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1.
Genes (Basel) ; 15(9)2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39336779

RESUMEN

BACKGROUND/OBJECTIVES: α-1 antitrypsin (AAT) deficiency is an inherited, genetic condition characterized by reduced serum levels of AAT and increased risk of developing emphysema and liver disease. AAT is normally synthesized primarily in the liver, but muscle-targeting with a recombinant adeno-associated virus (rAAV) vector for α-1 antitrypsin (AAT) gene therapy has been used to minimize liver exposure to the virus and hepatotoxicity. Clinical trials of direct intramuscular (IM) administration of rAAV1-hAAT have demonstrated its overall safety and transgene expression for 5 years. However, the failure to reach the therapeutic target level after 100 large-volume (1.5 mL) IM injections of maximally concentrated vector led us to pursue a muscle-targeting approach using isolated limb perfusion. This targets the rAAV to a greater muscle mass and allows for a higher total volume (and thereby a higher dose) than is tolerable by multiple direct IM injections. Limb perfusion has been shown to be feasible in non-human primates using the rAAV1 serotype and a ubiquitous promoter expressing an epitope-tagged AAT matched to the host species. METHODS: In this study, we performed a biodistribution and preclinical safety study in non-human primates with a clinical candidate rAAV1-human AAT (hAAT) vector at doses ranging from 3.0 × 1012 to 1.3 × 1013 vg/kg, bracketing those used in our clinical trials. RESULTS: We found that limb perfusion delivery of rAAV1-hAAT was safe and showed a biodistribution pattern similar to previous studies. However, serum levels of AAT obtained with high-dose limb perfusion still reached only ~50% of the target serum levels. CONCLUSIONS: Our results suggest that clinically effective AAT gene therapy may ultimately require delivery at doses between 3.5 × 1013-1 × 1014 vg/kg, which is within the dose range used for approved rAAV gene therapies. Muscle-targeting strategies could be incorporated when delivering systemic administration of high-dose rAAV gene therapies to increase transduction of muscle tissues and reduce the burden on the liver, especially in diseases that can present with hepatotoxicity such as AAT deficiency.


Asunto(s)
Dependovirus , Terapia Genética , Vectores Genéticos , Deficiencia de alfa 1-Antitripsina , alfa 1-Antitripsina , Animales , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/administración & dosificación , Dependovirus/genética , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Terapia Genética/métodos , Deficiencia de alfa 1-Antitripsina/terapia , Deficiencia de alfa 1-Antitripsina/genética , Humanos , Masculino , Músculo Esquelético/metabolismo
2.
Ther Adv Respir Dis ; 18: 17534666241271917, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39132722

RESUMEN

Severe alpha-1 antitrypsin deficiency (AATD) is associated with an increased risk of emphysema. However, the clinical manifestations are very heterogeneous, and an individual prognosis is very difficult to establish. Intravenous augmentation therapy with alpha-1 antitrypsin (AAT) from pooled blood donors is the only specific treatment available, but it requires weekly or biweekly administration for life. Several guidelines provide the indication criteria for the initiation of AAT augmentation therapy. However, in clinical practice, there are situations in which the decision as to when to start treatment becomes uncertain and some studies have shown great variability in the indication of this treatment even among specialists. The usual dilemma is between initiating augmentation therapy in individuals who may not develop significant lung disease or in whom disease will not progress or delaying it in patients who may otherwise rapidly and irreversibly progress. We illustrate this dilemma with five clinical cases: from the case of a patient with normal lung function who requests initiation of therapy to a moderately stable patient without augmentation or a mild patient who, after several years of remaining stable without treatment, deterioration in lung function initiated and, consequently, augmentation therapy was begun. All the nuances associated with the indication of augmentation justify a personalised approach and the decision about initiating augmentation therapy must be made after careful consideration of the pros and cons with the patient in reference centres with experience in treatment. These reference centres can work in collaboration with local hospitals where patients can be closely followed and augmentation therapy can be administered to avoid unnecessary travelling, making periodical administrations more comfortable for the patient.


Asunto(s)
Enfisema Pulmonar , Deficiencia de alfa 1-Antitripsina , alfa 1-Antitripsina , Humanos , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/diagnóstico , Deficiencia de alfa 1-Antitripsina/tratamiento farmacológico , Deficiencia de alfa 1-Antitripsina/fisiopatología , alfa 1-Antitripsina/administración & dosificación , Enfisema Pulmonar/fisiopatología , Enfisema Pulmonar/etiología , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/terapia , Masculino , Persona de Mediana Edad , Femenino , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Medicina de Precisión , Adulto , Progresión de la Enfermedad , Anciano
3.
Gastroenterology ; 167(5): 1008-1018.e5, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38964420

RESUMEN

BACKGROUND & AIMS: Homozygous ZZ alpha-1 antitrypsin (AAT) deficiency produces mutant AAT (Z-AAT) proteins in hepatocytes, leading to progressive liver fibrosis. We evaluated the safety and efficacy of an investigational RNA interference therapeutic, fazirsiran, that degrades Z-AAT messenger RNA, reducing deleterious protein synthesis. METHODS: This ongoing, phase 2 study randomized 40 patients to subcutaneous placebo or fazirsiran 25, 100, or 200 mg. The primary endpoint was percent change in serum Z-AAT concentration from baseline to week 16. Patients with fibrosis on baseline liver biopsy received treatment on day 1, at week 4, and then every 12 weeks and had a second liver biopsy at or after weeks 48, 72, or 96. Patients without fibrosis received 2 doses on day 1 and at week 4. RESULTS: At week 16, least-squares mean percent declines in serum Z-AAT concentration were -61%, -83%, and -94% with fazirsiran 25, 100, and 200 mg, respectively, vs placebo (all P < .0001). Efficacy was sustained through week 52. At postdose liver biopsy, fazirsiran reduced median liver Z-AAT concentration by 93% compared with an increase of 26% with placebo. All fazirsiran-treated patients had histologic reduction from baseline in hepatic globule burden. Portal inflammation improved in 5 of 12 and 0 of 8 patients with a baseline score of >0 in the fazirsiran and placebo groups, respectively. Histologic meta-analysis of histologic data in viral hepatitis score improved by >1 point in 7 of 14 and 3 of 8 patients with fibrosis of >F0 at baseline in the fazirsiran and placebo groups, respectively. No adverse events led to discontinuation, and pulmonary function tests remained stable. CONCLUSIONS: Fazirsiran reduced serum and liver concentrations of Z-AAT in a dose-dependent manner and reduced hepatic globule burden. (ClinicalTrials.gov, Number NCT03945292).


