Dental implications of Alzheimer's disease.
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Alzheimer Disease↗
Biomedical subjects
B Jackson
Publications and source records attributed to B Jackson.
Measurement of angiotensin converting enzyme inhibitors in serum by radioinhibitor binding displacement assay.
The principle of enzyme radioinhibitor binding displacement was developed to measure the concentration of angiotensin converting enzyme (ACE) inhibitors in rat serum. 125I MK351A, a tyrosyl derivative of enalaprilic acid, and a potent ACE inhibitor, bound in a concentration and time dependent manner to ACE. Binding of 125I MK351A to rat serum ACE was reduced in a concentration dependent manner in vitro by the ACE inhibitors MK521 (lisinopril), S9780, and Ro 31-3113-000 (Cilazapril diacid). This relationship was used to measure MK521 and S9780 in rat serum four hours after oral gavage with MK521, S9490-3 the prodrug ester of S9780, at 1, 2 and 4 mg/kg, or 1/2 hour after intraperitoneal injection of Ro 31-3113-000 (0.0125-0.7 mg/kg). Serum MK521 concentrations, estimated by radio inhibitor binding displacement, and radioimmunoassay, correlated well (r = 0.94, N = 9, P less than 0.001). Serum MK521, S9780 and Ro 31-3113-000 concentrations measured by radioinhibitor binding displacement assay were dose related, and inversely related to serum ACE enzymatic activity. The radioinhibitor binding displacement assay method using 125I MK351A as a ligand for ACE has application to the measurement of any competitive inhibitor of ACE.
Angiotensin-Converting Enzyme Inhibitors↗
Evidence for low brain penetration by the H1-receptor antagonist temelastine (SK&F 93944).
Competition by the potent selective H1-receptor antagonist temelastine (SK & F 93944) with [3H]mepyramine binding to mouse cortex H1-receptors has been measured in vitro and vivo. The data were compared with that obtained using the classical H1-receptor antagonists mepyramine and promethazine and indicated that temelastine has relatively low ability to penetrate the blood-brain barrier compared with the latter two compounds. These studies also revealed that temelastine has relatively low affinity for mouse cortex H1-receptors compared with its affinity for H1-receptors in guinea-pig ileum and cortex, suggesting that it may be a useful compound with which to investigate potential H1-receptor tissue and species-related differences.
Animals↗
Comparison of reverse transcriptase assay with the Retro-Tek viral capture assay for detection of human immunodeficiency virus.
The reverse transcriptase (RT) assay for human immunodeficiency virus (HIV) is tedious, expensive, and nonspecific for HIV activity. Because the Retro-Tek viral capture assay (VCA) (Cellular Products, Inc., Buffalo, NY) is relatively quick, inexpensive, and specific for HIV antigens, we compared the sensitivity and specificity of the two assays in a blinded fashion to see if the VCA could replace the RT assay. Specifically, peripheral mononuclear cells were cocultured from 11 Western blot-positive acquired immunodeficiency syndrome (AIDS) patients. The culture supernatant fluids were tested every 4-7 days for at least 28 days by VCA for HIV antigens, and by RT assay for retrovirus activity. Ten seronegative healthy donors with no risk factors were also cocultured and tested. Seven (64%) of 11 AIDS patients were positive by VCA and confirmed by RT assay in each instance. Concordance between VCA and RT assay was 100% in each patient. Time-to-positive detection was 7-28 days for both assays. Once a culture became positive by either assay, subsequent culture supernatant fluids remained positive by both assays until the culture was discarded, usually at day 28. The ten healthy seronegative donors were negative by both assays. These results suggest that the VCA is preferable to the RT assay for detection of HIV.
Acquired Immunodeficiency Syndrome↗
Tissue angiotensin converting enzyme (ACE) during changes in the renin-angiotensin system.
