Head and neck cancer in Australia between 1982 and 2005 show increasing incidence of potentially HPV-associated oropharyngeal cancers.

BACKGROUND: Although tobacco- and alcohol-associated head and neck cancers are declining in the developed world, potentially human papillomavirus (HPV)-associated oropharnygeal cancers are increasing. METHODS: We analysed oropharyngeal and oral cavity cancer rates in Australia in 1982-2005. Cancers from the oropharynx (base of tongue, tonsil and other specific oropharyngeal sites) were classified as potentially HPV associated (n=8844); cancers in other oral cavity and oropharyngeal sites not previously associated with HPV were classified as comparison (n=28,379). RESULTS: In 2000-2005, an average of 219, 159 and 110 cancers of the tonsil, base of tongue and other oropharyngeal sites were diagnosed annually, with incidences of 1.09 (95% CI: 1.03, 1.15), 0.79 (95% CI: 0.74, 0.84) and 0.55 (95% CI: 0.50, 0.59) per 100,000, respectively. An average of 1242 comparison cancers were diagnosed annually (6.17 (95% CI: 6.03, 6.31) per 100,000). In 1982-2005, there were significant annual increases in tonsil (1.39% (95% CI: 0.88, 1.92%)) and base of tongue cancers in males (3.02% (95% CI: 2.27, 3.78%)) and base of tongue cancer in females (3.45% (95% CI: 2.21, 4.70%)). There was a significant decrease in comparison cancers in men (-1.69% (95% CI: -1.96, -1.42%)), but not in females. CONCLUSION: Potentially HPV-associated oropharyngeal cancer in Australia is increasing; the impact of HPV vaccination on these cancers should be monitored.

The psychosocial burden of human papillomavirus related disease and screening interventions.

OBJECTIVES: (i) To assess the psychosocial burden of testing for human papillomavirus (HPV) related genital disease or of a HPV-related diagnosis; (ii) to compare an instrument specifically designed to measure HPV-related psychosocial burden with other generic quality of life (QoL) instruments. METHODS: A cross-sectional design. Researchers recruited women from outpatient clinics at a major tertiary women's hospital and a sexual health centre who completed surveys within 3 months of receiving RESULTS: 331 women, 18-45 years, who had experienced a normal cervical Papanicolaou (Pap) result, an abnormal Pap result, biopsy confirmed cervical intraepithelial neoplasia (CIN) or external genital warts (EGW). MAIN OUTCOME MEASURES: The HPV impact profile (HIP) designed to assess the psychosocial impact of HPV; two general health-related QoL surveys-the EuroQoL VAS and the Sheehan disability scale; and a HPV knowledge survey. RESULTS: Response rate was 78%. Significant psychosocial impacts were found for women screened for, or having a diagnosis of, HPV-related genital disease. The largest impact was in women with CIN 2/3 and EGW. This HPV-related psychosocial impact was most sensitively detected with the HIP. Relative to generic measures of QoL, the HIP provided insight into the full range of psychosocial impacts of HPV testing and diagnoses. CONCLUSIONS: Clinicians need to be aware of the potential psychosocial impact of testing for or diagnosing HPV-related genital disease, in particular CIN 2/3 and EGW. The HIP survey is a more sensitive measure of the psychosocial impact of HPV-related genital disease than generic QoL surveys.

Use of computerized neuropsychological tests (CANTAB) to assess cognitive effects of antihypertensive drugs in the elderly. Cambridge Neuropsychological Test Automated Battery.

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.

Localization of mRNA for the apoptosis-linked gene ALG-2 in young and aged rat brain.

ALG-2 is a recently described pro-apoptosis gene that codes for a Ca2+-binding protein involved in T-cell receptor-, Fas- and glucocorticoid-induced cell death. We have used in situ hybridization histochemistry to examine the regional distribution of ALG-2 mRNA in the brain of 3- and 24-month old rats. There was widespread, predominantly neuronal distribution of ALG-2 mRNA throughout the brain. Areas expressing high levels included the granule and pyramidal cell layers of the hippocampus, choroid plexus, area postrema, and a number of hindbrain nuclei. ALG-2 mRNA levels in aged rats were not significantly different to young animals. The pattern of expression of ALG-2 mRNA in adult brain is similar to other apoptosis-related genes and suggests it may be involved in neuronal survival.

