Quantitation of plasma thyroxine by enzyme immunoassay: a new approach.
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Biomedical subjects
Publications and source records attributed to T E Isles.
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Energy expenditure was measured during pregnancy in seven primigravid women at 12-15, 25-28, and 34-36 weeks and after the cessation of lactation. On each occasion the resting metabolic rate and the increase in metabolic rate after ingestion of a liquid test meal were measured by indirect calorimetry. In absolute terms the resting metabolic rate increased steadily during pregnancy but when expressed per unit of body weight no change was found. The energetic response to a mixed constituent meal was significantly reduced by 28% in the middle trimester of pregnancy. These findings suggest a possible maternal adaptation to increase energetic efficiency at a time when the energy demands of the fetus are high.
Six well controlled Type 2 diabetics who had received glipizide therapy ranging from 5 mg to 30 mg daily for at least the previous 2 months were studied. On Days 1 and 15 nifedipine 20 mg or placebo respectively were given in a random crossover design after an overnight fast and with the morning dose of glipizide. Nifedipine did not influence the disposition of glipizide since there was no significant alteration in the maximum concentration, time to peak plasma concentration, elimination half-life or area under the curve. Neither did it have a major effect on plasma glucose or insulin although there was an early preprandial decrease in insulin level which reached significance at 1 h only (22.66 v 18.50 mIU/l).
In the management of the non-insulin dependent diabetic patient, metformin often facilitates weight loss whereas sulphonylurea may predispose to weight gain. To investigate whether this is due to alterations in energy expenditure we have studied energy expenditure in seven non-insulin dependent diabetic subjects while on metformin or sulphonylurea therapy. Three components of energy expenditure were measured by indirect calorimetry, namely resting metabolic rate and the thermic responses to infused noradrenaline and to a mixed constituent meal. There was no significant difference in the resting metabolic rate on metformin (5.29 +/- 0.41 kJ/min; mean +/- SE) compared with sulphonylurea (5.34 +/- 0.34 kJ/min). The resting metabolic rate was also similar to predicted values for non-diabetic subjects (r = 0.96). The thermic response to infused noradrenaline was similar on metformin (23.14 +/- 1.87 kJ) and sulphonylurea (21.40 +/- 2.98 kJ). There was no significant difference in the thermic response to the meal on sulphonylurea (75.8 +/- 7.5 kJ) or on metformin (86.8 +/- 10.8 kJ; 95% confidence limits -17 to +39 kJ). We conclude that in non-insulin dependent diabetic subjects metformin does not enhance energy expenditure overall, compared with sulphonylurea.
To assess the role of insulin in the control of body weight energy expenditure was measured by indirect calorimetry in eight patients of normal weight with type I diabetes initially while poorly controlled during conventional insulin treatment and later during optimal glycaemic control achieved by using the continuous subcutaneous insulin infusion pump. Their response to seven days of fat supplementation was also assessed and the results compared with those in eight non-diabetic subjects. After a mean of 5.3 months of continuous subcutaneous insulin infusion the diabetic subjects had gained on average 3.5 kg. In the poorly controlled diabetic state the resting metabolic rate was raised but decreased by a mean of 374 kJ (90 kcal) per 24 hours with optimal glycaemic control. The thermic response to infused noradrenaline was reduced by 59% in the diabetic subjects, was not improved by continuous subcutaneous insulin infusion, but was improved when three of the subjects were given metformin in addition. The diabetic subjects had no abnormality in the thermic response to a meal while taking their usual diabetic diet. During fat supplementation, however, this thermic response was reduced when glycaemic control was poor but not when control was precise. Fat supplementation did not alter the resting metabolic rate or the reduced noradrenergic thermic response in the diabetic subjects. These findings suggest that precise glycaemic control could produce weight gain if energy intake remained unaltered, for diabetic subjects do not compensate for the decrease in metabolic rate by an increase in noradrenergic and dietary thermic responses. Also precise glycaemic control using continuous subcutaneous insulin infusion does not correct all the metabolic abnormalities of diabetes mellitus.
