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Biomedical subjects

H L Elliott

Publications and source records attributed to H L Elliott.

At least 181 records · Page 10Linked to original sources
PubMed1985

Verapamil pharmacokinetics and apparent hepatic and renal blood flow.

The effect of acute and continued administration of verapamil on pharmacokinetics and regional blood flow has been studied in eight normotensive subjects. Continued administration resulted in a significant decrease in verapamil clearance, compared to that following acute dosing, as assessed by increases in both terminal elimination half-life (from a mean +/- s.d. of 5.2 +/- 2.3 h to 6.7 +/- 2.0 h) and AUC (from a mean +/- s.d. of 800 +/- 353 ng ml-1 h to 1455 +/- 244 ng ml-1 h). The relative clearance of norverapamil was not changed. Acute administration of verapamil resulted in a significant increase (P less than 0.005) in apparent liver blood flow which with continued administration fell significantly (P less than 0.01) towards placebo values. Effective renal plasma flow similarly increased with acute verapamil administration (P less than 0.05) and with chronic administration reduced again to be not significantly different from placebo. Acute and chronic verapamil administration did not significantly alter glomerular filtration rates. These results suggest that there may be a relationship between the acute increase in liver blood flow and the relatively increased clearance of verapamil following acute dosing.

Adult↗
PubMed1985

Effects of verapamil and nisoldipine on human platelets: in vivo and in vitro studies.

Inhibition of platelet aggregation was observed after 4 days of oral dosing with the calcium antagonists, verapamil (160 mg) or nisoldipine (20 mg) but not following acute dosing. These effects were observed at plasma concentrations that had no effect on platelet aggregation when investigated in vitro. Verapamil added in vitro inhibited adrenaline-induced platelet aggregation at relatively low concentrations (IC50 16 microM) but only inhibited aggregation to adenosine diphosphate at very high concentrations (IC50 700 microM). Nisoldipine, a dihydropyridine, added in vitro had no effect on platelet aggregation induced by adenosine diphosphate but inhibited by 67%, the secondary phase of platelet aggregation induced by adrenaline. Verapamil but not nisoldipine displaced [3H]-yohimbine from the specific binding sites on human platelets, suggesting an interaction with alpha 2-adrenoceptors. Inhibition of adrenaline-induced aggregation by verapamil in vitro may be a result of antagonism of alpha 2-adrenoceptors but long term treatment with both verapamil and nisoldipine also inhibits platelet aggregation mechanisms other than by alpha 2-adrenoceptor blockade.

Adult↗
PubMed1985

The effect of nisoldipine on apparent liver blood flow and effective renal plasma flow.

The effects of the acute and continued administration of the calcium antagonist nisoldipine on hepatic and renal blood flow and on renal function were studied in nine normotensive volunteers. There were no significant changes in supine blood pressure or heart rate but acute administration significantly increased both apparent liver blood flow and effective renal plasma flow. With continued administration these increases were attenuated and were not significantly different from placebo after 4 days treatment. Acute nisoldipine administration was also associated with significant increases in glomerular filtration rate and urinary sodium excretion.

Adult↗
PubMed1985

Effects of nicardipine on aldosterone release and pressor mechanisms.

This study evaluated the effects of nicardipine, following intravenous infusion and oral administration, on the pressor and aldosterone responses to infused angiotensin II. Six healthy, normotensive male subjects were studied. Following administration of nicardipine, no significant change in blood pressure was seen. Nicardipine attenuated the pressor response produced by intravenous administration of angiotensin. Nicardipine did not inhibit the aldosterone response to angiotensin.

Adrenocorticotropic Hormone↗
PubMed1985

Comparison of radiometric and conventional culture systems in detecting Haemophilus influenzae type b bacteremia in rats.

