heme-arginate and Acute-Disease

Topics: Acute Disease; Alanine; Arginine; Carbohydrates; Heme; Humans; Ligases; Porphyrias, Hepatic

Acute intermittent porphyria (AIP) is a metabolic disease affecting hepatic heme biosynthesis. The clinical course in overt disease is characterized by acute attacks of neurovisceral symptoms. Treatment is based on symptomatic relief together with carbohydrate loading and in more severe attacks heme therapy. During an acute attack the heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) are produced in high amounts by the liver and are found in high concentrations in plasma and urine. These metabolites represent the acute phase reactants confirming an ongoing attack and are used to evaluate therapeutic measures. The aim of this study was to measure PBG and ALA in plasma and urine during an acute attack and to match the biochemical pattern with the clinical and therapeutical course.. Three consecutive AIP patients were included during four acute attacks. Plasma PBG and ALA were measured by a LC-MS method and in urine by ion-exchange chromatography. The patients received symptomatic and glucose treatment at admission to hospital, and four days later, if necessary, heme therapy.. In the three attacks that required heme therapy, plasma PBG concentrations had further increased after admission (p=0.01). In the patient that did not require heme therapy, plasma PBG had decreased after admission.. Biochemical monitoring of an acute attack was more accurately reflected by plasma PBG than plasma ALA or urinary PBG and ALA. Glucose administration, in contrast to heme therapy, was not sufficient to achieve clinical and biochemical remission in the more serious attacks.

Topics: Acute Disease; Adult; Aminolevulinic Acid; Arginine; Biomarkers; Chromatography, Ion Exchange; Drug Monitoring; Female; Glucose; Heme; Humans; Male; Porphobilinogen; Porphyria, Acute Intermittent; Sensitivity and Specificity

In acute porphyria, repletion of intrahepatic heme, with exogenously administered heme, suppresses the overproduction of delta-aminolaevulinic acid (ALA) and porphobilinogen (PBG). The effect of reducing heme breakdown has been assessed by administering tin protoporphyrin, a competitive inhibitor of heme oxygenase.. The effect of tin protoporphyrin, 1 mumol/kg, and heme arginate, 3 mg/kg, individually and combined was compared with placebo in patients with an acute porphyric crisis. The treatments were given by intravenous infusion on three successive mornings. Thirty-four attacks were studied in 8 patients (9 placebo, 10 heme arginate alone, 4 tin protoporphyrin alone, and 11 combination treatments).. Placebo and tin protoporphyrin alone had little effect on ALA and PBG excretion. Following heme arginate alone or combined with tin protoporphyrin, there was a marked and similar suppression of both ALA and PBG excretion (P < 0.005 for each, compared with pretreatment values). However, on the 5th day after discontinuing treatment, the excretion of ALA and PBG were both lower following combination therapy than following heme arginate alone (P < 0.005 and P < 0.01, respectively).. These findings suggest that inhibition of heme oxygenase by tin protoporphyrin prolongs the biochemical remission induced by heme arginate in the porphyric crisis.

Topics: Acute Disease; Adult; Arginine; Drug Synergism; Drug Therapy, Combination; Female; Heme; Humans; Male; Metalloporphyrins; Porphyrias, Hepatic; 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

Four forms of porphyria may present clinically with the acute attack, an episodic, severe, and potentially life-threatening manifestation characterized by abdominal and neurologic symptoms. We describe our experience with 112 consecutive attacks observed and treated in 25 patients with the 2 most common forms of acute porphyria in Cape Town, South Africa; 25 attacks in 10 patients with variegate porphyria and 87 attacks in 14 patients with acute intermittent porphyria. The remaining patient experienced more than 100 sequential, severe, and poorly remitting attacks, which are not included in our analysis. In our population, the relative risk of an acute attack in acute intermittent porphyria compared with that in variegate porphyria was 14.3 (confidence intervals, 6.3-32.7). Patients with variegate porphyria were significantly older (median age at first attack, 30 yr) than those with acute intermittent porphyria (median age at first attack, 23.5 yr; p < 0.0001), and demonstrated an equal sex ratio, whereas the male:female ratio in acute intermittent porphyria was 2:12 (p < 0.0001). There was a significant difference in the incidence of factors precipitating the acute attack. Drug exposure was a frequent precipitant of the acute attack in variegate porphyria, whereas hormonal factors were more important in acute intermittent porphyria (p < 0.00001). Patients with acute intermittent porphyria also showed a trend to earlier and more frequent recurrent acute attacks following the initial admission. Mean urine precursor levels, blood pressure, pulse rate, and heme arginate requirement were all significantly higher in patients with acute intermittent porphyria. No significant difference in the frequency of serious complications or in outcome could be shown. We describe our experience with treatment with heme arginate, and provide evidence that heme arginate results in a prompt and statistically significant improvement in symptoms. The incidence of serious complications and mortality in this series was low, confirming a trend to an increasingly good prognosis for patients with acute porphyria who receive expert treatment.

