Neuropsychological tests known to reveal abnormalities in patients with frontal lobe damage were used to explore cognitive function in 30 mildly disabled, right-handed patients with idiopathic Parkinson's disease. None of the patients had received treatment and all had normal CT brain scans. Patients with depression or high ischaemia scores were excluded from the study and similar selection criteria were used for the age-matched controls. No impairment of general intellectual function was found in the patients using the WAIS and New Adult Reading IQ tests and no abnormalities were apparent on cognitive estimates and two-choice Recognition Memory Tests. Patients with Parkinson's disease, however, had significantly greater difficulty in shifting conceptual sets and produced more perseverative errors on both the modified Wisconsin Card Sorting Test and Benton's Word Fluency Test. These subtle cognitive difficulties might underlie the mental inflexibility and rigidity of Parkinson's disease and could be attributed to destruction of the ascending dopaminergic mesocorticolimbic pathway.

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Thirty newly diagnosed patients with Parkinson's disease and 30 patients with primary depressive illness showed slowing of response on a computerized digit symbol substitution test when compared with 30 matched normal control subjects. Significant slowing was related, in the parkinsonian patients, to structural brain disorder and affective impairment and, in the depressed patients, to motor impairment. A second computerized test, cognitively simpler but requiring the same motor response, was also administered to each subject. Both cognitive and motor slowing seemed to contribute to slowing of response in the digit symbol test in both parkinsonian and depressed patients. The tests were repeated after about six months in 12 subjects from each group. The parkinsonian patients, on dopaminergic treatment, showed neither significant change in motor or affective impairment, nor improvement in response time for the digit symbol test, but change in response time was related to change in depression rating. The depressed patients, on conventional treatment, showed significant improvement in both affective and motor impairment and improvement in response time for the digit symbol test, due to improvement in cognitive slowing. It is proposed that bradyphrenia in Parkinson's disease and psychomotor retardation in depressive illness are closely related, and that impairment of dopaminergic systems may be involved in both.

Nitrochloromethylbenzindolines (nitroCBIs) are a new class of hypoxia-activated prodrugs for antitumor therapy. The recently reported prototypes undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents and are selectively toxic to some but not all hypoxic tumor cell lines. Here we report a series of 31 analogues that bear an extra electron-withdrawing substituent that serves to raise the one-electron reduction potential of the nitroCBI. We identify a subset of compounds, those with a basic side chain and sulfonamide or carboxamide substituent, that have consistently high hypoxic selectivity. The best of these, with a 7-sulfonamide substituent, displays hypoxic cytotoxicity ratios of 275 and 330 in Skov3 and HT29 human tumor cell lines, respectively. This compound (28) is efficiently and selectively metabolized to the corresponding aminoCBI, is selectively cytotoxic under hypoxia in all 11 cell lines examined, and demonstrates activity against hypoxic tumor cells in a human tumor xenograft in vivo.