RESUMO
OBJECTIVE: Hemin, a heme oxygenase 1 activator has shown efficacy in the prevention and treatment of acute pancreatitis in mouse models. We conducted a randomized controlled trial (RCT) to assess the protective effect of Hemin administration to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in patients at risk. METHODS: In this multicenter, multinational, placebo-controlled, double-blind RCT, we assigned patients at risk for PEP to receive a single intravenous dose of Hemin (4 mg/kg) or placebo immediately after ERCP. Patients were considered to be at risk on the basis of validated patient- and/or procedure-related risk factors. Neither rectal NSAIDs nor pancreatic stent insertion were allowed in randomized patients. The primary outcome was the incidence of PEP. Secondary outcomes included lipase elevation, mortality, safety, and length of stay. RESULTS: A total of 282 of the 294 randomized patients had complete follow-up. Groups were similar in terms of clinical, laboratory, and technical risk factors for PEP. PEP occurred in 16 of 142 patients (11.3%) in the Hemin group and in 20 of 140 patients (14.3%) in the placebo group (p = 0.48). Incidence of severe PEP reached 0.7% and 4.3% in the Hemin and placebo groups, respectively (p = 0.07). Significant lipase elevation after ERCP did not differ between groups. Length of hospital stay, mortality and severe adverse events rates were similar between groups. CONCLUSION: We failed to detect large improvements in PEP rate among participants at risk for PEP who received IV hemin immediately after the procedure compared to placebo. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT01855841).
Assuntos
Colangiopancreatografia Retrógrada Endoscópica , Pancreatite , Animais , Humanos , Camundongos , Anti-Inflamatórios não Esteroides/uso terapêutico , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Heme Oxigenase-1 , Hemina/uso terapêutico , Lipase , Pancreatite/etiologia , Pancreatite/prevenção & controle , Administração IntravenosaRESUMO
Given the complexity of the tumor microenvironment, multiple strategies are being explored to tackle hypoxic tumors. The most efficient strategies combine several therapeutic modalities and typically requires the development of multifunctional nanocomposites through sophisticated synthetic procedures. Herein, the G-quadruplex (G4)-forming sequence AS1411-A (d[(G2 T)4 TG(TG2 )4 A]) is used for both its anti-tumor and biocatalytic properties when combined with hemin, increasing the production of O2 ca. two-fold as compared to the parent AS1411 sequence. The AS1411-A/hemin complex (GH) is grafted on the surface and pores of a core-shell upconverted metal-organic framework (UMOF) to generate a UMGH nanoplatform. Compared with UMOF, UMGH exhibits enhanced colloidal stability, increased tumor cell targeting and improved O2 production (8.5-fold) in situ. When irradiated by near-infrared (NIR) light, the UMGH antitumor properties are bolstered by photodynamic therapy (PDT), thanks to its ability to convert O2 into singlet oxygen (1 O2 ). Combined with the antiproliferative activity of AS1411-A, this novel approach lays the foundation for a new type of G4-based nanomedicine.
Assuntos
Estruturas Metalorgânicas , Nanocompostos , Neoplasias , Fotoquimioterapia , Humanos , Estruturas Metalorgânicas/uso terapêutico , Hemina/uso terapêutico , Fotoquimioterapia/métodos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fármacos Fotossensibilizantes/uso terapêutico , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Neuronal ferroptosis plays an important role in secondary brain injuries after intracerebral hemorrhage (ICH). Edaravone (Eda) is a promising free radical scavenger that inhibits ferroptosis in neurological diseases. However, its protective effects and underlying mechanisms in ameliorating post-ICH ferroptosis remain unclear. We employed a network pharmacology approach to determine the core targets of Eda against ICH. Forty-two rats were subjected to successful striatal autologous whole blood injection (n=28) or sham operation (n=14). The 28 blood-injected rats were randomly assigned to either the Eda or vehicle group (n=14) for immediate administration and then for 3 consecutive days. Hemin-induced HT22 cells were used for in vitro studies. The effects of Eda in ICH on ferroptosis and the MEK/ERK pathway were investigated in vivo and in vitro. Network pharmacology-based analysis revealed that candidate targets of Eda-treated ICH might be related to ferroptosis; among which prostaglandin G/H synthase 2 (PTGS2) was a ferroptosis marker. In vivo experiments showed that Eda alleviated sensorimotor deficits and decreased PTGS2 expression (all p<0.05) after ICH. Eda rescued neuron pathological changes after ICH (increased NeuN+ cells and decreased FJC+ cells, all p<0.01). In vitro experiments showed that Eda reduced intracellular reactive oxygen species and reversed mitochondria damage. Eda repressed ferroptosis by decreasing malondialdehyde and iron deposition and by influencing ferroptosis-related protein expression (all p<0.05) in ICH rats and hemin-induced HT22 cells. Mechanically, Eda significantly suppressed phosphorylated-MEK and phosphorylated-ERK1/2 expression. These results indicate that Eda has protective effects on ICH injury through ferroptosis and MEK/ERK pathway suppression.