To establish if physiological manipulations of the renin-angiotensin system modulates tissue angiotensin converting enzyme (ACE), rats were fed low, normal, or high salt diets, or high salt and DOCA, for 3 weeks, and then plasma and tissue ACE levels were determined by radioinhibitor binding studies. Urinary sodium excretion (mmol/24 h) was 0.03 +/- 0.01 (low salt), 0.58 +/- 0.09 (normal salt), and 10.4 +/- 1.3 (high salt), and plasma angiotensin II (pg/ml) was 73.5 +/- 8.6 (low salt), 49.3 +/- 8.5 (normal salt), 32.2 +/- 8.5 (high salt), and 6.9 +/- 0.6 (high salt plus DOCA) in the third week of dietary treatment. ACE was studied by Scatchard analysis of radioinhibitor binding in plasma and tissue homogenates. [125I]MK351A bound to ACE was measured under standardized conditions in the presence of MK351A (10(-13) to 10(-5) M) and MK351A binding sites and equilibrium dissociation constant calculated. There were no significant changes in binding site concentration in plasma, lung, aorta, epididymus, brain, or kidney preparations across the range of salt states studied. The equilibrium dissociation constant appeared uniform within organs, but varied between organs. Further studies were undertaken with captopril, enalapril, and cilazoprilic acid in kidney and lung preparations. Concentration of inhibitor required for equal displacement of bound [125I]MK351A was consistently greater for kidney than for lung. Binding studies of rat ACE using [125I]MK351A showed that manipulation of salt status did not influence rat tissue ACE. Binding data suggest ACE from different tissues may have variations at the active site.
Animals↗
Blockade of angiotensin converting enzyme in circumventricular organs of the brain after oral lisinopril administration demonstrated by quantitative in vitro autoradiography.
1. To elucidate the central effect of lisinopril, a new angiotensin converting enzyme (ACE) inhibitor, ACE localization and levels were followed in the brain of Sprague-Dawley rats by quantitative in vitro autoradiography after administration of the drug. 2. Following acute lisinopril (10 mg/kg p.o.) treatment, serum ACE activity was acutely reduced, but returned to normal by 24 h. 3. Levels of ACE in most parts of the brain, including the basal ganglia and choroid plexus of all ventricles were not affected by lisinopril. Lisinopril inhibited brain ACE in the subfornical organ and organum vasculosum of the lamina terminalis, circumventricular organs, where the blood brain barrier is deficient. These regions are rich in ACE and angiotensin II receptors, and are known targets for angiotensin II-induced effects on fluid, electrolyte and blood pressure homeostasis. 4. These observations indicate that quantitative in vitro autoradiography is a powerful method to study the access of drugs to the central nervous system. 5. This study shows that blood brain barrier plays an important role in limiting the penetration of lisinopril into the central nervous system. The circumventricular organs may be important targets for ACE inhibitors.
Angiotensin-Converting Enzyme Inhibitors↗
Atrial natriuretic factor in chronic renal failure: studies in man and the rat.
1. Plasma concentration and atrial content of atrial natriuretic factor (ANF) were measured in rats with chronic renal failure induced by subtotal nephrectomy. 2. Plasma ANF was higher, and atrial ANF content lower in rats with renal failure when compared with sham-operated controls. 3. Plasma renin activity (PRA) and ANF were elevated at 1 week following subtotal nephrectomy. After 1 month plasma ANF had risen further, but PRA was suppressed to below control values. 4. Plasma ANF was also measured in six patients with chronic renal failure undergoing routine haemodialysis. 5. Elevated plasma ANF levels in patients with renal failure were lowered by haemodialysis, although extraction of ANF across the dialysis membrane was negligible. 6. Secretion of ANF is increased in chronic renal failure in man and the rat, possibly mediated by increased intravascular volume.
Animals↗
Plasma atrial natriuretic peptide: concentrations and circulating forms in normal man and patients with chronic renal failure.
A specific and sensitive radioimmunoassay has been developed and used to measure circulating atrial natriuretic peptide (ANP) in normal man and in patients with chronic renal failure. Circulating ANP levels rose with head-down tilt and exercise, and were raised in patients with chronic renal failure in proportion to volume status. This suggests that ANP release is mediated via increased atrial stretch, although other release mechanisms cannot be excluded. Extracts of normal human plasma subjected to reverse phase HPLC showed one major peak of immunoreactivity co-migrating with alpha-human ANP. However, when plasma extracts from patients with renal failure were chromatographed on a similar system, a second later eluting peak of ANP immunoreactivity was observed. This may represent circulating ANP precursors or degradation molecules. Significant arteriovenous differences in plasma ANP concentration were observed in patients with chronic renal failure. Arterial and venous plasma ANP levels decreased slightly after haemodialysis. Plasma ANP concentrations were inversely correlated with haematocrit in these patients.
