During the second part, of the 19th century,

many physicians believed in a uric acid “diathesis,” a predisposition for the accumulation of urea, in the body,29 that could cause a, variety of disorders from gout and rheumatism to cardiac disease and mental illness.27 Since acute symptoms of gout, develop suddenly and persist untreated for days or weeks before they remit, William Hammond, at the Bellevue Hospital in New York, had assumed that mood Inhibitors,research,lifescience,medical disorders might be a form of cerebral gout and employed ZD1839 solubility dmso lithium successfully in their treatment.30,31 On the basis of the same assumption, Carl Lange, a Danish neurologist, treated hundreds of patients with lithium and reported on its prophylactic effect in periodic mood disorders in 1896.32 Yet, Inhibitors,research,lifescience,medical without, the availability of the necessary technology for monitoring blood levels, lithium was too toxic a, substance to be clinically employed. Rediscovery in the 1940s In the late 1940s the therapeutic effect of lithium in mania was rediscovered by John Cade, an Australian psychiatrist.33 Inhibitors,research,lifescience,medical Operating on the assumption that manicdepressive

illness is analogous to thyrotoxicosis and myxedema, he hypothesized that mania, is a state of intoxication by a normal product of the body in excess, and melancholia is a state of deficiency of the same substance. To test, this hypothesis he compared the effects of intraperitoneally injected concentrated urine from manic subjects with urine from normal, subjects in guinea pigs, and found the former far more toxic in killing the animals Inhibitors,research,lifescience,medical than the latter. Cade identified urea as the culprit, that killed the animals, and established that creatinine decreased (“protected”)

whereas uric acid increased (“enhanced”) the toxicity of urine. Since the urine of manic patients was more toxic than could be neutralized by the protective action of creatinine, he decided to determine the toxicity-enhancing effect of uric acid. Because Inhibitors,research,lifescience,medical uric acid was virtually insoluble in water, he used the most soluble of the urates, lithium urate, in his experiments. To his surprise, instead L-NAME HCl of enhancing toxicity, lithium urate protected the animals from urea’s toxic effects. He attributed the protective effect to lithium, and demonstrated that injection of an 8% urea solution killed five of 10 guinea pigs, whereas a similar solution with lithium added killed none.34 To determine whether lithium salts alone have any discernable effects, Cade injected large doses of 0.5% aqueous solution of lithium carbonate into guinea, pigs, and found that after a latent period the animals became extremely lethargic and unresponsive to stimuli for about, 2 hours.