Philip Marsden

AMANTADINE DOSAGE IN TREATMENT OF PARKINSON'S DISEASE

Abstract Forty-three patients with parkinsonism were included in a trial of amantadine, doses of 100, 300, and 500 mg. per day being given each for a fortnight in random order to all patients. Every patient completed the trial. Results confirmed the benefit seen with amantadine in previous trials, and showed considerable individual variation in optimum dose, although the preferred dose was 300 mg. per day, resulting in a 26% reduction in initial disability score. The results at each dose level were independent of age, sex, duration of disease, concurrent medication, or type of disease. The response to amantadine at each dose level was greatest in the most disabled patients. Side-effects suggestive of atropine intoxication were seen in a quarter of patients at some stage of the trial, but could be abolished in some cases by reducing or stopping concurrent medication with benzhexol.

Predicting protein–ligand binding affinities: a low scoring game?

We have investigated the performance of five well known scoring functions in predicting the binding affinities of a diverse set of 205 protein-ligand complexes with known experimental binding constants, and also on subsets of mutually similar complexes. We have found that the overall performance of the scoring functions on the diverse set is disappointing, with none of the functions achieving r(2) values above 0.32 on the whole dataset. Performance on the subsets was mixed, with four of the five functions predicting fairly well the binding affinities of 35 proteinases, but none of the functions producing any useful correlation on a set of 38 aspartic proteinases. We consider two algorithms for producing consensus scoring functions, one based on a linear combination of scores from the five individual functions and the other on averaging the rankings produced by the five functions. We find that both algorithms produce consensus functions that generally perform slightly better than the best individual scoring function on a given dataset.

SERUM TRIIODOTHYRONINE CONCENTRATION IN THE DIAGNOSIS OF HYPERTHYROIDISM

The serum triiodothyronine concentration is superior to the serum thyroxine concentration, the resin uptake test and the free thyroxine index in the diagnosis of hyperthyroidism.

Serum triiodothyronine in solitary autonomous nodules of the thyroid.

Seventeen patients with solitary autonomous nodules of the thyroid were studied. Eight had clinical features of hyperthyroidism though in some the clinical manifestations were mild. The serum T3 concentration was elevated in all patients with hyperthyroidism but the serum T4 and free thyroxine index were within the normal range in five. All patients with hyperthyroidism subsequently responded to treatment. These findings suggest a high incidence of preferential T3 hypersecretion in hyperthyoidism associated with solitary autonomous thyroid nodules. A further nine patients with single autonomous nodules were clinically euthyroid with normal serum T3 and T4 concentrations and remained euthyroid from 6 to 24 months on serial review.

Post-secretory deiodination of iodothyronines released from normal human thyroid cells in vitro.

Abstract The stability of tri-iodothyronine (T3) and thyroxine (T4) in the presence of isolated, cultured normal human thyroid cells has been investigated by radioimmunoassay of the culture medium at intervals to 120 hours. T3 and T4 were both progressively degraded in the presence of cells, and although no significant deiodination was produced by fresh culture medium, the medium withdrawn from confluent cell cultures at 120 hours was capable of degrading subsequently - added iodothyronines. These findings provide evidence for the in vitro release of an iodothyronine deiodinase, and this is discussed in terms of the net decrease in medium iodothyronine levels observed in earlier studies of in vitro T3 and T4 release.

