Biomedical subjects

D M Hughes

Publications and source records attributed to D M Hughes.

At least 19 recordsLinked to original sources

PubMed1992

The effect of saturation of ACE binding sites on the pharmacokinetics of enalaprilat in man.

1. Eight healthy male volunteers received oral enalapril, 10 mg, in the presence and absence of pretreatment with captopril, 50 mg, twice daily for 5 days. 2. Enalaprilat pharmacokinetics were characterised after both doses of enalapril to investigate the effect of saturating ACE binding sites by pretreatment with captopril. 3. The pharmacokinetics of enalaprilat were best described by a one compartment model with zero order input incorporating saturable binding to plasma and tissue ACE. 4. Values of AUC (0.72 h) for enalaprilat were 419 +/- 97 and 450 +/- 87 ng ml-1 h in the presence and absence of captopril, respectively. The difference was not statistically significant nor were there any other differences in model parameters. 5. Induction of ACE by captopril resulting in an increase in the number of ACE binding sites, may have obscured any effect of captopril on the occupancy of ACE binding sites by enalapril.

Adult↗

PubMed1991

Controlled trial of a home and ambulatory program for asthmatic children.

Care of asthmatic children is often episodic and more therapeutic than preventive. A 2-year randomized, controlled trial involving 95 children measured the impact of a comprehensive home and ambulatory program for pediatric asthma management using objective outcome measures. Interventions for the study group during the first year included 3-month clinic visits, education, and home visits by a specially trained research nurse. Control subjects continued to receive regular care from a family physician or pediatrician. Eight-nine subjects (93%) completed the study. Study subjects had less school absenteeism than control subjects (10.7 vs. 16.0 days, P = .04) and showed significantly better small airway function after 1 year. Asthma severity improved in 13 study subjects and worsened in 5. The reverse was true for control subjects. Study subjects exhibited better metered aerosol technique than control subjects (P = .0005). Fewer days were spent in hospital by the study subjects admitted compared with control subjects (3.67 vs 11.2 days, P = .02). After 1 year, more study than control families (72.1% vs 33.1%, P = .006) reported that their asthmatic child took responsibility for the asthma management. The intervention failed to reduce exposure to secondhand smoke or to household pets. There were no significant differences in medical visits, theophylline levels, or records of asthma symptoms. One year after discontinuing the intervention, a marked "washout" effect was observed. Comprehensive ambulatory programs of childhood asthma management can improve objective measures of illness severity but must be sustained.

Adolescent↗

PubMed1990

Pharmacodynamic, pharmacokinetic and humoral effects of oral zabicipril, an angiotensin converting enzyme inhibitor in normotensive man.

1. Zabicipril, S9650, a new angiotensin converting enzyme inhibitor, was administered to salt-replete, normotensive males in single doses of up to 10 mg. 2. The safety, tolerance and dose-response relationship with regard to inhibition of plasma ACE activity were characterised initially in an open, pilot, dose-finding study in 12 subjects and further explored in a double-blind, parallel group, placebo controlled study in another 30 subjects. 3. The drug was generally well tolerated and produced no change in routine haematology or serum biochemistry tests. 4. Dose related (0.03 to 10 mg) inhibition of plasma converting-enzyme was observed, with 2.5 mg of zabicipril producing over 90% inhibition at 4 h and 60% at 24 h. 5. There were no significant changes in blood pressure or heart rate in normotensive subjects over the dose range studied. 6. A dose related rise in plasma renin activity and angiotensin I was observed. No dose related reduction in plasma aldosterone was observed. 7. These initial studies suggest that zabicipril is a well tolerated inhibitor of converting enzyme with near maximal inhibitory effect occurring at a dose of 2.5 mg. Further exploration of the dose range after single and multiple doses is indicated.

Adult↗

PubMed1989

Pharmacokinetics of perindopril: therapeutic consequences.

Perindopril has been studied in groups of normal young and elderly subjects, in patients with hepatic cirrhosis and in hypertensive patients. Plasma concentrations of perindoprilat are increased and renal clearance reduced in elderly subjects, resulting in an increase in the acute pharmacodynamic effect of perindopril. Compensated hepatic cirrhosis does not have any independent effect on the pharmacokinetics of perindopril. After intravenous administration, perindoprilat concentrations show multiexponential decay with a terminal half life of over 30 hours associated with sustained inhibition of ACE. During repeated dosing there is little accumulation of drug, and no evidence of increased haemodynamic effect after chronic treatment in hypertensives. The therapeutic consequences of these findings are: binding of perindoprilat to ACE prolongs the haemodynamic effect, giving the option of once daily administration; despite the long terminal elimination half life of the drug, significant accumulation is not a problem during chronic treatment; increased plasma concentrations of active metabolite in the elderly and reduced renal elimination may require reduced doses to be used; further dose adjustment in compensated hepatic cirrhosis is not routinely necessary.