Topics: Abdominal Pain; Acute Disease; Adult; Age Factors; Arginine; Epidemiologic Methods; Female; Heme; Humans; Hypertension; Male; Porphyria, Acute Intermittent; Porphyria, Variegate; Precipitating Factors; Psychotic Disorders; Remission, Spontaneous; Sex Factors; South Africa; Tachycardia

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

Zinc mesoporphyrin (ZnMP) is a potent inhibitor of heme oxygenase (HO) and represses 5-aminolevulinic acid synthase (ALAS). These properties make it a potential candidate for treatment of inducible acute hepatic porphyrias, diseases characterized by neurovisceral symptoms, and massive ALAS induction. Effects of intraperitoneal ZnMP (2.5-10 micromol/kg/d) and heme arginate (3-6 mg/kg/d) on plasma levels of 5-aminolevulinic acid (ALA), on messenger RNA (mRNA), and activity of hepatic ALAS and HO were studied in porphobilinogen deaminase-deficient mice treated with phenobarbital (100 mg/kg/d) to induce ALAS. ZnMP (5 micromol/kg/d) led to a significant reduction of plasma ALA levels to 31% of controls (P < .01) by lowering the activity of hepatic mitochondrial and cytosolic ALAS to 29% and 25% of controls, respectively (P < .03). ZnMP decreased the mRNA levels of hepatic ALAS to 53% (P < .03) of controls and this repression was more pronounced than that achieved with heme arginate. In contrast to heme arginate, ZnMP led to a significant reduction of HO activity. We conclude that the combined effect of ZnMP on highly induced ALAS and on HO may be of potential benefit for human acute hepatic porphyrias and therefore merits further in vivo investigations addressing questions raised by this study.

Topics: 5-Aminolevulinate Synthetase; Acute Disease; Aminolevulinic Acid; Animals; Arginine; Cytosol; Drug Combinations; Female; Heme; Heme Oxygenase (Decyclizing); Injections, Intraperitoneal; Liver; Metalloporphyrins; Mice; Mice, Inbred C57BL; Mitochondria, Liver; Phenobarbital; Porphyria, Acute Intermittent; Porphyrias, Hepatic; Reference Values; RNA, Messenger

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

The characterization of porphyrias as disorders of heme biosynthesis leading to hepatic heme deficiency and raised formation and secretion of heme precursors laid the basis for heme treatment. Although mild attacks sometimes respond to glucose administration, severe attacks or symptoms that are likely to progress should be treated with heme. The heme compounds used in treatment are hematin and heme arginate. In our opinion, heme arginate is preferable to hematin in the treatment of acute porphyrias because of its better stability, fewer side effects, and better documentation of its benefits.

Topics: Acute Disease; Arginine; Heme; Hemin; Humans; Porphyrias, Hepatic

1. The increased urinary excretion of porphyrins as well as of their precursors was studied in a patient with hereditary coproporphyria during two acute attacks in which symptoms differed markedly in character and severity. 2. The increase in urinary coproporphyrin was similar in the 'mild' and in the 'severe' attack, indicating a lack of correlation between coproporphyrin level and clinical symptoms. 3. Aminolaevulinic acid, porphobilinogen and uroporphyrin exhibited significantly higher values during the 'severe' attack than during the 'mild' attack. During the severe attack these three compounds were increased 18-, 14- and 46-fold, respectively, compared with increases of 3-, 3- and 8-fold, respectively, during the mild attack. 4. The striking rise in the formation of uroporphyrin was reflected in the plasma porphyrin profile, which revealed predominance of uroporphyrin. In accordance with this finding, an increase in erythrocyte porphobilinogen deaminase of 130% was recorded. 5. The fluorescence emission spectra of saline-diluted plasma (excitation of 405 nm) showed a distinct peak at 618 nm during the 'severe' episode and a small peak during the 'mild' attack, pointing to the possibility of diagnosing an attack simply by following the fluorometric screen of plasma. 6. The 'severe' attack of coproporphyria was treated with daily infusions of haem arginate, 3 mg/kg, every day for 4 days, at the end of which period a dramatic clinical response was observed. The relief of symptoms was found to be clearly related to the moderate decrease in uroporphyrin excretion observed rather than to the steep decline in the precursors.

Topics: Acute Disease; Adult; Arginine; Erythrocytes; Heme; Humans; Hydroxymethylbilane Synthase; Male; Porphyrias, Hepatic; Porphyrins; Spectrometry, Fluorescence; Uroporphyrins

Severe hepatic porphyrias (acute intermittent porphyria, variegate porphyria and hereditary coproporphyria) are hereditary diseases. Each type of porphyria is the result of a specific decrease in the activity of one of the enzymes of heme biosynthesis. Acute attacks are very serious: the abdominal pains are severe and the neurological manifestations can lead to death or incomplete recovery with irreversible sequelae (usually paralysis). Since 1985, the prognosis of acute attacks has been greatly improved by the introduction of heme-arginate. The 69 acute attacks (30 patients, 4 men and 26 women) that we treated with heme-arginate between 1988 and 1991 are described in this report. All patients were infused with 250 mg/d of heme-arginate for 4 days: the mean duration of abdominal pain was 2.5 days (SD 0.72). For 95 p. 100 of the attacks, the total hospitalization time was 5 days or less; side effects were very minor. In every case, a favorable response was dependent upon the early initiation of heme therapy.

Topics: Acute Disease; Arginine; Female; Heme; Hospitalization; Humans; Infusions, Intravenous; Male; Porphyrias, Hepatic; Time Factors

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

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

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

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

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