PubMed Health⌕ Search

Biomedical subjects

L M Wing

Publications and source records attributed to L M Wing.

At least 55 records · Page 3Linked to original sources
PubMed1987

Cross-over factorial studies with antihypertensive drugs.

In patients with uncomplicated mild to moderate hypertension, studies employing a double-blind randomized cross-over factorial design have been used to obtain more precise estimates of the hypotensive and biochemical effects of individual antihypertensive drugs and of their interactions when used in combination. Order and carry-over effects have been controlled. In studies with beta-blockers and diuretics, the hypotensive effects of the individual drugs have been confirmed and in combination their effects are additive. With the angiotensin-converting enzyme inhibitor, enalapril (20 mg daily) the hypotensive effect was additive with that of a diuretic, hydrochlorothiazide (50 mg daily). When enalapril was combined with the beta-blocker atenolol (50 mg daily) there was little additional hypotensive effect, despite similar hypotensive effects of the individual agents separately. The mechanism of this attenuated effect is unclear. The design is suitable for evaluation of other antihypertensive combinations.

Adrenergic beta-Antagonists↗
PubMed1987

Treatment of hypertension with enalapril and hydrochlorothiazide or enalapril and atenolol: contrasts in hypotensive interactions.

To determine the nature of the resultant effect on blood pressure when angiotensin converting enzyme (ACE) inhibitors are combined with other hypotensive agents in the treatment of uncomplicated essential hypertension, two randomized, double-blind, crossover trials were conducted. In each trial there were four treatment phases, each 4 weeks in duration, comprising a 2 X 2 factorial experiment. Twenty-one patients completed the first study in which the effects of enalapril (10 mg twice daily) were compared with hydrochlorothiazide (25 mg twice daily), with the two drugs in combination and with placebo. All blood pressure parameters were reduced in the three active treatment phases compared with placebo (P less than 0.001). Enalapril and hydrochlorothiazide were equally effective and in combination their hypotensive effects were fully additive. Sixteen patients completed the second study which compared the effects of enalapril (20 mg daily), atenolol (50 mg daily), the two drugs in combination and placebo. All blood pressure parameters were again reduced in all phases compared with placebo (P less than 0.001). Enalapril and atenolol were also equally effective, but in combination their hypotensive effects were less than fully additive, with attenuation of the potential additive response by 30-50%. These results indicate that a diuretic-ACE inhibitor combination can be expected to have a greater hypotensive effect than a beta-blocker-ACE inhibitor combination. Both hydrochlorothiazide and atenolol increased plasma atrial natriuretic peptide (ANP) concentrations (P less than 0.01), suggesting that ANP could contribute to the hypotensive effects of these two drug classes.

Angiotensin II↗
PubMed1986

Increases in plasma neuropeptide Y concentrations during sympathetic activation in man.

Neuropeptide Y (NPY) coexists with noradrenaline in postganglionic sympathetic neurons. In order to test the hypothesis that NPY may be released along with catecholamines by activation of the sympathoadrenal system we measured plasma NPY-like immunoreactivity (NPY-LI) concentrations during cold pressor test, head up tilt and bicycle exercise in healthy volunteers. All 3 manoeuvres resulted in elevation of blood pressure, heart rate and plasma noradrenaline and adrenaline concentrations. These were accompanied by increases in plasma NPY-LI concentrations on cold pressor test and exercise, but not with head up tilt. The increases in both NPY-LI and catecholamines were greatest with exercise. These findings suggest that NPY is released at the same time as noradrenaline when sympathetic noradrenergic nerves are activated.

Adult↗
PubMed1986

Effects of enalapril and hydrochlorothiazide on blood pressure, renin-angiotensin system, and atrial natriuretic factor in essential hypertension: a double blind factorial cross-over study.

