Johan Selmer

Diabetic Late Complications: Will Aldose Reductase Inhibitors or Inhibitors of Advanced Glycosylation Endproduct Formation Hold Promise?

Patients suffering from the severe complications associated with both insulin- (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM): nephropathy, retinopathy, neuropathy, and atherosclerosis are still largely left without a prospect of an efficient treatment. This is the case even if it has been assumed for decades and now finally proved by the results from the Diabetes Control and Complications Trial (DCCT) that hyperglycemia is the single main cause of these complications. Improved glycemic control as a result of intensive insulin treatment has the potential to reduce the incidence and progression of complications, but implementation and monitoring of improved glycemic control in all groups of IDDM and NIDDM patients in different communities will be difficult and expensive. Results from the recently terminated DCCT have shown that even with intensive insulin treatment, there will be a significant burden of complications on the diabetic population. It will, therefore, still be of immense importance for the long-term quality of life for the diabetic patient that additional possibilities are developed for prevention and intervention against diabetic complications. Almost two decades of research, animal model testing, and clinical trials have been conducted on various efficient aldose reductase inhibitors. Now the concept of inhibition of formation of advanced glycosylation endproducts on proteins and lipids resulting from extra- and intracellular hyperglycemia is entering the scene as an alternative or perhaps supplementary approach to reduce the occurrence of diabetic complications. An overview of the results from these two fields of research and associated drug-development programs will be presented along with thoughts on possible future developments.

Human Ventricular Myosin Light Chain Isotype 1 as a Marker of Myocardial Injury

A monoclonal enzyme immunoassay for measuring human ventricular myosin light chain isotype 1 (HVMLC1) in serum has been developed. To evaluate the method in patients with suspected myocardial injury, we studied 51 patients (16 acute myocardial infarction (AMI), 19 unstable angina pectoris (UAP), 9 stable angina pectoris, 3 nonischemic heart disease, 4 hip surgery patients), and 190 controls (blood donors). Serial blood-samples were drawn from patients; a single blood-sample from controls. The diagnostic value of the HVMLC1 assay was compared with total creatine kinase (CK), CKMB activity, CKMB mass concentration, lactate dehydrogenase isoenzyme 1 (LD1), troponin T (TnT) and mitochondrial-aspartate aminotransferase (m-ASAT). The detection limit of HVMLC1 was 0.4 microgram/l (linear range 0-20 micrograms/l). Sera from 190 reference persons did not contain detectable levels of HVMLC1 (< 0.4 microgram/l; 99% percentile). The coefficients of variation were 13% (1.0 microgram/l) and 3.1% (17.7 micrograms/l). Cross-reactivity with myosin from skeletal muscle was seen. Times to peak value were: CK 19.3 +/- 2.0, LD1 43.4 +/- 3.2, HVMLC1 72.9 +/- 7.0, and m-ASAT 67.3 +/- 5.6 h. Time-curves of HVMLC1 and m-ASAT were similar, whereas time-curves for HVMLC1 and TnT were quite different in most cases. Peak value of HVMLC1 was five times higher than CK peak value and eight times that of LD1. HVMLC1 appeared in the blood within hours after the onset of chest pain and in the majority remained for more than a week after AMI. Among patients with UAP 16% (3/19) had elevated HVMLC1 in serum, whereas elevated TnT was seen in 26% (5/19) and elevated CKMB mass in 26% (5/19). We conclude that the new HVMLC1 assay offers a sensitive diagnosis of myocardial injury. It is characterized by a wide diagnostic time window. The similarity of the HVMLC1 and m-ASAT curves indicates that it may be used to estimate the extent of myocardial necrosis.

Health Care Discovery, Novo Nordisk A/S, DK-2880 Bagsværd, Denmark

The discovery of the important metabolic and physiological role played by a family of transcription factors, the peroxisome proliferator activated receptors (PPAR), has opened up for a new understanding of the mode of action for the lipid lowering drugs known as fibrates and for the new glucose lowering compounds described as insulin sensitizers. Both of these classes of compounds have demonstrated significant efficacy in both animal models of the metabolic derangements characteristic for type 2 diabetes and in human clinical studies. The recognition of the role of these drugs as ligands for PPAR transcription factors and the development of new molecular and cellular tools to select and characterise new PPAR selective compounds will open up for the development of even better new drug candidates for the treatment of metabolic disorders associated with type 2 diabetes. With the combined strength of new transcriptional mapping technologies developed in the field of molecular biology, such as differential mRNA display and DNA microarray hybridisations, it will be possible to perform a detailed molecular characterisation of the transcriptional events involved in drug actions in cellular and tissue systems, and information gathered from such types of analysis will lead to an enormous amount of data, from which detailed knowledge of drug actions at the gene regulatory level will emerge.

Detection of deep venous thrombosis with indium 111-labelled monoclonal antibody against tissue plasminogen activator

The administration of a radiolabelled monoclonal antibody against tissue plasminogen activator allows detection of areas with increased fibrinolytic activity, i. e. those with an active thrombotic lesion. Eight patients with phlebographically verified deep venous thrombosis were examined. At the time of immunoscintigraphy study they were examined receiving anticoagulant therapy. Some 75–85 MBq indium 111-labelled antibody were injected, and scintigrams were obtained after 30 min and after 24 h. The precise site of the thrombus could not be visualized after 30 min due to high background activity, whereas after 24 h it was detectable in all patients. The thrombus/background ratios achieved are twice as high as those observed in a human antifibrin antibody study. These preliminary data suggest a high sensitivity of our t-PA-specific antibody for the detection of active deep venous thrombosis in man, and our antibody seems to offer theoretical advantages over both platelet and fibrin-specific antibodies.