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Biomedical subjects

R Donnelly

Publications and source records attributed to R Donnelly.

At least 127 records · Page 7Linked to original sources
PubMed1989

The effect of gallium on seeded hydroxyapatite growth.

Gallium chloride in solution at concentrations of 10-100 microM inhibits the seeded growth of hydroxyapatite from metastable calcium phosphate solutions. Using initial rate data, an effective rate constant for the process of crystal growth can be derived; this rate constant varies with gallium concentration in a log-dose/response fashion. The disappearance of gallium occurs disproportionately fast in the early stages of the experiments. This suggests that gallium acts by adsorbing to the crystal surface where it inhibits crystal growth.

Adsorption↗
PubMed1989

Predictability of antihypertensive responsiveness and alpha-adrenoceptor antagonism during prazosin treatment.

This study investigates concentration-effect relationships in nine patients who had essential hypertension treated with prazosin. Antihypertensive responsiveness was determined for each individual patient in terms of millimeters of mercury of blood pressure reduction per nanogram per milliliter of plasma prazosin concentration. The principal findings were that there was significant attenuation of antihypertensive responsiveness, from 11.5 mm Hg per nanogram per milliter after the first dose to 8.7 mm Hg per ng/ml after 1 week of treatment with prazosin. Correspondingly, there was significant attenuation of the degree of alpha 1-antagonism as assessed by the pressor response to intravenous phenylephrine. However, there was no significant further attenuation of either assessment during continued treatment for up to 3 months. These findings suggest that after an early adaptation, which occurs within the first week of treatment, there is no long-term attenuation of the antihypertensive effect of prazosin. Despite this initial adaptive change, the magnitude of the long-term antihypertensive effect of prazosin was predictable from the first dose response in individual patients.

Adrenergic alpha-Antagonists↗
PubMed1989

Prediction of response to antihypertensive therapy with enalapril and nifedipine.

We evaluated the usefulness of an integrated concentration-effect modelling technique in predicting the long-term response to antihypertensive therapy with enalapril and nifedipine. Two groups of essential hypertensives were given monotherapy with 20 mg nifedipine twice a day (n = 14) or 20 mg enalapril once a day (n = 13), and were studied following the administration of the drugs and after at least 6 weeks' treatment. For both drugs the predicted responses (predose and 4 h postdose) were in close agreement with the observed responses. With enalapril the observed and predicted profiles over a 12-h study period were well correlated in all subjects. In contrast, with nifedipine, although there was generally good agreement, the model over-predicted the profile of response in one patient and under-predicted the profile in one patient. Thus, there is evidence that application of concentration-effect analysis is useful in predicting the steady-state antihypertensive effect from the first dose-response to the drug.

Blood Pressure↗
PubMed1989

Concentration-effect relationships and individual responses to doxazosin in essential hypertension.

1. This study investigates aspects of the pharmacokinetics, pharmacodynamics and concentration-effect relationships in 10 patients with essential hypertension during acute and chronic treatment with doxazosin, an alpha 1-adrenoceptor antagonist. 2. Following the first dose of doxazosin (2 mg) there were significant reductions in blood pressure, increases in heart rate and in plasma noradrenaline, and parallel rightward shifts of the phenylephrine pressor response curves, consistent with alpha-adrenoceptor antagonism. There was no significant change in the pressor response to angiotensin II. 3. Using an integrated kinetic-dynamic model, individual blood pressure responsiveness was characterised as the fall in blood pressure (mm Hg) per unit drug concentration. Responsiveness to the first dose of doxazosin was directly correlated with the responsiveness after 1 and 6 weeks treatment although there was a systemic reduction (of approximately 30%) which occurred during the first week of treatment. 4. Neither the acute nor long-term responsiveness to doxazosin was related to age, plasma renin activity, plasma noradrenaline or the pretreatment sensitivity to phenylephrine. There was a significant relationship between responsiveness and the height of the initial (pretreatment) blood pressure. 5. Integration of pharmacokinetic and pharmacodynamic data provides a reproducible index of responsiveness which can be used to investigate the consistency of the long-term anti-hypertensive response, to identify factors which influence the magnitude of the response, and to optimise the choice of dose and dose interval.