Assuntos
Lesões Encefálicas , Hemina , Ratos , Animais , Edaravone/farmacologia , Edaravone/uso terapêutico , Ciclo-Oxigenase 2 , Hemina/farmacologia , Hemina/uso terapêutico , Farmacologia em Rede , Hemorragia Cerebral/complicações , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Lesões Encefálicas/metabolismo , Quinases de Proteína Quinase Ativadas por MitógenoRESUMO
Ferroptosis, characterized by the accumulation of reactive oxygen species and lipid peroxides, has emerged as an attractive strategy to reverse drug resistance. Of particular interest is the ferroptosis-apoptosis combination therapy for cancer treatment. Herein, a nanoplatform is reported for effective co-delivery of the anticancer drug sorafenib (S) and the ferroptosis inducer hemin (H), toward synergistic ferroptosis-apoptosis therapy of advanced hepatocellular carcinoma (HCC) as a proof-of-concept study. Liposome is an excellent delivery system; however, it is not sufficiently responsive to the acidic tumor microenvironment (TME) for tumor-targeted drug delivery. The pH-sensitive vesicles are therefore developed (SH-AD-L) by incorporating amphiphilic dendrimers (AD) into liposomes for controlled and pH-stimulated release of sorafenib and hemin in the acidic TME, thanks to the protonation of numerous amine functionalities in AD. Importantly, SH-AD-L not only blocked glutathione synthesis to disrupt the antioxidant system, but also increased intracellular Fe2+ and ·OH concentrations to amplify oxidative stress, both of which contribute to enhanced ferroptosis. Remarkably, high levels of ·OH also augmented sorafenib-mediated apoptosis in tumor cells. This study demonstrates the efficacy of ferroptosis-apoptosis combination therapy, as well as the promise of the AD-doped TME-responsive vesicles for drug delivery in combination therapy to treat advanced HCC.
Assuntos
Carcinoma Hepatocelular , Dendrímeros , Ferroptose , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Dendrímeros/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Hemina/farmacologia , Hemina/uso terapêutico , Apoptose , Lipossomos/farmacologia , Polímeros/farmacologia , Concentração de Íons de Hidrogênio , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Ferroptosis-based treatment strategies display the potential to suppress some malignant tumors with intrinsic apoptosis resistance. However, current related cancer treatments are still hampered by insufficient intracellular reactive oxygen species (ROS) levels and Fe2+ contents, posing considerable challenges for their clinical translation. Herein, an intracellular acid-biodegradable iridium-coordinated nanosheets (Ir-Hemin) with sonodynamic therapy (SDT) properties to effectively induce ferroptosis in tumor cells through multiple regulatory pathways are proposed. Under ultrasound (US) irradiation, Ir-Hemin nanosheets act as nanosonosensitizers to effectively generate ROS, subsequently causing the accumulation of lipid peroxides (LPO) and inducing ferroptotic cell death. Furthermore, these Ir-Hemin nanosheets decompose quickly to release hemin and Ir(IV), which deplete intracellular glutathione (GSH) to deactivate the enzyme glutathione peroxidase 4 (GPX4) and initiate the ferroptosis pathway. Specifically, the released hemin enables heme oxygenase 1 (HO-1) upregulation for endogenous ferrous ion supplementation, which compensates for the toxicity concerns brought about by the large uptake of exogenous iron. Surprisingly, Ir-Hemin nanosheets exhibit high tumor accumulation and trigger effective ferroptosis for tumor therapy. These Ir-Hemin nanosheets display pronounced synergistic anticancer efficacy under US stimulation both in vitro and in vivo, providing a strong rationale for the application of ferroptosis in cancer treatment.
Assuntos
Irídio , Neoplasias , Humanos , Irídio/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Hemina/farmacologia , Hemina/uso terapêutico , Morte Celular , Apoptose , Neoplasias/tratamento farmacológico , Glutationa/metabolismoRESUMO
One-year data from EXPLORE Part A showed high disease burden and impaired quality of life (QOL) in patients with acute hepatic porphyria (AHP) with recurrent attacks. We report baseline data of patients who enrolled in EXPLORE Part B for up to an additional 3 years of follow-up. EXPLORE B is a long-term, prospective study evaluating disease activity, pain intensity, and QOL in patients with AHP with ≥1 attack in the 12 months before enrollment or receiving hemin or gonadotropin-releasing hormone prophylaxis. Data were evaluated in patients with more (≥3 attacks or on prophylaxis treatment) or fewer (<3 attacks and no prophylaxis treatment) attacks. Patients in the total population (N = 136), and more (n = 110) and fewer (n = 26) attack subgroups, reported a median (range) of 3 (0-52), 4 (0-52), and 1 (0-2) acute attacks, respectively, in the 12 months prior to the baseline visit. Pain, mood/sleep, digestive/bladder, and nervous system symptoms were each experienced by ≥80% of patients; most received hemin during attacks. Almost three-quarters of patients reported chronic symptoms between attacks, including 85% of patients with fewer attacks. Pain intensity was comparable among both attack subgroups; most patients required pain medication. All groups had diminished QOL on the EuroQol visual analog scale and the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 versus population norms. Patients with AHP with recurrent attacks, even those having fewer attacks, experience a high disease burden, as evidenced by chronic symptoms between attacks and impaired QOL.
