RESUMO
Givosiran is a small synthetic double-stranded siRNA (small interfering RNA) conjugated with N-acetyl-galactosamine (GalNAc) for specific hepatocyte targeting via the asialoglycoprotein receptor. A prospective randomized multicenter study (Envision) demonstrated the clinical efficacy of monthly subcutaneous injection of Givosiran for the prevention of attacks of acute hepatic porphyria (AHP). This leads to highly selective transcriptional inhibition of the key hepatic enzyme, aminolaevulinate synthase 1, that is overexpressed in AHP. The success of the Envision study has led to the approval of Givosiran in the US and Europe for the treatment of severe AHP. This innovative guided siRNA therapy has opened up the possibility to selectively inhibit the expression of any hepatocyte gene whose overexpression that causes pathology, which can be considered a milestone development in hepatology. However, currently this treatment with givosiran is very costly. Moreover, since some patients experience worsening of kidney function and elevated aminotransferases, monthly monitoring of these parameters is necessary in the first half year of treatment.
Assuntos
Acetilgalactosamina/análogos & derivados , Sintase do Porfobilinogênio/deficiência , Porfirias Hepáticas/tratamento farmacológico , Pirrolidinas , RNA Interferente Pequeno , Terapêutica com RNAi , 5-Aminolevulinato Sintetase/antagonistas & inibidores , Acetilgalactosamina/administração & dosagem , Acetilgalactosamina/uso terapêutico , Humanos , Sintase do Porfobilinogênio/metabolismo , Porfirias Hepáticas/metabolismo , Porfirias Hepáticas/fisiopatologia , Porfirias Hepáticas/prevenção & controle , Pirrolidinas/administração & dosagem , Pirrolidinas/uso terapêutico , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/uso terapêutico , RNA Interferente Pequeno/ultraestrutura , Ensaios Clínicos Controlados Aleatórios como AssuntoAssuntos
Ácido Aminolevulínico , Anestesia Geral/métodos , Anestésicos Gerais/efeitos adversos , Neoplasias Encefálicas/cirurgia , Corantes Fluorescentes , Fluorometria , Glioblastoma/cirurgia , Cuidados Intraoperatórios , Ácido Aminolevulínico/administração & dosagem , Ácido Aminolevulínico/efeitos adversos , Ácido Aminolevulínico/farmacocinética , Ácido Aminolevulínico/efeitos da radiação , Anestésicos Gerais/administração & dosagem , Anestésicos Gerais/farmacocinética , Neoplasias Encefálicas/química , Craniotomia , Interações Medicamentosas , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/efeitos adversos , Corantes Fluorescentes/farmacocinética , Glioblastoma/química , Humanos , Complicações Intraoperatórias/induzido quimicamente , Complicações Intraoperatórias/prevenção & controle , Fotoquímica , Porfirias Hepáticas/induzido quimicamente , Porfirias Hepáticas/prevenção & controle , Distribuição Tecidual , Raios UltravioletaAssuntos
Ácido Aminolevulínico , Anestesia Geral/métodos , Anestésicos Gerais/efeitos adversos , Neoplasias Encefálicas/cirurgia , Corantes Fluorescentes , Fluorometria , Glioblastoma/cirurgia , Cuidados Intraoperatórios , Ácido Aminolevulínico/administração & dosagem , Ácido Aminolevulínico/efeitos adversos , Ácido Aminolevulínico/farmacocinética , Ácido Aminolevulínico/efeitos da radiação , Anestésicos Gerais/administração & dosagem , Anestésicos Gerais/farmacocinética , Animais , Neoplasias Encefálicas/química , Craniotomia , Interações Medicamentosas , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/efeitos adversos , Corantes Fluorescentes/farmacocinética , Glioblastoma/química , Humanos , Complicações Intraoperatórias/induzido quimicamente , Complicações Intraoperatórias/prevenção & controle , Fotoquímica , Transtornos de Fotossensibilidade/induzido quimicamente , Fármacos Fotossensibilizantes/efeitos adversos , Porfirias Hepáticas/induzido quimicamente , Porfirias Hepáticas/prevenção & controle , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/prevenção & controle , Raios UltravioletaRESUMO
Porphyrias are a peculiar group of diseases resulting from hereditary or acquired partial deficiencies in seven of the eight enzymes in the biosynthetic pathway of heme. Biosynthesis of heme takes place in the erythropoietic system or in the hepatic tissue. Depending on the main location of the enzyme defect, porphyrias can be classified as erythropoietic or hepatic. There are seven basic clinical forms of porphyria related to a deficiency of each of the involved enzymes. Clinical manifestations in porphyria may be neurovisceral or cutaneous. Patients may present with acute attacks (acute porphyrias), cutaneous lesions (cutaneous porphyrias), or both (mixed porphyrias). Study of patients supected of having porphyria should include several steps: 1) clinical evaluation, 2) biochemical study, which enables us to classify the patient to a specific form of porphyria, followed if possible by 3) enzymatic assay(s), and 4) genetic studies to confirm an enzyme deficiency and its level and the causal genetic mutation. Unfortunately no curative treatment is available for any of the porphyrias. However, symptomatic treatments are available and are discussed in this article.