Asunto(s)
Cirrosis Hepática , Deficiencia de alfa 1-Antitripsina , alfa 1-Antitripsina , Humanos , Deficiencia de alfa 1-Antitripsina/tratamiento farmacológico , Deficiencia de alfa 1-Antitripsina/diagnóstico , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/genética , Masculino , Femenino , Adulto , Persona de Mediana Edad , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/administración & dosificación , Resultado del Tratamiento , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/diagnóstico , Hígado/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Método Doble Ciego , Biopsia , Tratamiento con ARN de Interferencia , Relación Dosis-Respuesta a Droga , Adulto Joven , ARN Interferente Pequeño
4.
Otol Neurotol ; 45(7): 818-823, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38896787

RESUMEN

AIM: To characterize vestibular recovery in a mouse model of unilateral labyrinthotomy under local AAT and dexamethasone treatment. BACKGROUND: Alpha1-antitrypsin (AAT) is a circulating tissue-protective molecule that rises during inflammatory conditions and promotes inflammatory resolution. Its local concentration in human perilymph inversely correlates with the severity of inner ear dysfunction; concomitantly, mice that overexpress AAT and undergo inner ear trauma rapidly restore vestibular function. Locally applied AAT has yet to be examined in this context, nor has it been directly compared with anti-inflammatory corticosteroid treatment. METHODS: Wild-type mice C57BL/6 underwent a unilateral inner ear injury. Nine microliters of saline, clinical-grade AAT (180 µg/site), dexamethasone (4 mg/site), or both were applied locally on Days 0, 1, and 2 (n = 5/group). Vestibular function was assessed for 7 days. An in vitro human epithelial gap closure assay was performed using A549 cells in the presence of AAT and/or dexamethasone. RESULTS: Upon labyrinthotomy, all groups displayed severe vestibular dysfunction. Saline-treated mice showed the longest impairment. That group and the dexamethasone group displayed partial to no recovery, while AAT-treated mice exhibited complete recovery within 7 days; at this time point, dexamethasone-treated mice exhibited 50% recovery. Objective vestibular testing showed similar outcomes. In vitro, cotreatment with AAT and dexamethasone resulted in a gap closure dynamic that was superior to AAT alone at 6 h and superior to DEX alone at 48 h. CONCLUSION: Locally applied AAT treatment is superior to locally applied dexamethasone in promoting vestibular recovery in vivo. Ongoing studies are exploring the potential advantages of AAT combined with early low-dose dexamethasone therapy.


Asunto(s)
Dexametasona , Ratones Endogámicos C57BL , alfa 1-Antitripsina , Animales , Ratones , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , alfa 1-Antitripsina/administración & dosificación , Enfermedades Vestibulares/tratamiento farmacológico , Enfermedades Vestibulares/etiología , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Oído Interno/efectos de los fármacos , Modelos Animales de Enfermedad , Recuperación de la Función/efectos de los fármacos , Vestíbulo del Laberinto/efectos de los fármacos , Vestíbulo del Laberinto/lesiones , Humanos , Masculino
5.
J Surg Res ; 299: 179-187, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38759334

RESUMEN

INTRODUCTION: Renal ischemia reperfusion injury is a major cause of perioperative acute kidney injury. Alpha-1-antitrypsin (AAT), a protease inhibitor, might improve outcomes by reducing inflammation and apoptosis. We investigated the effects of a single intravenous dose of AAT immediately before ischemia in a rat bilateral renal clamping model. METHODS: Both renal pedicles of male Sprague-Dawley rats were clamped (45 min). Plasma and renal tissue were collected at 3 h, 24 h, and 7 d. Intravenous AAT (60 mg/kg) was administered 5 min before clamping. Controls received saline. Shams underwent surgery without clamping or injection. Kidney function was assessed by plasma creatinine; injury by aspartate aminotransferase, heart-type-fatty-acid-binding-protein, and histopathology. Renal gene expression of tumor necrosis factor α, interleukin (IL)-6, heat shock protein 70, Chemokine (C-X-C motif) ligand 2, cyclo-oxygenase 2, endothelin-1, IL-10, heme oxygenase 1, B-cell lymphoma 2, and bcl-2-like protein 4 were determined by quantitative reverse transcriptase polymerase chain reaction. RESULTS: None of the 3 h and 24 h end points were different between Control and AAT. In Sham, survival was 100% (6/6), 33% in Control (2/6), and 83% (5/6) in AAT (overall log-rank 0.03). At 7 d, plasma creatinine was lower with higher glomerular filtration rate in surviving AAT treated animals compared to Control (P < 0.001, P 0.03, respectively). These also had lower tumor necrosis factor α and IL-6 gene expression (P 0.001, P < 0.001, respectively). CONCLUSIONS: These data suggest that a single intravenous dose of AAT immediately before ischemia might affect proinflammatory gene expression, glomerular filtration rate and animal survival at 1 wk after reperfusion despite an absence of improvement in early renal function and injury. These findings deserve further investigating in sufficiently powered studies including both sexes.


