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Biomedical subjects

R Donnelly

Publications and source records attributed to R Donnelly.

At least 109 records · Page 6Linked to original sources
PubMed1993

The effect of gallium nitrate on healing of vitamin D- and phosphate-deficient rickets in the immature rat.

The effect of gallium on rapid in vivo mineralization was studied in a rachitic rat model in which rickets were induced in immature rats then reversed ("healed") with repletion of vitamin D and phosphate. Gallium was administered to selected groups of animals before and during the healing phase. In nonrachitic animals and rachitic animals before healing, the mineral content of diaphyseal and metaphyseal bone was increased, and the crystal size was decreased in those animals that received gallium compared with those that did not. Mineralization of the undermineralized osteoid appeared histologically normal by 72 hours in all animals. However, animals that received gallium both before and during the healing phase had less well-mineralized bones at 18 hours, and by 72 hours, they had lesser increases in osteocalcin and mineral content, which was associated with smaller crystal sizes, than did any animal that did not receive gallium at any time. Prior to the healing phase, the ratio of gallium to hydroxyproline in the metaphyses of rachitic animals was similar to that in nonrachitic animals. Likewise, this ratio did not change in the animals receiving gallium both before and during the healing phase. The ratio of gallium to calcium was higher in rachitic animals compared with controls, and this ratio lowered significantly by the end of the healing phase. Results may be explained in part by direct effect of gallium on the physical process of mineral formation during the rapid healing phase as well as by effects of gallium on osteoblasts and osteoclasts during the induction of rickets.

Alkaline Phosphatase↗
PubMed1993

Metabolic effects of lacidipine: a placebo-controlled study using the euglycaemic hyperinsulinaemic clamp.

1. Twelve healthy male volunteers received lacidipine 4 mg and matching placebo, each for 2 weeks, in a randomised, double-blind crossover study, and attended on 4 study days to evaluate the effects of single and multiple dosing using the euglycaemic hyperinsulinaemic 'clamp'. 2. On each study day, a primed constant-rate infusion of soluble insulin (1.5 mu kg-1 min-1) was administered for 180 min with a variable-rate infusion of 20% dextrose to maintain euglycaemia (5.2 mmol l-1). Whole-body insulin sensitivity was calculated during the past 40 min of the 'clamp'. At frequent intervals, measurements of BP and HR were recorded and venous blood samples collected for serum insulin, C-peptide, potassium, triglyceride (TG) and plasma noradrenaline concentrations. 3. Lacidipine was generally well tolerated and there were no adverse biochemical events. Mean values for insulin sensitivity +/- s.d. were 8.9 +/- 1.6 and 9.1 +/- 2.0 mg kg-1 min-1 after single doses of lacidipine and placebo respectively (95% CI, -1.0, 1.3), and correspondingly 9.6 +/- 2.1 and 9.7 +/- 1.5 mg kg-1 min-1 after 2 weeks (95% CI, -1.0, 1.3). 4. There was a significant reduction in fasting serum TG concentrations after 2 weeks of lacidipine: 0.7 +/- 0.3 mmol l-1 vs 0.9 +/- 0.6 (P < 0.001). However, changes in serum TG and potassium concentrations during the 'clamp' were not significantly different between the 4 study days. 5. Thus, in 'insulin sensitive' volunteers, lacidipine reduces fasting serum TG concentrations but has no effect on insulin-stimulated uptake of glucose, potassium and TG under euglycaemic hyperinsulinaemic conditions.

Adolescent↗
PubMed1992

Antihypertensive drugs: individualized analysis and clinical relevance of kinetic-dynamic relationships.

Individualized approaches to antihypertensive therapy are being widely advocated. Ideally these should incorporate rational prospective methods for drug and dosage selection but progress has been hampered by the paucity of information about dose- (and plasma concentration-) response relationships. However, in several recent clinical studies, concentration-effect analysis has been used to characterize kinetic-dynamic relationships in individual patients for a range of antihypertensive drugs. This approach provides an integrated mathematical description of drug response which has potential utility for quickly identifying poor or nonresponders and for determining individual dose requirements for optimum longterm blood pressure control.

