Heme in the treatment of porphyrias and hematological disorders.
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Hematologic Diseases↗
Biomedical subjects
R Tenhunen
Publications and source records attributed to R Tenhunen.
Effect of exogenous heme on hepatic iron-load and changes induced in hepatic heme metabolism by chronic iron-load.
It has recently been shown that heme arginate treatment can markedly improve blood cell counts in some severely cytopenic patients with a myelodysplastic syndrome (MDS). As MDS is often associated with iron overload, we have now studied in iron-loaded rats the hepatic effects of heme arginate given in a dose of 1.2 mg/100 g intraperitoneally twice a week for a period of 4.5 weeks. The heme injections caused a very marked increase in the mean hepatic iron content of the iron-loaded rats, which was more than twice the total amount of the heme-iron injected per rat. The heme treatment did not significantly affect the activities of the enzymes involved in the heme metabolism. Although no clinical side effects have been found in the MDS patients treated with heme arginate so far, the present study suggests that in iron-load the possible adverse hepatic effects should be taken into account and a minimum therapeutic dose of heme arginate should be used.
Animals↗
Heme arginate treatment for myelodysplastic syndromes.
Heme arginate was given to 26 patients with a myelodysplastic syndrome (MDS) as infusions of 2-3 mg/kg body weight weekly for 8-12 weeks. Most of the patients first received a loading dose on four consecutive days. Six of the patients showed improvement in cytopenias during the therapy. In three of the responders severely depressed blood cell counts recovered to normal or close to normal. So far the maximum duration of a response after the cessation of the treatment is 25 months, and the two ongoing responses have lasted for 11 and 12 months, respectively. In two responders of the eight patients with more than 15% ring sideroblasts the number of ring sideroblasts decreased during the treatment but remained unchanged in six non-responders. The responders were characterized by a low or low normal heme synthase activity which increased during the treatment, whereas the non-responders showed a higher mean heme synthase activity which decreased during the treatment. In general, the responders had significantly fewer defects in heme synthetic enzyme activities than the non-responders. FAB type, karyotype or growth pattern in in vitro cultures of hematopoietic progenitors did not predict the response. Apart from one case of mild venous irritation, no other adverse effects were seen. The present study shows that heme arginate induces beneficial effects on cytopenia in some MDS patients and has very few side-effects.
Adult↗
Disturbed iron metabolism among workers exposed to organic sulfides in a pulp plant.
The aim of this study was to investigate a possible relationship between exposure to sulfides and disturbances of the synthesis of heme and the erythrocytes. Eighteen workers exposed to sulfides at a pulp and paper plant were examined and compared with individually matched referents from a thermomechanical pulp plant without such exposure. The exposure levels of methylmercaptan, dimethylsulfide, and dimethyldisulfide were low. However, five subjects were exposed to high levels of short duration, and their data were analyzed separately. The activity of the enzymes delta-aminolevulinic acid synthase and heme synthase in reticulocytes, characteristics of the erythrocytes, and the iron status were analyzed. A minor decrease, not statistically significant, was observed for the enzymes among the five highly exposed subjects. However, the concentrations of iron and transferrin were elevated and the concentration of ferritin was low in comparison to the corresponding levels of the referents. This combination will not occur spontaneously. A previous study indicated that sulfides may inhibit heme synthesis, and the present study suggests that they may also disturb iron metabolism.
5-Aminolevulinate Synthetase↗
Heme arginate: effects on hemostasis.
Hematin, the drug used for acute porphyric attacks, has been shown to cause disturbances in hemostasis, mainly because of its degradation products. Lately a new heme compound, heme arginate, has been developed for the treatment of porphyrias. In experimental animal studies as well as in clinical use it has proved to be well tolerated. To find out whether heme arginate has any effects on hemostasis we have studied a number of parameters of coagulation and fibrinolysis after a heme arginate infusion in seven healthy volunteers. All parameters studied remained practically unchanged except the coagulation factor X, which showed a transient, insignificant decrease during the maximal heme concentration. We believe that the lack of side effects is due to a better stability of heme arginate, the degradation rates being 1% for heme arginate and 61% for hematin in four hours. Our data favor the use of heme arginate in acute porphyrias as well as in other deficiency states of heme.
Adult↗
Erythroid colony formation and effect of hemin in vitro in hereditary sideroblastic anemias.