Asunto(s)
Riñón , Daño por Reperfusión , alfa 1-Antitripsina , Animales , Masculino , Ratas , Lesión Renal Aguda/etiología , Lesión Renal Aguda/prevención & control , alfa 1-Antitripsina/administración & dosificación , Modelos Animales de Enfermedad , Riñón/irrigación sanguínea , Riñón/patología , Riñón/efectos de los fármacos , Ratas Sprague-Dawley , Daño por Reperfusión/prevención & control , Daño por Reperfusión/patología , Daño por Reperfusión/etiología
6.
Respir Res ; 22(1): 207, 2021 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-34271910

RESUMEN

BACKGROUND: Alpha-1 antitrypsin (AAT) is a major serine protease inhibitor. AAT deficiency (AATD) is a genetic disorder characterized by early-onset severe emphysema. In well-selected AATD patients, therapy with plasma-derived AAT (pAAT), "augmentation therapy", provides modest clinical improvement but is perceived as cumbersome with weekly intravenous infusions. Using mouse models of emphysema, we compared the effects of a recombinant AAT-IgG1 Fc-fusion protein (AAT-Fc), which is expected to have a longer half-life following infusion, to those of pAAT. METHODS: In an elastase model of emphysema, mice received a single intratracheal instillation of porcine pancreatic elastase (PPE) or human leucocyte elastase (hLE). AAT-Fc, pAAT, or vehicle was administered intraperitoneally 1 day prior to or 3 weeks following elastase instillation. Lung function and histology assessments were performed at 7 and 32 days after elastase instillation. In a cigarette smoke (CS) model of emphysema, mice were exposed to CS daily, 5 days a week, for 6 months and AAT-Fc, pAAT, or vehicle were administered every 10 days during the last 3 months of CS exposure. Assessments were performed 3 days after the last CS exposure. Immune responses to lung elastin peptide (EP) and the effects of AAT-Fc or pAAT treatment on dendritic cell (DC) function were determined ex vivo. RESULTS: Both elastase instillation and CS exposure triggered emphysema-like alveolar enlargement, increased lung compliance, and increased markers of inflammation compared to controls. Administration of AAT-Fc either prior to or following elastase instillation or during CS exposure provided greater protection than pAAT against alveolar enlargement, lung dysfunction, and airway inflammation. When challenged ex vivo with EP, spleen mononuclear cells from elastase-exposed mice exhibited dose-dependent production of IFNγ and IL-17, suggesting immune reactivity. In co-culture experiments with splenic CD4+ T cells isolated from elastase-exposed mice, AAT-Fc treatment prior to EP-priming of bone marrow-derived dendritic cells inhibited the production of IFNγ and IL-17. CONCLUSIONS: Compared to pAAT, AAT-Fc more effectively prevented or attenuated elastase- and CS-induced models of emphysema. These effects were associated with immunomodulatory effects on DC activity. AAT-Fc may provide a therapeutic option to individuals with AATD- and CS-induced emphysema.


Asunto(s)
Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Exposición por Inhalación/efectos adversos , Elastasa Pancreática/toxicidad , Enfisema Pulmonar/inducido químicamente , Enfisema Pulmonar/tratamiento farmacológico , Proteínas Recombinantes de Fusión/administración & dosificación , Humo/efectos adversos , alfa 1-Antitripsina/administración & dosificación , Animales , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Elastasa Pancreática/administración & dosificación , Enfisema Pulmonar/inmunología , Porcinos , Nicotiana
7.
Trials ; 22(1): 288, 2021 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-33874981

