12, 709) (16). 

Dose-dependent and reversible normochromic normo-cjrtic anemia was consistently noted within several days after starting interleukin-6, and required blood transfusion at the highest dose (3). Hemodilution was considered as the primary mechanism. 

Ribavirin accnmnlates in erythrocytes, resnlting in hemolysis by an nnknown mechanism, perhaps related to oxidative damage to the erythrocyte membrane. Time-dependent and dose-dependent hemolytic anemia (eventnaUy associated with hyperbilirubinemia and a high reticnlocyte connt) is the only major toxic effect associated with oral or intravenons ribavirin and is reversible on withdrawal. There was a fall in hemoglobin concentrations below 10.0 g/dl in 9% of patients with hepatitis C treated with ribavirin and interferon alfa (6,7). 

Dose-dependent bone marrow suppression is common aplastic anemia is rare (1 in 35,000). Gray baby syndrome in neonates (i glucuronysyl transferase) and optic neuritis in children. Inhibits metabolism of phenytoin, sulfonylureas, and warfarin. 

Chloramphenicol causes both dose-dependent and dose-independent hematologic reactions. Fatal aplastic anemia occurs in genetically susceptible patients taking chloramphenicol on a long-term basis. Reversible and dose-dependent disturbances of hemopoiesis can also arise, and are characterized by the altered maturation of red blood cells, vacuolated nucleated red blood cells in the marrow, and reticulocytopenia. 

Dose-dependent bone marrow suppression common aplastic anemia rare (1 in 35,000)... 

The appearance of markedly vacuolated, nucleated red cells in the marrow, anemia, and reticu-locytopenia are characteristic dose-dependent side effects of... 

Reversible, dose-dependent bone marrow maturation arrest occurs with chloramphenicol. Serum iron concentration increases and blood levels of phenylalanine decrease. These actions are unrelated to the rare occurrence of aplastic anemia. The answer is (B). 

Melhorn, D. K., Gross, S., and Childers, G., 1971a, Vitamin E dependent anemia in the premature infant. I. Effects of large doses of medicinal iron, J. Pediatr. 79 569. 

The comparative toxicity of retinoids and retinamides have also been studied by Sani and Meeks (1982). On the basis of clinical signs of toxicity, lethality, and histopathological findings in rats and mice, the toxicity of the retinoids and retinamides were ranked in the order tretinoin > 2-hydroxypropylretinamide > isotretinoin > 2-hydroxyethylretinamide > ethylretinamide > 3-hydroxypropyl-retinamide > 4-hydroxyphenylretinamide. Treatment with the retinoids (doses not stated) caused an anemia characterized by erythrocytopenia and decreases in hemoglobin concentration, packed-cell volume, and hematocrit. Dose-dependent increases in serum alkaline phosphatase activity and decreases in serum albumin were also observed. 

Myelosuppression is dose dependent monitoring white blood counts is usually sufficient for detecting bone marrow suppression. The nadir white blood cell count is usually encountered 9 days after an IV dose, but the range can be 6 to 21 days (215). Monocytosis is an early indicator of bone marrow recovery from chemotherapy, while low monocyte counts portend prolonged leukopenia (216). Anemia is a consequence of chronic CP use. Patients with hemoglobin levels of less than 11 gm% should be considered for erythropoietin therapy (217). 

The intravascular persistence of fluorocarbon emulsions needs to be improved further. The dose-dependent half-life of recent fluorocarbon emulsions is typically 4-12 h [161]. This is sufficient only for surgical procedures, but it is inadequate for cases of trauma and much too short for chronic anemia [161]. 

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