A review of the randomized controlled trials of tacrine in the treatment of Alzheimer's disease: methodologic considerations.

This review examines the features of the 16 randomized controlled trials that have been published on the use of oral tacrine for treating probable Alzheimer's disease and explores the methodologic problems associated with these studies. Patient selection using the standard National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria is now a feature of all studies; however, the specificity of the diagnosis, the severity of the dementia, the heterogeneity of the dementia with respect to disease and patient genotype, and the health status of the patients all are factors that may affect responsiveness to therapy. Most studies use crossover designs; however, because of the progressive nature of the disease and the variability in the rate of decline, parallel group studies over a length of time sufficient to produce worsening in disease severity in a placebo group appear to be most suited to detecting clinically relevant therapeutic effects. The close relation between dose, efficacy, and serious adverse events has been a problem in the tacrine trials, since many studies, titrating to maximum tolerated doses, have used clinically ineffective doses. This problem can be circumvented by the use of fixed-dose regimens. Three broad classes of outcome measures have been used to assess treatment efficacy: 1) performance-based tests of cognitive function, 2) global impressions of change on the part of the clinician or care giver, and 3) functional measures of daily living. Including a limited number of each type of measure provides strong evidence of clinically relevant therapeutic benefit; however, more widely accepted and better validated instruments need to be developed for all three areas.

Temporal changes in glial fibrillary acidic protein messenger RNA and [3H]PK11195 binding in relation to imidazoline-I2-receptor and alpha 2-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.

Computerized neuropsychological tests in the early detection of dementia: prospective findings.

This longitudinal study examines the sensitivity of 2 computerized neuropsychological tests, delayed matching to sample and paired associate learning, to early dementia of the Alzheimer type (DAT). Normal controls, patients in the early stages of DAT, and individuals with questionable dementia (QD) were studied. At 6 and 12 months after initial presentation, almost half of the QD group exhibited lower scores on the computerized subtests, maintaining their scores on standard testing. Over the same period NC subjects maintained their performance levels, while DAT patients continued to deteriorate. Linear discriminant function analyses of the computerized subtests at 6 and 12 months correctly classified 100% of the early DAT patients. Eighty-four and 79 percent of normal controls were correctly classified at 6 and 12 months respectively. Further development of these subtests for the detection of early dementia and the documentation of ongoing change in DAT is warranted. The findings are discussed in terms of the special sensitivity of these tests to the neuropathology of Alzheimer's Disease.

Effects of alpha 2-adrenoceptor antagonists and imidazoline2-receptor ligands on neuronal damage in global ischaemia in the rat.

1. In the present study the neuroprotective effects of 3 mg/kg idazoxan, an alpha 2-adrenoceptor antagonist and imidazoline2-receptor (I2-receptor) ligand, 3 mg/kg methoxyidazoxan, a specific alpha 2-adrenoceptor antagonist, and 0.6 and 3 mg/kg BU224, a selective I2-receptor ligand, were evaluated following 10 min of global ischaemia in rats. 2. Neuronal cell counts in the CA1 region of the hippocampus 8 days postischaemia indicated 46-96% cell loss compared with control (P < 0.001) and a 320% increase in [3H]-PK11195 binding (P < 0.001) used as a marker of gliosis. No significant neuroprotective effect could be detected on these markers of neuronal damage in the active treatment groups. In a subset of idazoxan-treated rats, neuronal loss and gliosis was minimal. 3. Mean body temperature over 3 h postischaemia was lower in idazoxan-treated rats than in the other treatment groups (P < 0.001) and there was a correlation between mean body temperature and cell counts (P < 0.01) and mean body temperature and gliosis in this group (P = 0.057). 4. These results indicate that at the doses used neither BU224 nor methoxyidazoxan are neuroprotective in this ischaemia model and they raise the possibility that any neuroprotective effect of idazoxan may be related to hypothermic effects of the drug.