Animals↗
Pharmacokinetics of angiotensin converting enzyme inhibition in tissues following oral lisinopril: studies in the rat using quantitative radioinhibitor binding.
1. The pharmacokinetics of angiotensin converting enzyme (ACE) inhibition in plasma and tissues were measured in the rat following 10 mg/kg lisinopril given by oral gavage. 2. Specific binding of 125I-351A to ACE was measured in plasma, and homogenates of lung, aorta, kidney, testis, epididymis and brain, and used as an index of ACE activity. 3. Plasma ACE binding of 125I-351A was reduced to 5% of that in untreated rats 2 h after treatment, and returned to normal by 48 h. Kidney ACE showed a similar time course. Angiotensin converting enzyme from lung, aorta and brain was inhibited at a slower rate, and to a lesser degree. No significant inhibition of ACE was detected in epididymis or testis. 4. Individual tissues in the rat had differences in time course and degree of ACE inhibition after a single dose of lisinopril.
Administration, Oral↗
Hormonal and blood pressure responses to tilting in beta-blocked essential hypertension treated with felodipine or prazosin.
A study was carried out of 22 patients with essential hypertension who were treated with metoprolol (100 mg/day) and placebo for 4 weeks. Felodipine (n = 11) or prazosin (n = 11) were then added in increasing doses (felodipine 5, 10, 20 mg bid; prazosin 1, 2, 4 mg bid) for 2 weeks until a diastolic blood pressure of less than or equal to 90 mm Hg was achieved. Acute haemodynamic and hormonal responses to 80 degrees tilting (measurements after 4 minutes' tilt) were obtained immediately prior to randomisation to felodipine or prazosin, and after 6 to 8 weeks of treatment. At randomisation, 80 degrees tilt produced no change in blood pressure and only a small increase in pulse rate. There was no significant change in the plasma renin-angiotensin system, vasopressin or adrenaline concentrations. Plasma noradrenaline concentration rose in response to 80 degrees tilt. Following substitution of felodipine (n = 11) or prazosin (n = 11) for placebo, and continuation of metoprolol, blood pressure fell. 80 degrees tilt caused no change in the plasma renin-angiotensin system, vasopressin or adrenaline concentration. Plasma noradrenaline concentration rose in response to tilt, as before. Felodipine is an effective antihypertensive agent when used with metoprolol.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Felodipine versus prazosin as an addition to a beta-blocker in the treatment of essential hypertension. The Australian Multicentre Study.
The efficacy and tolerability of felodipine and prazosin were compared in a double-blind randomised parallel group study of 100 patients with moderately severe essential hypertension, treated concomitantly with a beta-blocking drug. After a 2- to 8-week run in phase (beta-blocking drug plus placebo), patients with a diastolic blood pressure greater than or equal to 95mm Hg were randomly given felodipine (n = 50) or prazosin (n = 50). After an initial dose of either felodipine 2.5mg bid or prazosin 0.5mg bid for 3 days, the drugs were titrated at 2-week intervals (felodipine 5, 10, 20mg bid, prazosin 1, 2, 4mg bid) if the supine diastolic blood pressure was greater than or equal to 90mm Hg. Treatment was continued for 8 weeks. Baseline supine blood pressures of each group were similar (177/104mm Hg, felodipine; 176/103mm Hg, prazosin). At week 6, supine blood pressures in the felodipine group were 144/82mm Hg and 161/90 in the prazosin group. The reductions in systolic and diastolic blood pressures were significantly greater for the felodipine group than the prazosin group in both the supine and standing positions at all visits after baseline. At 8 weeks, supine diastolic blood pressure less than 90mm Hg was achieved in more patients in the felodipine (36/47) than in the prazosin group (20/43, p less than 0.01). The total number of adverse reactions was similar in both groups. During active therapy, a greater number of patients experienced vascular adverse reactions (oedema and flushing) with felodipine (23) than with prazosin (12). Most events were mild and did not necessitate withdrawal from therapy. There were no clinically significant changes in laboratory variables in either treatment group. Felodipine was an effective, well tolerated hypotensive agent when used concomitantly with a beta-blocking drug. In the doses used it was more effective than prazosin at reducing blood pressure.
