Trimethoprim and thyroid function.
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Biomedical subjects
Publications and source records attributed to H N Cohen.
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The effects on pituitary-thyroid function of the commonly prescribed anti-bacterial preparations co-trimoxazole and co-trifamole, and their component drugs, have been studied in the rat and compared to the changes caused by propylthiouracil. Co-trimoxazole and co-trifamole, in doses 20-fold in excess of a pharmacological dose administered for 10 days, produced marked changes in hormone levels consistent with blocking of hyperplastic goitre formation, were also demonstrated. Propylthiouracil produced less marked changes of thyroid hormone levels but higher levels of thyroid-stimulating hormone. Pharmacological doses of co-trimoxazole and co-trifamole and sulphamoxole, the sulphonamide component of co-trifamole, caused significant changes in thyroid hormone levels consistent with anti-thyroidal activity. In contrast, there was no evidence that trimethoprim, which is common to both preparations, or sulphamethoxazole, the sulphonamide component of co-trimoxazole, had an anti-thyroidal action, indeed, serum thyroxine levels were significantly increased at pharmacological dosage. We have concluded that the new commonly prescribed combination preparations retain the goitrogenic properties of the earlier sulphonamides.
In a randomized, crossover, multiple dose study, ten healthy volunteers received the recommended dosages of cotrimoxazole (80 mg trimethoprim and 400 mg sulfamethoxazole) and co-tri-famole (80 mg trimethoprim and 400 mg sulfamoxole) for five days each. Urinary levels of trimethoprim and each sulfonamide were measured daily for five days. The urinary ratios of trimethoprim and sulfonamide for both formulations were consistently lower than those considered optimal for synergy. Concentration of trimethoprim in the urine from both preparations was found to be greatly in excess of the MIC for trimethoprim-sensitive urinary pathogens (approximately 2 microgram/ml). The sulfonamide levels achieved were not consistently in excess of their MIC (approximately 200 microgram/ml) for either preparation.
24-h whole-body retention (WBR) of diphosphonate (a sensitive indicator of skeletal metabolism) was measured in 37 oophorectomised women. 14 women had been prescribed oestrogen supplements and 3 of these had defaulted from therapy. For the study group there was a significant correlation between WBR and both the rate of bone loss as measured by photonabsorptiometry (r = 0.7, p ¿ 0.001) and urinary hydroxyproline (r = 0.53, p < 0.001). The oestrogen-treated group had significantly lower values for WBR and rate of bone loss than the untreated group (p < 0.01, p < 0.01 respectively) indicating suppressed skeletal metabolism. However, the highest values were found in those who had defaulted from oestrogen therapy suggesting a rebound period of accelerated skeletal metabolism and bone loss. There was a significant negative correlation between WBR and oestrogen dosage (r = 0.75, p < 0.02) suggesting that it may be possible to adjust the dosage for optimal skeletal metabolic activity. WBR of diphosphonate provides a simple and sensitive measure of skeletal metabolism which correlates well with conventional measurements of bone loss. WBR may be useful in the screening and identification of women who have increased bone turnover just after the menopause and who may subsequently be at risk of osteoporosis developing.
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The growth hormone (GH) and prolactin (PRL) responses following administration of 10 mg i.v. metoclopramide (MCP) ('Maxolon'--Beecham Pharmaceuticals) have been examined in thirty adolescent males with short stature and delayed puberty, either of whom have isolated growth hormone deficiency. The results demonstrate that peak GH and PRL levels following stimulation were highly significantly correlated when all subjects were analysed together (r = 0.61, P < 0.001) but when the responses of the GH deficient and non-deficient groups of subjects were analysed separately no significant correlation was obtained (P > 0.1), this reflected the fact that the PRL response to MCP was significantly lower in the GH deficient group (P < 0.0002). In addition two boys who demonstrated biochemical GH deficiency prior to puberty only, showed PRL responses similar to boys with normal GH reserves. The results suggest that the PRL response to MCP may be of value in the assessment of stimulation tests of GH reserve, as well as in the selection of patients for treatment with GH.
