Recent advances in drug action and therapeutics: relevance of novel concepts in G-protein-coupled receptor and signal transduction pharmacology.

PROBLEM STATEMENT: During especially the past two decades many discoveries in biological sciences, and in particular at the molecular and genetic level, have greatly impacted on our knowledge and understanding of drug action and have helped to develop new drugs and therapeutic strategies. Furthermore, many exciting new drugs acting via novel pharmacological mechanisms are expected to be in clinical use in the not too distant future. SCOPE AND CONTENTS OF REVIEW: In this educational review, these concepts are explained and their relevance illustrated by examples of drugs used commonly in the clinical setting, with special reference to the pharmacology of G-protein-coupled receptors. The review also addresses the basic theoretical concepts of full and partial agonism, neutral antagonism, inverse agonism and protean and ligand-selective agonism, and the relevance of these concepts in current rational drug therapy. Moreover, the mechanisms whereby receptor signalling (and eventually response to drugs) is fine-tuned, such as receptor promiscuity, agonist-directed trafficking of receptor signalling, receptor trafficking, receptor 'cross-talk' and regulators of G-protein signalling (RGSs) are discussed, from theory to proposed therapeutic implications. CONCLUSIONS: It is concluded that the understanding of molecular receptor and signal transduction pharmacology enables clinicians to improve their effective implementation of current and future pharmacotherapy, ultimately enhancing the quality of life of their patients.

Characterization of two thioredoxins in pig heart including a new mitochondrial protein.

Heart tissue contains two different thioredoxins. One is a specific mitochondrial protein and is best prepared from pre-isolated, intact heart mitochondria (mt-thioredoxin) whereas mitochondria-depleted tissue homogenates contain the major cellular thioredoxin of cytoplasmic origin (c-thioredoxin). Both heat-stable proteins are clearly differentiated chromatographically. They exhibit slightly different molecular weights (12,300 vs. 12,000) and isoelectric points (4.7 vs. 4.8) but differ remarkably in their cysteine content: mt-Thioredoxin has two cysteine residues like the bacterial proteins, and c-thioredoxin possesses six cysteines. Heart extracts were also shown to contain a NADPH-specific thioredoxin reductase of the known mammalian type. A specific function or target enzyme of mt-thioredoxin has not as yet been established.

[A test for early detection of hypertonias conditioned by pregnancy (gestosis selection test - GST) (author's transl)]. / Ein Test zur Früherkennung schwangerschaftsbedingter Hypertonien (Gestose-Selektions-Test = GST).

72 patients were subjected to the gestosis selection test (= GST) during the 28th (+/- 3 weeks) week of pregnancy in the sense of a "screening" with regard to potential risk of gestosis. A detailed description of GST, which consists of the injection of a bolus of fenoterol is given. Depending upon the possibility of reducing the diastolic blood pressure, 2 groups of pregnant women can be distinguished with regard to the prospective assessment of the course of pregnancy: GST Group I: The diastolic blood pressure can be reduced by 30 mmHg and more - Development of gestosis is hardly probable. GST Group II: The diastolic blood pressure can be reduced by less than 30 mmHg - Development of gestosis probable. Of the prospectively examined 72 patients, 40 have meanwhile delivered. There was no gestosis in group I, whereas in group II there were 8 gestoses. The GST is compared with other screening methods based on blood pressure which were also carried out at the same time: the "roll over test" (ROT) as well as calculation of the mean arterial blood pressure during the second trimenon (MAP-2).