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Biomedical subjects

A Bobik

Publications and source records attributed to A Bobik.

At least 145 records · Page 8Linked to original sources
PubMed1981

No stereoselective first-pass hepatic extraction of propranolol.

The plasma level: time profile for l-propranolol and total propranolol concentrations were examined in normotensive subjects after intravenous and oral dl-propranolol. l-Propranolol concentrations in plasma accounted for about 60% of total propranolol. This was attributed to lower volume of distribution for the isomer. Mean plasma clearance of 1-propranolol was similarly affected while apparent plasma half-life for the l-isomer and total propranolol were of the same order. Oral bioavailability of 1- and total propranolol averaged 40.7 +/- 8.5% and 42.4 +/- 12.9%. Food and hydralazine increased oral bioavailability of total and l-propranolol by similar magnitudes. We conclude that difference in the kinetics of l- and total propranolol concentrations in plasma are small and probably of no clinical significance. Presystemic clearance of propranolol in man does not appear to be stereospecific.

Administration, Oral↗
PubMed1981

Low oral bioavailability of dihydroergotamine and first-pass extraction in patients with orthostatic hypotension.

The relative importance of the effect of absorption and first-pass extraction in bioavailability and clinical effectiveness of oraldihydroergotamine (DHE) was examined in six subjects with orthostatic hypotension. Maximum increases in systolic blood pressure of standing subjects occurred within 15 min of intravenous administration (10 micrograms/kg); after 30 min pressure declined linearly with respect to time over the ensuing 3 hr. Plasma DHE concentrations declined biexponentially with respect to time. Mean plasma half-life was 2.15 hr and plasma clearance averaged 862 ml/min. There was no rise in "standing" systolic blood pressure on oral administration (200 to 600 micrograms/kg). Peak plasma concentrations ranged from less than 0.1 to 2 ng/ml. Apparent oral absorption for DHE ranged from 19.5% to 53.3% while systemic bioavailability varied from less than 0.1% to 1.5%. when glyceryl trinitrate was taken orally with DHE, the bioavailability of the latter increased between 56% and 370% over the 0.1% to 1.5% without any apparent alteration in DHE absorption. Standing systolic blood pressure increased 27% (P less than 0.05) 2 hr after the same doses of DHE with glyceryl trinitrate. These findings suggest that the extent of first-pass extraction by the liver is the prime determinant of DHE bioavailability after oral administration and that factors that alter gastrointestinal and portal vein flow to the liver affect its bioavailability.

Absorption↗
PubMed1981

Effect of norepinephrine uptake blockers on norepinephrine kinetics.

We studied the effect of a single oral dose of the neuronal norepinephrine uptake blocker, desipramine 125 mg, on norepinephrine kinetics. Desipramine reduced the plasma norepinephrine clearance by approximately 20%, from 1.33 +/- 0.22 to 1.08 +/- 0.19 l/m2/min (p less than 0.01). Similarly, plasma norepinephrine clearance was slowed in patients with sympathetic nerves damaged by disease (idiopathic peripheral autonomic insufficiency). Desipramine also reduced the rate of spillover of norepinephrine to plasma, 0.27 +/- 0.07 to 0.15 +/- 0.04 micrograms/m2/min, leaving the plasma norepinephrine concentration unchanged. Disappearance of tritiated norepinephrine from plasma, after infusion to steady state, was biexponential, with half-time of the rapid-removal phase (t1 1/2) = 2.0 +/- 0.4 min and half-time of the second exponential (t2 1/2) = 34 +/- 10 min. The rapid-removal phase was sensitive to disturbances in the neuronal uptake of norepinephrine, the t1 1/2 being prolonged by desipramine and lengthened in the patients with peripheral autonomic insufficiency. In contrast, the selective extraneuronal norepinephrine uptake blocker, cortisol, 500 mg intravenously, had no effect in normal subjects on either plasma norepinephrine clearance or the t1 1/2 value. Neuronal uptake of norepinephrine contributes to the overall removal of norepinephrine from plasma. Extraneuronal uptake of norepinephrine could not be demonstrated at existing plasma norepinephrine concentrations.