Adolescent↗

PubMed1989

Pharmacokinetics of perindopril: therapeutic consequences.

Perindopril has been studied in groups of normal young and elderly subjects, in patients with hepatic cirrhosis and in hypertensive patients. Plasma concentrations of perindoprilat are increased and renal clearance reduced in elderly subjects, resulting in an increase in the acute pharmacodynamic effect of perindopril. Compensated hepatic cirrhosis does not have any independent effect on the pharmacokinetics of perindopril. After intravenous administration, perindoprilat concentrations show multiexponential decay with a terminal half-life of over 30 hours, associated with sustained inhibition of ACE. During repeated dosing, there is little accumulation of the drug and no evidence of increased hemodynamic effect after chronic treatment in hypertensives. The therapeutic consequences of these findings are: (1) Binding of perindoprilat to ACE prolongs the hemodynamic effect, giving the option of once daily administration. (2) Despite the long terminal elimination half-life of the drug, significant accumulation is not a problem during chronic treatment. (3) Increased plasma concentrations of active metabolite in the elderly and reduced renal elimination may require reduced doses to be used. (4) Further dose adjustment in compensated hepatic cirrhosis is not routinely necessary.

Adult↗

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

Shape of forced expiratory flow-volume curves in infants.

An inflatable cuff was used to generate partial forced expiratory flow-volume (FEFV) curves in 36 infants with and without obstructive airway disease. Curves were recorded in each infant over a range of compression pressures as high as and exceeding the pressure required for the maximal partial FEFV curve. The maximal curves were quantitated and compared with passive compliance and conductance of the respiratory system and absolute lung volume measured by whole-body plethysmography. In some infants, the transmission of pressure between cuff and pleural space was determined. Partial FEFV curve shapes generated with a standardized compression pressure calculated from the transmission of pressure data to give an increase in pleural pressure at FRC of 10 cm H2O were compared between infants. For these standardized compressions, infants with convex curves tended to have better respiratory function than did those with concave curves. The combination of a concave curve and flow limitation during tidal expiration was associated with the worst function. Two parameters, the ratio of forced maximal expiratory flow (measured from the maximal partial FEFV curve) to tidal expiratory flow (measured from the expiratory flow-volume curve of tidal breathing) at midtidal volume (Vm1d(forced/tidal] and the minimal compression pressure required to generate maximal expiratory flow at FRC (Pmin), satisfactorily quantified respiratory function without the need for size correction with absolute lung volume. In addition, Vm1d(forced/tidal) provides an index of expiratory flow reserve. We conclude that useful information can be provided from the shape of a partial FEFV curve in an infant, provided that curves are generated by a standardized compression pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchiolitis↗

PubMed1987

Lung function after pertussis.

The relationship between pertussis infection and subsequent abnormalities of pulmonary function is not clear. Thirty subjects (16 male, 14 female) aged 14.3 years (s.e.m. = 1.9) were studied who had been hospitalized with culture-proven pertussis when less than 6 months of age. Details of respiratory symptoms in the subjects and their families were obtained. Standard spirometry, lung volumes by body plethysmography, maximum flows at low lung volumes and histamine challenges were performed. Nine of 30 (30%) subjects were symptomatic with a history of recurrent cough and wheeze while 11 of 30 (37%) had abnormal pulmonary function tests. Seven of nine symptomatic subjects had abnormal pulmonary function including positive histamine challenges. Twenty-one per cent had a family history of asthma. This study indicates that children hospitalized in infancy with pertussis can subsequently be shown to have recurrent lower airways symptomatology and abnormal pulmonary function, but the incidence is not significantly higher than a control group from the same socio-economic background.

Adolescent↗

PubMed1987

Transpulmonary angiotensin II formation in patients with chronic stable cor pulmonale.

The activity of the renin-angiotensin (RA) system and the ability of the lungs to generate angiotensin II (AII) were studied in 11 patients with stable cor pulmonale and respiratory failure caused by chronic obstructive bronchitis and emphysema. Angiotensin I concentrations (18.7 +/- 8.3 pmol/L) were normal, and transpulmonary AII formation rates (TRAIIFR) (14.2 +/- 18.1 pmol/min) were not significantly different from those recorded in nonedematous cardiac subjects (19.9 +/- 20.1 pmol/min), matched for sex, age, and diuretic therapy. The main determinant of TPAIIFR was the mixed venous AI concentration. Administration of oxygen for 30 min led to a small increase in TPAIIFR in the majority of patients. This increase could not be accounted for by changes in mixed venous AI. There was no correlation between serum angiotensin-converting enzyme levels and either the TPAIIFR or the systemic arterial AII concentrations.