Assuntos
Porfiria Aguda Intermitente , Porfirias Hepáticas , Humanos , Estudos Prospectivos , Qualidade de Vida , Hemina/uso terapêutico , Porfirias Hepáticas/tratamento farmacológico , Dor , Porfiria Aguda Intermitente/complicações , Porfiria Aguda Intermitente/tratamento farmacológicoRESUMO
INTRODUÇÃO: A porfiria aguda intermitente (PAI) é um erro inato do metabolismo da biossíntese do heme, que acomete principalmente mulheres em idade menstrual. A doença se manifesta clinicamente com sintomas neuroviscerais agudos que podem ser esporádicos ou recorrentes, e que são potencialmente fatais. No Brasil, no âmbito do Sistema Único de Saúde (SUS), não há um Protocolo Clínico e Diretrizes Terapêuticas sobre o cuidado de Porfirias. Tendo em vista que a hemina (Panhematin®) é aprovada pela Anvisa para o tratamento dos ataques recorrentes de PAI relacionados com o ciclo menstrual em mulheres afetadas, quando o tratamento inicial com glicose é sabido ou suspeito de ser inadequado, o presente relatório foi desenvolvido com o objetivo de compreender a viabilidade da incorporação desse medicamento no SUS. PERGUNTA DE PESQUISA: O uso de hemina (Panhematin®) é eficaz, seguro e custo-efetivo para o tratamento de mulheres com ataques de PAI relacionados com o ciclo menstrual? EVIDÊNCIAS CLÍNICAS: Foi realizada uma revisão sistemática a partir de buscas nas bases de dados MEDLINE (via Pubmed); EMBASE; Cochrane Library; PEDRO; LILACS, IBECS BINACIS e BRISA/RedTESA (via BVS); OpenGrey; e ClinicalTrials.gov; considerando o tratamento de ataques agudos de PAI, em mulheres com idade igual ou maior a 16 anos, com hemina (Panhematin®). Foram estabelecidos critérios de elegibilidade abrangentes diante da escassez de evidências, mas ainda assim não foi encontrado nenhum ECR ou estudo observacional comparativo com resultados publicados. Foram incluídas três séries de casos que avaliaram pacientes com diferentes tipos de porfirias e sexos e 18 relatos de casos sobre mulheres com PAI. Em relação a eficácia, a redução da dor com o uso da hemina sugere que o medicamento contribua para a resolução de ataques porfíricos, mas a certeza dessa evidência é muito baixa. Somente 6 dos 18 relatos de casos avaliaram dor, sem que nenhum tenha avaliado o desfecho através de escalas, sejam elas validadas ou não. Esses estudos referiram melhora da dor na maioria dos casos. Quinze dos dezoito relatos de casos apresentam resultados para níveis urinários de ALA e PBG, sugerindo que a hemina contribui para a redução desses marcadores. Entretanto, deve-se levar em consideração a limitação das conclusões que podem ser tiradas a partir desse tipo de estudo. Quanto à segurança, os dados também são muito escassos. Duas séries de casos e três relatos de casos descreveram resultados para eventos adversos graves e não foram identificadas novas preocupações além daquelas descritas em bula. Todas as evidências incluídas neste relatório apresentaram risco de viés muito alto ou alto e certeza do conjunto de evidências avaliado como muito baixa, de acordo com o GRADE. Mais estudos são necessários para permitir conclusões mais robustas acerca da eficácia e, sobretudo, da segurança do medicamento. AVALIAÇÃO ECONÔMICA: Foi elaborado um modelo de custo-efetividade, baseando-se no desfecho de mortalidade, sob a perspectiva do SUS, com horizonte temporal de um ano, e incluindo apenas custos diretos (de tratamento com as terapias selecionadas e de internação). A análise foi conduzida a partir de em um modelo de árvore de decisão que projetou a relação entre custo da intervenção (hemina + glicose) e do comparador (glicose). O resultado da razão de custoefetividade incremental (RCEI) da hemina em comparação à glicose foi de R$ 1.101.525,27por vida salva, variando de R$450.511,78 a R$5.477.345,10 por vida salva na análise de sensibilidade probabilística. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Adotou-se uma perspectiva epidemiológica considerando os dados de prevalência e incidência de PAI disponíveis em literatura e aplicados ao contexto do Brasil, bem como proporção de mulheres que tinham a condição, o número de ataques e a utilização de hemina para o tratamento das crises. Foram considerados os mesmos recursos e custos associados utilizados na análise de custo-efetividade, assumindo disponibilidade da hemina no mercado de forma progressiva. A incorporação da hemina (Panhematin®), no SUS, geraria um impacto incremental de cerca de R$ 11,1 milhões no primeiro ano, atingindo quase R$ 83 milhões em cinco anos. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: não foram detectadas tecnologias para compor o esquema terapêutico de ataques de PAI relacionados com o ciclo menstrual. Vale ressaltar que o medicamento givosirana foi identificado nas buscas, entretanto, o ensaio clínico identificado no Clinicaltrials avalia o uso da givosirana no tratamento de porfirias hepáticas agudas de forma geral, sem especificar a inclusão de PAI relacionada ao ciclo menstrual. O mesmo acontece para a indicação clínica do medicamento aprovada na Anvisa (2020), FDA (2019) e EMA (2020). CONSIDERAÇÕES FINAIS: há escassez de evidências sobre a eficácia e segurança da hemina (Panhematin®) e as evidências disponíveis provém apenas de séries de casos e relatos de casos, o que torna a avaliação de eficácia e segurança um desafio. Além do delineamento dos estudos, a descrição incompleta e a avaliação subjetiva dos resultados são outras dificuldades. As limitações acabam por se estender para as análises econômicas, as quais foram baseadas em estudos que não atendiam à indicação de bula da tecnologia. A análise de custo-efetividade incremental e o impacto orçamentário mostram valores expressivos e a incorporação dela indica não colaborar para a sustentabilidade do SUS, embora a hemina seja a única alternativa farmacológica comercializada atualmente para o manejo de crises de PAI. RECOMENDAÇÃO PRELIMINAR: os membros presentes no plenário da Conitec, em sua 110ª Reunião Ordinária, realizada no dia 06 de julho de 2022, deliberaram que a matéria fosse disponibilizada em consulta pública com recomendação preliminar desfavorável à incorporação de Panhematin® para o tratamento da porfiria aguda intermitente relacionados com o ciclo menstrual. Para essa recomendação, a Conitec considerou que as evidências acerca da eficácia e segurança do medicamento são escassas e de baixa qualidade. RECOMENDAÇÃO FINAL DA CONITEC: Pelo exposto, o Plenário da Conitec, em sua 112ª Reunião Ordinária, realizada no dia 31 de agosto de 2022, deliberou por unanimidade recomendar a não incorporação da hemina para o tratamento da porfiria aguda intermitente relacionados com o ciclo menstrual. Os membros da Conitec consideraram que não houve argumentação suficiente para a mudança de entendimento acerca da recomendação preliminar, principalmente considerando as evidências para eficácia e segurança da tecnologia, inclusive após contribuição presente de especialista no assunto. Foi assinado o Registro de Deliberação nº 768/2022. DECISÃO: não incorporar, no âmbito do Sistema Único de Saúde - SUS, a hemina para o tratamento da porfiria aguda intermitente relacionada com o ciclo menstrual, conforme a Portaria nº 110, publicada no Diário Oficial da União nº 184, seção 1, página 76, em 27 de setembro de 2022.
Assuntos
Humanos , Porfiria Aguda Intermitente/tratamento farmacológico , Hemina/uso terapêutico , Ciclo Menstrual , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economiaRESUMO
Chemodynamic therapy (CDT), an emerging tumor-specific therapeutic modality, is frequently restrained by insufficient intratumoral Fenton catalysts and increasingly inefficient catalysis caused by the continuous consumption of limited H2O2 within tumors. Herein, we engineered a pH-responsive bortezomib (BTZ) polymer prodrug catalytic nanoreactor (HeZn@HA-BTZ) capable of self-supplying Fenton catalyst and H2O2. It is aimed for tumor-specific chemo/chemodynamic therapy via oxidative stress and endoplasmic reticulum (ER) stress dual-amplification and macrophage repolarization. A catecholboronate bond-based hyaluronic acid-BTZ prodrug HA-DA-BTZ was modified on Hemin and Zn2+ coordination nanoscale framework (HeZn), an innovative CDT inducer, to construct He-Zn@HA-BTZ. He-Zn@HA-BTZ with good stability and superior peroxidase-like activity preferentially accumulated at tumor sites and be actively internalized by tumor cells. Under the cleavage of catecholboronate bond in acidic endo/lysosomes, pre-masked BTZ was rapidly released to induce ubiquitinated protein aggregation, robust ER stress and elevated H2O2 levels. The amplified H2O2 was further catalyzed by HeZn via Fenton-catalytic reactions to produce hypertoxic â¢OH, enabling cascaded oxidative stress amplification and long-lasting effective CDT, which in turn aggravated BTZ-induced ER stress. Eventually, a dual-amplification of oxidative stress and ER stress was achieved to initiate cell apoptosis/necrosis with reduced BTZ toxicity. Intriguingly, He-Zn@HA-BTZ could repolarize macrophages from M2 to antitumor M1 phenotype for potential tumor therapy. This "all in one" prodrug nanocatalytic reactor not only enriches the CDT inducer library, but provides inspirational strategy for simultaneous oxidative stress and ER stress based excellent cancer therapy.