Aged↗
PubMed1989

Pharmacokinetic-pharmacodynamic relationships of alpha-adrenoceptor antagonists.

Competitive alpha1-adrenoceptor antagonists are effective in the treatment of both hypertension and cardiac failure. Prazosin has both a short half-life and a short duration of action, but other related quinazoline derivatives, such as doxazosin and terazosin, have pharmacokinetic and pharmacodynamic profiles which make them potentially suitable for once-daily administration. Acute reductions in blood pressure have been correlated with plasma concentrations of prazosin but in most instances, particularly during long term therapy, there is no simple, direct relationship between drug concentration and the fall in blood pressure. Using integrated pharmacokinetic-pharmacodynamic analysis, correlations have been described not only for reductions in blood pressure during short and long term treatment but also for alpha1-adrenoceptor antagonist activity. Furthermore, this integrated approach defines the drug concentration-effect relationship in individual subjects and provides a mathematical description of response that is potentially useful for investigating the factors (both kinetic and dynamic) which influence the inter- and intrasubject variability in antihypertensive effect of alpha-adrenergic blockers. Preliminary data suggest that the long term response to treatment with prazosin and doxazosin is mainly dependent upon the height of the pretreatment blood pressure and the response to the first dose.

Adrenergic alpha-Antagonists↗
PubMed1989

Pressor responsiveness in essential hypertension and the effects of treatment with an alpha blocker, calcium antagonist or ACE inhibitor.

We have studied the contribution of neurohumoral and structural factors to pressor responsiveness and peripheral resistance in mild/moderate hypertension. Pressor responses to intravenous infusions of phenylephrine (an alpha1 agonist) and angiotensin II were studied in groups of patients with essential hypertension before and after treatment, for 6 weeks with either nifedipine (20 mg bid), enalapril (20 mg daily) or doxazosin (2 mg daily). All drugs lowered blood pressure to a similar extent. Pressor responsiveness to both phenylephrine and angiotensin II showed wide intersubject variation when expressed as the dose of agonist required to raise mean arterial pressure by 20 mmHg (PD20). A group of age-matched normotensive controls showed a similar PD20 for phenylephrine to hypertensives. Angiotensin 11 sensitivity was greater in hypertensives. Drug treatment had different effects in hypertensive patients. Doxazosin, an alpha blocker, reduced the responsiveness to phenylephrine but had no effect on responses to angiotensin II. Nifedipine attenuated responses to both agonists while treatment with enalapril increased responsiveness to both phenylephrine and angiotensin II. We have not found evidence of systematic differences in alpha 1 receptor responses in hypertensives and different "vasodilator" drugs can lower blood pressure with widely different effects on adrenergic and non-adrenergic vascular responses.

Adrenergic alpha-Antagonists↗
PubMed1989

Clinical pharmacological evaluation of calcium antagonists and other drugs modifying myogenic tone in essential hypertension.

The factors determining the acute and long-term response to calcium antagonists have been studied in controlled trials in essential hypertension. The importance of dose and plasma level in determining the response has been confirmed. The blood pressure response has been modelled and mathematically described, with drug concentrations related to blood pressure falls by linear or Emax (maximum fall in blood pressure) models. The acute response predicted the response after 6 weeks of treatment. Neither age nor plasma renin activity independently influenced the response to calcium antagonists. The level of pretreatment blood pressure (starting blood pressure) was positively related to indices of response. In similar studies with other drugs modifying myogenic tone, while vascular reactivity to selective agonists was reduced, enhanced or unchanged, blood pressure falls were related to plasma levels in all cases.

Blood Pressure↗
PubMed1988

The effect of short-term treatment with vitamin D metabolites on bone lipid and mineral composition in healing vitamin D-deficient rats.

