Kaj Siersbæk-Nielsen

Carbamazepine-induced acceleration of diphenylhydantoin and warfarin metabolism in man.

Diphenylhydantoin half‐life was determined in 5 patients before and during treatment with carbamazepine. It caused a significant decrease in the diphenylhydantoin half‐life from 10.6 hours to 6.4 hours. Seven patients who for a period had been given diphenylhydantoin were also started on carbamazepine. This resulted in a fall in serum diphenylhydantoin levels in 3 of the patients. Alterations in warfarin half‐life, serum warfarin, and plasma prothrombin‐proconvertin concentration during carbamazepine treatment were compatible with a stimulation of warfarin metabolism. The effect of carbamazepine on diphenylhydantoin and warfarin metabolism is probably explained by an induction of the drug‐metabolizing enzyme system in the liver.

Free thyroxine measured in undiluted serum by dialysis and ultrafiltration: Effects of non-thyroidal illness, and an acute load of salicylate or heparin

In vitro dilution of serum during processing of a free T4 assay explains to some extent the divergent results obtained in non-thyroidal illness. If serum from such patients contains low affinity T4 protein binding inhibitors, as has been suggested, in vitro dilution will result in spuriously reduced serum free T4 measurements. If these inhibitors cross the dialysis membrane in an equilibrium dialysis assay, their inhibitory effect will be weakened, and in vitro free T4 levels will decrease, even in undiluted serum. In contrast, ultrafiltration methods on undiluted serum seem accurate. We have compared a new, commercially available dialysis technique with an in-house ultrafiltration method for free T4 measurements in undiluted serum. Control subjects (n = 41) had 14% higher free T4 (P < 0.02) by ultrafiltration. Non-thyroidally ill patients not receiving glucocorticoids or dopamine (n = 54) had unaltered free T4 levels, 28.4 +/- 10.3 pmol/l (dialysis) and 31.0 +/- 10.3 pmol/l (ultrafiltration). Dopamine infusion in somatic ill patients (n = 11) resulted in reduced free T4 in both assays but only significantly for dialysis, and subjects with familial dysalbuminemic hyperthyroxinemia (n = 8) had unaltered free T4 levels in both assays. Salicylate (1.5 g) given orally 09:00 h. (n = 5) resulted within 30 min, in increased (P < 0.01) free T4 as measured by both techniques, although more pronounced and sustained as measured by ultrafiltration. Serum TSH decreased concomitantly (P < 0.01). These findings were confirmed when salicylate was administered at 13:00 h. (n = 8). The dialysis procedure resulted in a decrease in serum salicylate of 14% (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of probenecid on the excretion of ampicillin in human bile

1 Ampicillin concentrations were determined in serum and bile after intravenous injection into patients with T‐tube bile drainage of 1 gram ampicillin before and during probenecid medication. The concentrations were followed up to fifteen hours after injection. 2 Probenecid increased the half‐life of ampicillin in serum from 74 minutes to 137 minutes. 3 Ampicillin concentrations in bile were higher following probenecid medication and a concentration over 5 μg/ml was obtained for 3 h longer than before probenecid. 4 The ampicillin concentrations in bile were approximately the same as those in serum both before and during probenecid medication suggesting passive transport of ampicillin from blood to bile. 5 A combined treatment of ampicillin and probenecid might be of clinical value in the therapy of cholangitis and typhoid carriers.

Folic acid and the half-life of diphenylhydantoin in man.

The half‐life of diphenylhydantoin in man was investigated before and after treatment with high doses of folic acid and no significant changes were found. It thus seems unlikely that the possible influence of folic acid on diphenylhydantoin metabolism is mediated by an increased liver metabolism; the possibility, however, remains that the pattern of diphenylhydantoin‐metabolites are altered.

METABOLIC CLEARANCE AND PRODUCTION RATES OF 3,3′‐DIIODOTHYRONINE, 3′,5′‐DIIODOTHYRONINE AND 3′‐MONOIODOTHYRONINE IN HYPER‐ AND HYPOTHYROIDISM

Complete turnover studies of thyroxine (T4), 3,5,3′‐triiodothyronine (T3), 3,3′,5′‐triiodothyronine (rT3), 3,3′‐diiodothyronine (3,3′‐T2), 3′,5′‐diiodothyronine (3′,5′‐T2) and 3′‐monoiodothyronine (3′‐T1) were performed in each of eight healthy subjects, eight hyperthyroid and eight hypothyroid patients, using the single injection, non‐compartmental approach. The median metabolic clearance rate (litre per day per 70 kg) in controls was, T4 1·19; T3 19·7. rT3 147; 3,3′‐T2 1073; 3′,5′‐T2 256 and 3′‐T1 518. Hyperthyroid patients had increased and hypothyroid patients reduced values. The median production rate (PR) (nmol per day per 70 kg) in controls was, T4 117, T3 39, rT3 52, 3,3′‐T2 35, 3′,5′‐T2 14 and 3′‐T1 27. The PR of all iodothyronines studied was increased in hyperthyroidism, the increase in PR of T3 being the most pronounced. Hypothyroid patients had reduced PRs, a reduction which was relatively less pronounced for T3. Assuming thyroidal secretion contributes little rT3 and 3′,5′‐T2, the conversion rates (CRs) of T4 to rT3 and further to 3′,5′‐T2 were calculated. CR of T4 to rT3 in controls was in median 34%. By comparison the CR in hyperthyroid patients was increased to 56% (P < 0·05). In contrast the CR of rT3 to 3′,5′‐T2 was similar in controls and hyperthyroid patients, 26% v. 31%.