Assuntos
Neoplasias , Pró-Fármacos , Bortezomib/farmacologia , Catálise , Catecóis , Hemina/uso terapêutico , Humanos , Ácido Hialurônico/química , Peróxido de Hidrogênio/metabolismo , Macrófagos/metabolismo , Nanotecnologia , Neoplasias/tratamento farmacológico , Peroxidases/uso terapêutico , Polímeros/uso terapêutico , Pró-Fármacos/uso terapêutico , Agregados ProteicosRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease-19 (COVID-19). More than 143 million cases of COVID-19 have been reported to date, with the global death rate at 2.13%. Currently, there are no licensed therapeutics for controlling SARS-CoV-2 infection. The antiviral effects of heme oxygenase-1 (HO-1), a cytoprotective enzyme that inhibits the inflammatory response and reduces oxidative stress, have been investigated in several viral infections. To confirm whether HO-1 suppresses SARS-CoV-2 infection, we assessed the antiviral activity of hemin, an effective and safe HO-1 inducer, in SARS-CoV-2 infection. We found that treatment with hemin efficiently suppressed SARS-CoV-2 replication (selectivity index: 249.7012). Besides, the transient expression of HO-1 using an expression vector also suppressed the growth of the virus in cells. Free iron and biliverdin, which are metabolic byproducts of heme catalysis by HO-1, also suppressed the viral infection. Additionally, hemin indirectly increased the expression of interferon-stimulated proteins known to restrict SARS-CoV-2 replication. Overall, the findings suggested that HO-1, induced by hemin, effectively suppressed SARS-CoV-2 in vitro. Therefore, HO-1 could be potential therapeutic candidate for COVID-19.
Assuntos
Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Heme Oxigenase-1/metabolismo , Hemina/uso terapêutico , Animais , Antivirais/química , Antivirais/farmacologia , COVID-19/virologia , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/genética , Hemina/química , Hemina/farmacologia , Humanos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , RNA Viral/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Regulação para Cima/efeitos dos fármacos , Células Vero , Replicação Viral/efeitos dos fármacosRESUMO
Radiofrequency ablation (RFA) is clinically adopted to destruct solid tumors, but is often incapable of completely ablating large tumors and those with multiple metastatic sites. Here we develop a CaCO3-assisted double emulsion method to encapsulate lipoxidase and hemin with poly(lactic-co-glycolic acid) (PLGA) to enhance RFA. We show the HLCaP nanoreactors (NRs) with pH-dependent catalytic capacity can continuously produce cytotoxic lipid radicals via the lipid peroxidation chain reaction using cancer cell debris as the fuel. Upon being fixed inside the residual tumors post RFA, HLCaP NRs exhibit a suppression effect on residual tumors in mice and rabbits by triggering ferroptosis. Moreover, treatment with HLCaP NRs post RFA can prime antitumor immunity to effectively suppress the growth of both residual and metastatic tumors, also in combination with immune checkpoint blockade. This work highlights that tumor-debris-fueled nanoreactors can benefit RFA by inhibiting tumor recurrence and preventing tumor metastasis.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Nanomedicina/métodos , Neoplasias/terapia , Ablação por Radiofrequência , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Carbonato de Cálcio/química , Carbonato de Cálcio/uso terapêutico , Catálise , Linhagem Celular Tumoral , Terapia Combinada , Ferroptose/efeitos dos fármacos , Hemina/química , Hemina/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio , Inibidores de Checkpoint Imunológico/uso terapêutico , Morte Celular Imunogênica/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoxigenase/química , Lipoxigenase/uso terapêutico , Camundongos , Metástase Neoplásica , Neoplasia Residual , Neoplasias/imunologia , Neoplasias/patologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/uso terapêutico , CoelhosRESUMO
The role of haem in the activity of cystathionine ß-synthase (CBS) is reviewed and a hypothesis postulating multiple effects of haem on enzyme activity under conditions of haem excess or deficiency is proposed, with implications for some therapies of acute hepatic porphyrias. CBS utilises both haem and pyridoxal 5'-phosphate (PLP) as cofactors. Although haem does not participate directly in the catalytic process, it is vital for PLP binding to the enzyme and potentially also for CBS stability. Haem deficiency can therefore undermine CBS activity by impairing PLP binding and facilitating CBS degradation. Excess haem can also impair CBS activity by inhibiting it via CO resulting from haem induction of haem oxygenase 1 (HO 1), and by induction of a functional vitamin B6 deficiency following activation of hepatic tryptophan 2,3-dioxygenase (TDO) and subsequent utilisation of PLP by enhanced kynurenine aminotransferase (KAT) and kynureninase (Kynase) activities. CBS inhibition results in accumulation of the cardiovascular risk factor homocysteine (Hcy) and evidence is emerging for plasma Hcy elevation in patients with acute hepatic porphyrias. Decreased CBS activity may also induce a proinflammatory state, inhibit expression of haem oxygenase and activate the extrahepatic kynurenine pathway (KP) thereby further contributing to the Hcy elevation. The hypothesis predicts likely changes in CBS activity and plasma Hcy levels in untreated hepatic porphyria patients and in those receiving hemin or certain gene-based therapies. In the present review, these aspects are discussed, means of testing the hypothesis in preclinical experimental settings and porphyric patients are suggested and potential nutritional and other therapies are proposed.