Antihypertensive Agents↗
PubMed1992

Angiotensin-converting enzyme inhibitors and insulin sensitivity: metabolic effects in hypertension, diabetes, and heart failure.

Angiotensin-converting enzyme (ACE) inhibitors are established in the treatment of hypertension and heart failure; both conditions are complicated by resistance to insulin-mediated glucose disposal. The defect in essential hypertension is both tissue and pathway specific, i.e., confined to nonoxidative (glycogen synthetic) routes of intracellular glucose utilization in skeletal muscle, whereas heart failure and non-insulin-dependent diabetes mellitus (NIDDM) are associated with more widespread abnormalities of carbohydrate and lipid metabolism. Thus, the mechanisms of the insulin resistance in hypertension, NIDDM, and heart failure are fundamentally different, so metabolic responses to drug therapy may not be the same in all insulin-resistant states. There have been conflicting reports about the effects of ACE inhibitors on insulin sensitivity and glycemic control. A number of studies, both with captopril and with enalapril, have shown small increases in insulin sensitivity, and there is evidence that this is due to enhanced glucose uptake into skeletal muscle. The interpretation of these studies, however, is often compromised by poor trial design, lack of full placebo data, various indirect measurements of insulin sensitivity, and heterogeneous patient populations in whom the biochemical mechanisms of insulin resistance (and drug responses) may not be the same. Overall, there probably is a modest class effect of ACE inhibitors that enhances insulin-mediated glucose disposal; the mechanism of this effect is likely to be a combination of increased muscle blood flow, local renin-angiotensin system blockade, and elevated kinin levels.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Combination of nifedipine and doxazosin in essential hypertension.

Pharmacodynamic and pharmacokinetic interactions have been reported when an alpha 1-antagonist is combined with a calcium antagonist. We evaluated the clinical usefulness of the combination of nifedipine (20 mg twice daily, b.i.d.) and doxazosin (2 mg once daily, o.d.) in hypertensive patients in whom blood pressure (BP) control was suboptimal after doxazosin (group A) or nifedipine (group B) as monotherapy and investigated the underlying kinetic and dynamic interactions, including changes in vascular responsiveness to i.v. infusions of angiotensin II (ANGII) and phenylephrine (PE). The combination was well tolerated and associated with further significant reductions in BP. After 4 weeks of combined therapy, average supine BP over 8 h was 122/77 in group A and 137/80 in group B as compared with 140/86 and 150/88 mm Hg, respectively, during monotherapy + placebo. The combination attenuated both phenylephrine and ANG-induced pressor responses: e.g., the mean PD15 values (dose of agonist required to increase systolic BP by 15 mm Hg) for group A at 1.5-3 h were 3.5 micrograms/kg/min for PE and 7.5 ng/kg/min for ANGII as compared with 2.9 and 2.3, respectively, during treatment with doxazosin and placebo. There was no evidence of a significant kinetic interaction between the two drugs and, in particular, addition of nifedipine had no effect on the steady-state kinetics of doxazosin. In conclusion, doxazosin and nifedipine are an effective antihypertensive combination in patients who require treatment with more than one drug.

Aged↗
PubMed1991

Bone particles from gallium-treated rats are resistant to resorption in vivo.

Gallium nitrate is a clinically effective agent for the treatment of cancer related hypercalcemia. The mechanism of action of this agent was investigated following development of a quantitative in vivo bone resorption assay modified from the method of Glowacki. In a preliminary study, the time course of resorption of 50 mg subcutaneous implants of bone powder in growing rats was followed by chemical analysis of mineral (ash and Ca) contents, enzymatic and histochemical assay of tartrate resistant acid phosphatase (TRAP) activity, and image analysis of changes in particle size using von Kossa stained sections. Day 21 was chosen as a single time point for the comparison of the extent of resorption of gallium-containing and control bone particles. Resorption of bone particles containing 0.39 micrograms Ga/mg bone was significantly inhibited relative to control particles. Mineral content (6.7 vs. 3.6 mg), Ca content (1.72 vs. 1.37 mg), and the percentage of the field covered by bone particles (12 vs. 9%) were greater in the animals which received gallium-containing bone particles. Similarly, the number of osteoclast-like cells and the TRAP activity in the gallium-containing bone particle implants at 21 days were increased relative to controls. These data indicate that gallium incorporation into bone matrix confers resistance to resorption.