Adult↗
PubMed1981

Age-dependence of noradrenaline kinetics in normal subjects.

1. The influence of age on the rate of spillover of noradrenaline into plasma, clearance of noradrenaline from plasma, and plasma noradrenaline concentration at rest was studied in 34 healthy subjects aged 20--69 years. 2. The plasma concentration of noradrenaline was dependent on age, values being higher in older subjects. 3. This age-dependence of plasma noradrenaline concentration was due principally to a reduced clearance of noradrenaline from the circulation in older subjects. 4. The rate of spillover of noradrenaline into plasma was little influenced by age. The higher plasma noradrenaline values found in older subjects do not seem to be due to an increase in sympathetic nervous system tone with aging.

Adult↗
PubMed1981

Effect of propranolol on noradrenaline kinetics in patients with essential hypertension.

1 The rates of noradrenaline spillover to, and removal from, plasma were measured in ten patients with essential hypertension treated with propranolol, to ascertain if long-term administration of this drug reduces sympathetic nervous system tone. 2 The plasma clearance of noradrenaline fell with propranolol, leading to a small rise in the mean plasma noradrenaline concentration. Sympathetic nervous activity in treated patients cannot be reliably gauged from plasma noradrenaline values because these are distorted by the reduction in noradrenaline clearance. 3 There was no consistent effect on noradrenaline spillover rates, which fell in six patients, but rose in the remaining four. The magnitude of the antihypertensive response was unrelated to these changes in noradrenaline release. During propranolol treatment, noradrenaline spillover rates were in every case within the normal range, much higher than in patients treated with the known sympathetic nervous systems suppressant, clonidine. 4 The principal mode of antihypertensive action of propranolol is something often than central suppression of sympathetic tone or pre-synaptic inhibition of noradrenaline release.

Adult↗
PubMed1981

Cardiac beta adrenoceptors and adenylate cyclase in normotensive and renal hypertensive rabbits during changes in autonomic activity.

The effects of hypertrophy and alterations in cardiac autonomic activity on left ventricular (LV) beta adrenoceptors and adenylate cyclase were measured in rabbits. Normotensive and renal hypertensive animals were exposed to three levels of chronic sympathetic activity: (i) "normal" activity; (ii) reduced activity after 2 weeks treatment with guanethidine; (iii) 2 weeks increased sympathetic activity following sino-aortic denervation. In hypertensive animals with "normal" activity LV beta receptor sarcolemma concentration was reduced by 36+ compared with the normotensive subgroup whilst total LV receptor numbers were unaltered. Isoprenaline activated adenylate cyclase was similarly affected whilst other sarcolemma marker enzymes were unaffected. Chronic guanethidine administration to normotensive rabbits increased beta receptor concentration (16%, P less than 0.05), basal and isoprenaline activated meters were unaffected. Sino-aortic denervation did not significantly affect beta receptor concentration in either group. The small changes in beta receptor concentration during alterations in sympathetic activity suggest that only a small proportion of LV beta receptors appear to be innervated. The reduction in sarcolemma beta receptor concentration in hypertensive animals appears to be a specific effect due to hypertrophy of the cardiocyte.

Adenosine Triphosphatases↗
PubMed1980

Simple and sensitive procedure for the assay of serotonin and catecholamines in brain by high-performance liquid chromatography using fluorescence detection.

A simple, rapid and specific method for the determination of serotonin and catecholamines in brain is described. After tissue homogenisation, catecholamines are isolated by adsorption onto alumina and elution with perchloric acid. Serotonin is isolated by extraction into n-heptanol and back-extraction into acid. High-performance liquid chromatography of the acid extracts is performed with a C18 reversed-phase column and simple mobile phases. Detection is by the intrinsic fluorescence of the amines on excitation at 200 nm. Detection limits are 100 pg for norepinephrine, 300 pg for dopamine and 20 pg for serotonin. The results are found to correlate well with a catechol O-methyl transferase radioenzymatic assay for catecholamines and a ninhydrin derivatisation procedure for serotonin.