RESUMEN

OBJECTIVES: The primary objective is to demonstrate that, in patients with PCR-confirmed SARS-CoV-2 resulting in Acute Respiratory Distress Syndrome (ARDS), administration of 120mg/kg of body weight of intravenous Prolastin®(plasma-purified alpha-1 antitrypsin) reduces circulating plasma levels of interleukin-6 (IL-6). Secondary objectives are to determine the effects of intravenous Prolastin® on important clinical outcomes including the incidence of adverse events (AEs) and serious adverse events (SAEs). TRIAL DESIGN: Phase 2, randomised, double-blind, placebo-controlled, pilot trial. PARTICIPANTS: The study will be conducted in Intensive Care Units in hospitals across Ireland. Patients with a laboratory-confirmed diagnosis of SARS-CoV-2-infection, moderate to severe ARDS (meeting Berlin criteria for a diagnosis of ARDS with a PaO2/FiO2 ratio <200 mmHg), >18 years of age and requiring invasive or non-invasive mechanical ventilation. All individuals meeting any of the following exclusion criteria at baseline or during screening will be excluded from study participation: more than 96 hours has elapsed from onset of ARDS; age < 18 years; known to be pregnant or breastfeeding; participation in a clinical trial of an investigational medicinal product (other than antibiotics or antivirals) within 30 days; major trauma in the prior 5 days; presence of any active malignancy (other than nonmelanoma skin cancer) which required treatment within the last year; WHO Class III or IV pulmonary hypertension; pulmonary embolism prior to hospital admission within past 3 months; currently receiving extracorporeal life support (ECLS); chronic kidney disease receiving dialysis; severe chronic liver disease with Child-Pugh score > 12; DNAR (Do Not Attempt Resuscitation) order in place; treatment withdrawal imminent within 24 hours; Prisoners; non-English speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available; IgA deficiency. INTERVENTION AND COMPARATOR: Intervention: Either a once weekly intravenous infusion of Prolastin® at 120mg/kg of body weight for 4 weeks or a single dose of Prolastin® at 120mg/kg of body weight intravenously followed by once weekly intravenous infusion of an equal volume of 0.9% sodium chloride for a further 3 weeks. Comparator (placebo): An equal volume of 0.9% sodium chloride intravenously once per week for four weeks. MAIN OUTCOMES: The primary effectiveness outcome measure is the change in plasma concentration of IL-6 at 7 days as measured by ELISA. Secondary outcomes include: safety and tolerability of Prolastin® in the respective groups (as defined by the number of SAEs and AEs); PaO2/FiO2 ratio; respiratory compliance; sequential organ failure assessment (SOFA) score; mortality; time on ventilator in days; plasma concentration of alpha-1 antitrypsin (AAT) as measured by nephelometry; plasma concentrations of interleukin-1ß (IL-1ß), interleukin-8 (IL-8), interleukin-10 (IL-10), soluble TNF receptor 1 (sTNFR1, a surrogate marker for TNF-α) as measured by ELISA; development of shock; acute kidney injury; need for renal replacement therapy; clinical relapse, as defined by the need for readmission to the ICU or a marked decline in PaO2/FiO2 or development of shock or mortality following a period of sustained clinical improvement; secondary bacterial pneumonia as defined by the combination of radiographic findings and sputum/airway secretion microscopy and culture. RANDOMISATION: Following informed consent/assent patients will be randomised. The randomisation lists will be prepared by the study statistician and given to the unblinded trial personnel. However, the statistician will not be exposed to how the planned treatment will be allocated to the treatment codes. Randomisation will be conducted in a 1:1:1 ratio, stratified by site and age. BLINDING (MASKING): The investigator, treating physician, other members of the site research team and patients will be blinded to treatment allocation. The clinical trial pharmacy personnel and research nurses will be unblinded to facilitate intervention and placebo preparation. The unblinded individuals will keep the treatment information confidential. The infusion bag will be masked at the time of preparation and will be administered via a masked infusion set to maintain blinding. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 36 patients will be recruited and randomised in a 1:1:1 ratio to each of the trial arms. TRIAL STATUS: In March 2020, version 1.0 of the trial protocol was submitted to the local research ethics committee (REC), Health Research Consent Declaration Committee (HRCDC) and the Health Products regulatory Authority (HPRA). REC approval was granted on April 1st 2020, HPRA approval was granted on April 24th 2020 and the HRCDC provided a conditional declaration on April 17th 2020. In July 2020 a substantial amendment (version 2.0) was submitted to the REC, HRCDC and HPRA. Protocol changes in this amendment included: the addition of trial sites; extending the duration of the trial to 12 months from 3 months; removal of inclusion criteria requiring the need for vasopressors; amendment of randomisation schedule to stratify by age only and not BMI and sex; correction of grammatical error in relation to infusion duration; to allow for inclusion of subjects who may have been enrolled in a clinical trial involving either antibiotics or anti-virals in the past 30 days; to allow for inclusion of subjects who may be currently enrolled in a clinical trial involving either antibiotics or anti-virals; to remove the need for exclusion based on alpha-1 antitrypsin phenotype; removal of mandatory isoelectric focusing of plasma to confirm Pi*MM status at screening; removal of need for mandatory echocardiogram at screening; amendment on procedures around plasma analysis to reflect that this will be conducted at the central site laboratory (as trial is multi-site and no longer single site); wording amended to reflect that interim analysis of cytokine levels taken at 7 days may be conducted. HRCDC approved version 2.0 on September 14th 2020, and HPRA approved on October 22nd 2020. REC approved the substantial amendment on November 23rd. In November 2020, version 3.0 of the trial protocol was submitted to the REC and HPRA. The rationale for this amendment was to allow for patients with moderate to severe ARDS from SARS-CoV-2 with non-invasive ventilation. HPRA approved this amendment on December 1st 2020 and the REC approved the amendment on December 8th 2020. Patient recruitment commenced in April 2020 and the last patient will be recruited to the trial in April 2021. The last visit of the last patient is anticipated to occur in April 2021. At time of writing, patient recruitment is now complete, however follow-up patient visits and data collection are ongoing. TRIAL REGISTRATION: EudraCT 2020-001391-15 (Registered 31 Mar 2020). FULL PROTOCOL: The full protocol (version 3.0 23.11.2020) is attached as an additional file accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , alfa 1-Antitripsina/uso terapéutico , Método Doble Ciego , Humanos , Irlanda , Proyectos Piloto , Plasma , Ensayos Clínicos Controlados Aleatorios como Asunto , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/diagnóstico , alfa 1-Antitripsina/administración & dosificación
8.
Anesthesiology ; 134(5): 792-808, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33721888

RESUMEN

Acute respiratory distress syndrome is characterized by hypoxemia, altered alveolar-capillary permeability, and neutrophil-dominated inflammatory pulmonary edema. Despite decades of research, an effective drug therapy for acute respiratory distress syndrome remains elusive. The ideal pharmacotherapy for acute respiratory distress syndrome should demonstrate antiprotease activity and target injurious inflammatory pathways while maintaining host defense against infection. Furthermore, a drug with a reputable safety profile, low possibility of off-target effects, and well-known pharmacokinetics would be desirable. The endogenous 52-kd serine protease α1-antitrypsin has the potential to be a novel treatment option for acute respiratory distress syndrome. The main function of α1-antitrypsin is as an antiprotease, targeting neutrophil elastase in particular. However, studies have also highlighted the role of α1-antitrypsin in the modulation of inflammation and bacterial clearance. In light of the current SARS-CoV-2 pandemic, the identification of a treatment for acute respiratory distress syndrome is even more pertinent, and α1-antitrypsin has been implicated in the inflammatory response to SARS-CoV-2 infection.