Colony formation by erythroid burst-forming units (BFU-E) and erythroid colony-forming units (CFU-E) and the effect of hemin on colony growth was studied in vitro in three Finnish families with hereditary sideroblastic anemia (HSA). Defective activity of heme synthase has been demonstrated in family A and that of delta-aminolevulinic acid synthase in family B. No biochemical defect has been recognized so far in family C. CFU-E colony growth was defective in seven of the eight persons studied. The formation of BFU-E colonies was normal in family A and increased in family C, whereas of the two members of family B one showed normal and one decreased BFU-E colony growth. Hemin in 30-120 microM concentration increased significantly both BFU-E (p less than 0.01) and CFU-E (p less than 0.005) colony formation in family C. No effect was seen in family A, and in family B the only effect was normalization of the decreased BFU-E colony growth by the highest hemin concentration in one person. This study indicates that differences exist between families with HSA in erythroid colony formation and in response to hemin in vitro, but the low number of investigated members in each family does not permit a conclusive evaluation of the impact of the carrier versus patient status or of sex on the results.
Adult↗
Rapid immunochemical detection of fecal occult blood by use of a latex-agglutination test.
A novel immunochemical test, "Hemolex," is characterized and compared with three guaiac tests: "Hemoccult" (Smith-Kline, U.S.A.), "Hemofec" (Boehringer Mannheim, F.R.G.), and "Fecatwin Sensitive" (Labsystems, Finland). We tested 191 stool specimens from patients, 144 from healthy persons. The sensitivity of Hemolex was 0.6 mL of blood per 100 g of stool. It reacts with neither animal hemoglobin nor human myoglobin, unlike the guaiac tests, nor does it react with the stool of healthy persons under no dietary restrictions, while the guaiac tests react variably. As a rule, Hemolex is insensitive to bleeding in the upper gastrointestinal tract, unlike the guaiac tests. However, Hemolex seems to be more sensitive to bleeding in the lower gastrointestinal canal than are the other tests, and we show it to be suitable for screening for occult blood originating there. It is unaffected by diet. It is simple to perform, requires no special equipment, and stool specimens, stored in the test diluent, are stable for testing for two weeks.
Animals↗
Optical and EPR spectroscopy studies on haem arginate, a new compound used for treatment of porphyria.
A protohaem compound, used for treatment of porphyrias, has been studied to elucidate its state of aggregation. EPR and absorption spectroscopy measurements reveal that 38.3 mM protohaem, dissolved in 40% 1,2-propanediol/10% ethanol/water solution, also containing 153 mM arginine, is partly EPR silent. It exists as high molecular weight aggregates and probably also as mu-oxo-dimers. Dilution in the aqueous alcohol solution dissolves the aggregates first to oligomers and dimers, and finally to monomers (Kdiss = 24 X 10(-6)M). When haem is diluted in 0.9% sodium chloride, a fully monomeric state is not reached even at 1 microM concentration. At 3.5 microM concentration, that used for infusion in patients, the haem is still totally aggregated.
Arginine↗
Haem arginate as a treatment for myelodysplastic syndromes.
We report on two patients with a myelodysplastic syndrome in whom the blood cell counts markedly improved during treatment with haem arginate. One patient received haem arginate only, the other haem arginate in combination with low dose androgen. The drug was given as weekly infusions of 2-3 mg/kg body weight for 8-12 weeks. In one patient the percentage of ringed and other abnormal sideroblasts in the bone marrow was clearly reduced as a result of the treatment. In both patients the effect on blood cell counts lasted for several months after the cessation of the haem arginate treatment. Eleven other patients showed no clear response. No adverse effects of the infusions were observed. Further studies on the possible therapeutic role of haem arginate are indicated.
Adult↗
Homozygous variegate porphyria. A severe skin disease of infancy.
A boy exhibited severe bullous skin disease a few days after birth, followed by increased fragility of the exposed skin in spring and summer. Examination at 2 1/2 years of age led to characteristic biochemical findings: increased excretion of fecal porphyrins (coproporphyrin 121 to 131 and protoporphyrin 467 to 576 nmol/g dry weight), and increased erythrocyte protoporphyrin concentration (3643 to 4840 nmol/l). Lymphocyte protoporphyrinogen oxidase activity was very low in the patient (0.4 nmol/mg protein/h) and half-normal (2.7 and 2.3 nmol/mg protein/h) in the parents, suggesting that the patient had homozygous variegate porphyria. Severe skin symptoms and a high concentration of red cell protoporphyrin concentration in an infant should prompt suspicion of homozygous acute hepatic porphyria.
Acute Disease↗
Impaired heme synthesis in a family with Pelger-Huët anomaly, recurrent abdominal pain attacks and impaired neutrophil motility in vitro.
