A heart in good health beats around 70 times a minute, triggered in the cells of the cardiac muscles by an electric charge that also ensures the coordinated contractions of the four heart chambers. The quality of this electric flux is fundamental for proper functioning of the heart. Too low a frequency or too high can result in cardiac insufficiency."The frequency and amplitude of these electric currents are controlled by potassium ions K+," explained Professor Guy Vassort, director of the cardiovascular physiopathology department at the University Hospital of Montpellier (Montpellier, France). "Three years ago we were able to show experimentally in rats and mice that the K+ charges crossing the cardiac cells are greatly reduced after an infarctus, resulting in arrythmias which may be mortal in some patients," he said. "Since then we have been investigating the effects of extracellular adenosine triphosphate (ATP) on K+ potentials."
Effectively, this neurotransmitter also can be released in large quantities by cardiac cells as a result of an ischemia (lack of oxygen) produced following a myocardial infarct. "Using electrophysiological techniques our experiments have shown increases in ATP concentrations which in turn activate an enzyme called cytosolic phosolipase A2 (cPLA2) which in turn results in the synthesis of arachidonic acid," Vassort said.
That is an important stop because the presence of this acid provokes specific K+ charges giving rise to new potential therapy approaches to control cardiac rythyms. "The idea is to find molecules which will specifically block the activation of the cPLA2 enzyme by ATP," Vassort noted. But this target is not easy to find. Extracellular ATP is a key molecule in the organism, which is also involved in many other cellular mechanisms of the nervous system. "How can we block its action in the heart without affecting the brain? That is the problem," he said. His team is continuing its research with the study of ATP analogs and those of other neurotransmitters like andrenalin, also known to be capable of regulating ionic channels.
Heparin therapy and monitoring
Heparin, a naturally occurring, highly sulfated polysaccharide, is widely used as an anticoagulant for the treatment and prevention of thrombotic diseases and for the maintenance of blood flow in extracorporeal devices. When heparin is used for prophylaxis (low-dose regimes), it largely prevents thrombin generation. In the case of acute thrombosis it is used to neutralize thrombosis that already has been formed and for preventing further thrombin formation (high-dose regimes). Some patients, however, do not respond properly to treatment and their heparin resistance may be due to a variety of causes such as increased heparin clearance, increased levels of procoagulants, reduced antithrombin levels or increased levels of heparin-binding proteins platelet factor 4 and histidine-rich glycoprotein.
The main complication with heparin therapy is occasional life-threatening bleeding. Laboratory monitoring to adjust dose-regimes is the main option available to improve the antithrombotic efficiency of heparin and to reduce the risk of hemorrhage. There are two types of heparin commercially available – unfractionated (UF) heparin or depolymerized low molecular weight (LMW) heparin. LMW heparins have greater bioavailability, a longer plasma half-life and a more predictable therapeutic response.
UF heparin activity is normally assessed by a conventional clotting test such as the activated partial thromboplastin time (APTT), thrombin clotting time or activated clotting time. These are produced by a significant number of companies including Axis-Shield Diagnostics (Dundee, Scotland), Diagnostica Stago (Asnieres, France), Immuno (Vienna, Austria), Ortho-Clinical Diagnostics (Raritan, New Jersey) and Roche Diagnostics (Mannheim, Germany), and are non-specific but useful since they reflect the ability of heparin to interfere with steps in the coagulation cascade reaction. APTT is the most widely used heparin test, largely because it is simple and readily automated. When APTT test results do not reflect the anticipated anticoagulant effect, a more specific assay may be needed.
These specific assays measure the effect of heparin-accelerated antithrombin activity on a single coagulation enzyme, either factor Xa or thrombin (factor IIa). The enzyme is measured by its clotting activity (chronometrically) – using a test such as the Heptest from Haemachem (St. Louis, Missouri) or chromogenically using the single-stage Coamatic heparin test from Chromogenix (Milan, Italy).
For patients receiving unfractionated heparin intravenously or by subcutaneous injection, laboratory monitoring is normally regarded as mandatory as bioavailability and protein binding can vary between patients. A limited half-life of 30 to 150 minutes, depending on dosage, emphasizes the need for regular monitoring. With LMW heparin, the situation is not as problematic, with a two- to four-fold longer half-life and a more predictable dose-response.
Batimastat-coated stent trials
Biocompatibles (Farnham, England) and British Biotech (Oxford, England) have initiated a pivotal European clinical trial of their Batimastat BiodivYsio stent. The drug-coated stent is designed to help combat restenosis following coronary angioplasty procedures, and combines Biocompatibles' drug-eluting stent technology with British Biotech's proprietary MMP inhibitor, Batimastat.
The European clinical trial – BRILLIANT II – is designed to secure CE mark approval. The company has filed for an investigational device exemption requesting FDA clearance to start a similar pivotal trial (BATMAN II) in the U.S. Biocompatibles has separately reported premarket approval clearance for its BiodivYsio small-vessel, over-the-wire coronary stent.
Cardiac genetic marker alliance
deCODE Genetics (Reykjavik, Iceland) and Pharmacia (Uppsala, Sweden) have formed a pharmacogenomics alliance to identify the role of genetics in the development of advanced forms of cardiac disease. Under the agreement, deCODE will use its population resources and Clinical Genome Miner discovery system to find genetic markers which can be used to identify those patients who are highly predisposed to progressing from an early to an advanced form of heart disease. The companies then plan to use this information as a basis for clinical trials aimed at establishing the usefulness of genetic markers in identifying patients most likely to benefit from cardiovascular drugs under development at Pharmacia.
Leaky blood vessels targeted
Keryx Biopharmaceuticals (Jerusalem, Israel/ Boston, Massachusetts) has licensed from Alfa Wassermann (Bologna, Italy) a heparin-type molecule, Sulodexide, which strengthens leaky blood vessels and is already marketed in Europe. The drug, known by Keryx as KRX-101, has received fast-track designation from the FDA as a treatment for diabetic nephropathy, and the company plans to start late-stage clinical trials in the near future.
Nephropathy is a common long-term complication of diabetes, globally affecting millions of patients and frequently progressing to a need for dialysis or a kidney transplant. KRX-101 is designed to slow the progression of kidney damage by strengthening leaky blood vessels in the kidney glomeruli, which leak albumin and further damage the kidney by inflammation and scarring. Keryx has worldwide marketing rights to the drug outside of Europe.
GSK licenses Natrecor for Europe
GlaxoSmithKline (GSK; London) said it has acquired European marketing rights for Natrecor, a therapy for acute heart failure, from Scios (Sunnyvale, California). Scios will continue to supply the bulk product to GSK and both firms will collaborate on clinical development of Natrecor in Europe.