Asunto(s)
Neutrófilos/efectos de los fármacos , Proteínas Inhibidoras de Proteinasas Secretoras/administración & dosificación , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , alfa 1-Antitripsina/administración & dosificación , Animales , COVID-19/enzimología , COVID-19/inmunología , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/inmunología , Pulmón/efectos de los fármacos , Pulmón/enzimología , Pulmón/inmunología , Neutrófilos/enzimología , Neutrófilos/inmunología , Proteínas Inhibidoras de Proteinasas Secretoras/inmunología , Síndrome de Dificultad Respiratoria/enzimología , Síndrome de Dificultad Respiratoria/inmunología , alfa 1-Antitripsina/inmunología , Tratamiento Farmacológico de COVID-19
9.
Pediatr Diabetes ; 22(2): 192-201, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33244872

RESUMEN

BACKGROUND: While circulating levels of alpha1 -proteinase inhibitor (alpha1 -PI) are typically normal, antiprotease activity appears to be compromised in patients with Type 1 diabetes mellitus (T1DM). Because alpha1 -PI [human] (alpha1 -PI[h]) therapy can inhibit pro-inflammatory mediators associated with ß-cell destruction and reduced insulin production, it has been proposed for T1DM disease prevention. The aim of this study was to evaluate safety, tolerability, and efficacy of intravenous (IV) alpha1 -PI[h] in preserving C-peptide production in newly diagnosed T1DM patients. PARTICIPANTS: Seventy-six participants (aged 6-35 years) were randomized at 25 centers within 3 months of T1DM diagnosis. METHODS: A Phase II, multicenter, partially blinded, placebo-controlled, proof-of-concept study evaluating four dosing regimens of alpha1 -PI[h] (NCT02093221, GTI1302): weekly IV infusions of either 90 or 180 mg/kg, each for either 13 or 26 weeks. Safety and efficacy were monitored over 52 weeks with an efficacy evaluation planned at 104 weeks. The primary efficacy endpoint was change from baseline in the 2-h area-under-the-curve C-peptide level from a mixed-meal tolerance test at 52 weeks. A battery of laboratory tests, including inflammatory biomarkers, constituted exploratory efficacy variables. RESULTS: Infusions were well tolerated with no new safety signals. All groups exhibited highly variable declines in the primary outcome measure at 52 weeks with no statistically significant difference from placebo. Interleukin-6 (IL-6) was reduced from baseline in all alpha1 -PI treatment groups but not the placebo group. CONCLUSION: Pharmacologic therapy with alpha1 -PI[h] is safe, well tolerated, and able to reduce IL-6 levels; however, due to variability in the efficacy endpoint, its effects on preservation of C-peptide production were inconclusive.


Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Inhibidores de Serina Proteinasa/administración & dosificación , alfa 1-Antitripsina/administración & dosificación , Adolescente , Adulto , Péptido C/sangre , Niño , Diabetes Mellitus Tipo 1/sangre , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Interleucina-6/sangre , Masculino , Prueba de Estudio Conceptual , Inhibidores de Serina Proteinasa/farmacocinética , Resultado del Tratamiento , Adulto Joven , alfa 1-Antitripsina/farmacocinética
10.
Med Hypotheses ; 146: 110394, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33239231

RESUMEN

No definitive treatment for COVID-19 exists although promising results have been reported with remdesivir and glucocorticoids. Short of a truly effective preventive or curative vaccine against SARS-CoV-2, it is becoming increasingly clear that multiple pathophysiologic processes seen with COVID-19 as well as SARS-CoV-2 itself should be targeted. Because alpha-1-antitrypsin (AAT) embraces a panoply of biologic activities that may antagonize several pathophysiologic mechanisms induced by SARS-CoV-2, we hypothesize that this naturally occurring molecule is a promising agent to ameliorate COVID-19. We posit at least seven different mechanisms by which AAT may alleviate COVID-19. First, AAT is a serine protease inhibitor (SERPIN) shown to inhibit TMPRSS-2, the host serine protease that cleaves the spike protein of SARS-CoV-2, a necessary preparatory step for the virus to bind its cell surface receptor ACE2 to gain intracellular entry. Second, AAT has anti-viral activity against other RNA viruses HIV and influenza as well as induces autophagy, a known host effector mechanism against MERS-CoV, a related coronavirus that causes the Middle East Respiratory Syndrome. Third, AAT has potent anti-inflammatory properties, in part through inhibiting both nuclear factor-kappa B (NFκB) activation and ADAM17 (also known as tumor necrosis factor-alpha converting enzyme), and thus may dampen the hyper-inflammatory response of COVID-19. Fourth, AAT inhibits neutrophil elastase, a serine protease that helps recruit potentially injurious neutrophils and implicated in acute lung injury. AAT inhibition of ADAM17 also prevents shedding of ACE2 and hence may preserve ACE2 inhibition of bradykinin, reducing the ability of bradykinin to cause a capillary leak in COVID-19. Fifth, AAT inhibits thrombin, and venous thromboembolism and in situ microthrombi and macrothrombi are increasingly implicated in COVID-19. Sixth, AAT inhibition of elastase can antagonize the formation of neutrophil extracellular traps (NETs), a complex extracellular structure comprised of neutrophil-derived DNA, histones, and proteases, and implicated in the immunothrombosis of COVID-19; indeed, AAT has been shown to change the shape and adherence of non-COVID-19-related NETs. Seventh, AAT inhibition of endothelial cell apoptosis may limit the endothelial injury linked to severe COVID-19-associated acute lung injury, multi-organ dysfunction, and pre-eclampsia-like syndrome seen in gravid women. Furthermore, because both NETs formation and the presence of anti-phospholipid antibodies are increased in both COVID-19 and non-COVID pre-eclampsia, it suggests a similar vascular pathogenesis in both disorders. As a final point, AAT has an excellent safety profile when administered to patients with AAT deficiency and is dosed intravenously once weekly but also comes in an inhaled preparation. Thus, AAT is an appealing drug candidate to treat COVID-19 and should be studied.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Modelos Biológicos , alfa 1-Antitripsina/uso terapéutico , Lesión Pulmonar Aguda/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , Antitrombinas/uso terapéutico , Antivirales/uso terapéutico , Apoptosis/efectos de los fármacos , COVID-19/fisiopatología , Trampas Extracelulares/efectos de los fármacos , Interacciones Microbiota-Huesped/efectos de los fármacos , Interacciones Microbiota-Huesped/fisiología , Humanos , Elastasa de Leucocito/antagonistas & inhibidores , Pandemias , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/patogenicidad , SARS-CoV-2/fisiología , Serina Endopeptidasas/efectos de los fármacos , Serina Endopeptidasas/fisiología , Internalización del Virus/efectos de los fármacos , alfa 1-Antitripsina/administración & dosificación
11.
JCI Insight ; 5(15)2020 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-32759494

