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Biomedical subjects

J R Stockigt

Publications and source records attributed to J R Stockigt.

At least 55 records · Page 3Linked to original sources
PubMed1989

Hyperthyroidism. Current drug therapy.

The choice of treatment for hyperthyroidism should be preceded by considering: (a) whether the diagnosis is correct; (b) the severity of the disorder; (c) the cause of the thyroid hormone excess; (d) factors such as patient age, size of goitre, associated diseases, previous treatment, and (e) patient preference. If hyperthyroidism appears to be severe, a judgement based on clinical rather than biochemical features, there is generally no safe alternative to the initial use of a drug from the thioamide thioureylene group (carbimazole, methimazole or propylthiouracil) to make the patient euthyroid as rapidly as possible. There are numerous different schedules for the use of these drugs, alone or in conjunction with surgery, radioactive iodine, or drugs such as beta-blocking agents, iodide or thyroxine. Patients can be made euthyroid with reasonable certainty, but an underlying abnormality often remains. The patient's understanding of the natural history of his or her condition is crucial in achieving adequate follow-up.

Humans↗
PubMed1989

The significance of subnormal, detectable TSH values: laboratory and clinical aspects.

In order to establish the significance of subnormal, detectable TSH values in the range 0.05-0.3 mU/L by sensitive immunoradiometric assay, we assessed 3150 consecutive tests of thyroid function in which TSH was measured on 1400. Sixty TSH values (4.3%) fell in this range and in 80% of these the result was confirmed on repeat assay. Conditions associated with subnormal detectable TSH values were treated hyperthyroidism (21), nonthyroidal illness (17), euthyroid multinodular goitre (10), T4 therapy for primary hypothyroidism (7), and pituitary disease (5). At follow-up 2-15 months later, a second sample showed that TSH remained in this range in only 9 of 41 patients (22%). These findings show a frequency of TSH values intermediate between normality and the suppressed values of hyperthyroidism sufficient to compromise the value of sensitive TSH measurement as the single initial test of thyroid function. While TSH values in the subnormal detectable range rule out hyperthyroidism, such results may merit follow-up in goitrous patients, in whom such a finding can precede overt hyperthyroidism.

Adult↗
PubMed1988

Furosemide, fenclofenac, diclofenac, mefenamic acid and meclofenamic acid inhibit specific T3 binding in isolated rat hepatic nuclei.

Previous studies with phenytoin (DPH) show that this inhibitor of thyroid hormone binding to plasma proteins also interacts with specific nuclear T3 binding sites. In order to further define the nuclear effects of drugs that inhibit plasma protein binding of thyroid hormones, we assessed furosemide and a number of non-steroidal antiinflammatory drugs using isolated rat liver nuclei. The effects were compared with those of DPH, ipodate and amiodarone. The T3 binding site in isolated nuclei (Ka 1.2 X 10(9)M-1) showed relative affinity triac approximately equal to T3 greater than T4. Drugs were studied over the concentration range 10(-3)-10(-7)M, approximating the known therapeutic total plasma concentrations, in competition with 125I-T3 0.1 nM, expressing inhibition as the percent decrement from maximum specific binding of 125I-T3 in drug vehicle (assay buffer or thanol 1-10%). Specific T3 binding was inhibited by furosemide to 78.8 +/- 3.5% at 2 mM, by fenclofenac to 37.6 +/- 2.8% at 1 mM, by meclofenamic acid to 70.2 +/- 2.4% at 0.1 mM, by mefenamic acid to 60.6 +/- 4.6% at 0.05 mM (each p less than 0.02) and by diclofenac to 87.4 +/- 5.6% at 0.2 mM (p less than 0.05). In comparison, DPH inhibited T3 binding to only 88.1 +/- 0.6% at 0.3 mM, as did calcium ipodate (68 +/- 3.5% at 1 mM, p less than 0.02). Amiodarone (0.3 mM), sodium salicylate (1 mM) and phenylbutazone (0.1 mM) were inactive. In order to achieve a level of nuclear receptor occupancy that approaches in vivo occupancy, the concentration 125I-T3 was increased over the range 0.1-0.5 nM.2+t

Amiodarone↗
PubMed1988

Amiodarone-induced hyperthyroidism: assessment of the predictive value of biochemical testing and response to combined therapy using propylthiouracil and potassium perchlorate.

