heme-arginate and Porphyrias

The porphyrias comprise a group of disorders of the haem biosynthesis pathway that can present with acute neurovisceral symptoms, skin lesions or both. Acute porphyrias present with severe abdominal pain, confusion and seizures which may be life-threatening. Specific treatment with haem preparations should be instituted as soon as possible following confirmation of increased excretion of porphobilinogen in the urine. Supportive treatment includes opiate analgesia, monitoring for and treating complications such as hypertension and hyponatraemia. Follow-up should include counselling on lifestyle modification involving avoidance of alcohol, smoking and known porphyrogenic drugs and diet. Identification and counselling of at risk relatives is essential. The cutaneous porphyrias result from porphyrin-induced photosensitivity and can present with either acute photosensitivity or skin fragility and blisters. All cutaneous porphyrias can be alleviated by avoidance of sunlight. Treatment of erythropoietic protoporphyria involves administering large doses of beta-carotene, which may improve tolerance to sunlight. Porphyria cutanea tarda can be effectively treated by phlebotomy or low dose chloroquine. Congenital erythropoietic porphyria is a rare, early onset, severe, photomutilating condition for which bone marrow transplantation has been shown to be successful.

Topics: Arginine; beta Carotene; Chloroquine; Estrogens; Ethanol; Heme; Humans; Phlebotomy; Porphyria Cutanea Tarda; Porphyria, Acute Intermittent; Porphyrias; Sunlight

Topics: Adult; Arginine; Female; Heme; Humans; Liver Diseases; Metalloporphyrins; Porphyrias; Prospective Studies; Protoporphyrins

A double-blind study comparing placebo and haem arginate was conducted in 12 patients with acute intermittent porphyria. 2 days after admission in attack patients were randomised to receive intravenous haem arginate 3 mg/kg per 24 h for 4 days or placebo. 9 patients were readmitted with a further attack and were given the alternative treatment. Before randomisation the paired attacks were of similar severity with respect to urinary porphobilinogen (PBG) excretion and clinical manifestations. With haem arginate the median PBG excretion of the 9 patients with two attacks (normal range 0-16 mumol per 24 h) fell significantly from 332 mumol per 24 h (range 137-722) on admission to a median lowest level of 40 (range 22-105). On placebo, median PBG excretion was 382 (range 196-542) on admission, falling to 235 (range 128-427). Median duration of admission after the start of treatment was 11 days (range 2-28) for placebo and 8 days (3-26) for haem arginate. Median total analgesic requirement between the start of treatment and discharge was 8150 mg pethidine equivalents (range 0-17,650) with placebo versus 6425 (range 50-20,650) with haem arginate. Phlebitis occurred in 5 patients on haem arginate and in 2 on placebo. Haem arginate effectively reduces porphyrin precursor overproduction in the acute porphyric attack but this reduction is not accompanied by striking resolution of the clinical manifestations of the attack.

Topics: Acute Disease; Adolescent; Arginine; Clinical Trials as Topic; Double-Blind Method; Female; Heme; Heroin; Humans; Infusions, Intravenous; Injections, Intravenous; Liver Diseases; Male; Meperidine; Pain; Phlebitis; Porphyrias; Random Allocation; Recurrence; Severity of Illness Index

Acute intermittent porphyria (AIP) is a rare metabolic disorder of heme biosynthesis characterized by enzymatic defect of porphobiligen desaminase with accumulation and increased excretion of porphyrins and their precursors. Clinical picture is characterized by attacks with a triad of abdominal pain, psychiatric disorder and neurological involvement (central and peripheral). Peripheral nervous system manifestations, often precipitated by porphyrinogenic medications are of poor outcome.. We report a new cases A 13-year-old girl who presented several attacks of AIP and developed acute severe axonal motor neuropathy, three weeks after porphyrinogenic medications (Famotidin, Phenobarbital and Nifedipine).. We stress on the importance of early diagnosis of AIP to prevent serious neurological complications often precipitated by medications and the efficiency of heme arginate treatment when administrated early during the attacks.

