Biomedical subjects
Publications and source records attributed to D S Cooper.
The clinical management of the hyperthyroid patient is controversial, because there is no perfect treatment. Factors that influence the choice of therapy include the patient's age, sex, and type of hyperthyroidism, as well as patient and physician preference.
The power dissipated in the vocal folds during phonation results from viscous loss in the fold tissues and can be estimated on the basis of a simplified representation of the geometry and movement of the folds. Assuming this power is converted into heat, it combines with the effects of muscle contraction, blood perfusion, and thermal conduction to the surface of the folds to determine fold temperature. To isolate the thermomechanical source of heat, the vocal folds of excised larynges were vibrated vertically over a range of frequencies and amplitudes, while the temperature rise in them was measured by inserted fine-wire thermocouples. The temperature rise observed was somewhat smaller than that predicted. This may be partly accounted for by convective and evaporative cooling of the vocal fold as it moved relative to the ambient air. Future studies should consider the time course of heating and vocal fold geometry in more detail.
It is a general practice to insert a single electrode pair per muscle for electromyographic recording. The location of electrode insertion influences the character of the signal obtained. The objective of the experiment was to study the relationships between electromyographic signals recorded simultaneously from different locations in an anatomically simple muscle involved in speech production. Signals from three pairs of fine wire electrodes placed high, middle, and low in the palatoglossus muscle of five speakers of American English were amplified, rectified, and integrated. The data were analyzed statistically to determine the patterns of similarity and degree of independence among simultaneous signals from different sites in the muscle for a given speaker. The middle signal was most often the best, and the low signal was most often the poorest representative of the group of signals. The greatest similarity was found between the high and middle signals; next most similar were the middle and low signals. Similarity between signals varied with utterance. In some cases, the relationship between two signals varied over time. This variation may be due to change in interelectrode distance during anisometric contraction or to different motor unit firing patterns.
Nine patients with hyperthyroidism due to Graves' disease did not respond to therapy with very large doses (800 to 2000 mg/d) of propylthiouracil. In eight patients, studies showed propylthiouracil was absorbed and metabolized normally. Five patients had no detectable propylthiouracil in their serum 2 to 3 hours after supposedly taking their medication at home, and three patients had markedly abnormal results of perchlorate discharge tests after receiving propylthiouracil under supervision. After evaluation, noncompliance was thought to be the reason for treatment failure in six of the nine patients; one patient was possibly resistant. In two patients, data were insufficient, although intermittent noncompliance could not be ruled out. Among patients who respond poorly to propylthiouracil therapy, noncompliance is the most likely reason. In such patients, methimazole should be substituted for continued massive doses of propylthiouracil.
Over the past four decades, a great deal has been learned about the pharmacology and mechanisms of action of antithyroid drugs. Their ability to inhibit hormone biosynthesis involves complex interactions with thyroid peroxidase and thyroglobulin, many of which are still poorly understood. Their spectrum of activity is much wider than previously thought, and a number of clinically important extrathyroidal actions have been identified. Despite a greater appreciation for the intricacies of antithyroid-drug pharmacology, controversies still surround the use of these agents in the treatment of thyrotoxicosis. These controversies are apt to continue until the pathophysiology of Graves' disease is fully elucidated.
The cytoprotective effects of propylthiouracil (PTU) were studied in rats treated with the hepatotoxin D-galactosamine (D-GNH2). Five days of PTU pretreatment prior to D-GNH2 caused hypothyroidism and a significant reduction in liver injury as assessed by serum transaminase levels. When PTU was administered as a single dose with D-GNH2, significant decreases in transaminase also occurred at times when thyroid function was unchanged. Furthermore, aminopyrine oxidation showed significant impairment after D-GNH2 and was normalized by one dose of PTU. Further studies were carried out in thyroidectomized rats. PTU caused significant reductions in transaminase levels when given for 5 days pretreatment or as a single dose. Animals receiving pretreatment with PTU plus thyroxine (T4) also had significant decreases in serum transaminase. The antithyroid drug methimazole also had a hepatoprotective effect, while two other potent antithyroid compounds (2-thiouracil and 2-thiobarbituric acid) did not. These data suggest that PTU can protect against liver injury induced by D-GNH2, that the effect is independent of thyroid function, and that this effect is not common to all thiol-containing antithyroid drugs.
Stress-strain curves were obtained from vocalis muscle tissue that was kept viable in an aerated Krebs-Ringer solution after excision of the larynx from live dogs. Results are compared to similar curves obtained from dead tissue and suggest that vocal fold elasticity depends on the level of strain, the elapsed time after elongation, the condition of the tissue, and the choice of rest length for strain computation. Tables of Young's moduli for various conditions are given.
