Perfluorocarbon Blood Substitutes and Medicines
Optimization of Complex Application of Medicines and Perfluorocarbon Blood Substitutes based on Studying of their Interactions with Transport Serum Protein
Tech Area / Field
- MED-DRG/Drug Discovery/Medicine
3 Approved without Funding
Scientific and Research Institute of Experimental Medicine, Russia, St Petersburg
- VNIITF, Russia, Chelyabinsk reg., Snezhinsk
- Johann Wolfgang Goethe-Universität / Klinikum der Johann Wolfgang Goethe-Universität, Germany, Frankfurt am Main\nUniversita degli Studi di Parma / Department of Biochemistry and Molecular Biology, Italy, Parma\nThe University of Texas Medical Branch / Clinical Pharmacology-Toxicology Unit, USA, TX, Galveston\nUniversity of Nottingham / School of Biology, UK, Nottingham\nUniversita degli Studi di Milano / Dipartimento di Scienze Farmacologiche, Italy, Milan\nUniversity of Colorado / Health Science Center / Division of Clinical Pharmacology and Toxicology, USA, CO, Denver
Project summaryWith the need to provide urgent help to people injured in severe disasters which are quite often today, the development of artificial blood substitutes is getting an increasingly important problem being attacked by scientists in many countries throughout the world. The development of oxygen-carrying blood substitutes proceeds mainly in two directions, specifically with the use of a) modified hemoglobin and b) perfluorocarbon emulsions. Each of these directions shows achievements and problems. The impartial evaluation of the two types of blood substitutes suggests that they are not alternative but complementing each other in the therapeutic effect. The proposed project focuses on perfluorocarbon blood-substituting emulsions which can be produced at relatively low costs and in large amounts that makes perfluorocarbon-based blood substitutes commercially attractive.
The development of perfluorocarbon-based artificial blood substitutes started in the second half of the last century. A number of perfluorocarbon emulsions have been designed by now, including Fluosol DA (Japan), Oxygent (USA), S-9156 (USA), PHER-02 (USA), Perftoran (Russia), Oxycyte PFC (USA), Oxyfluor (USA), NEO-PFC (Japan), Montanoks (France), Therox (Wilmington, DE), and Emulsion II (China). The main reason why perfluorocarbons are used as gas-transporting media is their unique ability to dissolve large amounts of gases (O2, CO2, NO, CO) plus their absolute chemical inertness making their use safe for man. Perfluorocarbon substitutes help improve blood rheology and recover central hemodynamics, they also act as membrane-stabilizing, cardioprotecting, detoxicating and immunostimulating agents.
Perfluorocarbons properties allow a wide clinical use of perfluorocarbon-based emulsions in such areas as emergency medicine, surgery, traumatology, transplantology, toxicology, ophthalmology, oncology, scheduled conservative vasotherapy, cosmetology, conservative crush-syndrome therapy and burn therapy. However, the full-fledged treatment effect can be reached if only blood substitutes are used in combination with medicinal therapy. The combined application of perfluorocarbon blood substitutes and medicines revealed a problem of their interaction which investigation began at the same time when the first perfluorocarbon emulsions were produced.
So, professor W.R. Snodgrass and his colleagues performed in the 80s of the last century a number of experiments to study the effect of Fluosol on pharmacokinetics of medicines. It should be noted here that Prof. W.R. Snodgrass is a leading US scientist in pharmacology and toxicology, who was engaged at that time in research with the US army. Parsons D.L. et al. (1985–1991, USA) studied absorption of drugs (tamoxifen, valproic acid, tryptophan, propranolol) on the surfaces of Fluosol particles and the effect of blood substitutes on the degree of binding between ligands and transport proteins of the blood. Obraztsov V.V. et al. (2000-2002, USA) stated that Perflubron (the perfluorocarbon component of Oxygent) gets into the lipid bi-layer of cellular membranes and modify their permeability to different substances including oxygen. Shrewsbury R.P. et al. (1986–1992, USA) studied the effect of Fluosol emulsion on metabolism of medicines in the liver of animals and found that perfluorocarbons significantly influenced pharmacokinetics of medicines apt to liver metabolism.
Our experiments on rabbits showed different effects of Perftoran on pharmacokinetics of amitryptyline, ampicillin, diazepam, methanol and ethanol. The pattern and intensity of the effects depended both on nature and properties of medicines and on the terms of Perftoran injection (Andreyeva N.B., Murzina E.V., Pshenkina N.N., Gubanov A.I., 1999-2004, Russia). Experiments on rats demonstrated that Perftoran reduced the formation of toxic metabolites at poisoning with dichloroethane, facilitating its excretion in the unchanged form (Sofronov G.A. et al., 1997-2003, Russia).