Vitamin D deficiency is known to cause alterations in the lipid and mineral components of bone and cartilage. In this study, second generation, normal phosphatemic, vitamin D-deficient rats, treated with low and high doses of three different vitamin D metabolites were sacrificed 24 h after treatment and their bones analyzed in order to determine which metabolites were most effective in altering the lipid composition. In the untreated vitamin D-deficient rats, tissues undergoing endochondral ossification (epimetaphyses), periosteal and endosteal bone formation (diaphyseal bone), and intramembranous bone formation (calvaria) all contained lower amounts of complexed acidic phospholipids, as well as decreased amounts of mineral. Twenty-four hours following treatment, the complexed acidic phospholipid content was significantly increased relative to both untreated and normal (vitamin D-replete) animals, the greatest increases occurring in animals treated with 1,25-dihydroxyvitamin D. All metabolites tested altered histomorphometric and/or mineral parameters, but only 1,25-dihydroxyvitamin D, in low and high doses, significantly increased the content of the complexed acidic phospholipids in all tissues studied. High doses of other metabolites increased complexed acidic phospholipid content in some tissues, perhaps due to their conversion to 1,25-dihydroxyvitamin D. Linear relationships between serum 1,25-dihydroxyvitamin D levels and tissue complexed acidic phospholipid content are reported. It is suggested that one way in which this metabolite may directly contribute to calcification is by facilitating formation of lipids involved in this process.

Animals↗
PubMed1988

Kinetic-dynamic relationships and antihypertensive mechanisms of ketanserin in essential hypertension.

This study of ketanserin illustrates the use of concentration-effect analysis in clinical investigations of antihypertensive mechanisms and the factors responsible for interindividual differences in blood pressure response. Using an integrated kinetic-dynamic model the acute and chronic responses to ketanserin were characterized for each individual patient in terms of blood pressure fall per unit drug concentration. Two principal findings were obtained from this approach. (1) There was a significant reduction in responsiveness to ketanserin during chronic treatment: on average, -0.47 after the first dose compared with -0.25 mmHg/ng per ml after 1 month. (2) There was a significant change in the parameter keq, which characterizes the temporal discrepancy between the time profiles for plasma drug concentration and effect: from a mean value of 0.49 (first dose) to 1.86/h (1 month). There was no significant relationship between the responsiveness to ketanserin and patient age, peripheral alpha 1-adrenoceptor blockade or initial blood pressure. These results suggest that there is a change in the relative contributions of the component antihypertensive mechanisms during continued treatment with ketanserin. Furthermore, there is no clear relationship between patient age and responsiveness to ketanserin.

Dose-Response Relationship, Drug↗
PubMed1988

Factors determining the response to calcium antagonists in hypertension.

Pharmacokinetic and pharmacodynamic variability account for the large interindividual differences in the antihypertensive response to treatment with a calcium antagonist. Using an integrated kinetic-dynamic model, the acute and chronic (4-6 weeks) responses to nifedipine (n = 14) and verapamil (n = 14) were characterized for individual hypertensive patients in terms of fall in blood pressure per unit drug concentration. The responsiveness to nifedipine, as the mean of the group, was -0.48 mm Hg/ng/ml following the first dose and -0.49 mm Hg/ng/ml after chronic dosing. The corresponding values for verapamil were -0.13 and -0.12 mm Hg/ng/ml, respectively. For nifedipine and verapamil, the responsiveness to the first dose was significantly correlated both with the height of the pretreatment blood pressure (p less than 0.001) and the responsiveness after 4-6 weeks of treatment (p less than 0.001). Parameters derived from an individual approach to concentration-effect analysis are useful for evaluating the determinants of response to calcium antagonists and form a potential basis for optimizing drug therapy in individual patients.

Adult↗
PubMed1988

Pharmacokinetics of calcium antagonists.

Calcium antagonists are a biochemically heterogeneous group of drugs that share the property of blocking the entry of calcium into cells by voltage-operated channels in cardiac and smooth muscle. They are useful in the management of angina pectoris and hypertension. The drugs available at present include nifedipine, verapamil, and diltiazem. All three drugs have similar pharmacokinetic properties of low and variable bioavailability, high first-pass metabolism, short elimination half-life, and active metabolites. The pharmacokinetics of calcium antagonists are relevant, because in individual patients the intensity and duration of the pharmacological effect is related to the level of drug in plasma. Amlodipine is a new dihydropyridine calcium antagonist in advanced clinical development. It has a completely different pharmacokinetic profile. It is water soluble and photostable, and has a long half-life of 35-50 h. Amlodipine is slowly absorbed, its absolute bioavailability is high, and it is extensively metabolized in the liver. The long half-life is associated with a prolonged (greater than 24 h) duration of pharmacodynamic action. Amlodipine, because of its novel pharmacokinetics, may offer practical advantages over existing calcium antagonists in the long-term treatment of cardiovascular disease.

