Therapie der blanden Struma: Erfahrungen mit einer Kombination von 100 µg L-Thyroxin und 10 µg L-Trijodthyronin

Dtsch med Wochenschr 1981; 106: 579-583 DOI: 10.1055/s-2008-1070359 © Georg Thieme Verlag KG Stuttgart · New York Therapie der blanden Struma: Erfahrungen mit einer Kombination von 100 µg L-Thyroxin und 10 µg L-Trijodthyronin Treatment of non-toxic goitre: results of combined treatment with 100 µg L-thyroxine and 10 µg L-triiodothyronine C. R. Pickardt, R. Gärtner, J. Habermann, K. Horn, P. C. Scriba, F. A. Horster, H. Wagner, K. Hengst Medizinische Klinik Innenstadt der Universität München, Klinik für Innere Medizin, Medizinische Hochschule Lübeck, Medizinische Klinik C und Poliklinik der Universität Düsseldorf sowie Medizinische Klinik und Poliklinik der Universität Münster Zusammenfassung Bei 96 Patienten mit blander Struma wurde eine offene Prüfung mit einem neuen Schilddrüsenhormonpräparat durchgeführt, das 100 µg L-Thyroxin (T4) und 10 µg L-Trijodthyronin (T3) pro Tablette enthält. Als Parameter für die therapeutisch wirksame Tagesdosis wurde die Suppression des TRH-stimulierten Thyreotropinspiegels im Serum gewählt. Hierbei war eine Tagesdosis von 50 µg T4 und 5 µg T3 bei 16 Patienten unwirksam; 75 µg T4 und 7,5 µg T3waren bei nur 4 von 12 Patienten suppressiv wirksam, während 100 µg T4 und 10 µg T3 bei allen Düsseldorfer und Münsteraner Patienten, aber nur bei 17 von 31 Patienten in München den TRH-stimulierten TSH-Anstieg supprimierte. Während der gesamten Therapiedauer blieben Thyroxin- und Trijodthyroninspiegel im Serum im Normbereich; bei einigen Patienten erhöhte sich der Quotient aus Thyroxin und thyroxinbindendem Globulin über die Norm. Zeichen einer Überdosierung oder Unverträglichkeit wurden nicht beobachtet. In pharmakokinetischen Untersuchungen an acht freiwilligen schilddrüsengesunden Probanden erreichte der mittlere Thyroxin- und Trijodthyroninspiegel etwa 2 Stunden nach Applikation sein Maximum und näherte sich nach sechs Stunden wieder der Norm. Es zeigten sich deutliche individuelle Schwankungen in den ersten Stunden nach Applikation. Wir empfehlen deshalb, Schilddrüsenhormonspiegel erst 12 oder 24 Stunden nach Applikation eines Schilddrüsenhormonpräparates zu bestimmen; zu dieser Zeit sollte auch der TRH-Test durchgeführt werden. Die Untersuchungen bestätigen die Notwendigkeit, bei der Strumatherapie mit einem Schilddrüsenhormonpräparat die suppressiv wirksame Dosis individuell zu ermitteln; diese Dosis beträgt vorzugsweise 100 µg Thyroxin und 10 µg Trijodthyronin oder 150 µg Thyroxin oder 100 µg Thyroxin und 20 µg Trijodthyronin pro Tag.A new thyroid hormone preparation (100 µg L-thyroxine [T4] and 10 µg L-triiodothyronine [T3] per tablet) was given to 96 patients with non-toxic goitre. Suppression of the TRH-stimulated thyrotropin level in serum was chosen as a measure of therapeutic effectiveness. Daily dose of 50 µg T4 and 5 µg T3 was ineffective in 16 patients; 75 µg T4 and 7.5 µg T3 was effective in only four of twelve patients, while 100 µg T4and 10 µg T3 was effective in all patients from clinics in Düsseldorf and Münster, but in only 17 of 31 patients from Munich, in suppressing the TRH-stimulated TSH rise. During the entire period of treatment serum thyroxine and triiodothyronine levels remained normal. In some patients the ratio of thyroxine to thyroxine-binding globulin was above normal. Signs of overdosage or intolerance were not observed. Pharmacokinetic studies on eight volunteers with normal thyroid function demonstrated that the mean thyroxine and triiodothyronine levels reached maximum about two hours after administration, returning towards normal after six hours. There were marked individual variations in the first hours after administration. It is therefore recommended that the thyroid hormone level be determined no earlier than 12 or 24 hours after the thyroid hormone preparation has been administered; TRH test should also be performed at this time. These results indicate the need for determining individually the effective suppressive dose of a thyroid hormone preparation in the treatment of goitre. Preferably the dose should be 100 µg thyroxine and 10 µg triiodothyronine, or 150 µg thyroxine or 100 µg thyroxine and 20 µg triiodothyronine per day

Energetic Components of Cooperative Protein Folding

A new lattice protein model with a four-helix bundle ground state is analyzed by a parameter-space Monte Carlo histogram technique to evaluate the effects of an extensive variety of model potentials on folding thermodynamics. Cooperative helical formation and contact energies based on a 5-letter alphabet are found to be insufficient to satisfy calorimetric and other experimental criteria for two-state folding. Such proteinlike behaviors are predicted, however, by models with polypeptide-like local conformational restrictions and environment-dependent hydrogen bonding-like interactions.Comment: 11 pages, 4 postscripts figures, Phys. Rev. Lett. (in press

Merging and scoring molecular interactions utilising existing community standards: tools, use-cases and a case study.