Analysis into the current status of perfluorocarbon emulsions research and development shows intensive studies in the area some of which are very close to clinical tests. However, as far as it is known to us and to our collaborators from different sources and from available published papers (Kim H.W. & Greenburg A.G., 2004, USA), Russian Perftoran is the only perfluorocarbon-based blood substitute which has passed all phases of clinical trials and has been certified for medical purposes. Perftoran is registered in Russia, Ukraine and Kazakhstan; in 2003 it was patented in Russia (Patent No. 2206319) and in the USA (Patent No.: US 6,562,872 B1).
Studies conducted by different teams of scientists, results obtained by our collaborators and our observation data on the effect of blood-substituting emulsions on the behavior of medicines in the body show that the interaction between perfluorocarbons and medicines proceeds in different manners and occurs at any pharmacokinetic stage one of which is distribution. It is known that the distribution of any bioactive substances depends largely on their binding with the transport proteins of the blood, primarily albumin.
The better understanding of mechanisms controlling the pharmacokinetic effects of perfluorocarbon emulsions will help resolve many problems related to the use of perfluorocarbon blood substitutes. Knowledge on the effect of perfluorocarbon emulsions on the distribution of medicines in the body is still insufficient to draw general inferences and to predict how medicines interact with perfluorocarbon emulsions. This project focuses on comprehensive research into the effect of perfluorocarbon emulsions on medicine distribution in the body.
The purpose of this project is to study the pattern of interactions in the system «drug + blood albumin + perfluorocarbon emulsion» through in vitro, in vivo and computer simulation experiments, and formulate science-based recommendations, which will help clinicians minimize detrimental effects in the combined use of perfluorocarbon blood substitute and medicines.
The objective of the project will be implemented through the accomplishment of the following tasks:
- Analysis of the existing world data on the effect of PFC emulsions upon drug-albumin interactions and on the experimental methods which help evaluate these interactions;
- Research of interactions in system «drug - albumin»;
- Studying of interactions in system «perfluorocarbon emulsion - albumin»;
- Research of interactions in system «drug - perfluorocarbon emulsion»;
- Investigation of interactions in system «drug – albumin - perfluorocarbon emulsion»;
- Development of predicting model on the basis of the experimental and calculating data, its experimental approbation on animals and formulation of recommendations for clinicians on combined application of medicines and perfluorocarbon blood substitute.
The project will be implemented in three stages. Stage I provides for the generation of a database on medicinal substances drugs categorized with respect to their interaction with blood albumin. Stage II involves in vitro and computer simulation experiments aimed to study the interaction of the perfluorocarbon emulsion and its components with albumin and with each of the drugs selected, and then interactions in a medium containing all the three substances. Stage III is focused on the analysis of data obtained in the in vitro and computer simulation experiments, and on the development of a mathematical model which will help predict the pattern of interactions in the system “drug – perfluorocarbon emulsion – blood albumin”. Some experiments on animals will be made to verify analytical and prognostic inferences. Generalized results will constitute a base for the development of practical recommendations on the combined use of perfluorocarbon -based blood substitutes and medicines.
Expected Results and their Application.
- Experimental data on interactions in system «drugs - blood albumin - perfluorocarbon emulsion» and revealing of medicines properties, determining the character of their interference.
- Computer modeling results on drug-albumin interactions in the presence of the perfluorocarbon emulsions and development of the QSAR-model, allowing predicting the character of these interactions depending on physical, chemical and pharmacological properties of medicinal substances.
- Elaboration of practical recommendations for clinicians on combined application of artificial perfluorocarbon blood substitutes and medicines.
In the project there will take part experts from 2 institutes. Institutes - participants have wide experience in all planned directions of activities, including carrying out of experiments with various xenobiotics and computer modeling of complicated processes. The participant’s allocation of responsibilities will be:
- State Institution the Scientific Research Institute of Experimental Medicine of the Russian Academy of Medical Sciences (SI NIIEM RAMS, St-Petersburg, Russia) – problem status analysis, choice of research methods of interactions in system «medicine + blood albumin + perfluorocarbon emulsion», carrying out of in vivo and in vitro experiments; results generalization and elaboration of practical recommendations.
- Russian Federal Nuclear Center - academic Zababakhin Institute of Technical Physics (RFNC VNIITF, Snezhinsk, Russia) – computer biomodeling, creation of prognostic model (software development, carrying out of calculations).
The project completely meets ISTC goals and objectives because its implementation will help scientists and engineers formerly engaged in development and improvement of means of protection against chemical weapons (SRC–IEM RAMS) and in nuclear weapons development (RFNC-VNNITF) shift their emphasis from military to peaceful research and integrate into the international scientific community.
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