Racemic (R,S)-propranolol versus half-dosed optically pure (S)-propranolol in humans at steady state: Hemodynamic effects, plasma concentrations, and influence on thyroid hormone levels.

In a randomized, double-blind, crossover study in 10 healthy volunteers the hemodynamic effects, drug plasma concentrations, and thyroid hormone profiles were compared after oral administration for 1 week of 40 mg t.i.d. racemic (R,S)-propranolol versus 20 mg t.i.d. optically pure (S)-propranolol. During exercise, both substances decreased heart rate (-14%, p less than 0.01), as well as the overall rate pressure product (-19%, p less than 0.01) to the same extent, indicating similar beta-blocking effects. After oral application of (R,S)-propranolol the maximal plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of (S)-propranolol were higher than those of (R)-propranolol (eudismic ratios (S)- over (R)-propranolol Cmax, 1.36 [p less than 0.01] and AUC, 1.42 [p less than 0.01]) despite dose-equivalence of both enantiomers in the administered racemic (R,S)-propranolol preparation indicating different pharmacokinetic properties. Mean values of Cmax and the AUC of (S)-propranolol did not differ significantly after 1 week of oral administration of 40 mg (R,S)-propranolol and 20 mg (S)-propranolol t.i.d., respectively. The ratio of triiodothyronine to thyroxine was decreased by (R,S)-propranolol (-25%, p less than 0.01) but not by (S)-propranolol, suggesting that only the (R)-enantiomer inhibits the conversion of thyroxine to triiodothyronine. Thus, half-dosed optically pure (S)-propranolol is an equally effective beta-adrenergic receptor antagonist compared with currently used racemic (R,S)-propranolol. By contrast, the conversion of thyroxine to triiodothyronine is inhibited by (R)-propranolol only.(ABSTRACT TRUNCATED AT 250 WORDS)

Gallium-67-citrate scintigraphy of high-grade T-cell non-Hodgkin's lymphoma.

Scintigraphy with 67Ga-citrate indicated the transition of an orbital pseudotumor into a lymphoma by a distinct increase in 67Ga avidity. The patient initially presented with a pseudotumor in the right orbit that was verified by CT and MRI. It was caused by a chronic reactive lymphocytic inflammation extending from the lacrimal gland. At that time, scintigraphy was negative. Six and a half weeks later, the tumor had not responded to therapy and scintigraphy then showed a striking increase in gallium avidity. Consequently the tumor was excised and histology ultimately revealed a high-grade non-Hodgkin's T-cell lymphoma.

Radiolabeled octreotide for the demonstration of somatostatin receptors in malignant lymphoma and lymphadenopathy.

UNLABELLED: This prospective study evaluated somatostatin receptor-specific scintigraphy as a clinical tool for routine detection of malignant lymphoma. METHODS: Forty-one consecutive patients were examined using 111In-DTPA-D-Phe-1-octreotide. Thirty-four patients had diagnoses of Hodgkin's disease (n = 11) or non-Hodgkin's lymphoma (n = 23) previously verified and staged by hematology, histology and imaging methods (CT, chest x-ray and abdominal ultrasonography). The remaining seven patients initially suspected of presenting lymphoma (n = 5) or lymphoma recurrence after chemotherapy and radiotherapy (n = 2) were subsequently shown to have other diseases. Planar images were recorded 4, 24 and 48 hr after intravenous injection and evaluated without knowledge of other results. In case of negative planar scintigraphy, additional SPECT images were obtained. Since these failed to increase sensitivity, they were omitted after 15 negative recordings. RESULTS: Octreotide scintigraphy did not yield false-positive results. The sensitivity for detecting Hodgkin's disease was 70% and varied from 88% in the neck and chest to 13% in the abdomen and pelvis. The sensitivity for non-Hodgkin's lymphoma was not influenced by localization and amounted uniformly to 35% but varied with the degree of malignancy between 44% (high-grade) and 29% (low-grade malignancy). CONCLUSION: Our results suggest that radiolabeled octreotide is better suited to characterize somatostatin receptor expressing lymphomas than to localize lesion sites. It is useful for imaging Hodgkin's disease, especially above the diaphragm.

