Haem arginate: a new stable haem compound

Abstract

Intravenous administration of haem in acute hepatic porphyrias inhibits the induction of delta-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 degrees 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-isopropylacetamide-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.(ABSTRACT TRUNCATED AT 250 WORDS)

Carbon monoxide: from toxin to endogenous modulator of cardiovascular functions

“…The use of heme to drive heme oxygenase activity in experimental settings is complicated by its tendency to aggregate in aqueous solutions at physiological pH (25,32) and to degrade during storage (32). An acetic environment may in some cases be used to increase porphyrin solubility, but such conditions may also damage porphyrin integrity (25).…”

“…For some experimental protocols, heme-L-arginate may create methodological problems, since L-arginine is a substrate for nitric oxide synthase-mediated formation of nitric oxide (29). Alternatively, an arginine-free preparation of heme-Llysinate can be made by replacing L-arginine with L-lysine (32). Since heme-L-arginate and heme-L-lysinate each demonstrate heme oxygenase substrate activities identical to that of hematin (32), these preparations seem particularly well suited as sources of heme for experimental purposes.…”

“…Some porphyrins are soluble in ethanol, but ethanol can alter porphyrin metabolism by driving the synthesis of dALA (24), the rate-limiting step in the formation of new heme. While disodium carbonate has been used to solubilize hematin for clinical applications (24), the resulting preparation is still susceptible to degradation during storage (32).…”

“…Heme-L-arginate is one such commercially available preparation (32,33) which is used in the treatment of porphyrin metabolic disorders (24). This preparation boosts the solubility of heme to 38 mmol/l, maximizes monomeric heme availability, and yields a preparation which can be stored for months without discernible degradation (32). For some experimental protocols, heme-L-arginate may create methodological problems, since L-arginine is a substrate for nitric oxide synthase-mediated formation of nitric oxide (29).…”

Structural basis of hereditary coproporphyria

“…If diagnosed early, HCP can be treated with a high carbohydrate diet and i.v. administration of heme in the form of heme arginate (14). In the majority of heterozygous HCP patients, CPO activity is reduced to Ϸ50% (15)(16)(17), resulting in the excretion of coproporphyrin in urine and stool.…”