In order to assess the value of thyroid function testing during amiodarone therapy, we reviewed all available tests in 128 patients treated with this drug. Nine patients (7.0%) developed biochemical hyperthyroidism with elevation of both free thyroxine index (FT4I) and free triiodothyronine index (FT3I) and marked suppression of serum thyroid stimulating hormone (TSH) after 1-46 months of therapy; six of these nine patients had clear clinical evidence of thyroid overactivity. Where serial tests were available before development of hyperthyroidism, this complication developed suddenly, despite previously stable normal indices of thyroid function, and could not be predicted by currently-available biochemical tests such as T4, T3, sensitive TSH, thyroglobulin or sex hormone binding globulin (SHBG) assays. Clinical features such as unexplained weight loss, proximal myopathy, exacerbation of arrhythmia, or heat intolerance appear to be the key to prompt diagnosis of this complication. Hyperthyroxinemia without T3 excess was found in 32.8% of patients without progression to true hyperthyroidism. Serum TSH remained detectable by sensitive assay in 17 out of 18 patients with amiodarone-induced euthyroid hyperthyroxinemia and was significantly higher than in patients with equivalent hyperthyroxinemia due to thyroxine therapy. Serial levels of SHBG were higher in patients with true hyperthyroidism than in those with euthyroid hyperthyroxinemia. The effect of combined treatment with propylthiouracil (800 mg/day) and potassium perchlorate (800 mg/day) was evaluated in five of the six clinically hyperthyroid patients. Biochemical euthyroidism was achieved after 7-19 weeks, a response slower than previously reported, indicating that this drug combination does not result uniformly in prompt resolution of amiodarone-induced hyperthyroidism.

Adolescent↗
PubMed1988

Drug and fatty acid effects on serum thyroid hormone binding.

We directly compared the competitor potency for serum T4 binding of 11 nonsteroidal antiinflammatory drugs; the diuretics furosemide, ethacrynic acid, and bumetanide; diphenylhydantoin; the cholecystographic contrast agents iopanoate and ipodate; and six long-chain nonesterified fatty acids (NEFA) using equilibrium dialysis. To avoid artefacts that occur in competitor studies with diluted serum or isolated binding proteins, we used undiluted normal serum, with drugs added at concentrations that achieved high therapeutic total and free serum levels at equilibrium. Drug addition was based on the measured free fraction of each drug in serum. The free T4 fraction in normal serum (Tris buffer, pH 7.4; 37 C) was between 1.40 X 10(-4) and 1.53 X 10(-4). Drug-induced increases in T4 free fraction were: fenclofenac, 90%; aspirin, 62%; meclofenamic acid, 39%; diflunisal, 37%; mefenamic acid, 31%; and furosemide, 31%. Significant increases of 7-15% occurred with diclofenac, flufenamic acid, phenylbutazone, and diphenylhydantoin. Indomethacin, ketoprofen, tolmetin, ethacrynic acid, bumetanide, iopanoate, and ipodate were inactive at the concentrations studied. Addition of 2.0 mmol/L oleic acid had a negligible effect, but 3.5 mmol/L oleic acid inhibited T3 and T4 binding significantly. Other long chain NEFA (addition of 1.5 mmol/L) gave increases in free T4 fraction as follows: arachidonic acid, 26%; linolenic acid, 23%; and linoleic acid, 11%. Stearic and palmitic acids were inactive. The effect of 5 mmol/L oleic acid in serum could be reproduced by addition of 0.5 mmol/L to serum diluted 1:10, indicating that protein binding of NEFA is the major determinant that limits their competitor potency. These findings provide a basis for anticipating which potential inhibitors may cause important changes in serum thyroid hormone binding. The time course of such effects will be influenced by the pharmacokinetics of the inhibitor itself as well as the equilibrium findings described here.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1987

Effect of oral frusemide on diagnostic indices of thyroid function.

