Elizabeth L. Conway

Paired associate performance in the early detection of DAT.

Subjects underwent longitudinal neuropsychological assessment in order to retrospectively determine which measures of cognitive function best predicted later development of dementia of the Alzheimer type (DAT). Three groups of subjects were studied: normal controls, patients with early DAT, and questionable dementia subjects (QD). All subjects were assessed using a battery of standard neuropsychological measures and two subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB), paired associate learning and delayed matching to sample. A structured interview was also used to elicit a profile of the subjects daily functioning. Subjects were assessed every 6 months for 2 years. At the 6 month assessment, almost half of the QD group exhibited significant deterioration in scores on the computerized paired associate learning subtest, while maintaining their scores on standard measures. At the conclusion of the study, all of this QD subgroup fulfilled the NINCDS-ADRDA criteria for probable DAT pertaining to significant cognitive and functional deterioration. Performance on the C

CLONIDINE: UNDERSTANDING ITS DISPOSITION, SITES AND MECHANISM OF ACTION

The hypotensive action of clonidine was discovered serendipitously in 1962 and its potential as an antihypertensive drug recognized. Subsequently it was first marketed as an antihypertensive drug in Germany in 1966 and its high potency as a hypotensive agent was documented by Knobloch & Morr (1966). These workers reported significant lowering of blood pressure with as small an oral dose as 75 pg (approximately 1 pg/kg) which makes clonidine the most potent antihypertensive drug in the pharmacopeia. Over the next 15 years physicians tended to use higher doses of clonidine (300-900 pg per day) and this led to a significant degree of side effects such as sedation, dry mouth and constipation (Jarrott 1984). However, recently there has been a swing back to the use of low dosage regimens such as 75 pg twice a day and a recent extensive study (Briickner et a/. 1987) of 6700 patients with mild to moderate hypertension on this regimen have confirmed the initial study of Knobloch and Morr (1966) that this dose produces satisfactory control of blood pressure with a low incidence of side effects. Although clonidine is known commonly as an antihypertensive drug, experimental and clinical studies have demonstrated that this drug has several effects other than on the cardiovascular system. For example, clonidine has an analgesic action in laboratory animals, particularly against noxious stimuli such as acetic acid-induced writhing (Paalzow 1974; Bentley et a/. 1977; Spaulding et a/. 1979). Clinically, epidural clonidine is an effective analgesic (Tamsen & Gordh 1984; Kalia et al. 1986) and oral clonidine reduces the required dose of fentanyl by 45% to produce satisfactory anaesthetic depth for procedures such as Iaryngoscopy (Ghignone et al. 1986). Another action of clonidine which is seen as a side effect with the use of clonidine as an antihypertensive drug is sedation (Jarrott 1984) although tolerance to sedation develops rapidly. In laboratory animals, this action is seen as a potentiation of hexobarbitone sleeping time (Timmermans et al. 1981), although this does not mean necessarily that clonidine has a barbiturate-like CNS depressant action. Instead, our studies on the effects of chronic infusion of clonidine (10 pg/kg per h for 9 days) on the spontaneous locomotor activity of normotensive Wistar-Kyoto rats showed that the marked reductions in locomotor activity during the 12 h dark phase were due largely to a clonidine-induced increase in overall sleep time. When awake, clonidine-infused rats were as active as saline-

Temporal changes in glial fibrillary acidic protein messenger RNA and [3H]PK11195 binding in relation to imidazoline-I2-receptor and α2-adrenoceptor binding in the hippocampus following transient global forebrain ischaemia in the rat

