Hematotoxicity potential

Qualification of the tier 1 assays with the limited number of compounds indicated that the cell lines were able to predict the in vivo hematotoxicity potential of compounds, but further qualification using more compounds and specifically noncytotoxic compounds are still required. 

Hydrolysis of the amide bond generally leads to inactivation of the substrate and accelerates excretion of the products. In the case of aminoacyl-anilides, however, such hydrolysis may represent a pathway of toxification, since it liberates aromatic amines, which are potentially hematotoxic, nephrotoxic, hepatotoxic, and/or carcinogenic. 

Mercaptopurine [6-MP] (Purinethol) [Antineoplastic/ Antimeta lite] Uses Acute leukemias, 2nd-line Rx of CML NHL, maint ALL in children, immunosuppressant w/ autoimmune Dzs (Crohn Dz) Action Antimetabolite, mimics hypoxanthine Dose Adults. 80-100 mg/mVd or 2.5-5 mg/kg/d maint 1.5-2.5 mg/kg/d Peds. Per protocol X w/ renal/hepatic insuff on empty stomach Caution [D, ] Contra Severe hepatic Dz, BM suppression, PRG Disp Tabs SE Mild hematotox, mucositis, stomatitis, D rash, fever, eosinophilia, jaundice. Hep Interactions T Effects W/ allopurinol T risk of BM suppression W/ trimethoprim-sulfamethoxazole X effects OF warfarin EMS May falsely T glucose OD May cause NA and liver necrosis symptomatic and supportive Meropenem (Merrem) [Antibiotic/Carbapenem] Uses lntra-abd Infxns, bacterial meningitis Action Carbapenem X cell wall synth, a [3-lactam Dose Adults. 1 to 2 g IV q8h Peds. >3 mo, <50 kg 10-40 mg/kg IV q 8h in renal insuff Caution [B, ] Contra [3-Lactam sensitivity Disp Inj 500 mg, 1 g SE Less Sz potential than imipenem D, thrombocytopenia Interactions T Effects W/ probenecid EMS Monitor for signs of electrolyte disturbances and... 

The last potential mechanism to be discussed in this chapter is drug-induced altered receptor expression. Hematopoiesis is a very intricate process that is regulated by cytokines and cell-cell interactions. Interruption with any of these processes can result in hematotoxicity. For example, zidovudine (AZT) decreases Epo [27], GM-CSFaand to lesser extent IL-3 receptor expression [7]. Decrease in the expression of the above receptors seems to lead to anemia and neutropenia, by decreasing the number of CFU-E and CFU-GM, respectively. 

Bloom JC, Lewis HB, Sellers TS, Deldar A. The hematologic effects of cefonicid and cefazedone in the dog a potential model of cephalosporin hematotoxicity in man. Toxicol Appl Pharmacol 1987 90(l) 135-42. 

Acute oral exposures of humans to large amounts of 2-butoxyethanol have been shown to cause coma and respiratory depression, in addition to hematotoxic effects. Although this route of exposure is the least likely for the general population, the existence of many household products containing 2-butoxyethanol or 2-butoxyethanol acetate makes accidental poisoning a potential problem, particularly for children. 

Hematotoxicity (neutropenia, anemia, granulocytopenia) is dose-limiting and may require transfusions. Other effects include headache, asthenia, myalgia, myopathy, and peripheral neuropathy. Rare, but potentially fatal, lactic acidosis has been reported for ZDV and other NRTIs. 

Myoclonic syndromes Myoclonic seizure syndromes are usually treated with valproic acid. Clonazepam can be effective, but the high doses required cause drowsiness. Lamotrigine is also reported to be effective in myoclonic syndromes in children. Felbamate has been used adjunctively with the primary drugs but has hematotoxic and hepatotoxic potential. 

Goren MP, Wright RK, Pratt CB, Horowitz ME, Dodge RK, Viar MJ, Kovnar EH. Potentiation of ifosfamide neurotoxicity, hematotoxicity, and tubular nephrotoxicity by prior d -diam-mmedichloroplatinum(II) erapy. Cancer Res ( 9i7) 47, 1457-60. 

Biological Applications Measuring membrane potential " detecting prostate cancer analyzing urine apoptosis assays ( vivo hematotoxicity assays ... 

Biological Applications Hematotoxicity assays measuring membrane potential detecting microorganisms treating diabetes-associated pain, mechanical aUodynia, oncological diseases food packaging... 

Hi. Biological Applications. Copper(II) bis(dithiocarbamate) complexes have a number of potential biological applications. For example, while dithio-carbamate salts (R = Me, Ft) are potent inhibitors of a clonogenic response in human C34 bone marrow cells, addition of copper sulfate greatly potentiates the hematotoxicity, suggesting a more general role for copper in dithiocarba-mate-induced hematotoxicity (1779). 

---