Haem arginate in the treatment of acute hepatic porphyrias.

Mustajoki, Pertti; Tenhunen, Raimo; Tokola, Olavi; Gothóni, G.

doi:10.1136/bmj.293.6546.538-a

Cited by 51 publications

(17 citation statements)

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“…) is usually administered at a dose of 3 mg/kg once daily for 4 days by infusions into a central vein delivered over at least 30 min. There is reasonable evidence for using haem arginate for patients having a single acute attack or infrequent attacks (Mustajoki et al 1986;Kostrzewska et al 1991). However, there is an important group of patients, predominantly as here women in the reproductive age group who have recurrent acute attacks usually requiring admission to hospital, opiate analgesia and emergency administration of haem arginate.…”

Section: Stopping Prophylactic Haem Arginate Treatmentmentioning

confidence: 98%

Audit of the Use of Regular Haem Arginate Infusions in Patients with Acute Porphyria to Prevent Recurrent Symptoms

et al. 2015

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The National Acute Porphyria Service (NAPS) provides acute care support and clinical advice for patients in England with active acute porphyria requiring haem arginate treatment and patients with recurrent acute attacks.This audit examined the benefits and complications of regular haem arginate treatment started with prophylactic intent to reduce the frequency of recurrent acute attacks in a group of patients managed through NAPS. We included 22 patients (21 female and 1 male) and returned information on diagnosis, indications for prophylactic infusions, frequency and dose, analgesia, activity and employment and complications including thromboembolic disease and iron overload.The median age at presentation with porphyria was 21 years (range 9-44), with acute abdominal pain as the predominant symptom. Patients had a median of 12 (1-400) attacks before starting prophylaxis and had received a median of 52 (0-1,350) doses of haem arginate. The median age at starting prophylaxis was 28 years (13-58) with a median delay of 4 years (0.5-37) between presentation and prophylaxis. The frequency of prophylactic haem arginate varied from 1 to 8 per month, and 67% patients were documented as having a reduction in pain frequency on prophylaxis. Only one patient developed clinically significant iron overload and required iron chelation, but the number of venous access devices required varied from 1 to 15, with each device lasting a median of 1.2 years before requiring replacement. Six patients stopped haem arginate and in three this was because their symptoms had improved. Prophylactic haem arginate appears to be beneficial in patients with recurrent acute porphyria symptoms, but maintaining central venous access may prove challenging.

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Section: Stopping Prophylactic Haem Arginate Treatmentmentioning

confidence: 98%

Audit of the Use of Regular Haem Arginate Infusions in Patients with Acute Porphyria to Prevent Recurrent Symptoms

et al. 2015

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“…Heme reduces hepatic ALA synthase levels in various experimental models of acute porphyria (9)(10)(11)(12) and apparently has the same effect in patients suffering from acute porphyria (5)(6)(7)(8). The mechanism(s) whereby heme exerts a repressive effect on hepatic ALA synthase may be manifold, including decreasing mRNA stability (13,14) and decreasing import of the enzyme into mitochondria (15,16).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of metalloporphyrins on messenger RNA levels of delta-aminolevulinate synthase and heme oxygenase. Studies in cultured chick embryo liver cells.

Cable¹,

Pepe²,

Karamitsios³

et al. 1994

J. Clin. Invest.

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The acute porphyrias in relapse are commonly treated with intravenous heme infusion to decrease the activity of 6-aminolevulinic acid synthase, normally the rate-controlling enzyme in heme biosynthesis. The biochemical effects of heme treatment are short-lived, probably due in part to heme-mediated induction of heme oxygenase, the rate-controlling enzyme for heme degradation. In this work, selected nonheme metalloporphyrins were screened for their ability to reduce 6-aminolevulinic acid synthase mRNA and induce heme oxygenase mRNA in chick embryo liver cell cultures. Of the metalloporphyrins tested, only zinc-mesoporphyrin reduced 8-aminolevulinic acid synthase mRNA without increasing heme oxygenase mRNA. The combination of zincmesoporphyrin and heme, at nanomolar concentrations, decreased 8-aminolevulinic acid synthase mRNA in a dosedependent manner. The combination of zinc-mesoporphyrin (50 nM) and heme (200 nM) decreased the half-life of the mRNA for 6-aminolevulinic acid synthase from 5.2 to 2.5