The hypotensive and hormonal effects of the angiotensin converting enzyme (ACE) inhibitor enalapril (10 mg twice daily) were compared with those of hydrochlorothiazide (25 mg twice daily), with the two drugs in combination and with placebo in 21 patients with essential hypertension. For each patient there were four randomised double-blind treatment phases, each of four weeks' duration, which comprised a 2 X 2 factorial experiment. All blood pressure parameters were reduced in the three active treatment phases compared to placebo (p less than 0.001). Supine mean blood pressures were 119 mmHg (placebo), 113 mmHg (hydrochlorothiazide), 108 mmHg (enalapril), and 98 mmHg (hydrochlorothiazide plus enalapril) (SEM 3 mmHg, ANOVA). Enalapril and hydrochlorothiazide were equally effective and well tolerated and their hypotensive effects were additive. Enalapril increased plasma renin activity (PRA), reduced plasma angiotensin II (AII) and aldosterone concentrations, and reduced ACE activity, whereas hydrochlorothiazide increased PRA, plasma AII, and aldosterone concentrations without altering ACE activity. With combination treatment the effects of enalapril on PRA and plasma AII concentrations were potentiated whereas those on plasma aldosterone concentration and ACE activity were additive. Atrial natriuretic factor plasma concentration in the placebo phase was 92 pg/ml and increased to 145 pg/ml in the hydrochlorothiazide phase (p less than 0.001, SEM 13 pg/ml), but there was no significant change in either the enalapril or combination phases.

Aged↗
PubMed1985

Effect of ketanserin on blood pressure and biochemical parameters in patients with essential hypertension.

Seventeen subjects with essential hypertension (14 men, 3 women, 40-69 years of age), 13 of whom continued their previous antihypertensive therapy, completed a double-blind crossover trial of ketanserin 40 mg twice daily versus placebo tablets twice daily. Each treatment phase was 6 weeks in duration. For the group as a whole, blood pressure (BP) was reduced in the ketanserin phase compared with the placebo phase: supine mean BP decrease: 4 +/- 1 mm Hg (p less than 0.05); standing mean BP decrease: 7 +/- 1 mm Hg (p less than 0.001). Heart rate (HR) was also significantly decreased in the ketanserin phase (5 +/- 1 beats/min) (p less than 0.001). When individual subgroups were analysed, the reductions in BP and HR were greater in subjects already receiving antihypertensive therapy, diuretics, and/or beta-adrenergic blockers. Changes were observed in 24-h urine sodium and potassium excretion: Sodium (mmol/day): placebo 137 +/- 17, ketanserin 174 +/- 19 (p less than 0.05); potassium (mmol/day): placebo 74 +/- 8, ketanserin 57 +/- 5. For the group as a whole, there were no significant adverse effects during the ketanserin phase, although two subjects had a dose reduction of ketanserin because of drowsiness and dizziness. Two additional subjects withdrew from the study owing to adverse effects, one in the placebo phase. In conclusion, ketanserin in the dose administered has a modest hypotensive effect, which is best seen in subjects already receiving other antihypertensive agents.

Adrenergic beta-Antagonists↗
PubMed1985

Verapamil disposition--effects of sulphinpyrazone and cimetidine.

The effects of separate 7 day pretreatments with sulphinpyrazone (800 mg daily) and cimetidine (1 g daily) on the disposition of (+/-)-verapamil have been examined in eight healthy volunteers (four male, four female). Each subject received single oral (80 mg) and intravenous (0.15 mg/kg) doses of verapamil on different occasions before and after each pretreatment. Following sulphinpyrazone pretreatment, verapamil apparent oral plasma clearance (CLpo) increased from 4.27 to 13.77 l h-1 kg-1 (s.e. mean 0.51--ANOVA) (P less than 0.001); CL increased from 1.05 to 1.20 l h-1 kg-1 (s.e. mean 0.05) (P less than 0.05) and Fpo decreased from 27 to 10% administered dose (s.e. mean 2) (P less than 0.001). Vss and t1/2,z were unchanged. There was no sex difference for any dispositional parameter in the control phase, but the increase in CLpo following sulphinpyrazone pretreatment was more marked in males (4.04 to 17.33 l h-1 kg-1) than in females (4.49 to 10.21 l h-1 kg-1) (s.e. mean 0.72) (P less than 0.01). There was no significant change in any verapamil disposition parameter following cimetidine pretreatment. Verapamil unbound fraction in plasma was 0.157 (s.e. mean 0.001, n = 40). There was no alteration in verapamil plasma protein binding associated with increasing verapamil concentration (25-250 micrograms l-1) or addition of sulphinpyrazone (50-500 mg l-1) or cimetidine (0.5-5 mg l-1). The results suggest that sulphinpyrazone induces the metabolic clearance of (+/-)-verapamil with a sex difference in the response.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