Topics: Acute Disease; Adolescent; Arginine; Electromyography; Famotidine; Female; Heme; Heme Oxygenase (Decyclizing); Humans; Nifedipine; Peripheral Nervous System Diseases; Phenobarbital; Porphyrias; Porphyrinogens; Time Factors

The porphyrias are a heterogeneous group of predominantly hereditary metabolic diseases resulting from a dysfunction of heme biosynthesis. Most of the porphyrias can manifest with a broad range of cutaneous symptoms on the sun-exposed areas of the body, whereas other variants reveal life-threatening acute neurological attacks. Further, mixed types of porphyrias exist. Besides the skin, other organs can be affected, such as the liver and the central nervous system. Therefore, interdisciplinary supervision of these patients is mandatory. In this review we will first present the clinical picture and diagnosis of the porphyrias, including the specific biochemical laboratory tests and a diagnostic algorithm. Thereafter, the current therapeutic concepts will be briefly addressed. Finally, we introduce the European Porphyria Initiative (EPI), an association of various European porphyria centers that is aiming at gathering the broad experience of internationally renowned porphyria experts for the development of European consensus guidelines for diagnosis and treatment of these metabolic disorders.

Topics: Algorithms; Arginine; Critical Care; Diagnosis, Differential; Dose-Response Relationship, Drug; Drug Administration Schedule; Genetic Predisposition to Disease; Heme; Humans; Photosensitivity Disorders; Porphyria Cutanea Tarda; Porphyrias

To characterize patients with various nosological unities [symbol: see text] of porphyria in accordance with their age, clinical symptoms, provoking factors, therapy and outcome.. Patients with acute intermittent porphyria (43), hereditary coproporphyria (8), variegate porphyria (3), porphyria cutanea tarda (7), hepatoerythropoietic porphyria (1), and hereditary erythropoietic porphyria (2) were studied. One patient was suspected of porphyria caused by deficiency of delta-aminolevulenic acid dehydrogenase.. The patients were from the CIS. The overwhelming majority of them were young and middle-aged subjects. Rapid development of the disease and severe neurological symptoms were predominantly observed in patients with acute forms of porphyria.. Early diagnosis of porphyrin metabolism disorders makes it possible to decrease abruptly the number of cases leading to severe complications, disability, and fatal outcome. The use of inexpensive methods of screening of porphyrin metabolism disorders provides a promising approach to solving this problem. These methods should be used in municipal hospitals. In addition, asymptomatic carriers of defective gene should be revealed at the preclinical stage using various methods of molecular genetic assay.

Topics: Acute Disease; Adolescent; Adult; Arginine; Chronic Disease; Female; Heme; Humans; Inosine Diphosphate; Middle Aged; Octreotide; Plasmapheresis; Porphyria, Acute Intermittent; Porphyria, Erythropoietic; Porphyrias; Porphyrins

A 30-year-old woman suffered from acute crises with abdominal, neurological and psychiatric complaints. Urinary haem precursors and faecal porphyrins were excessively elevated compared to the upper level of the normal range. Urinary coproporphyrin isomer III was increased and faecal coproporphyrin isomers I and III showed a complete inversion of the normal ratio. Thus, hereditary coproporphyria was diagnosed in this woman. The father, one brother and a sister were shown to be gene carriers of hereditary coproporphyria by their urinary and faecal excretory constellations. The excretory patterns of the mother and a second brother were normal. Coproporphyrinogen oxidase activity was decreased to 49% and 58%, in the patient and her father, respectively. The mother's enzyme activity was normal (98%). Coproporphyrinogen oxidase concentration was enhanced 1.8-fold and 2.7-fold in the patient and her father, respectively. Mutation analysis revealed the insertion of an adenine at position 857 in exon 4 of the coproporphyrinogen oxidase gene. The gene defect was confirmed by denaturing gradient gel electrophoresis in the patient and her father. The patient was treated by intravenous interval therapy with haem arginate for 10 months, with good clinical and metabolic response.