New continuous cell-line from human medullary-thyroid carcinoma - sinj - phenotypic analysis and invivo carcinogenesis.

SINJ is a new continuous human cell line derived from a lymph node metastasis of a probably sporadic medullary thyroid carcinoma. It is compared to MTC-SK, another medullary thyroid carcinoma cell line, established earlier (1). SINJ has been continuously cultivated in vitro for two years. The cells grow as a suspension of single cells and cell clusters. Repeated immunocytochemistry showed positive immunoreactivity with antibodies to CT, CGRP and GRP. The maintenance of NSE and chromogranins were proved. Northern blot analysis confirmed endocrine activity at mRNA level. Flow cytometry of 27 SINJ - clones showed 25 diploid and two tetraploid subpopulations. Cytogenetic analyses strengthened these findings. According to DNA analysis the cells are free of SV40 sequences. Tumorigenicity was proved in nude mice. The new cell line SINJ has potential use for in vitro studies of medullary thyroid carcinomas in sporadic as well as hereditary forms - the MEN2A syndrome.

[Sonography and cytology of cold thyroid nodules]. / Sonographie und Zytologie von kalten Schilddrüsenknoten.

270 patients with a scintigraphically cold thyroid nodule of sonographically increased (n = 34), diminished (n = 72) or neutral (n = 86) echogenity or cystic criteria (n = 78) were subjected to fine needle aspiration biopsy. This revealed unequivocal malignancy in 8 and follicular neoplasia in another 30 patients, 10 of whom proved to have malignomas on further evaluation. A total of 12 papillary and 2 follicular carcinomas, 2 non-Hodgkin lymphomas, 1 sarcoma and the metastasis of a breast carcinoma were diagnosed. The most sensitive criteria for malignancy were diminished echogenity, an inhomogeneous echo pattern and the occurrence of a solitary nodule. The incidence of malignancy was increased among males but not among especially young persons. There was no sonographic feature that would permit omission of fine needle aspiration.

[99mTc-BIDA: functional parameters in the differential diagnosis of obstructive and parenchymatous jaundice (author's transl)]. / Möglichkeiten in der Differentialdiagnose zwischen Parenchym- und Verschlussikterus mit 99mTc-BIDA durch Auswertung von Funktionsparametern.

75 Patients were examined with 99mTc-BIDA in order to find a reliable method of differentiating between obstructive and parenchymatous jaundice. Serial scans, repeated recordings of plasma radioactivity and external measurements over a temporal and a thigh region were taken between 1 and 30 min after injection. Serum half life of radioactivity, extraction coefficient and clearance rate, calculated from the first exponential slope over the temporal region curve, differed significantly in obstructive as compared to parenchymatous diseases and normals. In patients with extrahepatic obstruction the curves over the temporal and the thigh region differed; within the first 30 min the thigh values tend to increase. Clearance and extraction coefficients calculated from the third exponential slope of the plasma curve were significantly lower in obstructive jaundice than in other groups, although the great variation in these values did not allow a reliable differentiation in every patient. However, reliable results were obtained when these parameters were considered together with serial hepatic images.

[Results of hepatic scintigraphy with a new colloid (99mTc-Sn-Antipyrine D 77 1268) compared with 99mTc-Sn-phytate (author's transl)]. / Ergebnisse der Leberszintigraphie mit einer neuen Kolloidsubstanz (99mTc-Sn-AntipyrinR D 77 1268) im Vergleich mit 99mTc-Sn-Phytat.

Liver scans were performed on 84 patients, using a new colloidal substance 99mTc-Sn-Antipyrine colloid, and compared with 36 liver scans with 99mTc-Sn-phytate under identical conditions. The following differences were found: 99mTc-Antipyrine uptake in the spleen was higher in comparison with 99mTc-phytate, renal excretion was twenty times lower. The tin content was less then one fifth in the Sn-Antipyrine preparation. Antipyrine yields simultaneous imaging of liver and spleen even in normal patients.