Adrenergic beta-Antagonists↗
Preservation of renal structure and function in the rat remnant kidney model of chronic renal failure by enalapril treatment.
The remnant kidney model of chronic renal failure was established in rats subject to subtotal (1 7/8) nephrectomy and the evolution of renal injury studied over a period of 6 wk. One wk after subtotal nephrectomy, rats had a mean conscious systolic blood pressure of 158 +/- 5 mm Hg and serum creatinine of 128 +/- 9 mumol/l. Both systolic blood pressure and serum creatinine rose over the next 5 wk in concert with progressive glomerulosclerosis and proteinuria. Enalapril, an angiotensin converting enzyme inhibitor, was administered (5 mg/kg/day) to rats (n = 11) from 1 wk after subtotal nephrectomy. Enalapril lowered systolic blood pressure over the treatment period. Systolic blood pressure was 122 +/- 5 mm Hg compared with 176 +/- 7 mm Hg in untreated rats (p less than 0.001) at 6 wk. Serum creatinine 6 wk after subtotal nephrectomy was 110 +/- 9 mumol/l with enalapril treatment, compared with 159 +/- 21 mumol/l (p less than 0.025) in control animals. Enalapril treated rats had lower urinary protein excretion than controls (15 +/- 3 mg/24 hr vs 85 +/- 22 mg/24 hr, p less than 0.0001) at 6 weeks. Glomerulosclerosis, assessed by blinded histological score, was also reduced in the enalapril treated group (1.79 +/- 0.08 vs 2.36 +/- 0.16, p less than 0.01). Enalapril treatment was associated with a reduction in filtration fraction (51Cr-EDTA/125I-hippurate clearance). At 6 wk, filtration fraction was 0.30 +/- 0.03 in enalapril treated and 0.48 +/- 0.03 in control rats (p less than 0.001). Enalapril treatment in the subtotal nephrectomy model of renal failure preserved renal structure and function.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Angiotensin converting enzyme inhibition in plasma and tissues.
Angiotensin converting enzyme (ACE) and the ACE inhibitor lisinopril were measured in patients with renal impairment, by both radioinhibitor 125I MK351A binding studies, and by radioimmunoassay. Plasma concentration of lisinopril estimated by radioinhibitor binding displacement correlated closely with that measured by radioimmunoassay. Plateau lisinopril concentration in 8 patients with varying degrees of renal failure treated with 5 mg lisinopril per day for 1 week, was inversely related to renal function. Plasma lisinopril concentrations of 30-70 ng/ml were required for 50% inhibition of plasma ACE activity in vivo. Acute studies in the rat showed inhibition of ACE in different tissues had different time courses. These observations suggest that 125I MK351A binding studies in tissues will be useful in establishing the pharmacokinetic and pharmacodynamic profiles of newer ACE inhibitors, and may help delineate the contribution of ACE in different tissues to cardiovascular homeostasis.
Angiotensin-Converting Enzyme Inhibitors↗
Angiotensin-converting enzyme inhibitors: measurement of relative inhibitory potency and serum drug levels by radioinhibitor binding displacement assay.
Radioinhibitor binding displacement, a new method for the measurement of angiotensin-converting enzyme (ACE) competitive inhibitors, has been used to assess the relative potency of nine synthetic ACE inhibitors. MK351A, tyrosyl derivative of enalaprilic acid was iodinated with 125I and used as the radioligand. [125I]MK351A bound to human serum ACE in a concentration-dependent manner. It was displaced in a concentration-dependent manner by all ACE inhibitors tested. Fifty percent displacement of bound [125I]MK351A (DD50) for each ACE inhibitor correlated well with inhibitor potency ID50, estimated using an ACE enzymatic activity assay using Hip-His-Leu as substrate (r = 0.96, p less than 0.001; n = 9). The radioinhibitor binding displacement assay was used to measure serum concentration of enalaprilic acid (MK422) in human serum samples. Drug concentration estimated by radioinhibitor binding displacement assay correlated closely (r = 0.96, p less than 0.001; n = 22) with the drug concentration measured by a specific radioimmunoassay. The radioinhibitor binding displacement technique using [125I]MK351A as the ligand for human serum ACE has general application to all competitive ACE inhibitors, allowing comparison of in vitro ACE inhibitor potencies and estimation of serum ACE inhibitor concentrations.