Topics: Adult; Aminolevulinic Acid; Arginine; Coproporphyrinogen Oxidase; DNA Mutational Analysis; Feces; Female; Heme; Humans; Porphyrias; Protein Denaturation

Topics: Acute Disease; Adult; Arginine; Critical Care; Diagnosis, Differential; Female; Glucose; Heme; Humans; Infusions, Intravenous; Male; Middle Aged; Porphyrias; Pregnancy; Quality of Life; Respiration, Artificial

Topics: Arginine; Female; Heme; Humans; Infusions, Intravenous; Male; Porphyrias

An 11 year old boy presented with severe acute hereditary coproporphyria. Despite supportive measures his condition deteriorated after admission. Haem arginate, started two days after presentation, produced appreciable inhibition of porphyrin precursor overproduction and clinical improvement.

Topics: Arginine; Child; Coproporphyrins; Heme; Humans; Liver Diseases; Male; Porphyrias

Sex hormone-binding globulin (SHBG), thyroxine-binding globulin (TBG) and cortisol-binding globulin (CBG) were measured in plasma of 26 patients with acute intermittent porphyria (AIP). Twelve patients had clinically manifest disease and all had elevated SHBG levels. All but one of 14 patients with latent porphyria had normal SHBG levels. TBG was elevated in 9 of the patients with clinically manifest porphyria and CBG elevated in three. Levels of TBG and CBG were either normal or only slightly elevated in those with latent porphyria. In a prospective study of 30 attacks of AIP in 7 patients, SHBG levels fell between admission and discharge, the fall being significant in the group of 21 attacks treated with haem arginate (p less than 0.001). Our findings suggest that a close correlation exists between elevated SHBG and clinical expression of AIP.

Topics: Adolescent; Adult; Aminolevulinic Acid; Arginine; Carrier Proteins; Heme; Humans; Hydrocortisone; Liver Diseases; Porphobilinogen; Porphyrias; Prospective Studies; Sex Hormone-Binding Globulin; Testosterone; Thyroxine-Binding Proteins

Four patients with variegate porphyria (VP) were treated with repeated haem arginate infusions daily for 4 days and then weekly for 4 weeks. After the initial four daily doses of haem arginate (haem 3 mg/kg), the excretion of faecal protoporphyrin (mean 579 nmol/g dry wt) fell to an almost normal level (mean 123 nmol/g dry wt), and that of coproporphyrin (mean 162 nmol/g dry wt) to the normal level (mean 21 nmol/g dry wt) in all patients. However, during the period of the four weekly infusions of haem the excretion of porphyrins increased almost to the pretreatment level. Phototesting showed no changes in the photoreactivity of the skin, and no improvement in skin lesions was seen during the treatment. Except for one case of thrombophlebitis no side-effects occurred. In a child with homozygous VP, four daily infusions of haem arginate (2 mg/kg) normalized the faecal protoporphyrin content, but had no effect on the increased erythrocyte protoporphyrin concentration.

Topics: Adult; Arginine; Feces; Female; Heme; Humans; Infusions, Intravenous; Photosensitivity Disorders; Porphyrias; Protoporphyrins; Skin; Skin Diseases

In the course of four weeks, tetraparesis developed in a 28-year-old man with Crohn's disease for the last six years, treated with glucocorticoids and sulphasalazine. The cause was acute intermittent porphyria which had been previously overlooked because of the similar abdominal symptoms of Crohn's disease. Treatment with glucose, propranolol and haemarginate failed to bring about any improvement, but there was a remission of the porphyria. This case demonstrates that diagnosis of acute intermittent porphyria in the presence of Crohn's disease is difficult, and if delayed therapeutic measures in the face of persisting neurological complications are of little benefit.

Topics: Acute Disease; Adult; Arginine; Crohn Disease; Diagnosis, Differential; Drug Therapy, Combination; Glucose; Heme; Humans; Male; Porphyrias; Propranolol; Quadriplegia; Remission Induction

In three patients with attacks of acute intermittent porphyria we found markedly impaired functions of the left ventricle accompanied by ECG changes that returned to normal after administration of heme arginate or cytochrome C administration. In nine patients with other types of porphyria, and in one patient with acute intermittent porphyria not suffering an attack, no significant changes of left ventricle function were observed. The changes seen in patients with an acute attack may be ascribed to acute myocardial hypoxia resulting from defective biosynthesis of heme. We assume that the exogenous supply of heme may improve cellular hypoxia.