Methimazole [1-methyl-2-mercaptoimidazole (MMI)] was given to normal male rats in their drinking water in concentrations ranging from 0.0001-0.05% for either 1 week or 1 month. Serum MMI levels in the rats ranged from 0.008-19.6 micrograms/ml, and were similar after 1 week and 1 month of treatment. Serum MMI was linearly related to the MMI concentration in the drinking water (r = 0.98, P less than 0.001). In contrast, intrathyroid MMI content plateaued with increasing MMI concentrations in the water, and was linearly related to the logarithm of the MMI concentration. At the highest MMI concentration (0.05%), thyroid MMI contents were similar in the 1-week and 1-month groups (approximately 1 X 10(-4) M). Surprisingly, at lower MMI concentrations, thyroid MMI content was significantly higher in the 1-week group than the 1-month group. Thyroid function was inhibited by MMI with similar depression of serum T4 or T3 after 1 week or 1 month of MMI treatment. Although the MMI concentration for 50% suppression of thyroid PBI was 0.003% in both groups, thyroid MMI content at this MMI concentration was 97 microM after 1 week but only 15 microM after 1 month. The continued thyroid-inhibiting activity of MMI at 1 month, despite a striking decrease in thyroid MMI content, may relate to intrathyroid iodide depletion, which was more severe after 1 month (thyroid 127I = 40 microM) than after 1 week (thyroid 127I = 140 microM) or in controls (470 microM). Rats were given 0.05% MMI for either 1 week or 1 month, and the drug was then withdrawn. In the 1-week group, serum MMI disappeared biexponentially, with a rapidly declining phase (t1/2 = 3.2 h) and a second, slower disappearance phase (t1/2 = 47.7 h). Similar findings were noted after 1 month of treatment. The disappearance of thyroid MMI was also biexponential after 1 week, but this variable could not be evaluated after 1 month because thyroid MMI fell rapidly to undetectable levels. There was a highly significant correlation in the 1-week group between the disappearance of MMI from the thyroid and the recovery of thyroid function as assessed by thyroid PBI (r = 0.81, P less than 0.01). Despite the very rapid disappearance of MMI from the thyroid after 1 month of treatment, the recovery time of thyroid PBI was significantly longer than after 1 week of treatment (2.1 days vs. 1.4 days for 50% recovery, P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)
A RIA for the antithyroid drug methimazole [1-methyl-2-mercaptoimidazole (MMI)] has been developed. A MMI derivative, 5-COOH-MMI, was conjugated to porcine thyroglobulin, and antibodies to the conjugate were raised in rabbits. [35S]MMI was used as the tracer. At a final antibody dilution of 1:100, the assay could detect MMI in amounts as low as 2.5 ng. The putative MMI metabolites 3-methyl-2-thiohydantoin and 1-methylimidazole had minor cross-reactivities of 2.1% and 0.5%, respectively. There was no effect of serum proteins on MMI immunoactivity. MMI was given orally to normal subjects (n = 6), hyperthyroid patients (n = 5), patients with hepatic cirrhosis (n = 4), and normal lactating women (n = 4). After a single dose of 60 mg, peak MMI levels were similar in the normal subjects and the hyperthyroid patients (approximately 1.5 micrograms/ml). Patients with hepatic cirrhosis had similar peak MMI serum levels [1.31 +/- 0.3 (+/- SEM) micrograms/ml], but the half-time of MMI disappearance from serum was significantly prolonged compared with the normal value (21.2 vs. 6.0 h; P less than 0.001). The lactating women received 40 mg MMI as a single dose. Over the next 8 h, mean MMI levels in serum and milk were nearly identical, with a mean serum to milk ratio of 1.03 +/- 0.16. A total of 70.0 +/- 6.0 micrograms MMI was excreted in the milk over the 8-h time period. This amount of MMI could affect neonatal thyroid function.
The indications for treating patients with subclinical hypothyroidism (normal serum thyroxine and free thyroxine levels, but elevated serum thyrotrophin levels) are poorly defined. In this study, 33 patients with subclinical hypothyroidism were randomly assigned in a double-blind manner to receive placebo or L-thyroxine therapy and were followed for 1 year with thyroid function tests, serum lipid measurements, basal metabolic rate and systolic time interval determinations, and a questionnaire on hypothyroid symptoms. The placebo group showed no changes in thyroid function or peripheral indices of thyroid hormone action. In the thyroxine-treated group, serum lipids and the mean systolic time interval did not change, but the systolic time intervals became normal in the 5 patients with the most abnormal baseline values. Symptoms improved in 8 of 14 patients receiving thyroxine and in 3 of 12 patients receiving placebo (p less than 0.05). L-Thyroxine therapy may be useful for patients with subclinical hypothyroidism with abnormal myocardial contractility or symptoms consistent with mild hypothyroidism, or both.