The effect of ranitidine on the disposition of lignocaine.

The effect of pretreatment with ranitidine (150 mg twice daily for 5 days) on the disposition of lignocaine was examined in 10 healthy volunteers (five male, five female). Each subject received separate oral (250 mg) and intravenous (1.5 mg/kg) doses of lignocaine hydrochloride before and after ranitidine. Lignocaine systemic clearance was reduced by 9% (1.11 to 0.99 1 h-1 kg-1; P less than 0.01) following ranitidine pretreatment. The volume of distribution at steady-state was reduced by 15% (3.34 to 2.85 1 kg-1; P less than 0.005). Lignocaine oral clearance, elimination half-life and oral bioavailability were unchanged after ranitidine pretreatment. There was no sex difference in the effects of ranitidine pretreatment on lignocaine disposition. These results are consistent with small reductions in blood flow to the splanchnic and other vascular beds due to ranitidine.

Adolescent↗
PubMed1985

Selectivity and dose-dependency of the inhibitory effect of propranolol on theophylline metabolism in man.

The effects of separate 5 day pretreatments of propranolol 120 mg day-1 and 720 mg day-1 on theophylline clearance and metabolism at steady-state were determined in seven healthy males. Propranolol 120 mg day-1 decreased theophylline plasma clearance (CL) by 30%. Clearance of theophylline to each metabolite was reduced by this treatment, clearances to the two demethylated products by 42-43% and clearance to the 8-hydroxylation product by 27%. Propranolol 720 mg day-1 decreased theophylline CL by 52%. Again, clearance of theophylline to each metabolite was reduced by this treatment, clearances to the two demethylation products by 73-77% and clearance to the 8-hydroxylation product by 44%. These data are consistent with a dose-dependent and selective inhibitory effect of propranolol on the separate forms of cytochrome P-450 involved in theophylline demethylation and 8-hydroxylation.

Adult↗
PubMed1985

Cortisol does not inhibit prednisolone clearance.

The disposition of prednisolone has been studied in eight male subjects with and without the concomitant administration of cortisol which produced plasma cortisol concentrations 10-fold higher than endogenous levels. The clearance and steady-state distribution volume of total prednisolone were increased as was the prednisolone free fraction but the clearance of unbound prednisolone was unaltered by cortisol co-administration.

Adult↗
PubMed1985

Cotrimoxazole as an inhibitor of oxidative drug metabolism: effects of trimethoprim and sulphamethoxazole separately and combined on tolbutamide disposition.

The effect of separate pretreatments with cotrimoxazole, sulphamethoxazole and trimethoprim on the disposition of tolbutamide was studied in seven healthy males. Tolbutamide 500 mg intravenously was administered on four separate occasions--as a control without pretreatment and on the seventh day of separate twice daily administration of cotrimoxazole (sulphamethoxazole 800 mg plus trimethoprim 160 mg) (ST phase), sulphamethoxazole 1 g (S phase) and trimethoprim 150 mg (T phase). Tolbutamide total and unbound plasma clearance (CL) were reduced following each of the individual pretreatments compared to the control phase (P less than 0.001). For unbound CL the reductions were 14% in the S and T phases and 25% in ST phase. Tolbutamide elimination half-life was prolonged following each pretreatment (P less than 0.001) by 20% in the S phase, 19% in the T phase and 30% in the ST phase. Tolbutamide total steady-state volume of distribution (VSS) was increased by 10% in the S and ST phases (P less than 0.01), the increase being accounted for by an increase in tolbutamide unbound fraction. There was no change in tolbutamide unbound VSS following any of the pretreatments. These results are consistent with inhibition of tolbutamide oxidation by cotrimoxazole, an additive effect of the two components sulphamethoxazole and trimethoprim. Sulphamethoxazole also reduces tolbutamide plasma protein binding.