No evidence for involvement of angiotensin II in spatial learning in water maze in rats.

There is increasing evidence suggesting angiotensin II (AII) may inhibit memory formation in a range of conditioned avoidance and habituation learning tasks in rodents. We were interested to determine if AII might also play an inhibitory role in spatial learning. Angiotensin-converting enzyme (ACE) inhibitors, which block the formation of AII from AI, improve acquisition and/or retention of basal performance inhibited by the muscarinic receptor antagonist, scopolamine, in conditioned avoidance and habituation tasks. In hooded Wistar rats, over 5 days of training in a water maze neither the ACE inhibitor, ceranapril 5 and 50 micrograms/kg/day, nor the ACE inhibitor, ramipril 2 and 10 mg/kg/day, altered the increase in path length produced by administration of scopolamine 0.75 mg/kg/day. In probe trails (without platform), on the last day of training, ceranapril 50 micrograms/kg produced a 35% further deterioration in performance in the scopolamine-treated rats (P < 0.02). Administration of the substrate, renin, that leads to AII formation, did not alter water maze performance over 5 days of training. The angiotensin receptor antagonist, losartan, has been shown to improve basal and scopolamine-impaired performance in a habituation task and reverse the inhibition in long-term potentiation produced by diazepam. However, neither losartan 10 and 30 mg/kg/day nor ramipril 2 and 10 mg/kg/day reversed diazepam-impaired (3 mg/kg/day) acquisition of the spatial memory task over 5 days of training. These studies suggest AII does not inhibit spatial learning in rats in the constant platform position water maze task nor does it mediate the inhibitory effects of scopolamine or diazepam in this task.

The effect of levcromakalim (BRL 38227) on bladder function in patients with high spinal cord lesions.

The effects of the potassium channel opener levcromakalim (BRL 38227) 7.5 micrograms kg-1 were examined on urodynamic variables and blood pressure during inflow and voiding cystometry in six high spinal cord lesion patients. Levcromakalim administration significantly increased the duration of bladder contraction (197 +/- 128 s to 267 +/- 167 s, P < 0.05) and also reduced blood pressure (126 +/- 13/67 +/- 9 mm Hg to 104 +/- 25/52 +/- 12 mm Hg) but was without effect on other urodynamic parameters. Because of concerns about hypotensive responses, further studies involving higher doses of levcromakalim should be considered only if the drug was administered intravesically.

Efficacy of pravastatin in combination with captopril in hypertensive patients.

OBJECTIVE: To determine the efficacy of pravastatin in the treatment of primary hypercholesterolaemia in patients being treated with captopril for hypertension. DESIGN: A double-blind parallel group study comparing 12 weeks of pravastatin therapy (20-40 mg/day) with placebo. PARTICIPANTS: 25 patients (age, 37-73 years) with mild-to-moderate hypertension and hypercholesterolaemia (total cholesterol level, 5.5-8.8 mmol/L). RESULTS: Pravastatin reduced total cholesterol levels by 22% (from 7.1 +/- 0.29 [SEM] to 5.5 +/- 0.25 mmol/L; P < 0.001) and low-density-lipoprotein cholesterol levels by 32% (from 5.0 +/- 0.32 to 3.4 +/- 0.28 mmol/L; P < 0.001) in four weeks and these levels were maintained for the 12 weeks of therapy. Pre-pravastatin values returned three weeks after stopping therapy. Levels of total cholesterol, cholesterol fractions and triglycerides remained constant or deteriorated in the placebo group. Pravastatin therapy was well tolerated. An integrated coronary risk score showed a 40% reduction in risk. CONCLUSION: This study indicates that pravastatin (combined with captopril) is an effective cholesterol-lowering drug, but that treatment needs to be maintained.

Computerized delayed matching to sample and paired associate performance in the early detection of dementia.