Assuntos
Transtornos de Fotossensibilidade/diagnóstico , Transtornos de Fotossensibilidade/terapia , Porfirias Hepáticas/diagnóstico , Porfirias Hepáticas/terapia , Doença Aguda , Antimaláricos/uso terapêutico , Cloroquina/uso terapêutico , Heme/biossíntese , Humanos , Transtornos de Fotossensibilidade/fisiopatologia , Porfirias Hepáticas/fisiopatologia , Porfirias Hepáticas/prevenção & controle , Porfirinas/sangueRESUMO
The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the liver of C57BL/6J mice is a model for clinical sporadic porphyria cutanea tarda (PCT). There is massive uroporphyria, inhibition of uroporphyrinogen decarboxylase (UROD) activity, and hepatocellular damage. A variety of evidence implicates the CYP1A2 enzyme as necessary for mouse uroporphyria. Here we report that, 5 weeks after a single oral dose of TCDD (75 microg/kg), Cyp1a2(+/+) wild-type mice showed severe uroporphyria and greater than 90% decreases in UROD activity; in contrast, despite exposure to this potent agent Cyp1a2(-/-) knockout mice displayed absolutely no increases in hepatic porphyrin levels, even after prior iron overload, and no detectable inhibition of UROD activity. Plasma levels of alanine-aminotransferase (ALT) and aspartate aminotransferase (AST)-although elevated in both genotypes after TCDD exposure-were significantly less in Cyp1a2(-/-) than in Cyp1a2(+/+) mice, suggesting that the absence of CYP1A2 also affords partial protection against TCDD-induced liver toxicity. Histological examination confirmed a decrease in hepatocellular damage in TCDD-treated Cyp1a2(-/-) mice; in particular, there was no bile duct damage or proliferation that in the Cyp1a2(+/+) mice might be caused by uroporphyrin. We conclude that CYP1A2 is both necessary and essential for the potent uroporphyrinogenic effects of TCDD in mice, and that CYP1A2 also plays a role in contributing to TCDD-induced hepatocellular injury. This study has implications for both the toxicity assessment of TCDD and the hepatic injury seen in PCT patients.
Assuntos
Citocromo P-450 CYP1A2/deficiência , Dibenzodioxinas Policloradas/toxicidade , Porfirias Hepáticas/enzimologia , Porfirias Hepáticas/prevenção & controle , Uroporfirinas/urina , Animais , Atrofia/induzido quimicamente , Cruzamentos Genéticos , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Poluentes Ambientais/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Porfirias Hepáticas/induzido quimicamente , Timo/efeitos dos fármacos , Timo/patologia , Uroporfirinogênio Descarboxilase/metabolismo , Uroporfirinas/metabolismoRESUMO
The effect of vitamin E treatment on total porphyrin content, lipid peroxidation (LOOH) and 8-hydroxydeoxyguanosine (8-OHdG) was studied in the livers of C57BL/10ScSn mice following hexachlorobenzene (HCB) and iron treatment. HCB was administered i.p. (totalling 300 mg/kg) twice, with 1 week interval. Three days after the first HCB injection iron-dextran was given i.p. (500 mg Fe per kg). Vitamin E was administered weekly (20 mg/kg) by s.c. injection. Both total hepatic porphyrin and LOOH levels were significantly (P<0.001) increased in the HCB-iron treated group as compared with the control group. Mice treated additionally with vitamin E had significant (P<0.001) lower levels as compared with the HCB-iron group. Similarly, the levels of 8-OHdG were significantly (P<0.001) increased above controls after HCB-iron treatment and this increase was reduced after co-treatment with vitamin E (P<0.02). The data support the hypothesis that the mechanism of hepatic porphyrinogenicity of HCB with iron overload is an oxidative free radical process.