Calcium Channel Blockers↗
PubMed1988

Ketanserin concentration-effect relationships in individual hypertensive patients.

1. This study further investigates the relationship between ketanserin concentration and the fall in BP in individual hypertensive patients. 2. An integrated kinetic-dynamic model was used to characterise the response to ketanserin for each individual in terms of BP reduction per unit drug concentration and to describe the temporal discrepancy for the plasma concentration-effect relationship (keq). 3. Using the linear effect model ketanserin concentrations were well correlated with the fall in BP in individual patients. There was a significant reduction in the responsiveness to ketanserin (m) after 1 month: -0.25 mm Hg ng-1 ml-1, compared with -0.47 following the 1st dose. 4. There was a significant increase in keq from 0.49 (1st dose) to 1.86 h-1 (1 month). 5. There was no relationship between the responsiveness to ketanserin and patient age, starting BP or peripheral alpha-adrenoceptor blockade.

Aging↗
PubMed1988

Cavitating pneumonia caused by Corynebacterium group JK.

Corynebacterium group JK organisms were isolated from lung fluid aspirated with a fine needle from one of four thick-walled cavitary lesions in a 72-year-old female. Cultures and stains for mycobacteria and fungi were negative. The patient was successfully treated with an 8-week course of vancomycin.

Aged↗
PubMed1988

Nifedipine: individual responses and concentration-effect relationships.

Dynamic and kinetic variability account for the large intersubject differences in the antihypertensive response to nifedipine, and a clear concentration-effect relationship has not been established. The effects of placebo, first dose, and chronic (1 and 6 weeks) treatment with nifedipine were studied in 14 subjects with essential hypertension using an integrated kinetic-dynamic model to calculate individual subject responsiveness in terms of fall in blood pressure per unit change in drug concentration. Nifedipine concentrations were well correlated with the fall in systolic blood pressure in individual subjects, and the mean responsiveness was -0.48 mm Hg/ng/ml after the first dose, -0.45 mm Hg/ng/ml after 1 week, and -0.49 mm Hg/ng/ml after 6 weeks. The responsiveness to the first dose of nifedipine was significantly correlated with the responsiveness after 1 (r = 0.83) and 6 weeks (r = 0.78) of therapy and with the height of the pretreatment blood pressure (r = 0.6). This study incorporated kinetic as well as dynamic information to characterize the antihypertensive response to nifedipine and identify nifedipine concentration-effect relationships in individual hypertensive subjects.

Adult↗
PubMed1988

Effects of ketanserin on peripheral vascular pressor mechanisms in essential hypertension.

The principal aim of this study was to investigate the effects of ketanserin on peripheral vascular pressor mechanisms in nine patients with essential hypertension, including an assessment of the responsiveness to intravenous infusions of the alpha 1-adrenergic agonist, phenylephrine, and the nonadrenergic vasoconstrictor, angiotensin II. There were small but significant rightward shifts in the phenylephrine pressor dose-response curves (by 1.5- to twofold) following ketanserin but no shifts for angiotensin II. This modest shift in phenylephrine responsiveness contrasted with the fivefold shift obtained with a single oral dose (1 mg) of prazosin. The relationship between the phenylephrine-induced increase in blood pressure and the reduction in heart rate was used as an index of baroreflex responsiveness: there were no significant effects attributable to ketanserin. There were no significant differences in plasma aldosterone or renin activity, nor in 24-h urinary volume or electrolytes, following ketanserin. The principal mechanism underlying the antihypertensive effect of ketanserin is unlikely to involve peripheral vascular alpha 1-adrenoceptor antagonism, altered baroreflex responsiveness, or perturbation of the renin-angiotensin-aldosterone system.

Aldosterone↗