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Protecting Patients from Hemorrhages
October 26, 2012   
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A group of Cracow-based researchers are working on a drug to reverse the anticoagulant effects of heparin and thus better protect patients from hemorrhages. The new drug would replace protamine sulfate, the substance now used to remove excess heparin from the blood but notorious for causing allergies in patients.

The research project—entitled Synthesis and Application of Modified Polysaccharides to Neutralize Heparin and Extract Nucleic Acids: In-Vivo and In-Vitro Research—is being conducted by researchers from the Faculty of Chemistry at the Jagiellonian University in Cracow in conjunction with colleagues from the Jagiellonian University Collegium Medicum and researchers from the Medical University of Bia造stok.

“Heparin is a natural anticoagulant that prevents blood clotting and the formation of clots inside blood vessels,” says Kamil Kami雟ki, a Ph.D. student at the Jagiellonian University Department of Nanotechnology of Polymers and Biomaterials, part of the Faculty of Chemistry. Kami雟ki is one of the researchers involved in the project.

Heparin is administered to patients undergoing heart surgery and operations involving the use of cardiopulmonary bypass. Heparin is also used in the treatment of patients with venous thromboembolism and is administered to bed-ridden patients.

The main advantages of heparin are that it works quickly after administration and is of natural origin. Heparin is produced by mast cells, which are present in the liver, lungs and the mucous membranes of the nose.

However, heparin has some drawbacks. It may be overdosed and cause hemorrhaging. The reason is that the body’s response to heparin may differ among patients and even the same patient may react differently on different occasions. The action of heparin may depend on whether the patient’s kidneys function well and how much fluid the patient has drunk on a given day.

Large heparin concentrations in the body may cause hemorrhaging. If the level of heparin is too high the patient should immediately receive an antidote in the form of protamine sulfate, which neutralizes the anticoagulant effects of heparin.

Protamine sulfate is a protein derived from the sperm of salmon and other fish species. It effectively neutralizes heparin, but is also a strong allergen. Around 10 percent of people are allergic to protamine sulfate. The allergic response is intensive and dangerous to the patient. Protamine may also lower the patient’s blood pressure and prolong the patient’s stay in the hospital.

The researchers at the Department of Nanotechnology of Polymers and Biomaterials have started working on new drugs capable of effectively clearing heparin from the body. The researchers have already demonstrated that polysaccharides modified in a special way can neutralize heparin and have no allergenic effects.

Among the compounds neutralizing heparin are polysaccharides based on chitosan, a material obtained from the exoskeletons of crustaceans and insects. Another group of polysaccharides are those derived from dextran. This polymer is synthesized by a specific strain of bacteria.

“Dextran is broken down in the body to produce carbon dioxide and water,” says Kami雟ki. “The material is biocompatible and natural. But we have to give it the desired properties. We give it a positive charge by attaching quaternary amines to it. Dextran easily binds to heparin, which has a negative charge. This leads to the neutralization of heparin if there is too much of it in the blood.”

The advantage of dextran-derived polysaccharides over protamine sulfate is that they have no allergenic effect and can be produced on an industrial scale. Meanwhile, protamine sulfate can be only obtained from fish during the spawning season.

The research into heparin neutralization is at the stage of pre-clinical trials. The scientists have managed to prove the efficacy of chitosan and dextran on animals. They are hoping to establish collaboration with pharmaceutical companies, which could help them test the drugs during clinical trials.

The research team is made up of Kamil Kami雟ki, M.Sc., Krzysztof Szczubia趾a, Ph.D., and Prof. Maria Nowakowska from the Jagiellonian University’s Faculty of Chemistry, Department of Nanotechnology of Polymers and Biomaterials; Barbara Lorkowska, Ph.D., and Prof. Ryszard Korbut from the Jagiellonian University’s Collegium Medicum Faculty of Medicine, Department of Pharmacology; and Bart這miej Ka豉ska, M.Sc., Emilia Soko這wska, M.Sc., Karol Kramkowski, Ph.D., Andrzej Mogielnicki, Ph.D., and Prof. W這dzimierz Buczko from the Medical University of Bia造stok, Department of Pharmacodynamics.
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