This study examined the ability of two computerized neuropsychological tests, delayed matching to sample and paired associate learning, to detect early dementia. Three groups of subjects classified by NINCDS-ADRDA criteria and standard neuropsychological tests were studied: normal controls, patients believed to be in early stages of dementia of the Alzheimer type, and a group of questionable dementia subjects who reported memory loss but performed normally on standard measures of cognition. All subjects completed the two computerized tests. The early dementia group performed at a significantly lower level than the other two groups on all standard and computerized measures. A linear discriminant function analysis of the computerized tests classified 100% of the normal controls and 87.5% of the dementia patients into the same groups as standard testing. The majority of questionable dementia subjects were classified as nondemented. The concurrent validity and test-retest reliability of the computerised tests were also investigated. It is suggested that computerized tests are useful when screening for early dementia, and that longitudinal studies are required to evaluate the comparative reliability of the tests.

Short term effects of pravastatin on blood pressure in hypercholesterolaemic hypertensive patients.

In this study, which was primarily designed to determine the lipid-lowering efficacy of pravastatin in the setting of background antihypertensive therapy with ACE inhibitors and calcium antagonists, we took the opportunity to examine whether pravastatin interacts with antihypertensive therapy to produce additional falls in blood pressure. This may help clarify the mechanism of action of pravastatin's rapid beneficial effects on cardiovascular morbidity. We treated 25 hypertensive hypercholesterolaemic patients with 12 weeks of either pravastatin or placebo in this double blind, placebo controlled parallel group study. Placebo treatment did not alter plasma lipids, whereas 12 weeks' treatment with pravastatin reduced total cholesterol by 27% (from 7.1 +/- 0.27 to 5.2 +/- 0.18, p < 0.001 compared with placebo) and low density lipoprotein cholesterol by 35% (from 4.9 +/- 0.36 to 3.2 +/- 0.17, p < 0.001). There were no changes in systolic or diastolic blood pressure either following 12 weeks' treatment or 3 weeks' withdrawal of pravastatin. Thus, pravastatin remains efficacious as a lipid lowering agent in the presence of antihypertensive therapy but does not enhance the blood pressure lowering action of these drugs. Therefore it is unlikely that blood pressure reduction is the mechanism by which pravastatin mediates its reported short term effects on cardiovascular morbidity.

A risk-benefit assessment of carvedilol in the treatment of cardiovascular disorders.

Carvedilol is a nonselective beta-adrenoceptor blocking vasodilator drug that may be a promising new agent in the management of cardiovascular disease. The rationale for the development of agents of this type is that the alpha-blocking component may overcome the direct vasoconstrictor consequence of beta 2-blockade, whilst the beta-blocker component may inhibit the reflex tachycardia that occurs following alpha-blockade. In clinical trials published to date, carvedilol has been demonstrated to be effective as an antihypertensive agent as monotherapy and also as additional therapy in those patients whose blood pressure cannot be controlled on other standard agents. It is also effective in the management of angina. Carvedilol has beneficial haemodynamic effects in patients with congestive heart failure. beta-Blocker vasodilator drugs of this type may be particularly useful in this condition as the vasodilator component of the drug may overcome the initial negative inotropy of the beta-blocker. In addition, carvedilol possess potentially useful pharmacological actions. In particular, the drug has antimitogenic and free radical scavenging effects that may make it a useful therapy in the long term management of atherosclerotic vascular disease. Its metabolic profile is also favourable, presumably on the basis of its alpha-blocking properties. Thus, beta 2-mediated adverse effects on peripheral vascular tone, glycaemic control and lipid status appear to be offset by the alpha-blocking property of the drug. Carvedilol thus far appears to be well tolerated, with postural dizziness the major adverse effect, especially in the elderly. As with nonselective beta-blockers, carvedilol is contraindicated in patients with asthma.

A single-dose comparison of the bioavailability of aluminium from two formulations of sucralphate in normal volunteers.