We studied the acute effect of standard therapeutic doses of oral frusemide on indices of thyroid function in 34 hospital in-patients with congestive cardiac failure. A transient decrease in total T4, elevation in the T3 resin uptake and consequent increase in the free T4 index (FT4I) were seen 2-5 h after ingestion of frusemide at a chronic morning dosage of 80, 120 or 250 mg. The FT4I pre-vs post-frusemide values after 250 mg of drug were 109 +/- 12 vs 129 +/- 18 (P less than 0.05) after 120 mg 92 +/- 14 vs 119 +/- 12 (P less than 0.01), and after 80 mg 102 +/- 6 vs 112 +/- 4 (P less than 0.01) (mean +/- SEM). Similar increases in apparent free T4 measured by an analogue tracer assay (free T4 RIA sol, Henning, Berlin) were seen after frusemide. In a time course study, the major change in the T3 uptake 120 min after frusemide ingestion correlated with the change in serum frusemide concentration. When frusemide was added to serum in vitro its influence was greatest in methods that involved least dilution of serum. In two of the patients difficulty in clinical assessment of thyroid status was compounded by the effect of oral frusemide on FT4I. We conclude that oral frusemide may influence biochemical assessments of thyroid function in patients with congestive cardiac failure. It is necessary to consider the time interval between ingestion of high doses of oral frusemide and blood sampling in evaluating such results.

Administration, Oral↗
PubMed1987

Evaluation of T4 and T3 binding kinetics in the thyroxine binding globulin abnormality of Australian aborigines.

Low serum total T4 associated with subnormal concentrations of thyroxine binding globulin (TBG) has been reported in up to 40% of euthyroid Australian aborigines. It has been suggested that these subjects show both diminished concentration of TBG and reduced TBG affinity for T4 (Sarne et al., 1985). We have compared 12 euthyroid aborigines with low T4 (total T4 44 +/- 5 nmol/l) and aborigines with normal T4 (T4 99 +/- 9 nmol/l, n = 12) using measurements of free T4 and T3 by equilibrium dialysis. TBG was measured both by RIA (Henning, Berlin, FRG) and a method dependent on T4 binding (Corning Immophase). Aborigines with low T4 showed lower levels of free T4 (12.6 +/- 0.6 cf. 18.7 +/- 1.0 pM), free T4 index (66 +/- 8 cf. 98 +/- 13), total T3 (1.1 +/- 0.2 cf. 1.6 +/- 0.3 nmol/l), TBG RIA (14.0 +/- 0.6 cf. 25.0 +/- 1.2 ng/l), and TBG Immophase (9.0 +/- 0.5 cf. 22.0 +/- 1.2 mg/l) (P less than 0.01), but free T3 (5.3 +/- 0.4 cf. 4.7 +/- 0.4 pM) and TSH (1.9 +/- 0.2 cf. 1.8 +/- 0.2 mU/l) were not significantly different from the values found in aborigines with normal T4. Scatchard analysis of T4 and T3 binding was performed using serum diluted 1 : 20,000 for T4 and 1 : 500 for T3 (barbitone buffer pH 8.6, 4 degrees C, dextran-coated charcoal separation). In euthyroid low T4 aborigines compared to those with normal T4, both T4 capacity (106 +/- 14 cf. 238 +/- 13 nM, P less than 0.01) and affinity (5.05 X 10(10) cf. 8.47 X 10(10) M-1, P less than 0.05) were significantly reduced. Similarly, both T3 capacity (62 +/- 10 cf. 154 +/- 16 nM, P less than 0.01) and affinity (1.67 X 10(9) cf. 2.28 X 10(9) M-1, P less than 0.02) were reduced. A substantial minority of euthyroid Australian aborigines have a TBG variant characterized by both reduced capacity and affinity of T4 and T3. These findings suggest that TBG may be both qualitatively and quantitatively abnormal in these subjects.

Alpha-Globulins↗
PubMed1987

Anomalous binding characteristics of human thyroxine binding globulin due to a dilution-dependent separation artefact.