The evaluation of free thyroid hormones (FT4 and FT3) in the routine diagnosis of thyroid function.

The validity of the free thyroid hormone parameters (FT4 and FT3) was verified in a random sample of 154 ambulatory patients with thyroid conditions. The "euthyroid range" of FT4 was between 15.67 and 30.66 pmol/l; median 21.98 pmol/l. The distribution of the FT4 readings peaked on the left and sloped to the right (log normal). In our laboratory, the "euthyroid reference range" of FT4 is between 10-28 pmol/l. The "euthyroid range" of FT3 extended from 4.6 to 9.7 pmol/l; median 6.63 pmol/l. The distribution of the readings was likewise log normal. The values of FT4 and FT3 are not significantly influenced by TBG concentration anomalies in otherwise healthy thyroid patients. For purposes of discrimination between euthyroidism and hyperthyroidism, FT3 (95%) and FT4 (90%) are better suited than the corresponding quotients for the free hormone fraction or the total hormone concentrations. On the other hand, the free hormone parameters are less suitable for the diagnosis of hypothyroidism. These results were deduced theoretically from mathematical function analyses between the TBG-independent free hormone parameters and the TBG-dependent hormone concentrations.

[Determination of serum free thyroxine: normal range, relation to the free thyroxine ratio and total thyroxine (author's transl)]. / Bestimmung des freien Thyroxinspiegels: Normalbereich, Beziehung zum freien Thyroxinindex und Gesamtthyroxin.

The validity of a commercially available f-T4 radioimmunoassay was investigated in 122 patients with different thyroid status. The normal range of f-T4 was 0.60-2.20 ng/dl in euthyroid patients from an endemic goiter area. No significant difference was found between normals and a group taking oral contraceptives (mean = 1.37 ng/dl vs. 1.45 nd/dl). In patients on thyroid hormone or antithyroid drug therapy, f-T4-values showed a better correlation with the results of an oral TRH-test than total T4 or the free thyroxine ratio (ETR). Specificity of ETR was better than that of f-T4. Sensitivity of f-T4 was higher in the group with negative TRH-test, but lower in hypothyroidism as compared to ETR. Determination of f-T4 by radioimmunoassay is a simple diagnostic procedure. Since f-T4 RIA is not influenced by changes in TBG-levels its use is particularly recommended in cases where such changes are to be expected such as estrogen application or gravidity.

[Two generations of FT4-radioimmunoassays--results in euthyroid patients and in patients on thyroid hormone therapy]. / Zwei Generationen FT4-Radioimmunoassays--Ergebnisse bei Euthyreosen und bei Patienten unter Schilddrüsenhormontherapie.

In accordance with the TRH-test two generations of FT4-immunoassays were checked in order to find a substitute for the free thyroxine index. The euthyroid reference range of FT4 was between 0.69-1.91 ng/dl using GammaCoat (Clinical Assays) and 0.94-2.29 ng/dl using Amerlex (Amersham), respectively. In the euthyroid range, FT4 as measured by Amerlex was, on the average, 47% higher than the value obtained by using GammaCoat. During treatment by thyroid hormones and TSH-suppression following TRH application, Amerlex FT4 values were up to 59% higher than the GammaCoat FT4 values. During replacement therapy, the FT4 values obtained by Amerlex were within the euthyroid reference range so that a differentiation between substitution and suppression appears to be possible by means of determining FT4. An overdose was assessed by simultaneous determination of T3 and FT4. According to our results Amerlex FT4 meets the requirements of a modern radioimmunoassay and is suitable as a substitute for the free thyroxine index. For this purpose the earlier method of determining FT4 (GammaCoat) does not seem suitable.

[Continuous determination of the blood density during haemodialysis (author's transl)]. / Die kontinuierliche Messung der Blutdichte während der Hämodialyse.

Application of the mechanical oscillator technique for measurement of blood density, in combination with a reference method for the determination of the absolute value of the blood volume, enables precise and continuous monitoring of fluid shifts during haemodialysis. The significant correlation between blood volume and density or plasma volume and density allows each variation in blood volume to be calculated from the blood density and the slope of the regression line for each individual patient. The possibility of taking continuous measurements and the high accuracy of the mechanical oscillator technique commends this method for the measurement of short-term and small fluid shifts.