To compare the efficiency of detecting Haemophilus influenzae type b bacteremia by the BACTEC radiometric system (RS; Johnston Laboratories, Inc., Towson, Md.) and a conventional Trypticase soy broth (BBL Microbiology Systems, Cockeysville, Md.) blood culture system (TSB), we developed an in vivo model of bacteremia in rats. After intravenous injection of 50 to 200 CFU into adult rats, there was a linear logarithmic increase in CFU per milliliter of rat blood during the first 10 h (r = 0.98), allowing accurate prediction of the level of bacteremia with time. Culture bottles were inoculated with 0.5 ml of blood obtained by cardiac puncture and processed as clinical samples in the microbiology laboratory with our RS and conventional protocols. We found the following. (i) The first detection of bacteremia by RS was similar to that by TSB if a Gram stain of the TSB was done on day 1 and was superior if that smear was omitted (P less than 0.01). (ii) The detection times in both systems were comparable at different magnitudes of bacteremia (10(1) to 10(4) CFU/ml). (iii) Supplementation of inoculated bottles with 2 ml of sterile rat blood interfered with Gram stain detection in TSB but resulted in increased 14CO2 production in RS. (iv) No difference in detection time was found between RS and TSB for four different clinical isolates. These studies show that, in a biologically relevant model, the detection of positive blood cultures for H. influenzae type b by RS was comparable to or better than detection by TSB when blood was processed analogously to clinical specimens.

Animals↗
PubMed1985

Alpha-adrenoceptor number and function in platelets from treated and untreated patients with essential hypertension and age- and sex-matched controls.

Alpha 2-receptor number was measured on platelets from 19 healthy normotensive volunteers and 19 patients with essential hypertension, using [3H]-yohimbine binding. Platelet function was assessed using the primary aggregation response to adrenaline. The mean alpha 2-receptor number (Bmax fmol/10(8) platelets) in platelets from normotensive controls was 31 (188 sites/cell) and was significantly higher than in age- and sex-matched hypertensive subjects, for whom Bmax = 24 (144 sites/cell) (P < 0.01 by paired t-test). There was no change in the affinity for [3H]-yohimbine binding. Platelet aggregation responses to adrenaline did not differ between hypertensive and normotensive subjects. Blood pressure reduction with prazosin in eight hypertensive subjects did not alter receptor number either acutely or following 1 month of treatment. These findings may be interpreted as evidence for enhanced receptor coupling to functional responses of a significantly smaller receptor population in patients with essential hypertension.

Adult↗
PubMed1985

The effect of calcium channel blockers on alpha 1- and alpha 2-adrenoceptor-mediated vascular responsiveness in man.

This study investigated the effects in normotensive males of the calcium channel blockers, verapamil and nisoldipine, on the pressor responses mediated via alpha-adrenergic and non-adrenergic mechanisms. After the first doses of each drug and after 4 days continued treatment both verapamil and nisoldipine significantly attenuated the responses to angiotensin II with three- to fivefold rightward shifts of the pressor dose-response curves. Rightward shifts of comparable magnitude were obtained for phenylephrine (selective alpha 1-agonist), but with alpha-methylnoradrenaline (preferential alpha 2-agonist) only nisoldipine caused a significant twofold rightward shift and only during continued treatment. This study demonstrated that peripheral vascular adrenergic responses mediated via both alpha 1- and alpha 2-adrenoceptors in man are affected by calcium channel blocking drugs. There was no evidence that this effect was specifically linked to the alpha 2-adrenoceptor. The functional antagonism of peripheral vasopressor mechanisms was not significantly different for verapamil and nisoldipine.

Adult↗
PubMed1984

Preliminary experience with a hospital blood pressure follow up clinic with nurse practitioner assessment and microprocessor based data retrieval.

Experience over two years with 376 hypertensive patients managed at a clinic where the primary observations are made by a trained nurse, clinical information is held on a microprocessor, and treatment follows a standard stepped care approach has been assessed. Blood pressure control after both one and two years was appreciably improved, with over 70% of patients having diastolic pressure below 90 mm Hg compared with 22% of patients when they first attended the new clinic. The non-attendance rate was half that of the conventional hospital outpatient clinic. A computer based record system with a nurse run hypertension clinic is acceptable to patients and offers the possibility of more effective long term control of blood pressure in large numbers of patients.

Adolescent↗
PubMed1984

Clinical pharmacological studies with the vasodilator endralazine in patients with renal impairment.