Acid Phosphatase↗
PubMed1991

Polymerase chain reaction analysis of defective human T-cell leukemia virus type I proviral genomes in leukemic cells of patients with adult T-cell leukemia.

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia, and the clonally derived leukemic cells all contain proviral genomes. Polymerase chain reaction with a variety of primers which span the HTLV-I genome was used to determine that a significant fraction of patients (at least 32%) carry deleted viral genomes in their leukemic cells. The pX region of the HTLV-I genome encoding the regulatory genes tax and rex was preferentially retained. The fact that the tax coding region was retained provides supporting evidence that the tax protein contributes to leukemogenesis in vivo. The reasonably high fraction of patients with adult T-cell leukemia carrying deleted genomes in their tumor cells suggests that the deletions have a role in leukemogenesis.

Adult↗
PubMed1991

Clinical pharmacokinetics and kinetic-dynamic relationships of dilevalol and labetalol.

Dilevalol and labetalol are examples of a growing number of new beta-blockers which combine nonselective beta-adrenoceptor antagonism with vasodilator activity. Dilevalol is one of the 4 stereoisomers of labetalol, and is estimated to form approximately 25% of the racemic drug. Labetalol itself is an alpha 1-antagonist but dilevalol, which has negligible affinity for alpha-receptors, exerts its vasodilator effect via beta 2-agonism. Both drugs are rapidly and completely absorbed in 60 to 90 min and subject to extensive first-pass hepatic metabolism; the average bioavailability after oral administration is around 20 to 35%, and there is wide interindividual variability in plasma drug concentrations and dosage requirements. The volume of distribution of dilevalol (17 to 25 L/kg) is higher than that reported for labetalol (3 to 16 L/kg), although both drugs are concentrated in the extravascular compartment. Correspondingly, the elimination half-life of dilevalol at steady-state is around 15h compared with 8h for labetalol. There is evidence that the pharmacokinetics of dilevalol change (a reduction in clearance) in translation from single-dose to long term therapy. There is no clinically significant effect of age on the steady-state disposition of either drug and the pharmacokinetics of labetalol appear to be unchanged during pregnancy. Although there is a linear relationship between dose and area under the concentration-time curve, early studies found no evidence of a simple relationship between dose or plasma drug concentration and the fall in blood pressure. However, an integrated pharmacokinetic-pharmacodynamic model has been used to correlate concentrations of both drugs with reductions in systolic and diastolic blood pressure in individuals. This approach derives a mathematical description of antihypertensive response which integrates pharmacokinetic and pharmacodynamic information and also takes account of placebo effects and changes in drug concentration and blood pressure during the dosage interval. The pharmacokinetic-pharmacodynamic relationships of labetalol are characterised by a linear model. For example, in a group of healthy volunteers, the 'responsiveness' to labetalol was -0.19mm Hg/micrograms/L. In contrast, the relationships of dilevalol are best described by a Langmuir maximum effect model, and so individual responses to short and long term treatment have been quantified by the concentration-effect parameters of maximum effect and drug concentration required to produce 50% of this.(ABSTRACT TRUNCATED AT 400 WORDS)

Dose-Response Relationship, Drug↗
PubMed1990

Factors influencing the responses to calcium antagonists in elderly patients with hypertension and ischaemic heart disease.

The results of a variety of studies that have investigated the effect of age on the pharmacokinetics and pharmacodynamics of calcium antagonist drugs have produced the following conclusions. Primarily, as a result of an age-dependent decline in plasma drug clearance, there is a tendency for elderly patients to have higher plasma drug concentrations than young patients. In terms of pharmacological response, there is good evidence of therapeutic efficacy in both hypertension and ischaemic heart disease, but there is no convincing evidence of any preferential age-related effect, particularly in relation to blood pressure reduction. Similarly and conversely, there is no convincing evidence that the elderly are at greater risk from the adverse effects of calcium antagonist drugs, particularly those which reflect the negative effects on cardiac conduction. An integrated mathematical method for describing antihypertensive response, which incorporates both pharmacokinetic and pharmacodynamic information, has been used to investigate the variability in antihypertensive effect with nifedipine and verapamil. There was no relationship between responsiveness (in mmHg/ng/mL) and patient age and plasma renin activity; however, responsiveness during chronic treatment was directly correlated with the height of the starting blood pressure and the response to the first dose.