RESUMEN

Alpha 1-antitrypsin (AAT) deficiency, a hereditary disorder characterized by low serum levels of functional AAT, is associated with early development of panacinar emphysema. AAT inhibits serine proteases, including neutrophil elastase, protecting the lung from proteolytic destruction. Cigarette smoke, pollution, and inflammatory cell-mediated oxidation of methionine (M) 351 and 358 inactivates AAT, limiting lung protection. In vitro studies using amino acid substitutions demonstrated that replacing M351 with valine (V) and M358 with leucine (L) on a normal M1 alanine (A) 213 background provided maximum antiprotease protection despite oxidant stress. We hypothesized that a onetime administration of a serotype 8 adeno-associated virus (AAV8) gene transfer vector coding for the oxidation-resistant variant AAT (A213/V351/L358; 8/AVL) would maintain antiprotease activity under oxidant stress compared with normal AAT (A213/M351/M358; 8/AMM). 8/AVL was administered via intravenous (IV) and intrapleural (IPL) routes to C57BL/6 mice. High, dose-dependent AAT levels were found in the serum and lung epithelial lining fluid (ELF) of mice administered 8/AVL or 8/AMM by IV or IPL. 8/AVL serum and ELF retained serine protease-inhibitory activity despite oxidant stress while 8/AMM function was abolished. 8/AVL represents a second-generation gene therapy for AAT deficiency providing effective antiprotease protection even with oxidant stress.


Asunto(s)
Dependovirus/genética , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Oxidantes , Transgenes , Deficiencia de alfa 1-Antitripsina/terapia , alfa 1-Antitripsina/administración & dosificación , Animales , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo , alfa 1-Antitripsina/genética , Deficiencia de alfa 1-Antitripsina/genética , Deficiencia de alfa 1-Antitripsina/patología
12.
Artículo en Inglés | MEDLINE | ID: mdl-32103933

RESUMEN

Alpha-1 antitrypsin deficiency (AATD) is a rare and underdiagnosed genetic predisposition for COPD and emphysema and other conditions, including liver disease. Although there have been improvements in terms of awareness of AATD and understanding of its treatment in recent years, current challenges center on optimizing detection and management of patients with AATD, and improving access to intravenous (IV) AAT therapy - the only available pharmacological intervention that can slow disease progression. However, as an orphan disease with geographically dispersed patients, international cooperation is essential to address these issues. To achieve this, new European initiatives in the form of the European Reference Network for Rare Lung Diseases (ERN-LUNG) and the European Alpha-1 Research Collaboration (EARCO) have been established. These organizations are striving to address the current challenges in AATD, and provide a new platform for future research efforts in AATD. The first objectives of ERN-LUNG are to establish a quality control program for European AATD laboratories and create a disease management program for AATD, following the success of such programs in the United States. The main purpose of EARCO is to create a pan-European registry, with the aim of understanding the natural history of the disease and supporting the development of new treatment modalities in AATD and access to AAT therapy. Going further, other patient-centric initiatives involve improving the convenience of intravenous AAT therapy infusions through extended-interval dosing and self-administration. The present review will discuss the implementation of these initiatives and their potential contribution to the optimization of patient care in AATD.


Asunto(s)
Terapia de Reemplazo Enzimático , Atención Dirigida al Paciente , Enfermedad Pulmonar Obstructiva Crónica/terapia , Enfisema Pulmonar/terapia , Deficiencia de alfa 1-Antitripsina/terapia , alfa 1-Antitripsina/administración & dosificación , Terapia de Reemplazo Enzimático/efectos adversos , Humanos , Infusiones Intravenosas , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/epidemiología , Calidad de Vida , Resultado del Tratamiento , alfa 1-Antitripsina/efectos adversos , Deficiencia de alfa 1-Antitripsina/diagnóstico , Deficiencia de alfa 1-Antitripsina/epidemiología
13.
Eur Respir J ; 54(5)2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31467115

RESUMEN

Patients with inherited α1-antitrypsin (AAT) deficiency (ZZ-AATD) and severe chronic obstructive pulmonary disease (COPD) frequently experience exacerbations. We postulated that inhalation of nebulised AAT would be an effective treatment.We randomly assigned 168 patients to receive twice-daily inhalations of 80 mg AAT solution or placebo for 50 weeks. Patients used an electronic diary to capture exacerbations. The primary endpoint was time from randomisation to the first event-based exacerbation. Secondary endpoints included change in the nature of the exacerbation as defined by the Anthonisen criteria. Safety was also assessed.Time to first moderate or severe exacerbation was a median of 112 days (interquartile range (IQR) 40-211 days) for AAT and 140 days (IQR 72-142 days) for placebo (p=0.0952). The mean yearly rate of all exacerbations was 3.12 in the AAT-treated group and 2.67 in the placebo group (p=0.31). More patients receiving AAT reported treatment-related treatment-emergent adverse events compared to placebo (57.5% versus 46.9%, respectively) and they were more likely to withdraw from the study. After the first year of the study, when modifications to the handling of the nebuliser were introduced, the rate of safety events in the AAT-treated group dropped to that of the placebo group.We conclude that in AATD patients with severe COPD and frequent exacerbations, AAT inhalation for 50 weeks showed no effect on time to first exacerbation but may have changed the pattern of the episodes.


Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Inhibidores de Tripsina/administración & dosificación , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/tratamiento farmacológico , alfa 1-Antitripsina/administración & dosificación , Administración por Inhalación , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Inhibidores de Tripsina/efectos adversos , alfa 1-Antitripsina/efectos adversos
14.
Am J Respir Crit Care Med ; 200(3): 318-326, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-30965011

RESUMEN

Rationale: Augmentation therapy with intravenous AAT (alpha-1 antitrypsin) is the only specific therapy for individuals with pulmonary disease from AAT deficiency (AATD). The recommended standard dose (SD; 60 mg/kg/wk) elevates AAT trough serum levels to around 50% of normal; however, outside of slowing emphysema progression, its effects in other clinical outcomes have not been rigorously proven.Objectives: To evaluate the biological effects of normalizing AAT trough levels with double-dose (DD) therapy (120 mg/kg/wk) in subjects with AATD already receiving SD therapy.Methods: Clinically stable subjects were evaluated after 4 weeks of SD therapy, followed by 4 weeks of DD therapy, and 4 weeks after return to SD therapy. At the end of each phase, BAL fluid (BALF) and plasma samples were obtained.Measurements and Main Results: DD therapy increased trough AAT levels to normal and, compared with SD therapy, reduced serine protease activity in BALF (elastase and cathepsin G), plasma elastase footprint (Aα-Val360), and markers of elastin degradation (desmosine/isodesmosine) in BALF. DD therapy also further downregulated BALF ILs and cytokines including Jak-STAT (Janus kinases-signal transducer and activator of transcription proteins), TNFα (tumor necrosis factor-α), and T-cell receptor signaling pathways, cytokines involved in macrophage migration, eosinophil recruitment, humoral and adaptive immunity, neutrophil activation, and cachexia. On restarting SD after DD treatment, a possible carryover effect was seen for several biological markers.Conclusions: Subjects with AATD on SD augmentation therapy still exhibit inflammation, protease activity, and elastin degradation that can be further improved by normalizing AAT levels. Higher AAT dosing than currently recommended may lead to enhanced clinical benefits and should be explored further.Clinical trial registered with www.clinicaltrials.gov (NCT01669421).


Asunto(s)
Inhibidores de Tripsina/administración & dosificación , Deficiencia de alfa 1-Antitripsina/tratamiento farmacológico , alfa 1-Antitripsina/administración & dosificación , Adolescente , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/terapia , Adulto Joven , Deficiencia de alfa 1-Antitripsina/complicaciones
16.
Respir Investig ; 57(1): 89-96, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30416054

RESUMEN

BACKGROUND: Alpha1-Proteinase Inhibitor, Modified Process (Alpha-1 MP) is used for augmentation therapy in alpha1-antitrypsin deficiency (AATD), an extremely rare disease in Japan. Weekly doses of 60 mg/kg Alpha-1 MP have been shown to be safe and well tolerated in non-Japanese subjects, but the safety and pharmacokinetics (PK) have not been evaluated in Japanese subjects. The objectives of this study were to evaluate the safety and PK of 60 mg/kg Alpha-1 MP administered by weekly IV infusions over 8 weeks in Japanese subjects with AATD. METHODS: This was a multicenter, open-label trial in Japanese adults aged ≥20 years with AATD. Samples for evaluation of serum alpha1-PI concentration and PK parameters were collected at 10 time points until the seventh day after the last dose at Week 8: immediately before dosing, immediately after dosing (time 0), and 0.25, 2, 4, 8, 24, 48, 120, and 168 hours after dosing. RESULTS: Four subjects were analyzed. The median tmax was 0.534 h. Mean ± SD values for t½, Cmax, and AUC0-7days were 150.4 ± 36.18 h, 174.2 ± 30.51 mg/dL, and 14,913.2 ± 1633.45 mg*h/dL, respectively. Mean trough concentration at week 8 was 55.4 ± 7.23 mg/dL. Alpha-1 MP therapy was safe, with no serious adverse events or deaths reported. Two treatment-emergent adverse events of fatigue in one subject were considered to be possibly related. CONCLUSIONS: The PK and safety of Alpha-1 MP in Japanese subjects with AATD were consistent with the Alpha-1 MP profile in non-Japanese subjects (ClinicalTrials.gov: NCT02870309; JAPIC CTI: JapicCTI-163160).


Asunto(s)
Inhibidores de Serina Proteinasa/administración & dosificación , Inhibidores de Serina Proteinasa/farmacocinética , Deficiencia de alfa 1-Antitripsina/tratamiento farmacológico , alfa 1-Antitripsina/administración & dosificación , alfa 1-Antitripsina/farmacocinética , Anciano , Pueblo Asiatico , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Seguridad , Factores de Tiempo , Deficiencia de alfa 1-Antitripsina/metabolismo
18.
Pneumologie ; 72(8): 590-597, 2018 Aug.
Artículo en Alemán | MEDLINE | ID: mdl-30089330

