Hämoglobin-Hyperpolymere, künstliche Sauerstoffträger eines neuen Typs - Konzept und aktueller Stand der Entwicklung

Abstract

In the clinical setting, artificial oxygen carriers are needed when a patient has a tissue oxygen deficiency which he/she can not automatically compensate. There are two quite different situations where this might occur: (1) Heavy blood loss (e. g., following an accident) and (2) insufficient perfusion (e. g., as a result of arteriosclerosis or myocardial infarction) or anaemia, both without blood loss. In the first instance, an iso-oncotic oxygen-transporting plasma expander is required, whereas in the second instance a (hypo-oncotic) so-called blood additive is needed. This second type of situation also presents the greater range of very important indications. Experimental work has shown that, in comparison to erythrocytes, dissolved haemoglobin is able to release oxygen more rapidly (effective plasmatic transport), while at the same time also facilitating oxygen release from erythrocytes (mediator function). Blood additives occur naturally in lower forms of life (e. g., earthworm) where they can be found in the form of giant oxygen-carrying molecules. Using these natural forms as a basis, new oxygen-transporting blood additives were designed and developed (so-called haemoglobin hyperpolymers: HP (3)Hb) which exhibit a strong oxygen affinity (half saturation partial pressure p (50) = 16 Torr) and high cooperativity (n (50) = 2.1). One product has, up until now, been produced aseptically on a small technical scale and consists of highly purified, polymerised and pegylated porcine haemoglobin which is free of monomers and oligomers, with a mean molecular weight of approximately 800 kDa. It is sufficiently low in endotoxin (< 0,029 EU/mL), blood plasma compatible, and - at an effective concentration of 3 g/dL in blood plasma - causes only minor increases in oncotic pressure or viscosity. The product has a shelf-life of up to 2 years and is administered as a carbonyl derivative. Its half-life in the conscious rat is 30 h. This product was found to prevent death in rats where acute lung injury was induced using oleic-acid. In human self-experiments this product was repeatedly administered: No effects on blood pressure and heart rate, no increase in blood transaminase concentration and no immunological reaction were seen; the latter was also not found in selected sensitive mice. Furthermore, the blood additive is universally applicable as an oxygen transporter, since, when mixed with a conventional plasma expander, it can also be used to treat an oxygen deficiency occurring together with blood loss.