Aged↗

PubMed1987

Effect of salbutamol on respiratory mechanics in bronchiolitis.

The effect of inhaled bronchodilators in bronchiolitis has been difficult to evaluate due to problems with techniques for assessing respiratory function in infants. Two new techniques were used to assess the response to inhaled salbutamol in 17 infants with bronchiolitis. With one technique, expiratory flow, volume, and airway occlusion pressure were measured and used to derive compliance (Crs) and conductance (Grs) of the respiratory system from a passive expiration induced by a brief end-inspiratory airway occlusion. With the other technique, the maximum flow at functional residual capacity (VmaxFRC) was measured from a partial maximum expiratory flow-volume curve generated by external chest compression. For the group, there was no change in compliance or conductance after salbutamol, but salbutamol caused a fall in maximum flow at functional residual capacity (p less than 0.01) and in the time constant of tidal expiration (p less than 0.01). The decrease in maximum flow at functional residual capacity with salbutamol is consistent with increased airway collapse on forced expiration. The decrease in tidal time constant suggests that the drug decreases expiratory braking. Presence of such braking activity may be an important strategy for maintaining lung volume. In summary, salbutamol failed to produce a beneficial effect on airways in bronchiolitis, but did produce changes in expiration which may be harmful in some infants.

Administration, Inhalation↗

PubMed1986

Effect of compression pressure on forced expiratory flow in infants.

The effect of the force of compression on expiratory flow was evaluated in 19 infants (2-13 mo of age) with respiratory illnesses of varying severity. An inflatable cuff was used to compress the chest and abdomen. Expiratory flow and volume, airway occlusion pressure, cuff pressure (Pc), and functional residual capacity were measured. Transmission of pressure from cuff to pleural space was assessed by a noninvasive occlusion technique. Close correlations (P less than 0.001) were found between Pc and the change in pleural pressure with cuff inflation (delta Ppl,c). Pressure transmission was found to vary between two cuffs of different design and between infants. Several forced expirations were then performed on each infant at various levels of delta Ppl,c. Infants with low maximal expiratory flows at low lung volumes required relatively gentle compression to achieve flow limitation and showed decreased flow for firmer compressions. Flow-volume curves in each infant tended to become more concave as delta Ppl,c increased. These findings underline the importance of knowledge of delta Ppl,c in interpreting expiratory flow-volume curves in infants.

Aging↗

PubMed1985

The effect of cimetidine on the pharmacokinetics, pharmacodynamics and alpha 1-adrenoceptor responsiveness of trimazosin in man.

The effect of cimetidine treatment on the pharmacokinetics and pharmacodynamics of single doses of trimazosin was studied in 6 normotensive volunteers. Co-administration of cimetidine did not significantly affect the overall magnitude of the hypotensive effect of trimazosin. However, the time profile of the blood pressure response was significantly modified particularly with attenuation of the delayed component. Co-administration of cimetidine did not alter alpha 1-adrenoceptor antagonism by trimazosin. There was no significant change in the clearance and volume of distribution of trimazosin but there was a significant reduction in the area under the concentration-time curve for the metabolite, 1-hydroxy-trimazosin. The reduction in the AUC of 1-hydroxy-trimazosin corresponds in time with the attenuation of the delayed hypotensive response. This is consistent with the suggestion that the delayed hypotensive response is related to an active metabolite, probably 1-hydroxytrimazosin.

Adult↗

PubMed1985

Antisecretory effect and oral pharmacokinetics of omeprazole in patients with chronic renal failure.

The inhibitory effect of omeprazole on gastric acid secretion was tested in a group of patients on haemodialysis for chronic renal failure. Single 30 mg doses almost totally inhibited basal acid output on both dialysis and non-dialysis days. Plateau acid output was reduced by a mean of 77% and 90% on non-dialysis and dialysis days respectively. The absorption and pharmacokinetic profile of omeprazole were not affected by dialysis. Omeprazole was not recoverable from dialysis fluid. It is concluded that omeprazole is a potent inhibitor of gastric acid secretion in patients with chronic renal failure, and its effect is not influenced by haemodialysis.

Adult↗

PubMed1973