Age Factors↗
PubMed1990

Prediction of the antihypertensive response to enalapril.

This study investigates the potential utility of a drug concentration-effect modelling approach to predict the long-term response to antihypertensive treatment with enalapril. Concentration-effect relationships were characterized in 13 subjects following a single dose of enalapril (20 mg) and for each individual the derived parameters were used to predict the steady-state blood pressure profile. The predicted responses (before dosing and 4 h after dosing) were in close agreement with the responses observed after 6 weeks. In individual patients, the observed and predicted blood pressure profiles over a 12 h period were compared. In six of the 13 subjects, there were statistically significant (P less than 0.05) prediction errors. However, in all but one of these patients the error was less than 10%, and for the group as a whole the mean prediction error was small and not statistically significant (-0.6 +/- 2.1 mmHg). The kinetic-dynamic parameters derived from observations of the first dose were used to simulate steady-state responses to several alternative doses and dose frequencies. A regimen of 10 mg twice daily increased the ratio of blood pressure at trough-to-peak response to 75 +/- 5% compared to 33 +/- 16% when 20 mg was given once daily. In addition, a twice-daily regimen reduced the coefficient of variation of the hourly average blood pressure. Thus, concentration-effect parameters derived from the first dose response to enalapril have potential not only for predicting long-term antihypertensive response, but also for optimizing dosage regimens for individual patients.

Blood Pressure↗
PubMed1990

Vascular pressor responses in treated and untreated essential hypertension.

Thirty-seven essential hypertensives received placebo for 3 weeks followed by nifedipine retard (n = 14) or enalapril (n = 13) or doxazosin (n = 10) as monotherapy for 6 weeks and attended study days to evaluate the effects of placebo, first dose, and chronic (1-6 weeks) treatment. On each study day, pressor responses to i.v. infusions of phenylephrine (PE) and angiotensin II (AII) were measured 1.5-3 h after drug administration and the derived PD20 values (dose required to increase mean blood pressure by 20 mm Hg) compared. Each treatment produced comparable reductions in BP. Nifedipine significantly attenuated the pressor responses to AII and PE: for AII, the mean PD20 (ng/kg/min) increased from 8.2 (placebo) to 9.9 (first dose), 13.9 (1 week), and 17.4 (6 weeks). Pressor responsiveness to both AII and PE was unchanged following enalapril: for PE, the mean PD20 (micrograms/kg/min) was 2.1 (placebo), 1.5 (first dose), and 1.5 (6 weeks). Doxazosin produced rightward shifts of the PE pressor dose-response curves but had no effect on responses to AII. The relationship between the simultaneous BP and HR changes during the infusion of PE was used as an index of cardiac baroreflex activity. In contrast to enalapril and doxazosin, which had no effect, nifedipine reduced the slope of the HR/BP relationship from -0.62 (placebo) to -0.38 (first dose) and -0.31 beats/min/mm Hg (6 weeks). For comparable reductions in BP, doxazosin only affects adrenergic mechanisms whereas nifedipine affects both adrenergic and non-adrenergically mediated vasoconstriction. The ACE inhibitor enalapril had no effect on pressor responses to AII and PE.

Adult↗
PubMed1990

Clinical studies with the potassium channel activator cromakalim in normotensive and hypertensive subjects.

