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Pharmacology & Therapeutics Aug 2023Protoporphyrin IX (PPIX) is an intermediate in the heme biosynthesis pathway. Abnormal accumulation of PPIX due to certain pathological conditions such as erythropoietic... (Review)
Review
Protoporphyrin IX (PPIX) is an intermediate in the heme biosynthesis pathway. Abnormal accumulation of PPIX due to certain pathological conditions such as erythropoietic protoporphyria and X-linked protoporphyria causes painful phototoxic reactions of the skin, which can significantly impact daily life. Endothelial cells in the skin have been proposed as the primary target for PPIX-induced phototoxicity through light-triggered generation of reactive oxygen species. Current approaches for the management of PPIX-induced phototoxicity include opaque clothing, sunscreens, phototherapy, blood therapy, antioxidants, bone marrow transplantation, and drugs that increase skin pigmentation. In this review, we discuss the present understanding of PPIX-induced phototoxicity including PPIX production and disposition, conditions that lead to PPIX accumulation, symptoms and individual differences, mechanisms, and therapeutics.
Topics: Humans; Endothelial Cells; Protoporphyrins; Protoporphyria, Erythropoietic; 5-Aminolevulinate Synthetase
PubMed: 37392940
DOI: 10.1016/j.pharmthera.2023.108487 -
The New England Journal of Medicine Apr 2023Erythropoietic protoporphyria and X-linked protoporphyria are inborn errors of heme biosynthesis that cause elevated circulating levels of metal-free protoporphyrin and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Erythropoietic protoporphyria and X-linked protoporphyria are inborn errors of heme biosynthesis that cause elevated circulating levels of metal-free protoporphyrin and phototoxicity. Both disorders are characterized by excruciating phototoxic attacks after exposure to visible light. Dersimelagon is a new, orally administered, selective melanocortin 1 receptor agonist that increases levels of skin eumelanin.
METHODS
We conducted a randomized, placebo-controlled, phase 2 trial to investigate the efficacy and safety of dersimelagon with respect to the time to onset and the severity of symptoms associated with sunlight exposure in patients with erythropoietic protoporphyria or X-linked protoporphyria. Patients 18 to 75 years of age were randomly assigned in a 1:1:1 ratio to receive placebo or dersimelagon at a dose of 100 or 300 mg once daily for 16 weeks. The primary end point was the change from baseline to week 16 in the time to the first prodromal symptom associated with sunlight exposure. Patients recorded daily sunlight exposure and symptom data in an electronic diary. Quality of life and safety were also assessed.
RESULTS
Of the 102 patients (93 with erythropoietic protoporphyria and 9 with X-linked protoporphyria) who underwent randomization, 90% completed the treatment period. The mean daily time to the first prodromal symptom associated with sunlight exposure increased significantly with dersimelagon: the least-squares mean difference from placebo in the change from baseline to week 16 was 53.8 minutes in the 100-mg dersimelagon group (P = 0.008) and 62.5 minutes in the 300-mg dersimelagon group (P = 0.003). The results also suggest that quality of life improved in patients receiving dersimelagon as compared with placebo. The most common adverse events that occurred or worsened during treatment were nausea, freckles, headache, and skin hyperpigmentation.
CONCLUSIONS
At both doses evaluated, dersimelagon significantly increased the duration of symptom-free sunlight exposure in patients with erythropoietic protoporphyria or X-linked protoporphyria. (Funded by Mitsubishi Tanabe Pharma; Endeavor ClinicalTrials.gov number, NCT03520036.).