[The role of binding proteins in radioimmunologic determination of the free thyroxine concentration using thyroxine analog methods: thyroxine immunoextraction versus thyroxine analog immunoextraction]. / Die Rolle der Bindungsproteine bei der radioimmunologischen Bestimmung der freien Thyroxinkonzentration mit Thyroxinanalogmethoden: Thyroxinimmunextraktion versus Thyroxinanalogimmunextraktion.

Amerlex FT4-analogue one step RIA was investigated to estimate the 125-Iodine thyroxine immunoextraction in sera with normal and abnormal concentrations of binding proteins. The following results were found: Amerlex analogue FT4 RIA equals an equilibrium-immunoassay. Thyroxin-analogue tracer is strongly bound to an albumin (80%). During the assay procedure, there is no analogue binding to serum proteins. If serum and FT4-antibody diluted in an adequate manner, FT4-analogue values in all serum dilution steps are determined identically. FT4-analogue values are influenced only by thyroxine, bound to albumin and/or prealbumin and not by TBG-bound thyroxine. Serum albumin concentration does not influence FT4-analogue values.

[Oral TRH test: normal range and comparison with intravenous TRH test (author's transl)]. / Oraler TRH-Test mit 40 mg TRH: Stimulationsbreite und Vergleich mit 200 microgram TRH intravenös.

TRH (40 mg) was given orally to 122 patients with divers thyroid status. In euthyroidism, TRH induced TSH response ranged from 2.5 microU to 45 microU TSH, measured three hours after oral administration. TSH values were threefold higher following oral TRH (mean 24.5 microU) as compared to intravenous TRH-test using 200 microgram TRH (mean 7.05 microU). No exaggerated TSH response were found in patients on oral contraceptives and in euthyroid nodular goiter. Preclinical hypothyroidism was present in 50% in patients with previous partial thyroidectomy and only 15% of patients with blunted TSH response on an thyroid hormone regimen of 70 microgram thyroxine daily. Oral TRH test was negative in every patient with normal serum hormone levels under antithyroid drug therapy.

Long term follow-up after enucleation and resection for autonomously functioning thyroid nodules.

The aim of the study was to evaluate the influence of the operative method (i.e. std. resection vs. enucleation) on postoperative function of the thyroid. Uni- or multifocal thyroid autonomy was resected (group I & III) or selectively enucleated (group II & IV). Postoperative function was determined after 6 and 12 months and again after 3-5 years. "Selective" treatment showed minor postoperative hypothyroidism, but goitrous, nodular or functional disorders are more often present compared to resection cases (4.4% vs 12%).

[Diagnostic significance of immunoradiometric serum TSH determination]. / Diagnostische Bedeutung der immunradiometrischen TSH-Bestimmung im Serum.

TSH measurements using sensitive TSH-IRMA method makes differentiation of euthyroidism and hyperthyroidism possible without TSH stimulation after TRH. TSH-basal values less than 0.1 mU/L proof pituitary TSH suppression (clinical overt and latent hyperthyroidism, thyroid hormone therapy etc.). TSH-basal values between 0.4 and 4.0 mU/L are found in euthyroidism. TSH-basal values greater than 4.0 mU/L indicate latent or manifest hypothyroidism. With basal TSH values between 0.1 and 0.4 mU/L (borderline values between euthyroidism and "relative pituitary hormone excess") a TRH-test ist still necessary as it is not possible to predict stimulated TSH values from basal TSH concentrations with adequate accuracy. TSH measurements using sensitive IRMA methods may be recommanded as a screening test of thyroid function.

[Pharmacology and dosage of thyrostatic drugs]. / Pharmakologie und Dosierung der Thyreostatika.