Eight normotensive subjects received single and multiple doses of cromakalim (1 mg) and placebo in a randomised double-blind cross-over study to examine general tolerance to cromakalim and its effects on blood pressure (BP), heart rate (HR), and pressor responses to norepinephrine (NE) and angiotensin II (AII). In a second study, 10 hypertensive patients whose BP control was unsatisfactory with atenolol 50-100 mg received additional treatment with placebo followed by cromakalim 1 mg daily for 4 weeks. Assessments were made of BP, HR, apparent hepatic blood flow and renal blood flow (RBF), pulmonary function, and the pharmacokinetics of atenolol. Cromakalim was generally well tolerated in both normotensive and hypertensive subjects. In the normotensive group, cromakalim produced a reflex increase in HR without any detectable decrease in BP: average (placebo-subtracted) increases in HR at 4 h were 16 beats/min with subjects in an erect position after the single dose and 14 beats/min after 7 days. Cromakalim had no effect on pressor responses to NE and AII. Addition of cromakalim to atenolol was associated with modest further reductions in BP between 0.5 and 3 h after drug administration, with maximal reductions of 21/14 mm Hg (subjects in supine position) 2 h after the first dose. Cromakalim had no effect on apparent liver blood flow and RBF, pulmonary function, and the steady-state pharmacokinetics of atenolol. Single and multiple 1-mg doses of cromakalim are well tolerated but are associated with only modest vasodilator activity.

Adult↗
PubMed1990

Kinetic-dynamic relations and individual responses to enalapril.

Pharmacokinetic and pharmacodynamic variability largely account for interindividual differences in the response to antihypertensive drugs including angiotensin converting enzyme inhibitors. The factors determining the response to enalapril have been investigated in a placebo-controlled study in essential hypertension. The effects of placebo, the initial dose of enalapril, and long-term (1 and 6 weeks) treatment with enalapril were studied in 13 subjects. By using an integrated kinetic-dynamic model that incorporates a parameter for saturable protein binding, individual responses for blood pressure reduction and angiotensin converting enzyme inhibition were characterized in terms of the maximum effect (Emax) and the drug concentration required to produce 50% of Emax (Ce50). In individual subjects, plasma enalaprilat concentrations could be correlated with falls in blood pressure and changes in plasma angiotensin converting enzyme activity. For the group, Emax was -46.1 +/- 16.5 and -19.7 +/- 3.8 mm Hg for systolic and diastolic blood pressure, respectively, and the corresponding Ce50 values were 66.1 +/- 20.2 and 61.6 +/- 22.5 ng/ml. For angiotensin converting enzyme inhibition, Emax (%) and Ce50 (ng/ml) were, respectively, 102.4 +/- 5 and 19.8 +/- 13 after the first dose, 103 +/- 5 and 33.4 +/- 20.3 after 1 week, and 101.3 +/- 2.2 and 31.3 +/- 18.9 after 6 weeks. There was no relation between the responsiveness to enalapril (Emax or Ce50) and patient age or plasma renin activity, but there was a significant positive correlation between Emax and the pretreatment blood pressure. In individual subjects, Emax (first dose) was directly correlated with Emax after 1 and 6 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Factors determining the response to angiotensin-converting enzyme inhibitors in hypertension.

Converting enzyme inhibitors, alone or in combination, are a safe and effective treatment for many hypertensives. However, the range of responses varies between individual patients and it has been claimed that there are two or three phases to the response. Pretreatment plasma renin (as an indication of activation of the renin angiotensin system) and the patient's age have been claimed to predict blood pressure fall. We have investigated whether these factors are useful indications of clinical response in mild-moderate essential hypertension. We have also investigated how well the response to the first dose correlates with the response to long-term (6 weeks) treatment. In a placebo-controlled trial of enalapril (20 mg daily), the blood pressure fall was analysed using an integrated pharmacokinetic/dynamic model of the concentration-effect relationship. The relation between the active drug concentration and blood pressure fall was best described by a non-linear Langmuir (Emax) model: E = (Emax C/C50 + C), where E is the effect, C the drug concentration, Emax is the maximum blood pressure fall and C50 is the drug concentration which causes a fall in blood pressure of 50% of the maximum. For a group of 13 essential hypertensives Emax was 46/20 mm Hg and C50 77 +/- 17 ng/ml. Emax was not related to age or pretreatment renin, but was positively correlated with pretreatment blood pressure (r = 0.69; p less than 0.01). Emax after 6 weeks of treatment (48 +/- 22 and 50 +/- 20 mm Hg, respectively, r = 0.89; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