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“…administration of hemin, which provides exogenous heme for the negative feedback inhibition of ALAS1, thereby decreasing ALA and PBG production (11)(12)(13). Although patients generally respond well, its effect is slow, typically requiring three to four daily infusions to normalize the elevated plasma and urinary ALA and PBG concentrations (14).…”

mentioning

confidence: 99%

RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice

Yasuda

Gan

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

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The acute hepatic porphyrias are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks. Factors that induce the expression of hepatic 5-aminolevulinic acid synthase 1 (ALAS1) result in the accumulation of the neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which recent studies indicate are primarily responsible for the acute attacks. Current treatment of these attacks involves i.v. administration of hemin, but a faster-acting, more effective, and safer therapy is needed. Here, we describe preclinical studies of liver-directed small interfering RNAs (siRNAs) targeting Alas1 (Alas1-siRNAs) in a mouse model of acute intermittent porphyria, the most common acute hepatic porphyria. A single i.v. dose of Alas1-siRNA prevented the phenobarbital-induced biochemical acute attacks for approximately 2 wk. Injection of Alas1-siRNA during an induced acute attack significantly decreased plasma ALA and PBG levels within 8 h, more rapidly and effectively than a single hemin infusion. Alas1-siRNA was well tolerated and a therapeutic dose did not cause hepatic heme deficiency. These studies provide proof-of-concept for the clinical development of RNA interference therapy for the prevention and treatment of the acute attacks of the acute hepatic porphyrias.RNAi therapeutics | liver-targeted siRNA | heme biosynthetic disorders T he acute hepatic porphyrias are caused by the deficient activities of specific enzymes in the heme biosynthetic pathway and include three autosomal dominant diseases-acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP)-and the autosomal recessive 5-aminolevulinic acid dehydratase deficiency porphyria (ADP) (1). These inherited metabolic disorders are characterized by lifethreatening acute neurovisceral attacks that include severe abdominal pain, hypertension, tachycardia, constipation, motor weakness, seizures, and paralysis (1). Various factors, including cytochrome P450 (CYP)-inducing drugs, dieting, and hormonal changes precipitate the acute attacks by increasing the expression of hepatic 5-aminolevulinic acid synthase (ALAS1), the first and rate-limiting enzyme of the heme biosynthetic pathway (2-6). When hepatic ALAS1 is induced, the respective enzyme deficiencies create a metabolic bottleneck, thereby decreasing hepatic heme production and depleting the "free" heme pool. This leads to the loss of the negative feedback inhibition of heme on ALAS1 (7-9) and, consequently, further up-regulation of hepatic ALAS1 expression. As hydroxymethylbilane synthase (HMBS)-the third enzyme in the heme biosynthetic pathway-is less abundant in comparison with the other heme biosynthetic enzymes (10), it becomes rate-limiting when ALAS1 is markedly increased. As a result, the neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) are overproduced in the liver and are markedly accumulated in the plasma and urine during the acute attacks (only ALA accumulates ...

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Haem arginate in the treatment of acute hepatic porphyrias.

Cited by 51 publications

References 2 publications

Audit of the Use of Regular Haem Arginate Infusions in Patients with Acute Porphyria to Prevent Recurrent Symptoms

Audit of the Use of Regular Haem Arginate Infusions in Patients with Acute Porphyria to Prevent Recurrent Symptoms

Differential effects of metalloporphyrins on messenger RNA levels of delta-aminolevulinate synthase and heme oxygenase. Studies in cultured chick embryo liver cells.

RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice

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