Heme synthesis was studied by measuring the activity of delta-aminolevulinic acid synthase (AmLev synthase) in granulocytes, the activity of delta-aminolevulinic acid dehydratase (AmLev dehydratase) and of uroporphyrinogen I synthase in erythrocytes as well as the concentrations of coproporphyrin and protoporphyrin in erythrocytes of 6 patients with Pelger-Huët anomaly. 3 of these patients from the same kindred had a syndrome of recurrent attacks of fever and abdominal pains, a tendency to skin infections, delayed wound healing and impaired neutrophil motility. The other 3 patients were asymptomatic. The activity of AmLev synthase was depressed in all 3 symptomatic patients and normal in the asymptomatic patients. 1 symptomatic patient had a decreased erythrocyte protoporphyrin concentration. These findings indicate a derangement of heme synthesis in the symptomatic patients. Their abdominal pain attacks could be due to heme depletion. The findings suggest that the abdominal pains of patients with porphyria could be due to decreased heme synthesis rather than due to accumulation of porphyrin precursors in tissues. The cause of the impaired neutrophil motility may be a defect in energy metabolism due to decreased supply of heme for oxidative metabolism.
Abdomen↗
The effects of haem arginate and haematin upon the allylisopropylacetamide induced experimental porphyria in rats.
Biochemical disorders caused by allylisopropylacetamide in various animal species resemble human acute intermittent porphyria. The antiporphyrogenic efficacy and potency of haem arginate, a new haem compound, were compared with those of haematin in experimental porphyria of rats. Both haem arginate and haematin dose-dependently decreased the urinary excretions of porphyrin precursors. They inhibited significantly the induction of hepatic delta-aminola-evulinic acid synthase. Haem arginate and haematin could restore the activity of haem oxygenase and after higher doses they increased the activity. The dose-effect relationships of the two haem compounds were demonstrated.
5-Aminolevulinate Synthetase↗
Haem arginate: a new stable haem compound.
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)
Animals↗
Fate of haem after parenteral administration of haem arginate to rabbits.
Rabbits were injected either intravenously or intramuscularly with [14C]haem arginate and [59Fe]haem arginate (haem 5 mg kg-1). The main part (80%) of AUCINF of labelled haem was associated with the beta-phase, T1/2 being about 6 h. Only 1% of the haem dose had been taken up by the red blood cells. In contrast, the iron moiety from the haem molecule was effectively utilized. Thirty days post-injection of [59Fe]haem arginate, 40% of the dose after intravenous injection and 60% after intramuscular injection was circulating with the red cells. Radioactivity was shown to concentrate in the liver, where haem is mainly metabolized and eliminated. An accumulation of haem in the adrenals was also evident. Haem itself did not concentrate in the bone marrow, and a negligible amount of radioactivity was recovered from brain, implying a poor penetration of the blood brain barrier.
Adrenal Glands↗
Effect of exogenous heme on sulfide-induced changes in rat heme metabolism.
Intraperitoneal heme treatment (5 mg/kg body wt) reversed the effects of a preceding (2 h) intraperitoneally injected Na2 S (150 mumol/kg body wt) dose on blood delta-amino levulinic acid synthase and heme synthase activities. The sulfide dosing caused decreased activity of both enzymes of which that of heme synthase was overcorrected above controls by the heme treatment 25 h after the sulfide dose. Heme alone caused a transient induction in the heme oxygenase activity in liver 23 h after the injection. The effects on heme synthesis in the sulphide-dosed rats support the role of the inactivation of the heme-controlled translational inhibitor of protein synthesis by the supply of exogenous heme.
5-Aminolevulinate Synthetase↗
[Acute attacks of hepatic porphyria. Treatment with hematin. 5 cases].
The effectiveness of 2 hematins administered by intravenous infusion was compared in acute intermittent porphyria. Judging from subjective symptoms (abdominal pain), clinical improvement was complete and constant. There was a rapid decrease in urinary excretion of porphyrins precursors, with a clearer response of delta-aminolevulinic acid than of porphobilinogen. Urine levels of uroporphyrin often returned to normal after two infusions. The drugs were very well tolerated. Provided it is administered early, before neurological complications develop, treatment with hematin completely relieves abdominal symptoms and suppresses most of the biochemical changes associated with hepatic porphyria.
Acute Disease↗
Haem arginate in the treatment of acute hepatic porphyrias.
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Acute Disease↗
Pharmacokinetics of intravenously administered haem arginate.
The pharmacokinetics of haem were investigated after intravenous administration of a therapeutic dose of haem arginate (3 mg haem kg-1) to four healthy volunteers and four symptomless porphyric patients. Plasma haem concentrations were measured also during a treatment course of four infusions in six patients with porphyria. Plasma haem concentrations declined monoexponentially over 48 h in both healthy volunteers and porphyric patients, with a mean +/- s.e. mean elimination half-life of 10.8 +/- 0.6 h. Other kinetic parameters were also similar in the two groups, total plasma clearance was 3.7 +/- 0.4 ml min-1 and volume of distribution was 3.37 +/- 0.34 l. In the multiple dose study the elimination half-life increased significantly, from 11.3 +/- 0.4 h to 18.1 +/- 1.4 h over 4 consecutive days. Plasma haemopexin values decreased with time after a single haem arginate dose. The infusion of haem arginate did not cause thrombophlebitis.
Adult↗