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Mark L Brantly - One of the best experts on this subject based on the ideXlab platform.
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clinical and histologic features of adults with Alpha 1 antitrypsin Deficiency in a non cirrhotic cohort
Journal of Hepatology, 2018Co-Authors: Virginia Clark, George Marek, Chen Liu, Amy L Collinsworth, Jonathan J Shuster, Tracie L Kurtz, Joanna L Nolte, Mark L BrantlyAbstract:Background & Aims Alpha-1 antitrypsin Deficiency (AATD) is an uncommonly recognized cause of liver disease in adults, with descriptions of its natural history limited to case series and patient-reported data from disease registries. Liver pathology is limited to selected patients or unavailable. Therefore, we aimed to determine the prevalence and severity of liver fibrosis in an adult AATD population who were not known to have cirrhosis, while defining risk factors for fibrosis and testing non-invasive markers of disease. Methods A total of 94 adults with classic genotype ‘PI*ZZ’ AATD were recruited from North America and prospectively enrolled in the study. Liver aminotransferases and markers of synthetic function, transient elastography, and liver biopsy were performed. Results The prevalence of clinically significant liver fibrosis (F ≥ 2) was 35.1%. Alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase values were higher in the F ≥ 2 group. Metabolic syndrome was associated with the presence of clinically significant fibrosis (OR 14.2; 95% CI 3.7–55; p Conclusions Over one-third of asymptomatic and lung affected adults with ‘PI*ZZ’ AATD have significant underlying liver fibrosis. Liver biopsies demonstrated variable amounts of accumulated Z AAT. The risk of liver fibrosis increases in the presence of metabolic syndrome, accumulation of AAT in hepatocytes, and portal inflammation on baseline biopsy. The results support the hypothesis that liver disease in this genetic condition may be related to a “toxic gain of function” from accumulation of AAT in hepatocytes. Lay summary Individuals diagnosed with classic Alpha-1 antitrypsin Deficiency (ZZ) are at risk of liver injury and scarring, because of the accumulation of abnormal Alpha-1 antitrypsin in the liver. A liver biopsy in ZZ individuals can demonstrate the accumulation of Alpha-1 antitrypsin within the liver and identify if any associated liver scarring is present. Indviduals with large amounts of Alpha-1 antitrypsin on biopsy may be at risk of liver injury and fibrosis. Additional common medical conditions of diabetes, obesity, high cholesterol, and hypertension (known as metabolic syndrome) are associated with a greater degree of liver injury. Clinical Trial number clinicaltrials.gov NCT01810458.
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the diagnosis and management of Alpha 1 antitrypsin Deficiency in the adult
Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation, 2016Co-Authors: R A Sandhaus, Mark L Brantly, James M Stocks, Gerard M Turino, Michael A Campos, Carroll E Cross, Kenneth W Goodman, Douglas K Hogarth, Shandra L Knight, James K. StollerAbstract:Background: The diagnosis and clinical management of adults with Alpha-1 antitrypsin Deficiency (AATD) have been the subject of ongoing debate, ever since the publication of the first American Thoracic Society guideline statement in 1989.1 In 2003, the "American Thoracic Society (ATS)/European Respiratory Society (ERS) Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency" made a series of evidence-based recommendations, including a strong recommendation for broad-based diagnostic testing of all symptomatic adults with chronic obstructive pulmonary disease (COPD).2 Even so, AATD remains widely under-recognized. To update the 2003 systematic review and clinical guidance, the Alpha-1 Foundation sponsored a committee of experts to examine all relevant, recent literature in order to provide concise recommendations for the diagnosis and management of individuals with AATD. Purpose: To provide recommendations for: (1) the performance and interpretation of diagnostic testing for AATD, and (2) the current management of adults with AATD and its associated medical conditions. Methods: A systematic review addressing the most pressing questions asked by clinicians (clinician-centric) was performed to identify citations related to AATD that were published since the 2003 comprehensive review, specifically evaluating publications between January 2002 and December 2014. Important, more recent publications were solicited from the writing committee members as well. The combined comprehensive literature reviews of the 2003 document and this current review comprise the evidence upon which the committee's conclusions and recommendations are based. Results: Recommendations for the diagnosis and management of AATD were formulated by the committee. Conclusions: The major recommendations continue to endorse and reinforce the importance of testing for AATD in all adults with symptomatic fixed airflow obstruction, whether clinically labeled as COPD or asthma. Individuals with unexplained bronchiectasis or liver disease also should be tested. Family testing of first-degree relatives is currently the most efficient detection technique. In general, individuals with AATD and emphysema, bronchiectasis, and/or liver disease should be managed according to usual guidelines for these clinical conditions. In countries where intravenous augmentation therapy with purified pooled human plasma-derived Alpha-1 antitrypsin is available, recent evidence now provides strong support for its use in appropriate individuals with lung disease due to AATD.