Angiotensin-Converting Enzyme Inhibitors↗
Disparate effects of angiotensin converting enzyme inhibitor and calcium blocker treatment on the preservation of renal structure and function following subtotal nephrectomy or streptozotocin-induced diabetes in the rat.
Sprague-Dawley rats subjected to subtotal (1 7/8) nephrectomy or streptozotocin diabetes were treated with an angiotensin converting enzyme inhibitor or a calcium channel blocker and their course compared with untreated control animals. Subtotal nephrectomy led to hypertension, proteinuria, reduced creatinine clearance, and glomerulosclerosis over 6 weeks. Enalapril treatment (5 mg/kg/day, n = 11) or felodipine (30 mg/kg/day, n = 11) reduced systolic blood pressure to a comparable degree. Plasma creatinine (mumol/l) was lower after enalapril treatment (110 +/- 8, p less than 0.05) than with felodipine treatment (153 +/- 27) or no treatment (173 +/- 19, n = 18). Proteinuria (mg/24 h) was lower with enalapril treatment (15 +/- 3, p less than 0.001) than with no treatment (85 +/- 22) and increased with felodipine (221 +/- 35). Glomerulosclerosis was reduced with enalapril but not felodipine treatment. Diabetic rats were treated with enalapril (5 mg/kg/day, n = 17), verapamil (5 mg/kg/day, n = 17), or untreated. Diabetic rats had increased creatinine clearance (ml/min) compared with nondiabetic controls (1.52 +/- 0.06 vs. 1.15 +/- 0.05, n = 11, p less than 0.01). Enalapril and verapamil treatment reduced blood pressure equally. Enalapril but not verapamil reduced the elevated creatinine clearance of diabetic rats (enalapril, 1.37 +/- 0.04 ml/min, p less than 0.01; verapamil, 1.49 +/- 0.5 ml/min). Proteinuria (mg/24 h) was lower (p less than 0.05) with enalapril treatment (36 +/- 3) but not with verapamil treatment (58 +/- 10) in comparison to that in untreated diabetes (71 +/- 18).(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin-Converting Enzyme Inhibitors↗
Felodipine compared to prazosin as additional therapy to a beta-blocking drug.
Felodipine was compared with prazosin in patients with essential hypertension whose blood pressure was not controlled by a beta-blocking drug. One hundred patients with a supine diastolic blood pressure greater than or equal to mm Hg after 4 weeks or more on a beta-blocking drug and placebo were randomly assigned to felodipine or prazosin tablets. The drugs were titrated at 2-week intervals if diastolic BP was greater than or equal to 90 mm Hg. Titration steps of felodipine were 5, 10, 20 mg b.i.d. and of prazosin were 1, 2, 4 mg b.i.d. The fall in blood pressure with felodipine 32/21 mm Hg was greater than the fall with prazosin 16/12 mm Hg (p less than 0.001); 36 patients achieved a diastolic blood pressure of less than 90 mm Hg with felodipine, which was a significantly greater number than the 20 patients who obtained such a level with prazosin (p less than 0.01). Both drugs were well tolerated, but more patients complained of vascular type side effects (flushing, peripheral edema) with felodipine than with prazosin. There was significant weight gain with prazosin but not with felodipine. Felodipine was shown to be a well-tolerated, effective antihypertensive agent when used with a beta-blocking drug and to be suitable for people with hypertension who fail to be controlled with a beta-blocking drug.
Adrenergic beta-Antagonists↗
Implementation of a hospital information system: the use of a nursing task force.
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Attitude to Computers↗