Animals↗
PubMed1980

Interaction between oral propranolol and hydralazine.

Seven healthy subjects were given oral propranolol (1 mg/kg) alone or in combination with hydralazine 25, 50, or 100 mg on separate occasions. Hydralazine induced variable increases in the peak concentrations (p less than 0.05) and in the area under the propranolol concentration: time curves (p less than 0.02) without change in the recovery of 14 C-propranolol/metabolites in urine or in the systemic clearance of propranolol; i.e., oral hydralazine enhanced the systemic availability of propranolol by alteration of "first-pass" (hepatic) clearance. The results indicate the possibility of change in presystemic clearance without reciprocal change in systemic clearance and also suggest that propranolol or any other high-clearance drug should be administered in fixed relationship to hydralazine and other drugs capable of altering "first-pass" hepatic extraction (either due to alteration in splanchnic blood flow or competitive inhibition of metabolism) if large variations in plasma concentrations are to be avoided.

Administration, Oral↗
PubMed1980

Determination of noradrenaline uptake, spillover to plasma and plasma concentration in patients with essential hypertension.

1. The rates of entry of noradrenaline to plasma and of removal of noradrenaline from plasma, and plasma noradrenaline concentration, were determined in normal subjects and in patients with essential hypertension. Neuronal uptake of noradrenaline was assessed from the plasma tritiated noradrenaline disappearance curve, after infusion to steady state. 2. Noradrenaline disappearance was biexponential. Rapid removal was dependent on neuronal uptake, being slowed if neuronal noradrenaline uptake was reduced, either by desipramine in normal subjects, or in patients with sympathetic nerve dysfunction (autonomic insufficiency). 3. In 10 of 41 hypertensive patients the t 1 1/2 similarly was prolonged, presumptive evidence of a defect in neuronal noradrenaline uptake. Endogenous noradrenaline escaping uptake after release, and spilling over into plasma, and plasma noradrenaline concentration, were increased in these patients. 4. Defective neuronal uptake of noradrenaline, by exposing adrenoreceptors to high local transmitter concentration, may be important in the pathogenesis of essential hypertension in some patients.

Adult↗
PubMed1980

Relationship between maximum chronotropic response to isoproterenol in man and generation of cyclic adenosine monophosphate by lymphocytes.

The maximum change in heart period caused by bolus doses of isoproterenol was measured in 10 normal subjects. This was linearly related to the amount of cyclic adenosine monophosphate generated from lymphocytes in the same subjects in vitro after incubation with isoproterenol. This high correlation between cardiac and lymphocyte beta-adrenoceptor stimulation suggests that maximum response does not depend on innervation. Other factors, such as cell membrane properties or levels of circulating catecholamines, may be of greater importance.

Adult↗
PubMed1980

Study of noradrenaline uptake and spillover to plasma in normal subjects and patients with essential hypertension.

Noradrenaline uptake was studied in normal subjects, and in patients with essential hypertension. Uptake of noradrenaline by blood platelets was low-affinity in type. Platelets do not provide a satisfactory in vitro model of neuronal noradrenaline uptake. Study of disappearance of tritiated noradrenaline from the circulation was more helpful. Plasma disappearance was biexponential. The rapid removal component was slowed if neuronal noradrenaline uptake was reduced, either by desipramine in normal subjects, or in patients with idiopathic peripheral autonomic insufficiency, who have sympathetic nerve dysfunction. The t1 1/2 similarly was prolonged in a proportion of patients with essential hypertension, providing presumptive evidence of a defect in neuronal noradrenaline uptake. Spillover of endogenous noradrenaline to plasma, of transmitter escaping uptake after release, and plasma noradrenaline concentration, were increased in these patients. Defective neuronal uptake of noradrenaline, by exposing adrenergic receptors to high local transmitter concentration, may be important in the pathogenesis of essential hypertension in some patients.

Biological Transport, Active↗