OBJECTIVE:Moxonidine represents a new generation of centrally acting antihypertensive drugs. It binds to I1-imidazoline receptors and exerts its antihypertensive activity through a reduction in systemic vascular resistance, while cardiac output remains unchanged or even increases slightly. Moxonidine is prescribed for the treatment of mild to moderate hypertension. Typical doses are 0.4 to 2.0 mg given as one dose in the morning or as divided doses in the morning and evening.METHODS:The effects of moxonidine 0.4 mg once daily in combination with moclobemide or lorazepam were investigated in two, double-blind, randomised, placebo-controlled, two-way crossover studies in a total of 48 healthy volunteers. Safety assessments were made in each study and included pre- and post-study measurement of blood pressure, heart rate, ECG, haematology, blood biochemistry, and urinalysis, and recording of adverse events.RESULTS:In the first study, moxonidine alone was found to produce small but statistically significant impairments of vigilance detection speed at 4 h and 6 h. Lowering of subjective alertness was also observed. Repeat dosing with moxonidine produced an impairment of memory scanning performance. These findings were not reproduced in the second study, in which moxonidine alone produced an improvement in immediate word recall at 4 h and 6 h. No interactions were observed when moxonidine was co-administered with moclobemide. Moxonidine, when co-administered with lorazepam, produced interactions with three tasks requiring high levels of attention: choice, simple reaction time and digit vigilance performance; memory tasks; immediate word recall, delayed word recall accuracy; and visual tracking. A total of 47 adverse events were reported in study 1. Moxonidine produced a slight decrease of systolic and diastolic blood pressure. In study 2, a total of 55 adverse events were reported. In both trials, the most frequently reported events were tiredness and dryness of mouth, the latter occurring only under the moxonidine treatment. There were no clinically relevant changes observed in blood pressure, pulse rate, and laboratory tests in either study, nor was there any evidence of any interaction between moxonidine and either moclobemide or lorazepam.CONCLUSION:Moxonidine was found to be safe and well tolerated in healthy volunteers. However, the impairments on attentional tasks were greater when moxonidine was co-administered with lorazepam 1 mg. These effects should be considered when moxonidine is codosed with lorazepam, although they were smaller than would have been produced by a single dose of lorazepam 2 mg.

Twelve subjects (8 male) took part in a randomised double blind four way crossover design study comparing four treatments: (i) morphine sulphate 10 mg, (ii) morphine sulphate 15 mg, (iii) lorazepam 1 mg (positive control) and (iv) placebo. Cognitive function was assessed using choice reaction time, number vigilance, memory scanning, immediate and delayed word recall, word recognition, picture recognition, critical flicker fusion threshold (CFFT) and subjective measures of alertness, calmness and contentment. Lorazepam produced a marked impairment in the tests of attention and memory. CFFT was reduced from 1–4 h but this only reached significance at 4 hours. The subjective measures suggested impaired alertness but this did not reach significance. The effects of morphine were less dramatic; both doses of morphine produced significant impairment at 1 hour on tests of secondary memory retrieval (delayed word recall and picture recognition sensitivity). CFFT was reduced for the whole observation period (6 h) achieving statistical significance at 4 hours. Morphine 15 mg produced a significant improvement in accuracy on the choice reaction time test at the 2, 4 and 6 h assessments. These results show minimal impairment of cognitive and psychomotor function after single oral doses of morphine and with possible improvement in one test. Further studies are required to examine the effect of repeated doses.

The cognitive drug research computerized assessment system (COGDRAS) was evaluated in 98 unselected Hammer-smith Hospital Memory Clinic patients (mean age 64.9, range 28-83 years). They were divided into five groups (worried well, depressed, demented, minimally cognitively impaired and other brain disorders) on clinical assessment, Mini Mental State Examination (MMSE) and Cambridge Cognitive Examination (CAMCOG) scores. All but one patient completed the computer package, confirming its acceptability. The results of the COGDRAS in the five groups were analysed blind to diagnosis. The performance of the demented group was significantly impaired in comparison with the worried well group, showing that the COGDRAS is valid in mild dementia (mean MMSE 21.5, mean CAMCOG 73.9). The depressed group tended to perform slightly less well than the worried well, and the 'other' group showed a wide range of scores consistent with its diversity. The minimally impaired had scores intermediate between the demented and worried well, but an interesting speed/accuracy tradeoff was seen-patients appeared to maintain accuracy by taking longer to perform tasks. The heterogeneity of the minimally impaired group and the role of the measurement of task completion time in the diagnosis of early dementia are discussed.