Energy expenditure at rest and in response to a meal and to an infusion of noradrenaline was measured in 12 lactating women and compared with that in seven bottle feeding women and seven non-pregnant, non-lactating controls. The energy response of the lactating women was remeasured after lactation stopped. During lactation the resting metabolic rate was unaltered but there was a reduced response to infusion of noradrenaline and to a meal, which increased to normal control values after lactation stopped. Such reductions in expenditure were not found in women who had been bottle feeding and were tested at a similar six to eight weeks post partum. These findings suggest that metabolic efficiency is enhanced in lactating women, who may not need to increase energy intake to the extent suggested by current recommended dietary allowances.
The effect of nicardipine on insulin secretion was examined in two double-blind, randomised, cross-over, placebo-controlled studies in normal volunteers. In the first study, the effect of acute dosing (via an intravenous infusion of 5 mg h-1 for 3 h) on the glucose, insulin, hormonal, and intermediary metabolite responses to an intravenous glucose tolerance test was determined in six healthy male volunteers. In the second study, the glucose, insulin, and C-peptide responses to intravenous tolbutamide (200 mg) was determined in another six male volunteers after oral dosing with nicardipine 30 mg three times daily for 1 week. A relative increase in insulin secretion was the principal finding of the first study. No other response was affected significantly. No significant differences between the nicardipine- and placebo-treated groups were noted in the insulin, glucose, and C-peptide measurements of the second study. In conclusion, treatment with nicardipine does not appear to impair insulin secretion in response either to an intravenous glucose load or intravenously administered tolbutamide.
In a double-blind, placebo-controlled, randomised, cross-over study of six healthy male subjects, the effect of nicardipine (5 mg h-1 for 3 h) on basal and stimulated pituitary hormone release was examined. Statistically significant differences between nicardipine and placebo were seen occasionally for follicle-stimulating hormone, luteinising hormone and prolactin, but not for thyroid-stimulating hormone. These differences were always within the between-batch coefficient of variation of the assay. The overall differences in both basal and stimulated results for all four pituitary hormones were not statistically significantly different. It is concluded, therefore, that nicardipine has no significant effect on either basal or stimulated pituitary hormone release in healthy male subjects.
We have compared the clinical and metabolic responses of three groups of patients undergoing subtotal thyroidectomy for hyperthyroid Graves' disease. These patients were prepared for surgery with propranolol alone, propranolol plus potassium iodide or the long acting beta-adrenoceptor antagonist nadolol plus potassium iodide. Pre-treatment with potassium iodide reduced serum T4 to normal or subnormal in all patients. Patients in the propranolol group had significantly higher pulse rates and temperatures after operation and one patient developed an exacerbation of the hypermetabolic state. The perioperative rise in serum cortisol and blood glucose was delayed in patients in the propranolol group and this was also noted in one severely hyperthyroid patient on propranolol + potassium iodide. Nadolol was administered once daily as compared to multiple daily doses with propranolol. Despite this, plasma nadolol levels were consistently higher throughout the perioperative period while propranolol levels in patients on both propranolol alone and propranolol + potassium iodide were highly variable and sometimes undetectable. We conclude that, in the rapid preparation of patients with hyperthyroid Graves' disease for surgery, the combination of nadolol + potassium iodide has significant advantages over the other two regimens.
In a single-blind randomized placebo-controlled cross-over study in hypertensive patients we have examined the effects of treatment with the non-selective beta-adrenoceptor antagonist nadolol on the responses of glucose, intermediary metabolites and the hormones of the enteroinsular axis to the ingestion of a mixed meal. During treatment with nadolol the plasma insulin concentration 30 min after ingesting the meal was significantly lower than on placebo and the plasma glucose rose more slowly. Plasma concentrations of GIP tended to be higher during nadolol than placebo treatment. No significant effects of treatment with nadolol were noted on pancreatic glucagon or intermediary metabolites.
During a randomised placebo controlled trial of the effects of nadolol in hypertensive patients serum lipid profiles were obtained while the patients were fasting and during and after a meal and an exercise test. Treatment with nadolol was associated with a significant reduction in high density lipoprotein cholesterol at all time points. Serum triglyceride concentrations during treatment with nadolol were higher in the fasting state, though not significantly so, increased further postprandially, and were significantly higher during and after exercise. The changes in high density lipoprotein cholesterol and triglyceride concentrations during beta adrenoceptor blockade may be secondary to a reduction in lipoprotein lipase activity.