Topics: Humans; Infant, Newborn; Prodromal Symptoms; Protoporphyria, Erythropoietic; Quality of Life; Skin; Light; Photosensitivity Disorders; Receptor, Melanocortin, Type 1; Administration, Oral; Dermatologic Agents
PubMed: 37043653
DOI: 10.1056/NEJMoa2208754 -
Annales de Dermatologie Et de... Feb 2019The porphyrias are a group of metabolic disorders resulting from an innate abnormality in haem biosynthesis, and the clinical settings of which vary according to the... (Review)
Review
The porphyrias are a group of metabolic disorders resulting from an innate abnormality in haem biosynthesis, and the clinical settings of which vary according to the genetic enzyme abnormality in question. These are genetic disorders with autosomal dominant or recessive inheritance of varying penetrance, and whose clinical expression differs according to the preferential location of haem precursors. Different classifications have been proposed according to genetic inheritance, the enzyme anomaly at issue, and clinical expression. The clinical classification distinguishes between acute porphyria (acute intermittent porphyria, porphyria variegata, hereditary coproporphyria), bullous cutaneous porphyrias (porphyria cutanea tarda, porphyria variegata and hereditary coproporphyria), painful photosensitive acute cutaneous porphyrias (erythropoietic protoporphyria and X-linked dominant protoporphyria), and rare recessive porphyrias (congenital erythropoietic porphyria, Doss porphyria, hepatoerythropoietic porphyria and harderoporphyria). Treatment depends on the clinical expression of the disorder.
Topics: Biopsy; Coproporphyria, Hereditary; Diagnosis, Differential; Heme; Humans; Photosensitivity Disorders; Porphyria Cutanea Tarda; Porphyria, Erythropoietic; Porphyrias; Protoporphyria, Erythropoietic; Skin; Skin Diseases, Metabolic
PubMed: 30709634
DOI: 10.1016/j.annder.2018.12.005 -
Journal of Cutaneous Medicine and... 2022
Topics: Humans; Protoporphyria, Erythropoietic
PubMed: 33945342
DOI: 10.1177/12034754211016295 -
Journal Der Deutschen Dermatologischen... Oct 2020Increased photosensitivity is a common cutaneous adverse effect associated with the BRAF inhibitor vemurafenib. Clinically, it presents as an immediate sensation of heat... (Review)
Review
Increased photosensitivity is a common cutaneous adverse effect associated with the BRAF inhibitor vemurafenib. Clinically, it presents as an immediate sensation of heat and edematous erythema during sun exposure, as well as a sunburn reaction in terms of a late reaction. Phototesting has shown that the UVA range (320 nm to 400 nm), triggers both the immediate and the late reaction. In terms of pathogenesis, photochemical studies have suggested that exposure of vemurafenib to UVA radiation produces an UVA-absorbing photoproduct. In vitro studies on various cell models have also demonstrated that the phototoxic effects of vemurafenib are exclusively caused by UVA irradiation. This latter mechanism is probably responsible for the photosensitivity clinically observed in patients receiving vemurafenib. In addition, vemurafenib is able to inhibit ferrochelatase. The resulting increase in protoporphyrin IX has also been observed in some human studies involving the drug. However, it is yet unproven whether porphyrins actually contribute to the immediate skin reactions seen in individuals on vemurafenib, even though the clinical presentation is similar to that found in erythropoietic protoporphyria with a comparable pathomechanism. Other BRAF inhibitors, such as dabrafenib and encorafenib, are associated with significantly lower photosensitivity. It is essential that patients treated with vemurafenib are informed about immediate and delayed reactions potentially caused even by low doses of UVA. This includes counseling on photoprotective measures.
PubMed: 32558291
DOI: 10.1111/ddg.14140 -
Der Internist Dec 2018Porphyrias are caused by enzyme defects of heme biosynthesis. According to their clinical presentation and to each affected pathway, they are categorized into acute and... (Review)
Review
Porphyrias are caused by enzyme defects of heme biosynthesis. According to their clinical presentation and to each affected pathway, they are categorized into acute and non-acute as well as hepatic and erythropoietic porphyrias. Acute hepatic porphyrias, e.g. acute intermittent porphyria (AIP), porphyria variegata (VP), hereditary coproporphyria (HCP) and 5‑aminolevulinic acid dehydratase-deficient porphyria (ALADP) are characterized by accumulation of the porphyrin precursors 5‑aminolevulinic acid (ALA) and porphobilinogen (PBG) that correlate with severe abdominal, psychiatric, neurological or cardiovascular symptoms. Additionally, skin photosensitivity can occur in VP and less frequently, in HCP. Decisive for the diagnosis of acute hepatic porphyrias are a >4-fold elevated urinary excretion of ALA in ALADP and ALA and PBG in all other acute porphyrias. First-line treatment of an acute porphyria attack includes intensive care with pain management, sufficient caloric supply, strict avoidance of porphyrinogenic drugs and elimination of other triggering factors. Heme therapy is indispensable in case of developing neurological symptoms and clinical worsening despite first-line measures. Non-acute porphyrias, mainly porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP) and X‑linked protoporphyria (XLP) display accumulation of porphyrins in the skin and/or liver resulting in photosensitivity up to possible liver damage. Patients with PCT benefit from iron depletion, low-dose chloroquine treatment and/or hepatitis C virus elimination. Afamelanotide is associated with better sunlight tolerance in patients with EPP and XLP. Moreover, innovative therapies that highly selectively address dysregulated steps of the heme biosynthetic pathway are currently under clinical trial.