Demeneted elderly patients (N = 23, aged 60–94) and controls (N = 22, aged 52–86) performed a version of the Cognitive Drug Research computerized Assessment System comprising cognitive tasks measuring choice reaction time, vigilance, and the sensitivity and speed of digit, word and picture recognition. The demented patients showed large and highly significant impairments in the speed of choice reaction and in the sensitivity and speed of all memory tasks. Correlations between the various scores from the computerized tests and those from the Folstein Mini-Mental State Examination, the Kendrick Battery and the Kew were high and significant, implying that the computerized tasks measure similar aspects of cognition to procedures used to assess dementia. In 16 memory clinic patients, high correlations were also found between the Stockton Rating Scale and the scores from the computerized tests, suggesting that the latter have relevance to the general behavioural condition of the patients. These findings, together with evidence of good test-retest reliability, indicate that, for demented patients, the utility of this system to assess cognitive change should be comparable to that of previous versions used with the young and with non-demented elderly.

The mental ability of the elderly is frequently compromised by age-associated cognitive declines, which may be result of cholinergic deterioration. Depression is accompanied by cognitive performance impairments, and recent work suggests these may be more severe in the elderly. Antidepressants with anticholinergic side-effects, such as the tricyclics, should thus be used with caution in the elderly. A potential advantage of new antidepressants which are relatively free of anticholinergic effects, may be in a reduced liability to impair cognition, whilst maintaining at least equal antidepressant potency. The effects of moclobemide, a novel reversible monoamine oxidase inhibitor, have been studied in both young and elderly volunteers using computerized assessment of a variety of aspects of cognition. In the young the drug was studied within a scopolamine model of the cognitive effects of aging and dementia, while, in the elderly, the cognitive effects of the drug were compared to those of trazodone. In the scopolamine model, moclobemide was significantly superior to placebo and other compounds in antagonizing the cognitive impairments resulting from cholinergic blockade. In the elderly, some improvements were found with moclobemide, particularly in memory, and while an impairment to vigilance was observed, this effect was considerably less marked than with trazodone. Moclobemide would thus appear to have an advantage over antidepressant compounds such as the tricyclics of having a lower liability to impair cognitive efficiency. However, to establish this in depressed patients it will be necessary to incorporate sensitive assessments of cognitive efficiency into trials of the drug in young and elderly populations.

AbstractThe present study was conducted to determine the degree to which impairments in attention accompany the memory deficits produced by scopolamine. Eighteen healthy young volunteers received scopolamine 0·6 mg subcutaneously on three experimental sessions and placebo on three others. On each session, prior to, and 60 min after injection, the subjects underwent an automated computerized battery of 11 cognitive tasks. The study was run double‐blind and the order of treatment conditions over successive visits was counterbalanced between subjects. Scopolamine produced marked and significant decrements on all major aspects of performance from the battery. The drug lowered the efficiency of the detection and processing of information in tests of visual vigilance, rapid information processing, choice reaction, letter cancellation and logical reasoning. These effects were accompanied by a lowering of critical flicker‐fusion frequency and subjective alertness. Memory was also impaired on tests of immediate recall, delayed recall, recognition and memory scanning. These findings confirm and extend previous work, demonstrating that scopolamine impairs the selection and evaluation of environmental information, as well as reducing the likelihood of information being subsequently recalled or recognized. Whether the former effects contribute to the latter is not known, but this must be considered a possibility. This potential role of processing deficits in memory loss associated with cholinergic blockade is briefly considered in relation to the cholinergic hypothesis of geriatric memory loss.