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safety and pharmacokinetics of 120 mg kg versus 60 mg kg weekly intravenous infusions of Alpha 1 proteinase inhibitor in Alpha 1 antitrypsin Deficiency a multicenter randomized double blind crossover study spark
COPD: Journal of Chronic Obstructive Pulmonary Disease, 2013Co-Authors: Michael A Campos, James M Stocks, Charlie Strange, Friedrich Kueppers, Junliang Chen, Rhonda Griffin, Laurene Wangsmith, Mark L BrantlyAbstract:Augmentation therapy with the approved dose of 60 mg/kg weekly intravenous (IV) Alpha-1 proteinase inhibitor (Alpha1-PI), achieves a trough serum level of 11 μM in individuals with Alpha-1 antitrypsin Deficiency (AATD), yet this is still below the level observed in healthy individuals. This study assessed the safety and pharmacokinetic profile of weekly infusions of a 120 mg/kg dose of Alpha1-PI in 30 adults with AATD. Subjects with symptomatic, genetically determined (genotypes PI*ZZ, PI*Z(null), PI*(null)(null) or PI*(Z)Mmalton) AATD were randomly assigned to weekly infusions of 60 or 120 mg/kg Alpha1-PI (Prolastin-C®) for 8 weeks before crossing over to the alternate dose for 8 weeks. Adverse events (AEs) (including exacerbations), vital signs, pulmonary function tests, and laboratory assessments were recorded. Pharmacokinetic measurements included AUC0-7days, Cmax, trough, tmax, and t1/2, based on serum Alpha1-PI concentrations. In total for both treatments, 112 AEs were reported, with exacerbation of COPD being the most frequent, consistent with the subjects' diagnoses. Mean steady-state serum Alpha1-PI concentrations following 120 mg/kg weekly IV Alpha1-PI were higher than with the 60 mg/kg dose and mean trough concentrations were 27.7 versus 17.3 μM, respectively. Dose proportionality was demonstrated for AUC0-7days and Cmax, with low inter-subject variability. The 120 mg/kg Alpha1-PI weekly dose was considered to be safe and well tolerated, and provided more favorable physiologic Alpha1-PI serum levels than the currently recommended 60 mg/kg dose. The effect of this dosing regimen on slowing and/or preventing emphysema progression in subjects with AATD warrants further investigation.
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the challenge of detecting Alpha 1 antitrypsin Deficiency
COPD: Journal of Chronic Obstructive Pulmonary Disease, 2013Co-Authors: James K. Stoller, Mark L BrantlyAbstract:Alpha-1 antitrypsin Deficiency (AATD) is relatively common but under-recognized. Indeed, fewer than 10% of the estimated 100,000 Americans with AATD have been diagnosed currently, with common reports of long delays between initial symptoms and first detection and the need to see multiple physicians before diagnosis. Because detection can confer benefits (e.g., identification of at-risk family members, lower smoking likelihood, consideration of augmentation therapy), targeted detection of AATD in at-risk groups such as all symptomatic adults with COPD has been endorsed. Two general approaches to detection have been studied: population-based screening (in which testing is performed in a group for whom no increased risk of having AATD exists) and targeted detection or case-finding (in which testing is confined to those with an attributable condition such as COPD or chronic liver disease). Studies to date have suggested that population-based screening is not cost-effective, whereas targeted detection of AATD has been advocated by official society guidelines. Efforts to enhance detection of AATD individuals have included various approaches, including educational campaigns, provision of free test kits, issuance of reminders with medical reports or within an electronic medical record, and empowering respiratory therapists to conduct testing for AATD in pulmonary function laboratories. Such programs have identified individuals with severe Deficiency of Alpha-1 antitrypsin in up to 12% of subjects, with considerable variation across series by testing criteria. Overall, the persistence of under-recognition of AATD underscores the need for continued efforts to optimize detection of this potentially debilitating genetic disease.