Assuntos
Cistationina beta-Sintase/metabolismo , Heme/metabolismo , Hemina/uso terapêutico , Homocisteína/sangue , Porfirias Hepáticas/tratamento farmacológico , Animais , Hemina/efeitos adversos , Humanos , Cinurenina/metabolismo , Estado Nutricional , Porfirias Hepáticas/sangue , Porfirias Hepáticas/diagnóstico , Porfirias Hepáticas/enzimologia , Resultado do Tratamento , Triptofano/metabolismo , Complexo Vitamínico B/sangueRESUMO
Combining photodynamic therapy (PDT), chemodynamic therapy (CDT), and ferroptosis is a valuable means for an enhanced anticancer effect. However, traditional combination of PDT/CDT/ferroptosis faces several hurdles, including excess glutathione (GSH) neutralization and preparation complexity. In this work, a versatile multifunctional nanoparticle (HCNP) self-assembled from two porphyrin molecules, chlorin e6 and hemin, is developed. The as-constructed HCNPs exhibit a peroxidase-mimic catalytic activity, which can lead to the in situ generation of endogenous O2, thereby enhancing the efficacy of PDT. Furthermore, the generation of hydroxyl radicals (â¢OH) in the tumor environment in reaction to the high level of H2O2 and the simultaneous disruption of intracellular GSH endow the HCNPs with the capacity of enhanced CDT, resulting in a more effective therapeutic outcome in combination with PDT. More importantly, GSH depletion further leads to the inactivation of GSH peroxide 4 and induced ferroptosis. Both in vitro and in vivo results showed that the combination of PDT/CDT/ferroptosis realizes highest antitumor efficacy significantly under laser irradiation. Therefore, by integrating the superiorities of O2 and â¢OH generation capacity, GSH-depletion effect, and bioimaging into a single nanosystem, the HCNPs are a promising single therapeutic agent for tumor PDT/CDT/ferroptosis combination therapy.
Assuntos
Antineoplásicos/uso terapêutico , Hemina/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Catálise , Linhagem Celular Tumoral , Clorofilídeos , Feminino , Ferroptose/efeitos dos fármacos , Glutationa/metabolismo , Hemina/química , Hemina/efeitos da radiação , Células Endoteliais da Veia Umbilical Humana , Humanos , Radical Hidroxila/metabolismo , Luz , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/efeitos da radiação , Oxigênio/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Porfirinas/química , Porfirinas/efeitos da radiaçãoRESUMO
The term 'porphyria' comes from the Greek 'porphyra'. It refers to a heterogeneous group of metabolic disorders caused by the enzymatic deficiency in the biosynthesis of the heme group. Acute intermittent porphyria is caused by a deficiency of the porphobilinogen deaminase enzyme. A 40-year-old woman presented with abdominal pain for ten days (which required laparotomy that evidenced no surgical pathology), severe hydroelectrolytic disorder due to hyponatremia and resistant hypokalemia, persistent tachycardia and hypertension. Seven days later, she developed acute flabby quadriparesis and presented a single generalized tonic-clonic convulsive crisis. Neurophysiological studies supported mixed axonal polyneuropathy and urine results of porphobilinogen and porphyrins were elevated. After acute intermittent porphyria was diagnosed, hemin was administered, which stabilized the patient's clinical signs and normalized the porphobilinogen. The prevalence of this entity is 1 in 2,000 people. It is an autosomal dominant disease, which affects mainly women between 20 and 40 years of age. This entity manifests with neurological and visceral symptoms. Management consists of hematin and dextrose administration avoiding hypotonic solutions because of the risk of exacerbating hyponatremia.
El término 'porfiria' proviene del griego 'porphyra' y alude a un grupo heterogéneo de trastornos metabólicos causados por una deficiencia enzimática en la biosíntesis del grupo hemo. La causa de la porfiria intermitente aguda es la deficiencia de la enzima deaminasa del porfobilinógeno. Se presenta el caso de una mujer de 40 años que presentó dolor abdominal de 10 días de evolución, trastorno hidroelectrolítico grave debido a hiponatremia e hipopotasemia, taquicardia e hipertensión arterial sistémica persistentes, por lo cual fue sometida a una laparotomía en la que no se encontró ninguna afección de origen quirúrgico, A los siete días del examen inicial, la paciente desarrolló cuadriparesia flácida aguda y presentó una crisis convulsiva tónico-clónica generalizada. Los estudios neurofisiológicos evidenciaron una polineuropatía axonal mixta, y los valores de porfobilinógeno y porfirinas en orina eran elevados. Tras diagnosticarse porfiria intermitente aguda, esta se trató con hemina, lo que estabilizó los signos clínicos y normalizó el porfobilinógeno. La prevalencia de esta enfermedad es de 1 en 2.000 personas. Tiene un patrón de herencia autosómico dominante y se manifiesta principalmente en mujeres con edades entre los 20 y los 40 años. La enfermedad cursa con síntomas neurológicos y viscerales, y se trata con la administración de hemina y dextrosa, evitando las soluciones hipotónicas por el riesgo de exacerbar la hiponatremia.