Adult↗
PubMed1985

Normal metabolism of debrisoquine and theophylline in a slow tolbutamide metaboliser.

The metabolism of debrisoquine and theophylline has been studied in a healthy male who was identified as a slow hydroxylator of tolbutamide. Tolbutamide clearance in this subject was three-fold lower than the lowest tolbutamide clearance observed in other healthy males and the drug's half-life was approximately three-fold longer. Despite this, his ability to 4-hydroxylate debrisoquine and both N-demethylate and 8-hydroxylate theophylline was normal. Along with previously published information the data from this subject suggest that tolbutamide hydroxylation, debrisoquine hydroxylation, theophylline N-demethylation, and theophylline 8-hydroxylation involve four distinct isozymes of cytochrome P-450. Furthermore, this report illustrates the difficulties of using the metabolic clearance of a model drug to predict the ability of an individual to clear a range of metabolised drugs.

Adult↗
PubMed1985

Slow-release nifedipine as a single or additional agent in the treatment of essential hypertension--a placebo-controlled crossover study.

The efficacy and safety of a new slow-release formulation of nifedipine ("Adalat Retard") were assessed in a double-blind cross-over trial in 19 subjects with essential hypertension (14 male, 5 female--ages: 34-72 years), 14 of whom continued previous antihypertensive medication. There were two 6 week treatment phases in which nifedipine 20 mg twice daily and placebo tablets twice daily were administered in random order. Supine mean blood pressure was 115 +/- 2 mm Hg during the placebo phase and 105 +/- 2 mm Hg during the nifedipine phase (p less than 0.001); and standing mean blood pressure was 121 +/- 2 mm Hg after placebo and 110 +/- 2 mm Hg after nifedipine (p less than 0.001). The magnitude of the blood pressure difference between the two phases was not related either to age or to the placebo phase blood pressure. The hypotensive effect of nifedipine was observed when administered as a single agent or in combination with diuretic and/or beta blocker. Heart rate was increased after nifedipine--75 +/- 2 beats/minute compared with 71 +/- 2 beats/minute after placebo (p less than 0.01). In this dose nifedipine (as "Adalat Retard") is an effective hypotensive agent which is a useful addition to presently available therapy.

Adult↗
PubMed1984

Lidocaine disposition--sex differences and effects of cimetidine.

The effects of pretreatment with cimetidine (1 gm daily for 3 days) on the disposition of lidocaine were examined in 18 healthy subjects, seven of whom were chronic cigarette smokers. Each subject received separate oral (200 mg) and intravenous (75 or 100 mg) doses of lidocaine before and after cimetidine. After cimetidine, lidocaine apparent oral clearance (Clo) reduced 42% +/- 7%; oral bioavailability increased 35% +/- 10%; and systemic clearance (Cls) and volume of distribution at steady-state (Vdss) decreased 21% +/- 6% and 20% +/- 7%. Elimination t 1/2 was unchanged. Calculated values for Cls after cimetidine based on reduction in Clo and consequent decrease in hepatic extraction ratio correlated significantly with observed values for Cls (r = 0.67). Women had larger Vdss (64% +/- 19%), longer t 1/2 (50% +/- 18%), and greater oral lidocaine bioavailability (63% +/- 29%) than did men. There was no sex difference in and no influence of cigarette smoking on the effects of cimetidine. The results indicate that cimetidine reduces metabolic clearance of lidocaine. The consequent reduced hepatic extraction explains the observed reduction in Cls.