The iodine organification in thyroid gland was inhibited by application of Thyrostatic (Methimazole, Carbimazole) and consequently, thyroid hormone production and excretion were diminished. Carbimazole is converted to Methimazole in vivo and in vitro. Equivalent doses of Carbimazole and Methimazole are 0.6 to 1.0. Methimazole penetrates through the placenta, therefore established therapy with Methimazole (or Carbimazole) and thyroid hormone are contradicted in states of gravidity. In hyperthyroidism, preferred therapy strategy is accepted as Methimazole and/or Carbimazole only and in low doses, respectively (40-60 mg Methimazole as first step, consequently to doses down to 5-10 mg daily); accompaning rates of hematopoetic damage are dose responded.

[Hypotheses on the validity of the radioimmunologic measurement of FT4]. / Hypothesen zur "Validität" radioimmunologischer FT4-Messergebnisse.

In patients undergoing long-term thyroid hormone therapy with constant doses the results of FT4 concentrations measured by radioimmunoassay (FT4-AMERLEX) were compared with calculated FT4 values and related to total thyroxine, serum TBG levels, respectively T4/TBG, to control the validity of radioimmunologic FT4 measurements for clinical routine diagnostic purposes. Based on mathematical analyses on the interdependence of these values the following principles were confirmed: free thyroxine measurements are dependent on total thyroxine with a power of x to the exponent and on T4/TBG-ratio with an exponential function. The percentage of free thyroxine (FT4/TT4 ratio) is inversely and exponentially related to serum TBG concentrations. Indeed, the RIA-FT4 results are largely independent of the concentration of binding globulin within certain limits. In thyroid patients without extrathyroid disorders no grossly false hypo- or hyperthyroid FT4 values are to be expected by deviating thyroxine globulin concentrations.

[Determination of the free thyroxine concentration (FT4) in serum using the FT4 fraction and total thyroxine concentration]. / Bestimmung der freien Thyroxinkonzentration (FT4) im Serum mit Hilfe der FT4-Fraktion und der Gesamtthyroxinkonzentration.

A new equilibrium assay for the determination of serum free thyroxine was evaluated in 514 patients. The assay comprises a two-vial-procedure to measure total thyroxine and free thyroxine fraction by use of monoclonal antibodies. Free thyroxine concentrations are calculated from fT4-fraction and total thyroxine concentration readings. In euthyroidism the average free thyroxine fraction (%fT4) was 0.011%, in hyperthyroidism this fraction was elevated, in hypothyroidism it was below normal. In patients with TBG anomalies, TBG values were inversely correlated with fT4 fraction readings. The "euthyroid reference range" of FT4 (SPAC ET) was between 0.70 to 1.78 ng/dl. This euthyroid range of FT4 was determined from TT4 concentrations measured by T4-RIA (SPAC T4 MONO) which were 30% above TT4 values measured by conventional T4-RIA (SPAC T4 POLY; polyclonal antibodies). However, a different euthyroid range of FT4 between 0.55 to 1.30 ng/dl was observed as well as by other investigators when conventional T4-RIA measurements were used for calculation of FT4 values. Our results indicate that calculated FT4 concentration values are highly dependent on the methods used for determination of total thyroxine concentrations. Precision and reproducibility of this two vial equilibrium assay did not meet the requirements mandatory for the application as a clinical routine diagnostic procedure, and its general use for this purpose can as yet not be recommended.

[Comparative study on the saluretic activity of etacrynic acid and BAY g 2821 in patients with cardiac decompensation (author's transl)]. / Saluretischer Wirkungsvergleich von Etacrynsäure mit BAY g 2821 bei Patienten mit kardialer Dekompensation.

In a randomised double-blind comparative study 40 mg 3-amino-1-(3,4-dichloro-alpha-methyl-benzyl)-2-pyrazolin-5-one (BAY g 2821), a novel diuretic agent, were tested against 50 mg etacrynic acid in patients with cardiac decompensation. BAY g 2821 has a rapid onset of action which slowly decreases until 12 h after administration. Within a period between the second and the fourth hour after administration, the efficacy of BAY g 2821 is superior to that of etacrynic acid. The difference is statistically significant. The total elimination of BAY g 2821 is markedly more pronounced than that of etacrynic acid throughout the 5-day treatment course. Neither subjective nor objective side effects were observed.