Treatment of the Porphyrias

Kauppinen, Raili; Timonen, Kaisa; Mustajoki, Pertti

doi:10.3109/07853899409147324

Cited by 46 publications

(21 citation statements)

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“…Acute intermittent porphyria is the second most common form of porphyria [48]. The acute attacks are currently treated with intravenousheme, but a more continuous therapy is needed, particularly for patients experiencing frequent attacks [49]. To date, several efforts have been made by using non-viral methods, which were unsuccessful, as they were incapable of achieving sufficient HMBsynthase levels due to their poor transfection efficiency in vivo [50].…”

Section: Acute Intermittent Porphyriamentioning

confidence: 99%

Gene Therapy in Liver Diseases: State-of-the-Art and Future Perspectives

Domvri¹,

Porpodis²,

Koffa³

et al. 2012

CGT

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Gene therapy is a fundamentally novel therapeutic approach that involves introducing genetic material into target cells in order to fight or prevent disease. A number of different strategies of gene therapy are tested at experimental and clinical levels, including: a) replacing a mutated gene that causes disease with a healthy copy of the gene, b) inactivating a mutated gene that its improper function causes pathogenesis, c) introducing a new gene coding a therapeutic compound to fight a disease, d) introducing to the target organ an enzyme converting an inactive pro-drug to its cytotoxic metabolite. In gene therapy, the transcriptional machinery of the patient is used to produce the active factor that exerts the intended therapeutic effect, ideally in a permanent, tissue-specific and manageable way. The liver is a major target for gene therapy, presenting inherited metabolic defects of single-gene etiology, but also severe multifactorial pathologies with limited therapeutic options such as hepatocellular carcinoma. The initial promising results from gene therapy strategies in liver diseases were followed by skepticism on the actual clinical value due to specificity, efficacy, toxicity and immune limitations, but are recently re-evaluated due to progress in vector technology and monitoring techniques. The significant amount of experimental data along with the available information from clinical trials are systematically reviewed here and presented per pathological entity. Finally, future perspectives of gene therapy protocols in hepatology are summarized.

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Section: Acute Intermittent Porphyriamentioning

confidence: 99%

Gene Therapy in Liver Diseases: State-of-the-Art and Future Perspectives

Domvri¹,

Porpodis²,

Koffa³

et al. 2012

CGT

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“…O tratamento da AIP é baseado na profilaxia, em terapias especí-ficas para diminuir os níveis de precursores do heme e no tratamento dos sintomas da doença. Vários tipos de terapia têm sido propostos para atenuar as sintomas da AIP 49 , como a ingestão de grande quantidade de carboidratos 50 , a infusão intravenosa de hematina 51 , o uso de heme arginato 52 , de metaloporfirinas sintéticas 53 , zinco mesoporfirina 54 , e outras drogas em estudo como propanolol, a 3,5,3'-triiodotreonina, esteróides, agentes quelantes 5 , cimetidina 55 e agentes antioxidantes 56 . Algumas doenças têm sido associadas à AIP.…”

Section: Porfiria Aguda Intermitenteunclassified

Danos ao DNA promovidos por ácido 5-aminolevulínico: possível associação com o desenvolvimento de carcinoma hepatocelular em portadores de porfiria aguda intermitente