The influence of renal impairment on the pharmacokinetics of endralazine was studied in 12 patients; 4 patients on regular haemodialysis therapy (creatinine clearance less than 5 ml/min) and 8 patients with varying degrees of renal impairment (creatinine clearance 11-52 ml/min). Following an oral dose of 10 mg endralazine the mean terminal elimination half-life (beta t1/2) in the dialysis sub-group was prolonged at 7.1 h (range 3.3 to 14 h), compared to 3.6 h in the other renal patients (and compared to 2.3 h in hypertensive patients with normal renal function). After one week's therapy with 10 mg B.D. endralazine in the 8 patients with moderate renal impairment there was a significant increase in beta t1/2 to 8.6 h but there was no significant change in the area under the drug concentration-time curve and no evidence of drug accumulation. In this study those patients with the poorest renal function had the longest beta t1/2 after acute dosing. There was a significant correlation between creatinine clearance and acute beta t1/2 but there was considerable variability in individual patients and, even with severe degrees of renal impairment, major dose adjustments do not appear necessary.

Acetylation↗
PubMed1984

The determination of trimazosin and its metabolite CP23445 in whole blood by high performance liquid chromatography using fluorescence detection.

A sensitive and specific assay for trimazosin and its metabolite CP23445 is described. The method employs reverse-phase high performance liquid chromatography (HPLC) with fluorescence detection. The limit of detection of the assay is 1 ng/ml whole blood for trimazosin and 0.5 ng/ml for CP23445. The coefficient of variation for trimazosin and CP23445 over a typical calibration size is 5.4% and 4.9%, respectively. Various drugs that may be coadministered with trimazosin are shown not to interfere in the assay. The method has been extensively employed to study the pharmacokinetics of trimazosin and CP23445, both in man and in animals.

Chromatography, High Pressure Liquid↗
PubMed1984

The alpha adrenoceptor antagonist properties of idazoxan in normal subjects.

The imidazoline derivative idazoxan, which has been shown to be a potent, selective alpha 2-adrenoceptor antagonist, was injected intravenously to eight men with normotension. There was a transient small increase in blood pressure and a decrease in heart rate within 20 min of injection, with a slight increase in plasma norepinephrine levels. These effects are consistent with antagonism of prejunctional alpha 2-adrenoceptors. In response to infusions of the relatively selective alpha 2-adrenoceptor agonist alpha-methylnorepinephrine, the pressor dose-response curve shifted to the right with idazoxan. These data provide evidence for receptors with alpha 2-adrenoceptor characteristics on resistance vessels in man. In vitro platelet aggregation studies provide further evidence of selective alpha 2-adrenoceptor antagonism by idazoxan, with greater potency and affinity than alpha-yohimbine. These observations are consistent with both pre- and postjunctional peripheral alpha 2-adrenoceptors in man and provide further support that idazoxan is a selective alpha 2-adrenoceptor antagonist.

Adrenergic alpha-Antagonists↗
PubMed1984

Trimazosin in normotensive subjects.

Oral and intravenous trimazosin, a quinazoline derivative, resulted in a significant reduction in blood pressure of normal subjects, particularly when the subjects rose from a supine position to standing. This hypotensive effect was maximal between 4 and 6 hr after dosing and was accompanied by a significant increase in heart rate. The responses to intravenous infusions of phenylephrine indicated that trimazosin had significant, selective, peripheral alpha 1-antagonist properties. Kinetic analysis showed oral bioavailability of 63%, a clearance rate of 66 ml/min, and a terminal elimination t1/2 of approximately 3 hr. The correlation between drug levels and hypotensive effect was significantly improved by inclusion of the concentrations of trimazosin's major metabolite, 1-hydroxy-trimazosin (CP 23445), particularly for the period of maximum effect. Our data show that acute administration of trimazosin is associated with a fall in blood pressure, an increase in heart rate, and a significant degree of alpha 1-antagonism and that the overall hypotensive effect may in part be mediated by an active metabolite. It seems 1-hydroxy-trimazosin is a likely candidate for this role, but it is not clear whether this metabolite also has significant alpha-adrenoceptor antagonist properties.

Absorption↗
PubMed1984

Combined alpha adrenoceptor antagonism and calcium channel blockade in normal subjects.