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development of predictive models for airflow obstruction in Alpha 1 antitrypsin Deficiency
American Journal of Epidemiology, 2009Co-Authors: Peter J Castaldi, Mark L Brantly, Noel G Mcelvaney, Dawn L Demeo, Edward Eden, Stephen I Rennard, David M Kent, Edward J Campbell, A J Barker, James M StocksAbstract:Alpha-1-Antitrypsin Deficiency is a genetic condition associated with severe, early-onset chronic obstructive pulmonary disease (COPD). However, there is significant variability in lung function impairment among persons with the protease inhibitor ZZ genotype. Early identification of persons at highest risk of developing lung disease could be beneficial in guiding monitoring and treatment decisions. Using a multicenter, family-based study sample (2002–2005) of 372 persons with the protease inhibitor ZZ genotype, the authors developed prediction models for forced expiratory volume in 1 second (FEV1) and the presence of severe COPD using demographic, clinical, and genetic variables. Half of the data sample was used for model development, and the other half was used for model validation. In the training sample, variables found to be predictive of both FEV1 and severe COPD were age, sex, pack-years of smoking, bronchodilator responsiveness, chronic bronchitis symptoms, and index case status. In the validation sample, the predictive model for FEV1 explained 50% of the variance in FEV1, and the model for severe COPD exhibited excellent discrimination (c statistic ¼ 0.88). Alpha-1-Antitrypsin Deficiency; genetics; polymorphism, single nucleotide; pulmonary disease, chronic obstructive
Marc Miravitlles - One of the best experts on this subject based on the ideXlab platform.
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Alpha 1 antitrypsin Deficiency outstanding questions and future directions
Orphanet Journal of Rare Diseases, 2018Co-Authors: Maria Torresduran, Marc Miravitlles, Jose Luis Lopezcampos, Miriam Barrecheguren, Beatriz Martinezdelgado, Silvia Castillo, Amparo Escribano, Adolfo Baloira, Maria Mercedes NavarrogarciaAbstract:Alpha-1 antitrypsin Deficiency (AATD) is a rare hereditary condition that leads to decreased circulating Alpha-1 antitrypsin (AAT) levels, significantly increasing the risk of serious lung and/or liver disease in children and adults, in which some aspects remain unresolved. In this review, we summarise and update current knowledge on Alpha-1 antitrypsin Deficiency in order to identify and discuss areas of controversy and formulate questions that need further research. 1) AATD is a highly underdiagnosed condition. Over 120,000 European individuals are estimated to have severe AATD and more than 90% of them are underdiagnosed. 2) Several clinical and etiological aspects of the disease are yet to be resolved. New strategies for early detection and biomarkers for patient outcome prediction are needed to reduce morbidity and mortality in these patients; 3) Augmentation therapy is the only specific approved therapy that has shown clinical efficacy in delaying the progression of emphysema. Regrettably, some countries reject registration and reimbursement for this treatment because of the lack of larger randomised, placebo-controlled trials. 4) Alternative strategies are currently being investigated, including the use of gene therapy or induced pluripotent stem cells, and non-augmentation strategies to prevent AAT polymerisation inside hepatocytes.
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long term clinical outcomes following treatment with Alpha 1 proteinase inhibitor for copd associated with Alpha 1 antitrypsin Deficiency a look at the evidence
Respiratory Research, 2017Co-Authors: Franck Rahaghi, Marc MiravitllesAbstract:Alpha-1 antitrypsin Deficiency (AATD) is a common hereditary disorder caused by mutations in the SERPINA1 gene, which encodes Alpha-1 antitrypsin (AAT; also known as Alpha 1-proteinase inhibitor, A1-PI). An important function of A1-PI in the lung is to inhibit neutrophil elastase, one of various proteolytic enzymes released by activated neutrophils during inflammation. Absence or Deficiency of A1-PI leads to an imbalance between elastase and anti-elastase activity, which results in progressive, irreversible destruction of lung tissue, and ultimately the development of chronic obstructive pulmonary disease with early-onset emphysema. AATD is under-diagnosed, patients can experience long delays before obtaining an accurate diagnosis, and the consequences of delayed diagnosis or misdiagnosis can be severe. Currently, A1-PI therapy is the only available treatment that addresses disease etiology in patients with AATD; however, demonstrating clinical efficacy of A1-PI therapy is challenging. In order to show therapeutic efficacy with traditional endpoints such as forced expiratory volume in one second and mortality, large sample sizes and longer duration trials are required. However, AATD is a rare, slow progressive disease, which can take decades to manifest clinically and recruiting sufficient numbers of patients into prolonged placebo-controlled trials remains a significant obstacle. Despite this, the Randomized, placebo-controlled trial of augmentation therapy in Alpha 1-Proteinase Inhibitor Deficiency (RAPID) and RAPID Extension trial, the largest clinical program completed to date, utilized quantitative chest computed tomography as a sensitive and specific measure of the extent of emphysema. Findings from the RAPID/RAPID Extension program definitively confirmed the benefits of A1-PI therapy in slowing disease progression and provided evidence of a disease-modifying effect of A1-PI therapy in patients with AATD. These findings suggest that the early introduction of treatment in patients with severe emphysema-related AATD may delay the time to death, lung transplantation or crippling respiratory complaints. In addition, there is now limited evidence that A1-PI therapy provides a gain of more than five life-years, supporting previous observations based on registry data. With the clinical efficacy of A1-PI therapy now demonstrated, further studies are required to assess long-term outcomes.