Assuntos
Desoxiguanosina/metabolismo , Hexaclorobenzeno/toxicidade , Ferro/toxicidade , Porfirias Hepáticas/prevenção & controle , Vitamina E/farmacologia , 8-Hidroxi-2'-Desoxiguanosina , Animais , Desoxiguanosina/análogos & derivados , Ferro/metabolismo , Peróxidos Lipídicos/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Porfirias Hepáticas/induzido quimicamente , Porfirias Hepáticas/metabolismo , Porfirinas/metabolismo , Vitamina E/metabolismoRESUMO
Three hepatic porphyrias--acute intermittent porphyria, hereditary coproporphyria and variegate porphyria--are characterized by episodic acute attacks that consist of various neuro-psychiatric symptoms and signs, such as abdominal pain, vomiting, constipation, hypertension and tachycardia associated with increased excretion of porphyrins and porphyrin precursors. Peripheral neuropathy is manifested as pain in the extremities, and it may progress to a severe motor neuropathy. Measurement of porphobilinogen in the urine gives a prompt diagnosis during acute attacks. Attacks are often induced by precipitating factors such as drugs, alcohol, infection, fasting or changes in sex-hormone balance, and they should be eliminated when a patient is treated during an attack. Heme, the end biosynthetic product, is the most effective therapy for restoration of porphyrin biosynthesis to normal, and it is usually infused at 3 mg/kg daily for 4 days. Adequate calories are necessary and parenteral nutrition with carbohydrates may be necessary. Attacks may also require therapy for hypertension, pain and epileptic seizures. Strict avoidance of all precipitating factors may not be necessary in the asymptomatic phase.
Assuntos
Porfirias Hepáticas , Doença Aguda , Humanos , Porfirias Hepáticas/diagnóstico , Porfirias Hepáticas/prevenção & controle , Porfirias Hepáticas/terapia , PrognósticoRESUMO
Between 1962 and 1944, 300 families with acute hepatic porphyrias were seen at the Porphyria Centre in Warsaw. Among members of these families, 443 overt and 707 latent cases were diagnosed, and 211 persons had intermediate values of enzyme activity without clinical symptoms and biochemical changes in urine and stool. Three dual porphyrias were detected. Five children with acute symptoms were also seen. The patients and their relatives were registered and routine prophylactic measures were introduced. The treatment of the attacks was based on glucose and hemearginate infusions, a high carbohydrate diet and maintenance of body homeostasis. As a late consequence of the attack acute intermittent porphyria arterial hypertension was observed.
Assuntos
Porfirias Hepáticas/terapia , Doença Aguda , Humanos , Polônia/epidemiologia , Porfirias Hepáticas/diagnóstico , Porfirias Hepáticas/epidemiologia , Porfirias Hepáticas/prevenção & controleRESUMO
The organization, activities and experience of Porphyria Reference Centre of the Institute of Hematology in Poland is shown. A total of 214 families with acute hepatic porphyria were collected. The family studies in search of latent cases were conducted, and measures for preventing the disease attacks were taken. The therapy of the attacks consisted in glucose and heme arginate infusions, and hyperalimentation in the patients is stressed. The incidence rate of porphyrias in Poland, according to the material collected at the Institute of Hematology is 1:15,000 inhabitants, however, it is suggested that the true value is much higher.