Because both verapamil and prazosin act on peripheral vascular smooth muscle and undergo extensive first-pass metabolism, the possibility of dynamic and kinetic interactions with their concurrent use was investigated. The acute hemodynamic effects of oral prazosin (1 mg), oral verapamil (160 mg), and their combination were evaluated in eight men with normotension. The kinetics of both drugs, alone and in combination, were also assessed. Verapamil did not change blood pressure or heart rate, but prazosin induced a fall in blood pressure, particularly on standing (lowest systolic pressure was 98 mm Hg). The combination of prazosin and verapamil had an earlier, longer, and greater hypotensive effect that was maximal 4 hr after dosing, with a standing systolic pressure of 89 mm Hg. Increases in heart rate were less after the combination (maximum of 102 bpm) than after prazosin alone (maximum of 112 bpm), although there were greater falls in blood pressure with the combination than with prazosin alone. Increases in plasma catecholamine and aldosterone levels and plasma renin activity were greatest with the combination. No differences were found in the kinetics of verapamil when combined with prazosin, but the combination affected prazosin kinetics, with increases in peak prazosin concentrations and AUC. Our data suggest that the greater hypotensive activity of the combination results at least in part from a kinetic interaction that enhances the bioavailability of prazosin, but it is possible that a dynamic interaction at the level of vascular smooth muscle or compensatory cardiac activity also plays a role.

Administration, Oral↗
PubMed1984

Comparison of medroxalol and labetalol, drugs with combined alpha- and beta-adrenoceptor antagonist properties.

Medroxalol, a new drug which has been reported to possess both alpha- and beta-adrenoceptor antagonist properties, was compared with labetalol in single dose studies in normotensive males. Oral doses of 400 mg of each drug significantly reduced blood pressure, both supine and erect, without significant changes in heart rate. The chronotropic and diastolic depressor responses to isoprenaline were significantly antagonised by both drugs, for at least 6-8 h after drug administration. Medroxalol was associated with significantly greater beta-adrenoceptor antagonism than labetalol. There was no significant antagonism by either drug of the pressor response to noradrenaline. However, in a sub-group of subjects the responses to the selective alpha 1-adrenoceptor agonist, phenylephrine, were consistent with modest alpha 1-adrenoceptor antagonism. This was significant only for labetalol. The ratios of beta 1- to alpha 1-adrenoceptor antagonism as calculated from the relative shifts of the isoprenaline and phenylephrine dose-response curves, were 3 to 1 for labetalol and about 7 to 1 for medroxalol.

Adrenergic alpha-Antagonists↗
PubMed1984

Comparison of the clinical pharmacokinetics and concentration-effect relationships for medroxalol and labetalol.

The pharmacokinetics of medroxalol are described in normal subjects and compared with those of labetalol. Both drugs were administered in doses of 400 mg orally and 1 mg/kg intravenously. The data for both drugs was most appropriately described by a two compartment model. For oral medroxalol the clinical pharmacokinetic parameters were a terminal elimination half-life (t 1/2,Z) of 15.6 h, a peak level of 450 ng/ml and a time to peak of 2-3 h. Following intravenous medroxalol the bioavailability was calculated as 64%, the plasma clearance was 948 ml/min and the t 1/2,Z was 7.3 h. The t 1/2,Z following intravenous administration was significantly shorter than that following oral administration. The significant differences between medroxalol and labetalol were in time to peak, respectively 2.3 and 1.1 h; oral t 1/2,Z, 15.6 and 5.5 h; clearance 948 and 1560 ml/min; and bioavailability, 64 and 20%. Despite the pharmacokinetic differences a similar plasma concentration-hypotensive effect relationship was described for each drug.

Adrenergic alpha-Antagonists↗
PubMed1984

Whole-body elemental composition in patients with renal failure and after transplantation studied using total-body neutron-activation analysis.

Whole body elemental composition in seventy-five patients with either renal failure or a kidney transplant was measured by neutron-activation analysis and whole-body counting. Comparison was made with expected normal values and with a control group; between undialysed, dialysed and transplanted patients; and between those receiving dialysis treatment for various periods. A frequent finding was low body calcium, reflecting the prevalence of renal osteodystrophy. Sodium and chlorine were increased in undialysed patients, a consequence of their renal disease. Patients with transplanted kidneys had reduced amounts of most elements, indicating decreased lean body mass, but increased body weight, probably due to excess fat.

Body Composition↗