Contrary to the accepted view, a recent study using Sephadex column separation suggested that thyroxine binding globulin (TBG) binds T4 and T3 with similar affinity, but with a much larger capacity for T4 than T3. We have evaluated this finding by comparing this separation method with equilibrium dialysis, taking account of the effect of serum dilution with each method. Estimates of free T4 fraction by equilibrium dialysis (with magnesium chloride precipitation) were valid over a wide range of serum dilutions. In contrast, Sephadex column separation gave a major overestimate of free hormone (underestimate of binding) in less diluted serum, indicating that this method cannot be used to establish a value for T4 affinity independent of serum dilution. Such a systematic error will result in a greater underestimate of affinity for the ligand with higher affinity when two ligands are compared at a single serum dilution. By equilibrium dialysis at 37 degrees C, the affinity of T4 for TBG was approximately 13-fold higher than that of T3, while the capacity of TBG for both T4 and T3 was close to the concentration of immunoreactive TBG. The previous report of similar T4 and T3 affinities appears to be due to a dilution-dependent underestimate of T4 affinity inherent in Sephadex column separation. Direct comparison of binding kinetics of various ligands requires a separation method that is valid over a wide range of binding protein concentrations.

Alpha-Globulins↗
PubMed1987

Long term evolution of glucocorticoid-suppressible hyperaldosteronism.

It is generally held that idiopathic hyperaldosteronism and glucocorticoid-suppressible hyperaldosteronism (GSH) are distinct entities, distinguishable by thorough investigation. We report a patient who presented in 1974 at age 15 yr with blood pressure of 240/120 mm Hg, serum K of 3.1 mM, low renin, and high normal aldosterone excretion, with findings diagnostic of GSH. After dexamethasone treatment (2 mg/day for 4 weeks), urinary aldosterone was undetectable (less than 1 microgram/24 h), associated with correction of hypertension and hypokalaemia. While untreated, plasma aldosterone increased in response to ACTH infusion at a dose that did not influence plasma cortisol. Plasma aldosterone at 0800 h while recumbent was higher than in subsequent samples taken while ambulant, consistent with ACTH dependence of aldosterone secretion. Blood pressure, renin, and potassium remained normal for 4 yr during treatment with dexamethasone (0.5-0.75 mg/day), but hypertension then slowly returned. After 7 yr, the original studies were repeated. Urinary aldosterone excretion was again in the high normal range after 3 weeks of no treatment, but both plasma renin and aldosterone consistently increased in response to upright posture. After dexamethasone treatment (2 mg/day) for 4 weeks, urinary aldosterone was not suppressed (excretion rate, 10.8, 9.2, and 5.7 micrograms/day; urinary Na, greater than 100 mmol/day; urinary cortisol, less than 1 microgram/day). At this time, dexamethasone did not alleviate hypertension or increase renin. Control of blood pressure has been readily achieved, 8-12 yr after diagnosis, with a low dose of beta-adrenergic antagonist and amiloride. Aldosterone remains incompletely suppressible during sodium loading, so that the findings now resemble those of idiopathic hyperaldosteronism. This sequence indicates that glucocorticoids may not permanently control hypertension in GSH. The transient dominance of ACTH in control of aldosterone secretion indicates that the relationship between GSH and idiopathic hyperaldosteronism merits further evaluation in long term studies.

Adolescent↗
PubMed1986

Familial dysalbuminaemic hyperthyroxinaemia: studies of albumin binding and implications for hormone action.