A comparison has been made between themetabolic consequences of daily administration for 6 weeks of 1.0 micrograms and 0.5 micrograms 1 alpha hydroxyvitamine D3 (1 alpha(OH)D3) in twenty patients with senile osteoporosis. There was no significant difference in the increase of calcium absorption which occurred in the two treatment groups between the beginning and end of the trial period. Serum and urinary calcium rose significantly in those receiving 1.0 micrograms 1 alpha(OH)D3 but not in the lower dosage group. Serum parathyroid hormone levels were suppressed in the higher dosage group only. There was a significantly greater rise of serum inorganic phosphate, and fall of serum magnesium, on the higher dosage, but no significant change in serum creatinine occurred in either group. It is, therefore, suggested that in long term therapy regimes for osteoporosis incorporating 1 alpha(OH)D3, 0.5 micrograms may be a more suitable daily dose than 1.0 micrograms 1 alpha(OH)D3.
The clinical value of four laboratory methods of assessing free thyroxine status was compared in 82 consecutive patients newly referred to a thyroid clinic with suspected thyroid dysfunction. The methods of determining free thyroxine used were: (1) free thyroxine index using a thyroid hormone uptake test (FTI (THUT)); (2) a free thyroxine index using thyroxine binding globulin (FTI (TBG)); (3) a kinetic radioimmunoassay (Immophase); and (4) an equilibrium dialysis method. The definitive thyroid status was evaluated by a combination of clinical assessment (including Wayne index), routine tests of thyroid function (total T4, T3, TSH, and TRH tests where appropriate), and by therapeutic trial in one case. The diagnostic efficiency of the tests was markedly dependent upon the method of determining the reference range for euthyroid patients. Best efficiency for each test was achieved using an amended range after excluding outliners. Test efficiency was then 97.6% for FTI (THUT) and the kinetic RIA and 96.8% for FTI (TBG). Misclassification by one or more of these tests occurred in only four patients (mild hypothyroid, euthyroid on phenytoin, euthyroid on oral contraceptive and valium, T3 hyperthyroid). In contrast, free T4 by equilibrium dialysis was much less efficient (86.6%) and was technically the most complex. Overall the kinetic T4 RIA provided similar diagnostic information to the indirect indices. However, further studies of cost benefit in settings other than a thyroid clinic are required to assess whether this method might replace total T4 and/or FTI as a first-line test of thyroid function.
Growth hormone is essential for sustaining longitudinal growth in man. However, during the last 20 years, it has become evident that the actions of growth hormone, at a cellular level, are mediated by specific growth promoting factors. This paper describes the nature and actions of mammalian growth factors and summarises the immense contribution that the measurement of these substances has made towards the elucidation of many problems in the science of human growth and development.
We describe a rapid, precise, and reliable procedure for assay of trimethoprim in serum and urine by ion-pair chromatography. Trimethoprim concentrations in urine are determined by an externally standardized, direct-injection procedure; assay in serum involves a simple preliminary extraction and internal standardization. The assays are suitable for pharmacokinetic studies and have been applied to determination of trimethoprim concentrations in serum and urine during therapy with Co-trimoxazole, a sulfonamide/trimethoprim preparation.
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A comparison was made between the growth hormone (GH) response to metoclopramide ('Maxolon'--Beecham Laboratories) and insulin induced hypoglycaemia in thirty-five short adolescent males. Both tests initially caused adequate release of GH from the pituitary gland in 86% of those subjects who had normal GH reserve. The peak growth hormone responses of the two tests were similar in magnitude and were strongly correlated (r = 0.80, P less than 0.001). Both tests raised serum GH to a similar degree in twenty-nine out of the thirty-five boys (83%), but four boys who responded satisfactorily to hypoglycaemia failed to respond to metoclopramide (MCP) stimulation, and two boys who failed to respond to hypoglycaemia responded satisfactorily to MCP stimulation. MCP stimulation does not require prior preparation of the patient and is relatively free of side effects. Consequently, it is suggested that MCP stimulation may be a useful 1 hour out-patient test for growth hormone deficiency in this relatively common group of patients.
The growth hormone (GH) response to 10 mg intravenous metoclopramide (MCP) ('Maxolon'--Beecham Laboratories) was determined in ten hypogonadal adult males. All the subjects responded with a peak growth hormone level greater than 14 mU/l within 1 hour of administration of MCP. Seven normal adult males did not respond to MCP administration. It is concluded that MCP stimulation may be a useful test for both prolactin and growth hormone reserve in hypogonadal males.
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Six patients with longstanding physical and mental symptoms who had not been helped by many years of conventional medical investigation and treatment experienced immediate relief of symptoms when they avoided certain foodstuffs. This clinical study supports the view that some foods may cause widespread and disabling symptoms in people who are sensitive to them.
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