Topics: Humans; Liver Diseases; Porphobilinogen Synthase; Porphyria, Acute Intermittent; Porphyrias; Porphyrias, Hepatic
PubMed: 30328490
DOI: 10.1007/s00108-018-0509-z -
Acta Clinica Belgica Jun 2022Porphyrias are disorders of the haem biosynthesis which are encountered infrequently and which often present themselves atypically as a combination of gastrointestinal,... (Review)
Review
Porphyrias are disorders of the haem biosynthesis which are encountered infrequently and which often present themselves atypically as a combination of gastrointestinal, neurologic and/or dermatologic symptoms. Although they are primarily caused by enzyme defects, inheritance patterns are mostly not evident. Considering all of these characteristics, it is not surprising that there is a long delay between the onset of symptoms and the diagnosis of the disease, with as possible consequences impaired quality of life, irreversible neurologic damage and even death. This review aims to increase the clinical suspicion of the three most common porphyrias in adults: acute intermittent porphyria (AIP), porphyria cutanea tarda (PCT) and protoporphyria. Their relevant pathophysiology, clinical manifestations, diagnosis and treatment are discussed aiming at increasing the awareness of these diseases among physicians.
Topics: Adult; Humans; Porphyria Cutanea Tarda; Porphyria, Acute Intermittent; Porphyrias; Quality of Life
PubMed: 33938396
DOI: 10.1080/17843286.2021.1918876 -
Photodiagnosis and Photodynamic Therapy Jun 2022Erythropoietic protoporphyria (EPP) is caused by deficiency of the enzyme converting protoporphyrin IX (PpIX) into heme resulting in accumulation of PpIX; leading to... (Review)
Review
BACKGROUND
Erythropoietic protoporphyria (EPP) is caused by deficiency of the enzyme converting protoporphyrin IX (PpIX) into heme resulting in accumulation of PpIX; leading to photosensitivity and liver toxicity. Cimetidine might inhibit δ-aminolevulinic acid synthase influencing the heme biosynthesis. We present cases with EPP treated with cimetidine at our department, and a literature review.
METHODS
Systematic searches were performed to identify literature describing EPP patients treated with cimetidine. On that ground we treated EPP patients with cimetidine through spring and summer in 2020 and 2021 at our department. Their erythrocyte PpIX level and standard blood and liver parameters were collected before and during 4 months of treatment. Using a questionnaire, patients were asked about change in photosensitivity, side effects, and whether they would like to resume treatment in the spring of 2022.
RESULTS
Literature searches identified 9 patients treated with cimetidine. Four were outpatients reporting decreased photosensitivity. At our department 18 outpatients started treatment. Fifteen used oral cimetidine daily for 4 months or more providing a significant decrease in erythrocyte PpIX with a median of 20% (range: -18% to 53%) after 4 months. Eleven of the 15 patients reported a decrease in photosensitivity during treatment, 3 patients were unsure, and 1 patient experienced unchanged photosensitivity. Only mild side effects were reported. Fourteen patients requested to resume treatment in the spring of 2022.
CONCLUSIONS
These cases suggest that cimetidine can lower erythrocyte PpIX in patients with EPP.
Topics: Cimetidine; Ferrochelatase; Heme; Humans; Photochemotherapy; Photosensitivity Disorders; Protoporphyria, Erythropoietic; Protoporphyrins
PubMed: 35245673
DOI: 10.1016/j.pdpdt.2022.102793