The abnormal intermediate-affinity T4 binding to albumin which is characteristic of familial dysalbuminaemic hyperthyroxinaemia (FDH) is dependent on buffer, temperature, and ionic composition. Scatchard analysis of T4-binding to isolated albumin preparations from FDH subjects showed that half the circulating albumin showed the higher-affinity T4 binding site, assuming one site per molecule. Using dextran-charcoal separation at 4 degrees C the T4 affinity (Kd) of purified albumin from FDH subjects was 7.5 nmol/l in phosphate and 17 nmol/l in Tris-Cl- buffer. T4 binding to FDH albumin was inhibited by a range of substances in the order: 8-anilino-1-naphthalene sulphonic acid greater than merthiolate greater than propylthiouracil greater than methyl-thiouracil greater than carbimazole greater than salicylate greater than barbitone. Binding of T4 was competitively inhibited by low concentrations of dithiothreitol (DTT). The effect of DTT 0.1-0.5 nmol/l was reversed by removal of DTT by dialysis. Competition with a range of iodothyronines indicated that the 3', 5'-iodine atoms are most important for binding to this site. Serum binding of salicylate, frusemide, fenclofenac and barbituric acid, and a range of steroid hormones was similar in FDH and normal sera. Serum levels of sex hormone binding globulin (SHBG), were not significantly different from sex-matched controls. Nuclear [125I]-T3 binding sites in circulating lymphocytes from two FDH subjects showed affinities (Kd) of 59 and 79 pmol/l (normal 67 +/- 7 pmol/l, n = 6). These findings suggest that the highly specific binding anomaly of FDH is due to a disulphide-dependent structural change in albumin.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Protein Disorders↗
PubMed1986

Treatment of mineralocorticoid-resistant renal hyperkalemia with hypertension (type II pseudohypoaldosteronism).

A 16 year old girl with the rare syndrome characterised by hypertension, hyperkalemia, and acidosis was treated with a range of drugs, including thiazides, frusemide, and beta-adrenoceptor antagonists. None of the agents normalised the hypertension and biochemical abnormalities. Best results were obtained with methyclothiazide in full dosage, which normalised the blood pressure, serum potassium level, and bicarbonate level in the face of increased plasma renin activity. Empirical treatment with thiazides is the most satisfactory method for long term management.

Acidosis↗
PubMed1986

Non-isotopic spectrophotometric determination of the unbound fraction of drugs in serum.

A spectrophotometric method to measure the free fraction of highly-bound drugs in serum has been established for a range of non-steroidal anti-inflammatory drugs (NSAIDs) and for frusemide. Spectrophotometry is used to measure fractional transit of drug from a large volume of dialysate to a small volume of serum during dialysis to equilibrium. The method, which depends on the principle that drug transit from dialysate to serum is proportional to serum binding, requires neither isotopic drug preparations nor specific drug assays, is independent of extraction efficiency from the dialysate and requires no measurements from the serum compartment. Estimates of percent unbound fraction (% UF) for aspirin (6.0 +/- 0.9%), phenylbutazone (0.9 +/- 0.2%), and frusemide (1.8 +/- 0.2%) were comparable with those obtained with 14C drug preparations. Values for % UF were determined for eleven additional NSAIDs. The method was valid for a four-fold change in serum: dialysate ratio. Kinetics of frusemide binding to serum were comparable using [14C]frusemide and the test method. This technique may have general application in establishing the % UF for substances that are extensively bound to serum proteins and for identifying sera that show abnormal binding.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1986

Specific methods to identify plasma binding abnormalities in euthyroid hyperthyroxinemia.

Methods to identify the plasma T4-binding abnormalities that can cause euthyroid hyperthyroxinemia were evaluated in patients with excess T4-binding globulin, familial dysalbuminemic hyperthyroxinemia, prealbumin-associated hyperthyroxinemia, and autoantibody binding of T4. Familial dysalbuminemic hyperthyroxinemic serum showed a unique persistence of abnormal [125I]T4 binding when diluted 1:100 in phosphate buffer with added 1000-fold excess of unlabeled T4 (10(-6) M T4). Immunoprecipitation of [125I]T4 by antibody to prealbumin, precipitation of [125I]T4 by polyethylene glycol 6000 19%, and in vitro resin uptake of T3 were specific for prealbumin-associated hyperthyroxinemia, autoantibody binding of T4, and T4-binding globulin excess, respectively. These simple methods facilitate investigation of patients with euthyroid hyperthyroxinemia and will identify individuals and families at risk of misdiagnosis by standard methods. Use of these techniques rules out the known binding abnormalities in hyperthyroxinemic patients and may make the diagnosis of generalized hormone resistance more specific.

Humans↗