Development of hyperthyroidism in nodular goiter and thyroid malignancies in an area of relatively low iodine intake

A high incidence of toxic nodular goiter has recently been described in areas of relatively low iodine intake. We studied the development of hyperthyroidism in nodular goiter and thyroid malignancies in an area of relatively low iodine intake (median 87 μg/24 h). The material comprised a total of 557 patients admitted to our department in the period 1978–88. The follow-up material consisted of 214 patients with a median age of 55 yr (19–86). Eighty-eight percent were females. The period of observation was 33 months (1–205). All patients had technetium thyroid scans, serum T3, serum T4, T3 uptake test and serum TSH performed. TRH tests were performed in 58 patients. During the follow-up period 45 initially euthyroid patients became hyperthyroid (18%). The incidence increased with age, and the median age in the group, who developed hyperthyroidism, was 65 yr. An estimated minimal incidence of toxic nodular goiter was 23/100,000/yr. Contrary to previous assumption, hyperthyroidism developed frequently in elderly patients with nodular goiter in a low iodine intake area. Thyroid cancer was found in 13 patients corresponding an estimated incidence of 1.5/100,000/yr. The cancer incidence was very low compared to other nordic countries with high iodine intake. This finding may suggest a possible influence of iodine intake on the incidence of thyroid cancer.

The prognostic value of parallel measurements of thyrotropin binding inhibiting immunoglobulins (TBII) and thyroid adenylate cyclase stimulating antibodies (TSAb) in Graves’ disease after longterm antithyroid treatment

Thyroid stimulating immunoglobulins were measured in 43 patients with Graves’ disease both before and at the end of longterm antithyroid treatment. Parallel determinations were performed of thyrotropin binding inhibiting immunoglobulins (TBII) and thyroid adenylate cyclase stimulating antibodies (TSAb). Before treatment 33 patients were TBII positive and 32 TSAb positive, and at the end of treatment 19 remained TBII positive and 14 TSAb positive. The frequency of relapse was about 70% in the positive patients and about 40% in the patients, who became negative in either test for thyroid stimulating immunoglobulins. By combination of the two assays 23 patients were positive in both before treatment. In these patients 5 relapsed of the 6 who remained positive for both, while none relapsed of the 5 patients, who became negative during treatment. In the remaining 12 patients either TBI I or TSAb became negative during treatment and 7 of these relapsed. It is concluded, that the combined measurement of TBII and TSAb in this study seemed superior to the separate determinations of either activity in predicting relapse after medical treatment of Graves’ disease, though this evaluation was only possible in part of the patients.

Increased urinary excretion of antidiuretic material in encephalitis.

Two cases of encephalitis with electrolyte and osmolality disturbances typical for hypersecretion of antidiuretic hormone are described. Increased amounts of antidiuretic material were found in the urine using bioassay procedures. Both patients had symptoms suggesting lesions in the limbic region.

ESTIMATION OF FREE THYROXINE INDEX IN THE NEWBORN USING MICRO-METHODS

Abstract. Rogowski, P., Siersbæk‐Nielsen, K. and Mølholm Hansen, J. (Medical Department E, the Obstetrical Department, and the Department of Clinical Chemistry, Frederiksberg Hospital, Copenhagen, Denmark). Estimation of free thyroxine index in the newborn using micro‐methods. Acta Paediat Scand, 63: 201, 1974.–Thyroid function in the newborn has been studied with the purpose of establishing normal values for total plasma thyroxine, T‐3 test and free thyroxine index in the neonatal period using new micro‐methods. Total thyroxine determinations were carried out using the Sephadex column method (Tetralute®) which requires 25 to 50 µ1 plasma. The unbound TBG binding sites were evaluatid using a T‐3 Sephadex retention test (Trilute®) requiring 50 μl plasma. Free thyroxine index were calculated as the product of the two tests. 202 fullterm newborns were examined in the period 19 to 71 hours after birth and the normal range (95 % limits) for plasma thyroxine were found to be 9.2–26.0 μg/100 ml. Normal values for the T‐3 test varied between 42.5 and 64.9 % and free thyroxine index values between 510–1378 arbitrary units. The mean values of total thyroxine, T‐3 test and free thyroxine index were found to be significantly increased compared with cord blood and adult mean values indicating a physiological thyroid hyperfunction in the neonatal period. The new thyroid function tests used in the present study were found to be technical simple and are suggested to be used whenever thyroid diseases in the newborn are suspected.

URINARY EXCRETION OF 3,3′,5′-TRIIODOTHYRONINE (REVERSE T3)

A simple and sensitive radioimmunoassay for reverse T3 in urine using small Sephadex G25 fine columns is described. The recovery of rT3 added to urine was on average 101.0 ± 4.2% (mean ± SEM). Detection limit was 4 pg/column. Urine excretion of rT3 (mean ± SD) was 72.0 ± 32.1 ng/24 hin 61 healthy euthyroid subjects with a slight increase with age (P < 0.05), 28.8 ± 18.2 ng/24 h in 12 hypothyroid patients and 183.6 ± 79.7 ng/24 h in 25 hyperthyroid patients.