Research Project
3437783
The antidepressant amoxapine (AMOX) is effective in treating psychotic delusional depression, has limited cardiotoxicity in overdose, and enjoys a comparatively rapid onset of effect. Disadvantages include a high rate of seizures, rhabdomyolysis and acute renal failure in some subjects with AMOX overdose. AMOX was found in pilot studies to cause direct injury to muscle in vitro, and suspiciously similar effects in vivo. These myotropic actions of AMOX are important since the following events are believed to occur in man: amoxapine greater than seizures greater than rhabdomyolysis greater than myoglobinuria greater than renal casts greater than acute renal failure. Seizures also produce acidosis. Since depressed patients are a target group for suicide by amoxapine overdose, understanding the etiology of the associated renal failure is important. Seizures, acidosis and rhabdomyolysis are hypothesized to be necessary factors in amoxapine-associated renal failure. If the hypothesis is true, then reducing, removing or blocking the effect of these factors should mitigate or prevent the development of AMOX-related renal impairment. Pilot studies showed that rats receiving toxic, seizure-producing doses of AMOX die, and thus do not permit analysis of any aspect of renal function. We have developed a model (ASRA) of acute renal failure that involves Amoxapine, Seizures, Rhabdomyolysis and Acidosis which will allow us to pursue the folllowing specific objectives and test the hypothesis above: 1. To determine the effects of blocking, reducing and omitting the element of acidosis on the development of acute renal failure in the ASRA model of amoxapine overdose in the rat, 2. To determine the effects of blocking, reducing and omitting the element of seizures on the development of acute renal failure in the ASRA model of amoxapine overdose in the rat, and 3. To determine the potential correlation of rhabdomyolysis with the development of acute renal failure in the ASRA model.