Onuki¹,

Teixeira²,

Medeiros³

et al. 2002

Quím. Nova

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Recebido em 26/6/01; aceito em 1/10/01 DNA DAMAGE INDUCED BY 5-AMINOLEVULINIC ACID: A POSSIBLE ASSOCIATION WITH THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA IN ACUTE INTERMITTENT PORPHYRIA PATIENTS. 5-Aminolevulinic acid (ALA) is a heme precursor accumulated in acute intermittent porphyria (AIP), which might be associated with hepatocellular carcinoma (HCC) in symptomatic patients. Under metal catalyzed oxidation, ALA and its cyclic dimerization product, 3,6-dihydropyrazine-2,5-dipropanoic acid, produce reactive oxygen species that damage plasmid and calf thymus DNA bases, increase the steady state level of 8-oxo-7,8-dihydro-2´-deoxyguanosine in liver DNA and promote mitochondrial DNA damage. The final product of ALA, 4,5-dioxovaleric acid (DOVA), is able to alkylate guanine moieties, producing adducts. ALA and DOVA are mutagenic in bacteria. This review shows an up-to-date literature data that reinforce the hypothesis that the DNA damage induced by ALA may be associated with the development of HCC in AIP patients.Keywords: 5-aminolevulinic acid; acute intermitent porphyria; DNA damage. PORFIRIASAs porfirias são definidas como doenças inatas ou adquiridas, relacionadas à deficiência de enzimas -inibição ou insuficiência -da via biossintética do grupo heme (Esquema 1) 1 . Esta deficiência resulta na produção excessiva e excreção de porfirinas e de seus precursores 2-6 . As porfirias são tradicionalmente classificadas com base no principal órgão que produz os metabólitos porfíricos em excesso (fígado ou os tecidos eritropoiéticos), na ocorrência ou não de ataques agudos e nas lesões cutâneas (fotossensibilidade) e/ou neurológicas produzidas 5,7,8 . Tipo de porfiria Aguda Hepática CutâneaPorfiria deficiente em ALA desidratase X X Porfiria aguda intermitente (AIP) X X Coproporfiria hereditária (HCP) X X X Porfiria variegata (VP) X X X Porfiria cutânea tarda (PCT) X X Porfiria eritropoiética congênita (CEP) X Protoporfiria eritropoiética (EPP) X A natureza molecular do defeito genético é altamente heterogê-nea e defeitos múltiplos têm sido demonstrados em cada tipo de porfiria 3,5 . Alguns modelos animais para os estudos dos diferentes tipos de porfiria já existem naturalmente, no caso de EPP e CEP e alguns foram desenvolvidos em laboratório, para EPP e porfirias hepáticas 9,10

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“…to patients in the 'quiescent phase' of the disease (which includes subjects in remission, as well as those with no Attempts to centralise information gathering have been made by the establishment of an international Committee previous attacks) has been advocated with respect to alcohol, the use of female sex hormones and other drugs [50,56]. It on the Review of Porphyrinogenicity of Drugs (CORP).…”

Section: Drug Indicationmentioning

confidence: 99%

Drug treatment in acute porphyria

Gorchein

1997

Brit J Clinical Pharma

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The acute hepatic porphyrias are rare pharmacogenetic diseases inherited as autosomal dominant conditions of low penetrance. The genetic defect is a 50% deficiency of an enzyme of the haem biosynthetic pathway. Patients may develop ‘neurovisceral attacks’ which include severe abdominal pain, neuropsychiatric manifestations and potentially fatal respiratory paralysis. Attacks occur generally after puberty, are much commoner in females and may be precipitated by endogenous hormonal changes, dieting, alcohol, severe infections, and many drugs. Treatment includes analgesia, early administration of haem, and general supportive measures. Patients are at greater risk of a severe attack on first presentation since an abdominal emergency may be simulated and inappropriate medication, including that for general anaesthesia may exacerbate the crisis. The urine should be tested for raised porphobilinogen, which is pathognomonic of the acute attack, if there is the slightest doubt about diagnosis. The genotype of blood relatives of index cases must be determined so that carriers may avoid drug and other precipitants. Some drugs have been established as safe or unsafe by clinical use, but information about many drugs is not available or is based only on their properties in rodents or in tissue culture systems. The relevance of these to the human condition remains controversial, but drugs shown to be porphyrinogenic in animal systems should be avoided if there is a known safe alternative. Where it is essential to use a drug not known to be safe, close biochemical and clinical observation may warn of an impending attack.

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Treatment of the Porphyrias

Cited by 46 publications

References 64 publications

Gene Therapy in Liver Diseases: State-of-the-Art and Future Perspectives

Gene Therapy in Liver Diseases: State-of-the-Art and Future Perspectives

Danos ao DNA promovidos por ácido 5-aminolevulínico: possível associação com o desenvolvimento de carcinoma hepatocelular em portadores de porfiria aguda intermitente

Drug treatment in acute porphyria

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