Immunohistochemical studies have demonstrated that following global forebrain ischaemia the selective neuronal loss that occurs in the CA1 pyramidal cell layer of the hippocampus is accompanied by a reactive astrocytosis, characterized by increases in glial fibrillary acidic protein, and activation of microglia. In this study the spatial changes in glial fibrillary acidic protein messenger RNA levels in the hippocampus have been mapped four, eight, 12, 16 and 20 days following 10 min of global forebrain ischaemia in the rat and related to changes in [3H]PK11195 binding to peripheral benzodiazepine receptors, a putative marker of activated microglia. Recent studies have suggested that the imidazoline-I2-receptor, one of a class of non-adrenergic receptors related to, but structurally and functionally distinct from alpha 2-adrenoceptors, may have a functional role in controlling the expression of glial fibrillary acidic protein. To explore this possibility further we have also mapped changes in imidazoline-I2-receptor and alpha 2-adrenoceptor binding sites. Following transient ischaemia there was a marked, biphasic increase in glial fibrillary acidic protein messenger RNA levels throughout the vulnerable CA1 region of the hippocampus, peaking four days after ischaemia and then increasing gradually during the remainder of the study period. There was also a sustained increase in [3H]PK11195 binding, however, in contrast to the initial increase in glial fibrillary acidic protein messenger RNA levels that peaked four days after ischaemia the density of [3H]PK11195 binding increased rapidly in all strata of the CA1 region over the first eight days and then increased more slowly throughout days 12 to 20. Despite the marked increase in glial fibrillary acidic protein messenger RNA levels there was no concomitant alteration in imidazoline-I2-receptor binding sites detected using the specific radioligand, [3H]2-(2-benzofuranyl)-2-imidazoline, although alpha 2-adrenoceptor binding was decreased at eight days after ischaemia and did not recover. The time-course and biphasic nature of the changes in the astrocytic marker, glial fibrillary acidic protein messenger RNA, in the hippocampus following ischaemia may reflect different functions of glial fibrillary acidic protein-reactive astrocytes in the post-ischaemic period. Differences in temporal expression of glial fibrillary acidic protein messenger RNA and [3H]PK11195 binding support the proposed localization of peripheral benzodiazepine receptors on activated microglia, as distinct from reactive astrocytes. There was no evidence in the present study that imidazoline-I2-receptors are functionally linked to glial fibrillary acidic protein expression as the reactive astrocytosis in the hippocampus following ischaemia was not associated with changes in imidazoline-I2-receptor binding site density.

Vascular dopamine receptors in the canine hindlimb.

1 Increases in femoral blood flow were produced by intra‐arterial injections of dopamine (5–50 μg) in some but not all anaesthetized dogs studied, following treatment with the α‐adrenoceptor antagonist, phentolamine. 2 The dilator effect of dopamine was not due to inhibition of adrenergic vasomotor tone as it was not affected by pharmacological procedures which completely abolished the activity of vasomotor nerves. 3 Blockade of vascular β‐adrenoceptors using propranolol reduced the flow increases produced by dopamine much less than it did those produced by isoprenaline. 4 Responses to dopamine were significantly depressed by intra‐arterial administration of ergometrine (0.5 mg). This dose of ergometrine did not reduce femoral dilator responses to acetylcholine, histamine, isoprenaline, bradykinin or 5‐hydroxytryptamine. 5 It is concluded that the femoral vascular bed in the dog contains specific vasodilator receptors for dopamine. Ergometrine appears to be a selective antagonist of dopamine at these receptors.

Ergometrine and apomorphine as selective antagonists of dopamine in the canine renal vasculature.

1 Increases in renal blood flow were produced by intra‐arterial injections of dopamine (5–50 μg) in anaesthetized dogs pretreated with α‐ and β‐adrenoceptor antagonists. 2 Intra‐arterial administration of ergometrine (0.5 mg) or apomorphine (1 mg) produced a depression of the renal dilator responses to dopamine, without affecting renal dilatations in response to intra‐arterial acetylcholine (0.1–1 μg) or histamine (2–50 μg). 3 The depression of dopamine responses lasted 10–15 min, and was greater with ergometrine than with apomorphine. 4 It is concluded that both ergometrine and apomorphine can be used as specific blocking agents at vascular dopamine receptors. Ergometrine is the preferred drug for this purpose.

Clonidine distribution in the rat: temporal relationship between tissue levels and blood pressure response.

1 The time course of the distribution of clonidine (20 μg/kg, i.v.) was determined in the rat by use of a sensitive and specific radioimmunoassay, and was compared with the hypotensive response following this dose. 2 Levels of clonidine were determined in tissues at 2 min, corresponding to the beginning of the hypotensive phase of the drug, and then at 10, 30 and 120 min during recovery of blood pressure to the pre‐dose level. The peak tissue concentrations of clonidine were found at 2 min, after which they declined in a mono‐exponential manner. The half‐lives of clonidine in the various tissues were similar to the half‐life of the recovery of blood pressure. 3 Regional variations in clonidine distribution in the brain were not very great; however, the half‐life was longer in the corpus striatum and shorter in the cerebellum than in other brain regions. 4 Clonidine concentrations were highest in the kidney and similarly distributed between the cortex and medulla. Concentrations of the drug in other tissues approximated those in brain. 5 Although clonidine is thought to act primarily through the central nervous system, this distribution study shows that at the peak of the hypotensive response less than 2% of the injected dose is present in brain and at least equal concentrations of the drug are found in most peripheral tissues. Thus the possibility of peripheral mechanisms contributing to the hypotensive effect cannot be dismissed.