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We have studied the effects of dopamine on the secretion of TSH and its subunits in vivo and in vitro. Four normal controls, seven patients with primary hypothyroidism, two patients with peripheral resistance to thyroid hormone (PRTH), and two patients with alpha-secreting pituitary tumours underwent a 3-h dopamine infusion (4 micrograms/kg/min). Serial blood samples were drawn for TSH, PRL, alpha, and TSH-beta subunit. In normal subjects, TSH fell from 2.1 +/- 0.9 (+/- SE) to 0.7 +/- 0.1 microU/ml (P less than 0.05), and alpha declined from 1.5 +/- 0.4 to 1.0 +/- 0.1 ng/ml (P less than 0.01). TSH-beta was at or slightly above the detection limits of the assay before and after dopamine. In hypothyroidism, basal serum TSH was 81 +/- 14 microU/ml. With dopamine, TSH fell to 35 +/- 8 microU/ml (P less than 0.001), while alpha decreased from 3.2 +/- 0.4 to 2.0 +/- 0.3 ng/ml (P less than 0.01). Serum TSH-beta also declined from 0.97 +/- 0.06 to 0.57 +/- 0.05 ng/ml (P less than 0.001). A similar fall in TSH and alpha was seen in the two patients with PRTH. In normals and hypothyroid patients, the percentage change in alpha concentration was significantly less than that observed for intact TSH. This is due presumably to the contribution of the gonadotrophs to the circulating alpha pool. TSH and TSH-beta were undetectable in the two pituitary tumour patients, and alpha declined only slightly in each patient after dopamine. The in vitro effects of dopamine were studied using cultured bovine anterior pituitary cells. Dopamine (10(-4)-10(-8) mol/l) did not change basal TSH, alpha, or TSH-beta release. However, dopamine at all doses significantly blunted TRH (10(-7) mol/l)-stimulated TSH and TSH-beta release, and blunted TRH-mediated alpha release at the two highest dopamine doses. These data suggest that dopamine modulates both TSH and TSH subunit secretion. These effects may be exerted directly at the level of the thyrotroph.
We have developed a highly sensitive and specific RIA for propylthiouracil (PTU) which uses 125I-labeled PTU as the radioactive ligand. At a final antibody dilution of 1:10,000, the detection limit for PTU was 100 pg; cross-reactivity with circulating, urinary, and intrathyroid PTU metabolites was negligible. Using this assay, serum and thyroid PTU levels were determined after short term (1 week) and long term (1 month) PTU treatment at doses of 0.0001-0.05%. Serum PTU was a linear function of the PTU dose (r = 0.99; P less than 0.001), whereas thyroid PTU was a linear function of the logarithm of the PTU dose (r = 0.99; P less than 0.001). Serum PTU levels were higher after 1 month of treatment than after administration for 1 week, probably because steady state conditions were not achieved after 1 week. At several doses, thyroid PTU levels were also higher after 1 month of treatment, but the differences were not as striking as those seen in the serum levels. The pharmacokinetic data are consistent with a multicompartmental model for PTU distribution. The logarithmic relationship between thyroid PTU and PTU dose suggests a saturable uptake mechanism for PTU by the thyroid; inhibition of thyroid PTU uptake by PTU itself could also explain these observations.
Using a sensitive and specific RIA for propylthiouracil (PTU), we examined the effects of short term (1 week) and long term (1 month) PTU treatment on thyroid function in the rat, and correlated changes in thyroid function with serum and thyroid PTU levels. After 1 week, dose-dependent decreases in thyroid PBI, serum T4, and serum T3 were observed, with concomitant elevations in the serum rT3 to T4 ratio and serum TSH. Fifty percent suppression of thyroid PBI occurred at a PTU concentration in the drinking water of 0.0005% (ED50), with concomitant serum and thyroid PTU levels of 0.3 micrograms/ml and 300 ng/thyroid, respectively. After 1 month of PTU, serum T4 values were lower than after 1 week of treatment for all PTU concentrations, but values for the other thyroid functional variables were similar to those in the 1 week group at comparable PTU dosage. The PTU dose-response curve for thyroid PBI was similar to that seen after 1 week of treatment, with an ED50 of 0.0004%. After discontinuation of PTU treatment, PTU disappeared from serum in a biexponential fashion, with an early rapid distribution phase (t 1/2 = approximately 4 h) and a second slower elimination phase (t 1/2 = approximately 2.6 days). In the thyroid, an initial increase in PTU content was seen up to 18 h after PTU withdrawal; thereafter, thyroid PTU declined linearly, with a t 1/2 of 1.4 days in both groups. After PTU withdrawal, thyroid PBI recovered with a t 1/2 of 1.09 days after 1 week on PTU, but recovery was prolonged (t 1/2 = 2.8 days) after 1 month of treatment. Log thyroid PTU and log thyroid PBI were linearly related after PTU withdrawal (r = 0.97; P less than 0.001) after 1 week but not after 1 month. Serum T4 and serum T3 remained below control values for 2 days, but then rapidly normalized, with T3 values rising transiently above the control value. This rebound occurred at a time when PTU was still present within the thyroid, before thyroid PBI had returned to baseline. These data indicate a close inverse relationship between PTU dose and both thyroid hormone biosynthesis and peripheral T4 deiodination. In addition, short and long term PTU treatments have quantitatively similar effects on thyroid function, although recovery of thyroid function is prolonged after long term treatment. The biexponential disappearance of PTU from the serum is compatible with a two-compartment model of PTU distribution. The early increase in thyroid PTU after drug withdrawal is suggestive of an inhibitory effect of PTU upon its own uptake by the thyroid, whereas the faster disappearance of PTU from the thyroid than from serum is consistent with intrathyroid drug metabolism.