In order to examine the significance of differences in the triiodothyronine/thyroxine (T3/T4) ratio in the control of euthyroidism in a normal population, we measured the serum T3, T4 and FT4 index (FT4I) in 121 healthy men and 68 women. The correlation between T3 and T4 was poor (r = 0.24), suggesting that most of the natural variation in T3 among normal individuals occurs independently of the T4 level. There was, however, a strong inverse correlation (r = 0.59, p less than 0.001) between T3/T4 ratio and FT4I. This correlation reflected a constancy in mean T3 at different levels of T4 such that the T3 changed by only 0.35 nmol/l (22%) throughout the range of normal T4. Furthermore, the T3/T4 ratios of 48 hypothyroid individuals with subnormal T4 represented a simple extension of the relationship found in the healthy individuals, indicating that the rise in T3/T4 classically associated with falling T4 in primary hypothyroidism is merely part of a continuous process of change which begins in euthyroidism. It is proposed that the relationship between T3 and T4 is finely controlled in healthy individuals in such a way that differences in hormone activity due to the wide range of serum T4 among normals may be buffered by systematic adjustment of the T3/T4 ratio. Those with the highest T4 appear to maintain euthyroidism with a minimal T3/T4 ratio. The remainder, with T4 levels towards the lower limit of normal, are subject to a progressive increase in the T3 fraction and may depend on it to remain euthyroid.(ABSTRACT TRUNCATED AT 250 WORDS)
1 The relationship between plasma chlorpropamide concentration and thyroid function was examined in 87 maturity onset diabetic patients receiving chronic therapy. 2 Although plasma chlorpropamide concentration was weakly negatively correlated with serum thyroxine (r = 0.33, P less than 0.01) the mean serum thyroxine and thyrotrophin (TSH) were not different from that of a matched control group of diabetics treated with diet alone. 3 Serum thyroxine was negatively correlated with the duration of diabetes in both groups. 4 These results suggest that chlorpropamide does not have a clinically significant antithyroid effect.
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With the two aims of rapidly reducing circulating thyroid hormone levels and controlling the symptoms of thyrotoxicosis, we have prepared 17 thyrotoxic patients for subtotal thyroidectomy, using a combination of potassium iodide administered for 10 days and the long acting beta-adrenoceptor antagonist nadolol. All 17 patients had normal serum thyroxine levels after 10 days of such treatment although 10 still showed elevation of serum tri-iodothyronine and considerable elevation in the most severely toxic patient. All patients were, however, clinically euthyroid preoperatively. Nadolol was administered once daily, hence avoiding the problems of drug administration in the immediate postoperative period, and plasma nadolol concentrations were high throughout the perioperative period. Serum thyroxine and tri-iodothyronine levels were significantly lower and reverse tri-iodothyronine levels higher 24 h postoperatively than before operation. All patients remained stable throughout the perioperative period. We conclude that this regimen has a number of advantages in the preparation of patients for thyroidectomy, in reducing the degree of thyrotoxicosis, in convenience of drug administration and in ensuring adequate circulating concentrations of beta-adrenoceptor antagonist whilst still retaining a relatively short preoperative phase of drug treatment.
1 Twenty outpatients with thyrotoxicosis received the non-selective beta-adrenoceptor antagonist nadolol as sole treatment for 3 weeks. 2 Clinical improvement as measured by reduction in thyrotoxicosis therapeutic index occurred during the first week of treatment and was continued thereafter, and was accompanied by a significant reduction in serum T3 and elevation of serum reverse T3. 3 As measured by reduction in exercise heart rate, during chronic dosing nadolol 160 mg once daily produced blockade of beta-adrenoceptors for 12 h in all patients and 24 h in all but 2. 4 Wide interindividual variability was noted in steady state plasma nadolol concentrations, in part related to age and renal function. 5 Steady state plasma nadolol concentrations were related to reduction in heart rate.
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