Haem arginate: a new stable haem compound

Abstract

Abstract Intravenous administration of haem in acute hepatic porphyrias inhibits the induction of β-aminolaevulinic acid synthase, reduces the formation of potentially harmful metabolites of porphyrin synthesis and corrects the haem deficiency. Typically, haem therapy has been given in the form of haematin—haem dissolved in alkali. Such haematin solutions are, however, extremely unstable. Thus, the rapid decomposition of this therapeutic agent may have been responsible for the ineffectiveness of treatment in some clinical states and adverse reactions may have been caused by haematin degradation products. There is, therefore, a need for a stable, effective and well-tolerated haem preparation. We have prepared certain highly soluble haem compounds of which haem arginate has proved to be the most promising. Pure haemin was isolated from HIV and hepatitis B negative human blood. The haem derivatives prepared were screened as substrates for haem oxygenase. Haem arginate and haem lysinate were found to be as good substrates as methaemalbumin. Stock solutions of haem arginate were stable for 2 years at +6 °C. After dilution with sterile isotonic saline the haem arginate infusion was clearly more stable than haematin solutions made in the laboratory or prepared by dissolving commercial lyophilized haematin. The antiporphyrogenic effect of haem arginate (even after storage for two years) in 2-allyl-2-isopropylacet-amide-induced experimental porphyria of rats was equal to that of freshly prepared haematin. The acute oral toxicity of haem arginate was low compared with the parenterally administered drug, indicating poor oral bioavailability. The acute toxic effects after high intravenous or intraperitoneal doses were directed to the liver. Conventional haematin caused thrombophlebitic reactions at the site of infusion in all rabbits, but haem arginate did not cause any thrombophlebitis even after repeated infusions. The dose of haem arginate used in clinical trials, 0ṁ2 mg of haem kg−1 min−1 during 15 min (= total dose 3 mg kg−1 diluted in 100 mL isotonic saline), did not cause any clinically significant changes in the numerous haemostatic parameters measured in patients, and ten times higher infusion rates or total doses were needed to cause a decrease in the blood pressure of rats. Haem arginate has proven to have many advantages over conventional haematin solutions.