Assuntos
Porfiria Aguda Intermitente/diagnóstico , Diagnóstico Tardio , Feminino , Gastroenteropatias/etiologia , Hemina/uso terapêutico , Humanos , Neurônios/metabolismo , Porfobilinogênio/urina , Porfiria Aguda Intermitente/complicações , Porfiria Aguda Intermitente/tratamento farmacológico , Porfiria Aguda Intermitente/epidemiologia , Porfirinas/urina , Prevalência , Quadriplegia/etiologia , Respiração Artificial , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Convulsões/etiologia , Avaliação de Sintomas , Desequilíbrio Hidroeletrolítico/etiologia , Adulto JovemRESUMO
Here, we report a case of a 15-year-old girl who presented to the emergency department with symptoms of abdominal pain, nausea, vomiting and seizures. She was diagnosed with acute intermittent porphyria. Treatment was started by removing all porphogenic drugs, providing high glucose intake (oral and intravenous), which initially resulted in good clinical outcomes. However, she deteriorated again and also developed neurological manifestation (paraplegia) for which she required mechanical ventilation because of acute respiratory failure. This time she was initiated on human hemin for four consecutive days. After 2 days of therapy, her porphobilinogen levels decreased to 50% of the initial raised value. Increased lactic acid and blood urea nitrogen were the two side effects observed after the treatment, with no apparent signs of acute kidney injury. To the best of our knowledge, in paediatric population, this is the first reported case of treatment of acute intermittent porphyria with human hemin in Pakistan.
Assuntos
Hemina/uso terapêutico , Porfiria Aguda Intermitente/tratamento farmacológico , Dor Abdominal , Adolescente , Países em Desenvolvimento , Feminino , Humanos , Paquistão , VômitoRESUMO
Background and aims: Patients with acute intermittent porphyria (AIP) may suffer from acute non-specific attacks that often result in hospitalizations or emergency room (ER) visits. Prior to the recent approval of givosiran (November 2019), hemin was the only FDA-approved therapy for AIP attacks in the US. Our aim was to estimate the annual healthcare utilization and expenditures for AIP patients treated with hemin using real-world data.Methods: Patients with ≥1 hemin claim and confirmed AIP diagnosis - 1 inpatient claim or 2 outpatient claims ≥30 d apart for AIP (2015-2017) or acute porphyria (prior to 2015) - were identified in MarketScan administrative claims dataset between 2007 and 2017. Continuous enrolment for ≥6 months from confirmed diagnosis was required. A secondary analysis ("active disease population") limited the sample to adult patients with ≥3 attacks or 10 months of prophylactic use of hemin within a 12-month pre-index period. AIP-related care was defined by hemin use during an attack (daily glucose and/or hemin use) or prophylaxis (non-attack hemin use). Outcomes were annualized and expenditures were inflated to 2017.Results: Across 10 years, patients with a confirmed AIP diagnosis (N = 8,877) and ≥1 hemin claim (N = 164) were restricted by ≥6 months continuous follow-up (N = 139). AIP patients were mostly female (N = 112; 81%), had median age of 40 and 3 years average follow-up. Annualized average total expenditures for AIP-related care were $113,477. Annualized average all-cause (any diagnosis) hospitalizations were statistically significantly lower for patients treated with hemin prophylaxis vs. acute treatment (1.0 vs. 2.1; p < .001). In the secondary analysis (N = 27), annualized average total expenditures for AIP-related care were higher ($187,480).Conclusions: For AIP patients treated with hemin, patients treated for acute attacks may use a greater number of resources compared to patients treated prophylactically.
Assuntos
Gastos em Saúde/estatística & dados numéricos , Hemina/economia , Hemina/uso terapêutico , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Porfiria Aguda Intermitente/tratamento farmacológico , Adolescente , Adulto , Idoso , Quimioprevenção/economia , Quimioprevenção/métodos , Criança , Feminino , Recursos em Saúde , Hemina/administração & dosagem , Hospitalização/economia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Econométricos , Estudos Retrospectivos , Adulto JovemAssuntos
Hemina/administração & dosagem , Deslocamento do Disco Intervertebral/diagnóstico , Vértebras Lombares/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Porfiria Aguda Intermitente/diagnóstico , Porfiria Aguda Intermitente/terapia , Dor Abdominal/etiologia , Diarreia/etiologia , Feminino , Hemina/uso terapêutico , Humanos , Deslocamento do Disco Intervertebral/complicações , Porfiria Aguda Intermitente/complicações , Vômito/etiologia , Adulto JovemAssuntos
Fármacos Dermatológicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Porfiria Aguda Intermitente/tratamento farmacológico , Protoporfiria Eritropoética/tratamento farmacológico , Aprovação de Drogas , Hemina/uso terapêutico , Humanos , Porfiria Aguda Intermitente/fisiopatologia , Protoporfiria Eritropoética/fisiopatologia , Luz Solar , Estados Unidos , United States Food and Drug Administration , alfa-MSH/análogos & derivados , alfa-MSH/uso terapêuticoRESUMO