Evidence for differential synthesis of thyroxine and tri-iodothyronine by cultured human thyroid cells following exposure to thyrotrophin or dibutyryl cyclic AMP

Abstract Cultured human thyroid cells treated with thyrotrophin (TSH) or dibutyryl cyclic AMP release more tri-iodothyronine (T3) and thyroxine (T4) than unsupplemented cells. Column chromatography was used to investigate the secretion of newly-synthesised 125-I labelled T3 and T4 from cells cultured with 125-I and TSH or dibutyryl cyclic AMP. Radioimmunoassays were used to determine total T3 and T4 release from cells cultured with unlabelled iodide. Iodothyronines released after TSH addition contained more 125-I than those released after dibutyryl cyclic AMP. This increase in 125-I was primarily in “new” T4. Release of “new” T3, however, was increased more by dibutyryl cyclic AMP than by TSH. Dibutyryl cyclic AMP and TSH were comparable in their stimulation of total T3 and total T4 release. Interpretation of these observations suggests that TSH and dibutyryl cyclic AMP may differ in some aspects of their in vitro effects on cellular iodination and iodothyronine coupling systems.

CLOMIPHENE AS A TEST OF PITUITARY FUNCTION

Abstract Clomiphene citrate has been used as a test for pituitary reserve of luteinising hormone in eleven patients with pituitary disease and has been compared with standard tests of pituitary function. The test seemed to separate quite clearly patients with complete hypopituitarism from those with partial hypopituitarism and may prove to be a useful diagnostic test.

Thyroid ‘hot’ nodules

A retrospective analysis of thyroid scintiscanning at one hospital over a 3-year period revealed nineteen patients in whom a solitary, hyperfunctioning thyroid nodule was producing thyrotoxicosis. Most of the patients had clinical features referable to hyperthyroidism and in the majority a solitary nodule was palpable in the neck which was found to correlate well with the location of the ‘hot’ nodule on scanning. Cardiac failure was present in 21% and atrial fibrillation occurred in 37%. The 131I uptake by the thyroid was of little value in deciding whether or not the patient was toxic, but there was good agreement between serum protein bound iodine determinations and measurement of serum thyroxine and resin uptake tests. There appeared to be no relationship between the size of the nodule and its degree of activity.

Studies of the in vitro sensitivity of iodothyronine synthesis to methimazole in normal human thyroid cells

The comparative effects of methimazole (MMI) on resting and thyrotropin (TSH) — stimulated human thyroid cell cultures were investigated in terms of the release of iodoprotein and newly — synthesised iodothyronine hormones into the culture medium during a 48h period of incubation. Iodoprotein recovery was increased after TSH, but both basal and TSH — enhanced iodoprotein release were depressed by MMI. TSH increased the release of tri-iodothyronine (T3) and thyroxine (T4), and although the TSH — enhanced T3 and T4 levels were depressed after MMI, (i) the basal levels found in control cultures were not attained, and (ii) T3 was more susceptible than T4 to MMI suppression, at high TSH levels. These findings indicate a retention of the in vivo thyroidal sensitivity to MMI, under basal conditions and moderate TSH stimulation in vitro. The system may therefore facilitate further investigation into the mode of MMI suppression of peroxidase systems involved in iodothyronine hormone synthesis within the intact human thyroid cell.

A comparison of thyrotropin- and dibutyryl cyclic AMP-induced thyroglobulin iodination in cultured human thyroid cells

The relative degree of 125-I labelling of thyroglobulin-- bound mono-iodotyrosine (MIT) and di-iodotyrosine (DIT) in isolated, cultured human thyroid cells has been compared following exposure of 125-I supplemented cells to 100 mU/ml of bovine thyrotropin (TSH) or 1.0 mM dibutyryl cyclic AMP (dBcAMP) for 96 hours. Pronase digestion of the lysed cells and Sephadex G-10 fractionation of the digested lysates revealed a predominance of [125-I]MIT over [125-I]DIT in both sets of experimental cells as well as in controls. Levels of [125-I]DIT, however, were only enhanced above control values in cells incubated with TSH. These findings suggest that an increase in availability of intracellular iodide, following cellular exposure to TSH, may facilitate a preferential synthesis of DIT relative to that of MIT. This theory offers an explanation for the differential effects of TSH and dibutyryl cyclic AMP on the levels of newly--synthesised T4 recovered from the cells used in this study, and from the culture medium in a previous investigation.