The evidence that two molecules interact in a living cell is often inferred from multiple different experiments. Experimental data is captured in multiple repositories, but there is no simple way to assess the evidence of an interaction occurring in a cellular environment. Merging and scoring of data are commonly required operations after querying for the details of specific molecular interactions, to remove redundancy and assess the strength of accompanying experimental evidence. We have developed both a merging algorithm and a scoring system for molecular interactions based on the proteomics standard initiative-molecular interaction standards. In this manuscript, we introduce these two algorithms and provide community access to the tool suite, describe examples of how these tools are useful to selectively present molecular interaction data and demonstrate a case where the algorithms were successfully used to identify a systematic error in an existing dataset

Introduction of Macromolecules into Bovine Adrenal Medullary Chromaffin Cells and Rat Pheochromocytoma Cells (PC12) by Permeabilization with Streptolysin O: Inhibitory Effect of Tetanus Toxin on Catecholamine Secretion

Conditions are described for controlled plasma membrane permeabilization of rat pheochromocytoma cells (PC12) and cultured bovine adrenal chromaffin cells by Streptolysin O (SLO). The transmembrane pores created by SLO invoke rapid efflux of intracellular 86Rb+ and ATP, and also permit passive diffusion of proteins, including immunoglobulins, into the cells. SLO-permeabilized PC12 cells release [3H]dopamine in response to micromolar concentrations of free Ca2+. Permeabilized adrenal chromaffin cells present a similar exocytotic response to Ca2+ in the presence of Mg2+/ ATP. Permeabilized PC12 cells accumulate antibodies against synaptophysin and calmodulin, but neither antibody reduces the Ca2+-dependent secretory response. Reduced tetanus toxin, although ineffective when applied to intact chromaffin cells, inhibits Ca2+-induced exocytosis by both types of permeabilized cells studied. Omission of dithiothreitol, toxin inactivation by boiling, or preincubation with neutralizing antibodies abolishes the inhibitory effect. The data indicate that plasma membrane permeabilization by Streptolysin O is a useful tool to probe and define cellular components that are involved in the final steps of exocytosis

Transport of Proteins into Mitochondria

The mitochondrial ADP/ATP carrier is an integral transmembrane protein of the inner membrane. It is synthesized on cytoplasmic ribosomes. Kinetic data suggested that this protein is transferred into mitochondria in a posttranslational manner. The following results provide further evidence for such a mechanism and provide information on its details. 1. In homologous and heterologous translation systems the newly synthesized ADP/ATP carrier protein is present in the postribosomal supernatant. 2. Analysis by density gradient centrifugation and gel filtration shows, that the ADP/ATP carrier molecules in the postribosomal fraction are present as soluble complexes with apparent molecular weights of about 120000 and 500000 or larger. The carrier binds detergents such as Triton X-100 and deoxycholate forming mixed micelles with molecular weights of about 200000–400000. 3. Incubation of a postribosomal supernatant of a reticulocyte lysate containing newly synthesized ADP/ATP carrier with mitochondria isolated from Neurospora spheroplasts results in efficient transfer of the carrier into mitochondria. About 20–30% of the transferred carrier are resistant to proteinase in whole mitochondria. The authentic mature protein is also largely resistant to proteinase in whole mitochondria and sensitive after lysis of mitochondria with detergent. Integrity of mitochondria is a prerequisite for translocation into proteinase resistant position. 4. The transfer in vitro into a proteinase-resistant form is inhibited by the uncoupler carbonyl-cyanide m-chlorophenylhydrazone but not the proteinase-sensitive binding. These observations suggest that the posttranslational transfer of ADP/ATP carrier occurs via the cytosolic space through a soluble oligomeric precursor form. This precursor is taken up by intact mitochondria into an integral position in the membrane. These findings are considered to be of general importance for the intracellular transfer of insoluble membrane proteins. They support the view that such proteins can exist in a water-soluble form its precursors and upon integration into the membrane undergo a conformational change. Uptake into the membrane may involve the cleavage of an additional sequence in some proteins, but this appears not to be a prerequisite as demonstrated by the ADP/ATP carrier protein