The oral bioavailability of aluminium was compared after administration of 1 g sucralphate as either a tablet or a suspension (1 g/5 ml) in a crossover study in 16 healthy volunteers. Aluminium levels were detectable in all subjects pre-dose (21.4 +/- 8.8 micrograms l-1 before tablet; 21.4 +/- 7.4 micrograms l-1 before suspension) and there was a measurable increase in the plasma concentrations of aluminium in all subjects after administration of the suspension, and in 14 of the subjects after administration of the tablet formulation, with Cmax reached within the first 8 h in most subjects. Plasma levels were still elevated 72 h after dosing. The variability in plasma levels of aluminium was significantly higher after administration of the suspension (CV 39-53%) than after administration of the tablet (CV 29-44%), reflecting greater absorption of aluminium from the suspension formulation in three subjects. Similarly, the variance of the Cmax, AUC(0-72 h), and AUC(0-infinity) (for both the raw data and the baseline adjusted data) were all higher for the suspension than for the tablet. A point estimate of the difference of the pharmacokinetic parameters (determined from the median of the arithmetic Walsh averages) indicated little or no difference in Cmax, Tmax, or AUC(0-infinity) in the two formulations. In summary, the performance of the suspension formulation of sucralphate is more variable than the tablet formulation in vivo and some patients may therefore have higher circulating levels of aluminium on therapy with the suspension formulation.

Steady-state pharmacokinetics and pharmacodynamics of cilazapril in the presence and absence of cyclopenthiazide.

Twenty-two patients with essential hypertension received a single dose of 2.5 mg cilazapril and were then randomised into a double-blind parallel group study to receive either placebo, 1.25 mg cilazapril + 0.5 mg cyclopenthiazide (CPTZ), 2.5 mg cilazapril + 0.5 mg CPTZ, or 2.5 mg cilazapril alone for 1 month. After oral administration of a single dose of 2.5 mg cilazapril, the active diacid cilazaprilat appeared rapidly in the plasma (Tmax 2.0 +/- 0.2 h). With the radioinhibitor assay used in this study, a single elimination phase of cilazaprilat was evident, with a half-life (t1/2) of 2-3 h. At steady state, the pharmacokinetics of cilazaprilat were similar to single-dose administration and were not altered by CPTZ. The Cmax and area under the curve (AUC) of cilazaprilat were directly proportional to dose. Cilazapril administration in the dose range of 1.25-2.5 mg produced a dose-proportional inhibition of angiotensin-converting enzyme (ACE) activity that was maximum 2 h after drug administration. The degree of ACE inhibition correlated with the plasma concentration-time profile of cilazaprilat and the maximum decrease in blood pressure (BP). The EC50 for ACE inhibition by cilazaprilat was 7.7 ng/ml after acute treatment and was not significantly altered during chronic administration or by concomitant administration of CPTZ. There was no evidence of a dose-related antihypertensive effect of cilazapril at steady state and, with the small numbers of subjects used in this study, there was no evidence of 24-h BP control with monotherapy.

Single-dose and steady-state pharmacokinetics and pharmacodynamics of perindopril in hypertensive subjects.

In a double-blind, placebo-controlled, parallel group study, 24 essential hypertensive subjects were randomised to receive either placebo or 2, 4, or 8 mg perindopril. Perindopril, its deesterified metabolite, perindoprilat, and perindoprilat glucuronide were separated with an ion-exchange resin and determined by a radioimmunoassay (RIA). Pharmacokinetic and pharmacodynamic parameters were estimated for 96 h after the first dose and after 4-week once-daily treatment. Perindopril peak levels were achieved in less than or equal to 2 h after dosing with an elimination t1/2 of 1-2 h. Peak levels of perindoprilat were achieved more slowly, reaching a maximum level 5-8 h after dosing, and had an elimination t1/2 of 40 h. Levels of the perindopril glucuronide peaked approximately 0.5 h later than perindopril, with an elimination t1/2 of approximately 2 h. Perindopril, perindoprilat, and its glucuronide conjugate followed linear kinetics in the dose range of 2-8 mg, and there was no evidence of accumulation with chronic dosing. Perindopril 4 and 8 mg produced significant decreases in predose blood pressure (BP) with chronic dosing, with maximal decreases occurring 5-7 h after dosing. Perindopril also produced a prolonged dose-dependent inhibition of plasma angiotensin-converting enzyme (ACE) activity that was maximum after 4 h and had not fully recovered by 48 h after a single dose.