RESUMEN

BACKGROUND: Augmentation with human alpha-1 proteinase inhibitor is the only specific treatment for Alpha-1-Antitrypsin Deficiency (AATD), a rare genetic disease with symptoms of progressive COPD. OBJECTIVES: A prospective long-term exploration of outcomes during the "Alpha-1-Mobile" home care AAT augmentation program in seven advanced-stage patients. METHODS: Patients received weekly i. v. AAT augmentation and COPD therapy. Symptoms, lung function, health status, quality-of-life aspects, and safety were documented continuously. Outcomes during six years of home care augmentation therapy were observed and evaluated on an inter- and intraindividual basis. FEV1 profiles were compared to pre-program data. RESULTS: The seven patients had a mean age of 56.7 (40-68) years and had previously received augmentation for 8.8 (1-19) years. Compared to the three-year preprogram period, functional decline of FEV1 (ΔFEV1 0.47 L vs 0.17 L) slowed. Mean QoL scores showed seasonal fluctuations in the first three years of observation, and then stabilized. All blood samples tested exceeded the protective threshold of 50 mg/dL with a dose of 60 mg AAT/kg/week. Less than one exacerbation-related hospitalization occurred per patient-year. No adverse events of related to augmentation therapy were observed. CONCLUSIONS: Home care with i. v. augmentation therapy by medical professionals contributes to optimum care through consistent treatment and close health-status monitoring in our collective. Exacerbation-related hospitalizations were largely avoided. "Alpha-1-Mobile" was well accepted, practical, and safe.


Asunto(s)
Servicios de Atención de Salud a Domicilio , Pulmón/fisiopatología , Enfisema Pulmonar/tratamiento farmacológico , Deficiencia de alfa 1-Antitripsina/tratamiento farmacológico , alfa 1-Antitripsina/administración & dosificación , Anciano , Estado de Salud , Humanos , Persona de Mediana Edad , Evaluación de Programas y Proyectos de Salud , Estudios Prospectivos , Enfisema Pulmonar/genética , Enfisema Pulmonar/psicología , Calidad de Vida , Deficiencia de alfa 1-Antitripsina/genética , Deficiencia de alfa 1-Antitripsina/psicología
19.
Panminerva Med ; 60(3): 101-108, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29696962

RESUMEN

Alpha-1 antitrypsin deficiency (AATD) is a clinically under-recognized inherited disorder affecting the lungs and the liver. The most common manifestations are pulmonary emphysema, bronchiectasis and liver disease. The recent publication of the European Respiratory Society statement on diagnosis and treatment of pulmonary diseases has replaced the 2003 American Thoracic Society and European Respiratory Society one. New outcome parameters have been introduced and validated by observational and randomized clinical trials, and new information about efficacy and safety of augmentation therapy have been published. In this narrative review we have commented the crucial points of the new European Respiratory Society statement on AATD, including a review of the literature on liver involvement and treatments.


Asunto(s)
Neumología/métodos , Deficiencia de alfa 1-Antitripsina/diagnóstico , Deficiencia de alfa 1-Antitripsina/terapia , alfa 1-Antitripsina/administración & dosificación , Administración por Inhalación , Aerosoles , Ensayos Clínicos como Asunto , Humanos , Hepatopatías/complicaciones , Pulmón , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/terapia , Trasplante de Pulmón , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/terapia , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/terapia , Sociedades Médicas , alfa 1-Antitripsina/sangre
20.
J Cardiovasc Pharmacol ; 71(6): 375-379, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29634656

RESUMEN

BACKGROUND: Despite the benefits of reperfusion in limiting myocardial injury, the infarct size continues to expand after reperfusion because of secondary inflammatory injury. Plasma-derived alpha-1 antitrypsin (AAT) inhibits the inflammatory injury in myocardial ischemia and reperfusion. To explore the effects of plasma-derived AAT on the inflammatory response to ischemia-reperfusion injury, we analyzed time-to-reperfusion and enzymatic infarct size estimates in a post hoc analysis of the VCU-α1RT clinical trial (clinicaltrials.gov NCT01936896). METHODS: Ten patients with ST-segment elevation acute myocardial infarction (STEMI) were enrolled in an open-label, single-arm treatment study of Prolastin C, plasma-derived AAT, at 60 mg/kg infused intravenously within 12 hours of reperfusion. Biomarkers were measured serially over the first 72 hours, and patients were followed clinically for the occurrence of new-onset heart failure, recurrent MI, or death. Twenty patients with STEMI who had been enrolled in previous randomized trials with identical inclusion/exclusion criteria and had been assigned to placebo served as historical controls. RESULTS: Time to percutaneous coronary intervention and time to drug did not significantly differ between groups. AAT-treated patients had a significantly shorter time-to-peak creatine kinase myocardial band (CK-MB) values (525 [480-735] vs. 789 [664-959] minute, P = 0.005) and CK-MB area under the curve (from 1204 [758-2728] vs. 2418 [1551-4289] U·day, P = 0.035), despite no differences in peak CK-MB (123 [30-196] vs. 123 [71-213] U/mL, P = 0.71). CONCLUSIONS: A single administration of Prolastin C given hours after reperfusion in patients with STEMI led to a significant shorter time to peak and area under the curve for CK-MB, despite similar peak CK-MB values. These preliminary data support the hypothesis that Prolastin C shortens the duration of the ischemia-reperfusion injury in patients with STEMI.


Asunto(s)
Antiinflamatorios/administración & dosificación , Inflamación/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Intervención Coronaria Percutánea/efectos adversos , Infarto del Miocardio con Elevación del ST/cirugía , alfa 1-Antitripsina/administración & dosificación , Antiinflamatorios/efectos adversos , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Forma MB de la Creatina-Quinasa/sangre , Humanos , Inflamación/sangre , Inflamación/etiología , Mediadores de Inflamación/sangre , Infusiones Intravenosas , Daño por Reperfusión Miocárdica/sangre , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/patología , Miocardio/metabolismo , Miocardio/patología , Proyectos Piloto , Infarto del Miocardio con Elevación del ST/sangre , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Factores de Tiempo , Resultado del Tratamiento , alfa 1-Antitripsina/efectos adversos
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