The records of all patients with antithyroid drug-related agranulocytosis at two Boston hospitals (Group 1, 14 patients), as well as the published case reports of 36 patients with this syndrome (Group 2) were reviewed. The clinical characteristics of these patients were then compared with those of 50 hyperthyroid patients who had taken antithyroid medication without untoward hematologic reactions (Group 3). The mean ages of patients in Group 1 and Group 2 were significantly greater than that of Group 3 (50.6 +/- 16 years versus 35.7 +/- 13.7 years, p less than 0.001; 46.3 +/- 18.7 years versus 35.7 +/-- 13.7 years, p less than 0.02). By chi-square analysis, the relative risk of developing agranulocytosis in patients over age 40 was 6.4 times that among younger patients (p less than 0.001). The mean doses of methimazole in Group 1 and Group 2 were significantly higher than that in Group 3 (43.8 +/- 9.9 mg/d versus 29.5 +/- 10.4 mg/d, p less than 0.001; 40.7 +/- 15.7 mg/d versus 29.5 +/- 10.4 mg/d, p less than 0.02), with and 8.6-fold increased risk of agranulocytosis with doses greater than 40 mg/d (p less than 0.01). In contrast, the mean doses of propylthiouracil did not differ among the three groups. These data suggest that antithyroid drugs should be administered cautiously to patients over age 40. Because no cases of agranulocytosis were seen with methimazole doses less than 30 mg/d, low-dose methimazole therapy may be safer than high-dose therapy or treatment with conventional doses of propylthiouracil.
The metabolic, cardiovascular, renal, and pulmonary responses of 10 hypothyroid patients were studied during the first week of therapy with intravenous levothyroxine (L-thyroxine), 100 micrograms per day. Mean serum thyroxine, triiodothyronine, and reverse triiodothyronine concentrations were normalized within four days. Significant decreases in serum thyrotropin, creatine phosphokinase, and cholesterol levels, and an increase in the basal metabolic rate, were observed. An early cardiovascular response was demonstrated by serial measurement of the mean pre-ejection period (138 to 134 msec, p less than 0.05), its ratio to left ventricular ejection time (0.49 to 0.46, p less than 0.02), and pulse-wave arrival time (236 to 224 msec, p less than 0.05). The mean renal excretion of a water load (four hours) increased (54 to 77 percent, p less than 0.02) by the fourth day. The blunted ventilatory responses to hypercapnea seen in two patients were improved. We conclude that a physiologic replacement dose of intravenous L-thyroxine for one week produces significant responses in organ systems responsible for the common clinical complications of myxedema.
Six patients with hyperthyroxinemia (five men and one woman) were evaluated for possible hyperthyroidism. All were taking large daily doses of propranolol--480 +/- 155 (+/- SE) mg--for treatment of angina pectoris. The patients had no clinical evidence of hyperthyroidism, although three had small goiters. Further evaluation of the patients revealed elevated serum free thyroxine levels and/or free thyroxine index, low-normal serum triiodothyronine levels, and elevated serum reverse triiodothyronine levels in all six. The thyroid-stimulating hormone response to thyrotropin-releasing hormone was normal in two patients, subnormal in three patients, and absent in one patient. One patient was restudied while receiving low-dose propranolol (80 mg a day), with normalization of all thyroid functional parameters. The data suggest that the abnormalities seen in patients taking high doses of propranolol were due to drug-induced blockade of iodothyronine deiodination. Signs and symptoms of hyperthyroidism are lacking in patients taking large doses of propranolol. If such a patient is discovered to have an elevated serum thyroxine level, a more complete evaluation of thyroid function is necessary before the diagnosis of thyrotoxicosis can be made. The thyrotropin-releasing hormone test may be of particular value in this circumstance.