Sepsis-related acute lung injury (ALI) remains a major cause of mortality in critically ill patients and lacks specific therapy. Mitochondrial dysfunction is involved in the progression of septic lung injury. Mitochondrial dynamics, mitophagy, and biogenesis converge to constitute the assiduous quality control of mitochondria (MQC). Heme oxygenase-1 (HO-1) protects against sepsis-induced ALI through the modulation of mitochondrial dynamics. However, the causal relationship between HO-1 and the general processes of MQC, and their associated cellular pathways in sepsis-related ALI remain ill-defined. Herein, lipopolysaccharide (LPS)-induced ALI in Sprague-Dawley rats together with LPS-induced oxidative injury in RAW264.7 macrophages were used to investigate whether the PI3K/Akt pathway-mediated induction of HO-1 preserves MQC and alleviates septic lung injury. After pretreatment with hemin, a potent inducer of HO-1, LPS-induced cell apoptosis, enhanced mitochondrial fragmentation, and mitochondrial membrane potential damage were significantly reduced in macrophages. In rats, these effects were accompanied by a higher survival rate, less damage to lung tissue, a 28.5% elevation in lung mitochondria MnSOD activity, and a 39.2% increase in respiratory control ratios. Concomitantly, HO-1 induction preserved the dynamic process of mitochondrial fusion/fission (Mfn2, OPA1, Drp1), promoted mitochondrial biogenesis (NRF1, PGC1α, Tfam), and facilitated the key mediators of mitochondrial mitophagy (Parkin, PINK1) at mRNA and protein levels. Notably, LY294002, a PI3K inhibitor, or knockdown of PI3K by small interfering RNA significantly suppressed Akt phosphorylation, attenuated HO-1 induction, and further reversed these beneficial effects evoked by hemin pretreatment in RAW264.7 cells or rats received LPS, indicating a direct involvement of PI3K/Akt pathway. Taken together, our results indicated that HO-1 activation, through PI3K/Akt pathway, plays a critical role in protecting lung from oxidative injury in the setting of sepsis by regulating MQC. HO-1 may therefore be a therapeutic target for the prevention sepsis-related lung injury.
Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Heme Oxigenase-1/metabolismo , Hemina/uso terapêutico , Renovação Mitocondrial/efeitos dos fármacos , Sepse/complicações , Lesão Pulmonar Aguda/etiologia , Animais , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática , Hemina/farmacologia , Lipopolissacarídeos , Pulmão/enzimologia , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células RAW 264.7 , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
Although heme oxygenase-1 (HO-1) is part of an endogenous defense system implicated in the homeostatic response, its role in cell proliferation and tumor progression is still controversial. Endometrial hyperplasia (EH) is associated with high risk of endometrial cancer (EC). Therefore, we aimed to evaluate the effect of hemin, a HO-1 inducer, against EH. Thirty-two female rats (60-70 days old) were divided into 4 groups treated for 1 week: vehicle control group, hemin group (25 mg/kg; i.p. 3 times/week), estradiol valerate (EV) group (2 mg/kg per day, p.o.), and hemin plus EV group. Sera were obtained for reduced glutathione level. Uterine malondialdehyde, superoxide dismutase, total nitrite/nitrate, and interleukin-1ß levels were estimated. HO-1 and p38 mitogen-activated protein kinase expressions were obtained in uterine tissue. Uterine histological and immunohistochemical assessment of iNOS and Ki67 were also done. Results demonstrated that upregulation of HO-1 expression in hemin plus EV rats led to amelioration of EH which was confirmed with histological examination. This was associated with significant decrease in oxidative stress parameters, p38 mitogen-activated protein kinase expression, and interleukin-1ß level. Also, uterine iNOS and Ki67 expressions were markedly suppressed. In conclusion, upregulation of HO-1 expression via hemin has ameliorative effect against EH through its antioxidant, anti-inflammatory, and antiproliferative actions.
Assuntos
Hiperplasia Endometrial/tratamento farmacológico , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Hemina/farmacologia , Antígeno Ki-67/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Hiperplasia Endometrial/genética , Hiperplasia Endometrial/metabolismo , Hiperplasia Endometrial/patologia , Estrogênios/farmacologia , Feminino , Hemina/uso terapêutico , Interleucina-1beta/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , Ratos , Ratos WistarRESUMO
Type 2 diabetes mellitus (T2DM) is associated with pancreatic ß-cell dysfunction which can be induced by oxidative stress. Deuterohemin-ßAla-His-Thr-Val-Glu-Lys (DhHP-6) is a microperoxidase mimetic that can scavenge reactive oxygen species (ROS) in vivo. In our previous studies, we demonstrated an increased stability of linear peptides upon their covalent attachment to porphyrins. In this study, we assessed the utility of DhHP-6 as an oral anti-diabetic drug in vitro and in vivo. DhHP-6 showed high resistance to proteolytic degradation in vitro and in vivo. The degraded DhHP-6 product in gastrointestinal (GI) fluid retained the enzymatic activity of DhHP-6, but displayed a higher permeability coefficient. DhHP-6 protected against the cell damage induced by H2O2 and promoted insulin secretion in INS-1 cells. In the T2DM model, DhHP-6 reduced blood glucose levels and facilitated the recovery of blood lipid disorders. DhHP-6 also mitigated both insulin resistance and glucose tolerance. Most importantly, DhHP-6 promoted the recovery of damaged pancreas islets. These findings suggest that DhHP-6 in physiological environments has high stability against enzymatic degradation and maintains enzymatic activity. As DhHP-6 lowered the fasting blood glucose levels of T2DM mice, it thus represents a promising candidate for oral administration and clinical therapy.