Topics: Acute Disease; Adult; Arginine; Cytochrome c Group; Female; Heart; Heme; Humans; Liver Diseases; Male; Middle Aged; Porphyrias

Topics: Arginine; Drug Evaluation; Heme; Humans; Porphyrias

1. The elimination of antipyrine was investigated before and after intravenous administration of haem arginate (3 mg haem kg-1 day-1 on three or four successive days) to six patients with variegate porphyria in remission. 2. Haem arginate decreased the faecal content of protoporphyrin from 557 +/- 91 to 118 +/- 32 (mean +/- s.e. mean) and of coproporphyrin from 144 +/- 19 to 19 +/- 3 nmol g-1 dry weight. 3. Before haem treatment antipyrine elimination half-life was long (30.5 +/- 5.6 h), but the treatment decreased it to 6.3 +/- 0.8 h. Antipyrine clearance increased from 0.25 +/- 0.05 to 1.03 +/- 0.11 ml min-1 kg-1 (P less than 0.001), being 4.6 times higher after haem arginate infusions. 4. The volume of distribution of antipyrine did not change. 5. The severe impairment of hepatic mixed function oxidase activity even in the symptomless stage of porphyria indicates cautious dosage of drugs primarily eliminated by hepatic oxidative reactions.

Topics: Adult; Antipyrine; Arginine; Feces; Female; Heme; Humans; Liver; Oxidation-Reduction; Porphyrias; Porphyrins

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.

Topics: Arginine; Electron Spin Resonance Spectroscopy; Heme; Humans; Mathematics; Molecular Weight; Porphyrias

The effect of haem arginate on porphyrin metabolism and haemoprotein function was studied during seven attacks of acute hepatic porphyria in 5 patients. In each attack it greatly reduced the overproduction of porphyrin precursors and repressed the overactivity of the rate-controlling enzyme of haem synthesis delta-aminolaevulinic acid (ALA) synthase measured in leucocytes. Antipyrine clearance, an index of the oxidative function of cytochromes P-450, the major group of hepatic haemoproteins, was increased during haem therapy. Thus, haem arginate not only suppresses the overproduction of haem precursors but also improves hepatic oxidative metabolism in acute porphyria.

Topics: Acute Disease; Adult; Antipyrine; Arginine; Cytochrome P-450 Enzyme System; Depression, Chemical; Female; Heme; Humans; Hydroxymethylbilane Synthase; Leukocytes; Liver; Liver Diseases; Male; Mitochondria, Liver; Mixed Function Oxygenases; Porphobilinogen Synthase; Porphyrias; Porphyrins

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)

Topics: Animals; Arginine; Blood Coagulation; Blood Pressure; Drug Stability; Heme; Heme Oxygenase (Decyclizing); Hydrogen-Ion Concentration; Lethal Dose 50; Mice; Porphyrias; Spectrophotometry, Ultraviolet

Topics: Acute Disease; Adolescent; Arginine; Female; Heme; Humans; Porphyrias

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.

Topics: 5-Aminolevulinate Synthetase; Allylisopropylacetamide; Animals; Arginine; Heme; Hemin; Liver; Male; Porphobilinogen; Porphyrias; Rats; Rats, Inbred Strains

Topics: Acute Disease; Adult; Arginine; Heme; Humans; Male; Middle Aged; Porphyrias

Topics: Acute Disease; Arginine; Heme; Humans; Liver Diseases; Porphyrias

Topics: Arginine; Heme; Humans; Porphyrias

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.

Topics: Adult; Arginine; Female; Haptoglobins; Heme; Hemopexin; Humans; Injections, Intravenous; Kinetics; Male; Metabolic Clearance Rate; Middle Aged; Porphyrias