Administration, Oral↗
PubMed1984

Plasma concentrations of unbound phenytoin in the management of epilepsy.

In 46 epileptic patients the range of the unbound fraction of phenytoin in plasma measured by ultrafiltration (at 37 degrees C) and tracer-labelling with [14C]-phenytoin was 6.7%-33.3% with a median of 11.9%. The total and unbound phenytoin plasma concentrations were significantly correlated (r = 0.93, P less than 0.001), but in six patients the unbound concentration fell on or outside the 90% predictability limits for a single value. In all patients the unbound concentration reflected the clinical status of the patient equally or better than the total concentration. An inverse relationship was found between the plasma albumin concentration (within the normal reference range) and the phenytoin unbound fraction (r = -0.83, P less than 0.001) indicating that plasma albumin concentration is one of the important overall determinants of phenytoin protein binding. Saliva and plasma unbound phenytoin concentrations were significantly correlated (r = 0.98, P less than 0.001) but both collection of plasma samples and preparation of plasma ultrafiltrate using the Amicon micropartition system are simpler than collection and processing saliva, and interpretation of plasma unbound concentration does not require allowance for potential contamination. The additional value of the unbound phenytoin concentration in a clinically significant number of individuals would justify routine measurement of unbound phenytoin concentration in monitoring therapy, once available simplified methodology has been adequately characterised.

Adolescent↗
PubMed1984

Alterations in prednisolone disposition as a result of oral contraceptive use and dose.

The disposition of total and free prednisolone has been studied in eight female subjects who used combined oestrogen-progestogen oral contraceptives and in eight female subjects who did not, each of whom received separate intravenous doses of 0.1 mg/kg (low) and 1.0 mg/kg (high) of prednisolone. Mean free prednisolone clearance was reduced congruent to 30% in oral contraceptive users compared to control subjects (P less than 0.001), the difference being greater for the low dose (39%) than for the high dose (24%). Pre-dose plasma cortisol concentrations were elevated two-fold (P less than 0.001) in oral contraceptive users compared to control subjects. These effects are consistent with a mechanism in which the competitive inhibition of free prednisolone clearance by cortisol contributes to the reduction of free prednisolone clearance by oral contraceptive use. Mean total prednisolone clearance and steady state distribution volume showed an approximate two-fold dose dependent increase consistent with a similar increase in plasma prednisolone free fraction (P less than 0.001). Free prednisolone clearance showed an 18% dose dependent decrease (P less than 0.001) but free steady-state distribution volume did not change with dose. At plasma prednisolone concentrations less than 400 ng/ml, prednisolone free fractions at any prednisolone concentration were greater after the low, than after the high dose. This effect is consistent with the displacement of prednisolone by cortisol from transcortin but not from albumin.

Adolescent↗
PubMed1984

Theophylline-rifampicin interaction: non-selective induction of theophylline metabolic pathways.

The effect of rifampicin pre-treatment (600 mg daily for 6 days) on theophylline disposition at steady state was investigated in six healthy males. Following rifampicin treatment total plasma clearance of theophylline increased by 82%. Theophylline clearance through each metabolic pathway was increased, 1-demethylation by (116 +/- 34%) (mean +/- s.e. mean), 3-demethylation by (91 +/- 16%) and 8-oxidation by (81 +/- 17%). Renal clearance of unchanged drug was not altered. Previous studies have suggested that two forms of cytochrome P-450 are involved in theophylline metabolism, one mediating the N-demethylations and the other 8-oxidation. Thus, unlike the selective inductive effect of rifampicin on antipyrine metabolic pathways, rifampicin does not differentially affect those forms of cytochrome P-450 involved in theophylline metabolism. The extent to which theophylline metabolism is induced by rifampicin is likely to have important clinical consequences.

Adult↗