Tacrine toxicity

Serious hepatotoxicity of tacrine has been documented. More recent data suggest, however, that this toxicity can be reduced by carehiUy monitoring semm alanine aminotransferase levels (125). The side effects of tacrine also include gastrointestinal disturbances and emesis, and alternative AChE therapies are being advanced. Velnacrine (20), a metaboUte of tacrine, was expected to have reduced hepatotoxicity. However, its limited efficacy and side-effect profile, which includes dmg-related hematological changes, caused it to be dropped from further development. 

When Hie cholinesterase inhibitors are administered with the anticholinergic drugp, there is a potential decrease in activity of the anticholinergic drug. There is an increased risk of toxicity of theophylline when the cholinesterase inhibitors are administered with tacrine There is a synergistic effect when tacrine is administered with succinyl-choline, cholinesterase inhibitors, or cholinergic agonists (eg, bethanechol). 

Tacrine is not without its problems. It produces typical cholinergic side effects (nansea, cramping, loss of appetite, rnnny nose, and diarrhea). In addition, tacrine can be toxic to the liver in some patients. If liver problems develop while taking tacrine, they reverse when the medication is discontinued. Nevertheless, all patients shonld routinely undergo blood tests of liver function before starting tacrine and periodically dnring tacrine therapy. 

Donepezil (Aricept). Donepezil is the second cholinesterase inhibitor approved for the treatment of dementia. Most physicians find it much easier to use than its predecessor. It can be given once a day and carries none of the risk of liver toxicity seen with tacrine. It has been shown in multiple clinical trials to delay the decline in cognitive function in patients with Alzheimer s disease. 

Tacrine was the first cholinesterase inhibitor approved for the enhancement of memory associated with Alzheimer s disease in the United States. Because of its short half-life, drug interactions, and hepatic toxicity, it is currently considered second-line therapy for patients who fail to respond to donepezil. Its psychophar-... 

Exposure to a toxic dose of OP results in inhibition of acetylcholinesterase and butyrylcholinesterase activities. The most common method to measure OP exposure is to assay acetylcholinesterase and butyrylcholinesterase activities in blood using a spectrophotometric method (EUman et al, 1961 Wilson et al, 2005 Worek et al, 1999). The drawbacks of activity assays are that they do not identily the OP. They show that the poison is a cholinesterase inhibitor but do not distinguish between nerve agents, OP pesticides, carbamate pesticides, and tightly bound, noncovalent inhibitors like tacrine and other anti-Alzheimer drugs. In addition, low-dose exposure, which inhibits less than 20% of the cholinesterase, carmot be determined by measuring acetylcholinesterase and butyrylcholinesterase activity because individual variability in activity levels is higher than the percent inhibition. 

The synthesis, toxicity, neuroprotection, and human acetyl-cholinesterase/butyrylcholinesterase inhibition properties of ft-naphthotacrinesl-14 have been reported [176]. p-Naphthotacrines 1-14 showed lower toxicity than tacrine. 

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