A pharmacokinetic study of carvedilol (BM 14.190) in elderly subjects: preliminary report.

Summary: This study in eight elderly male volunteers examined the pharmacokinetics of carvedilol following intravenous and oral administration of the drug. Blood pressure and pulse rate responses were also determined and compared with those to labetalol. Carvedilol was absorbed rapidly after oral administration with a bioavailability of approximately 45% and obeyed linear pharmacokinetics over the dose range 25–50 mg. The terminal elimination half‐life varied between 5 and 14 h. Administration of the drug with food did not alter the bioavailability or kinetic handling of carvedilol. The hemodynamic responses to carvedilol followed the same pattern as those to labetalol. There was a rapid dose‐related fall in blood pressure maximal after 4–5 h and disappearing by 12 hours. Tachycardia that was evident on placebo was inhibited by both drugs. Postural hypotension and dizziness were also apparent with both drugs.

Use of computerized neuropsychological tests (cantab) to assess cognitive effects of antihypertensive drugs in the elderly

OBJECTIVE To establish reliability and ease of use of the Cambridge Neuropsychological Test Automated Battery (CANTAB) in assessing changes in cognitive function induced by antihypertensive drugs. DESIGN AND METHODS Standard neuropsychological testing was combined with CANTAB in a double-blind 18-week cross-over study in elderly hypertensives taking perindopril or hydrochlorothiazide/triamterene (HT). Cognitive effects were assessed by employing tests of attention, visuospatial and verbal memory, learning, reasoning, planning, problem solving, speed and coordination. Affect was assessed using two different depression-rating scales. RESULTS Perindopril and the diuretic had no adverse effects on the various aspects of cognitive function. Mood, as assessed by the Hamilton Depression Rating Scale and the Beck Depression Inventory, was improved on Perindopril, and the error rate in the motor screening test was lower. Ambulatory blood pressure monitoring showed both drugs achieved effective 24-h control. CONCLUSIONS The ease of use and the ability to adjust the level of testing to the requirements of individual patients, together with the reliability of longitudinal test/re-test results, indicates that CANTAB is an important addition to the methods available to quantitate adverse central nervous system drug effects. The other purpose of the study was to assess any adverse cognitive effects of perindopril against a drug HT believed to have no adverse central nervous system effects. In this context, perindopril was free of adverse effects in all the objective tests employed. In addition, there was a benefit seen in two independent assessments of depression (the Hamilton and the Beck rating scales).

Brain lesions and delayed water maze learning deficits after intracerebroventricular spermine.

The effects of spermine on the acquisition and retention of spatial learning in the Morris water maze were studied. Spermine 25 and 125 nmol i.c.v. did not alter the ability of rats to find a hidden platform in the water maze when administered before training over 5 days. However, the inhibitory effect of the benzodiazepine, diazepam (3 mg/kg i.p., 30 min prior to training), on path length to target was markedly potentiated by the higher dose of spermine, consistent with spermine acting as a functional antagonist at the NMDA receptor. This drug combination did not affect performance on visible platform trials. Administration of doses of 125 and 250 nmol (but not 62.5 nmol) of spermine i.c.v. in the week prior to training (daily for 5 days) dose-dependently inhibited subsequent learning of a platform position in the absence of drug. These higher doses of spermine produced neuronal loss and increased [3H]PK11195 binding indicating microglial activation predominantly in the hippocampus and to a lesser extent in the striatum, septum, thalamus and amygdala. Spermine 125 nmol i.c.v. (daily for 7 days) also abolished retention of a previously learned platform position when administered in an interval between training and retention testing. The inhibitory effects of spermine 125 nmol i.c.v. (daily for 7 days) on subsequent spatial learning were not antagonised by concomitant administration of 30 nmol dizocilpine. These results demonstrate that spermine produces a delayed neurotoxic effect in particular neuronal populations in the brain that selectively impair spatial learning and recall.

COMPARISON OF THE PHARMACOKINETICS AND PHARMACODYNAMICS OF PERINDOPRIL, CILAZAPRIL AND ENALAPRIL

1. The pharmacokinetic and pharmacodynamic responses to enalapril, perindopril and cilazapril have been studied in essential hypertensives (2, 4 and 8 mg perindopril and 2.5 mg cilazapril, single dose and steady state) and normotensive volunteers (10 mg enalapril, single dose).