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Augmentation therapy for Alpha-1 antitrypsin Deficiency: towards a personalised approach
Orphanet Journal of Rare Diseases, 2013Co-Authors: Robert A Stockley, Marc Miravitlles, Claus VogelmeierAbstract:Background Intravenous augmentation therapy is the only specific treatment available for emphysema associated with Alpha-1 antitrypsin Deficiency. Despite large observational studies and limited interventional studies there remains controversy about the efficacy of this treatment due to the impracticality of conducting adequately powered studies to evaluate the rate of decline in lung function, due to the low prevalence and the slow progression of the disease. However, measurement of lung density by computed tomography is a more specific and sensitive marker of the evolution of emphysema and two small placebo-controlled clinical trials have provided evidence supporting a reduction in the rate of decline in lung density with augmentation therapy. The problem Where augmentation therapy has become available there has been little consideration of a structured approach to therapy which is often introduced on the basis of functional impairment at diagnosis. Data from registries have shown a great variability in the evolution of lung disease according to patient acquisition and the presence of recognised risk factors. Avoidance of risk factors may, in many cases, stabilise the disease. Since augmentation therapy itself will at best preserve the presenting level of lung damage yet require intravenous administration for life with associated costs, identification of patients at risk of continued rapid or long term progression is essential to select those for whom this treatment can be most appropriate and hence generally more cost-effective. This represents a major reconsideration of the current practice in order to develop a consistent approach to management world wide. Purpose of this review The current review assesses the evidence for efficacy of augmentation therapy and considers how the combination of age, physiological impairment, exacerbation history and rate of decline in spirometry and other measures of emphysema may be used to improve therapeutic decision making, until a reliable predictive biomarker of the evolution of lung impairment can be identified. In addition, individual pharmacokinetic studies may permit the selection of the best regimen of administration for those who need it. Summary The rarity and variable characteristics of the disease imply the need for an individualised approach to therapy in specialised centres with sufficient experience to apply a systematic approach to monitoring and management.
Alice M Turner - One of the best experts on this subject based on the ideXlab platform.
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systematic review the natural history of Alpha 1 antitrypsin Deficiency and associated liver disease
Alimentary Pharmacology & Therapeutics, 2018Co-Authors: Alice M Turner, Ross Edgar, Sarah Townsend, Paul R Ellis, Dimitris Kantas, Philip N NewsomeAbstract:BACKGROUND Alpha-1 antitrypsin Deficiency (AATD) is estimated to affect three million people worldwide. It causes liver disease in a proportion of carriers of the PiS and PiZ allele due to the formation and retention of polymers within the endoplasmic reticulum of hepatocytes. The reason for this selective penetrance is not known. Although clinical trials are underway, liver transplantation is the only effective treatment for liver disease due to AATD. AIMS To report the prevalence and natural history of liver disease among individuals with AATD, and assess the outcomes of liver transplantation through systematic review. METHODS A comprehensive search was conducted across multiple databases. Two independent authors selected the articles and assessed bias using the Newcastle-Ottawa Scale. Data were pooled for analysis, where comparable outcomes were reported. RESULTS Thirty-five studies were identified related to disease progression and 12 for the treatment of AATD. Seven per cent of children were reported to develop liver cirrhosis, with 16.5% of individuals presenting in childhood requiring liver transplantation. Of those surviving to adulthood, 10.5% had liver cirrhosis and 14.7% required transplantation. Liver transplantation was the only effective treatment reported and outcomes compare favourably to other indications, with 5-year survival reported as over 90% in children and over 80% in adults. DISCUSSION The clinical course of liver disease in individuals with AATD remains poorly understood, but affects about 10% of those with AATD. More research is required to identify those patients at risk of developing liver disease at an early stage, and to provide alternative treatments to liver transplantation.
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treatment of lung disease in Alpha 1 antitrypsin Deficiency a systematic review
International Journal of Chronic Obstructive Pulmonary Disease, 2017Co-Authors: Alice M Turner, Ross Edgar, Mitesh Patel, Susan Bayliss, Diana Crossley, Elizabeth SapeyAbstract:BACKGROUND Alpha-1 antitrypsin Deficiency (AATD) is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD). The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management. METHODS Standard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354). Eligible studies were those of any treatment used in severe AATD. Randomized controlled trials (RCTs) were the primary focus; however, case series and uncontrolled studies were eligible. All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months). Risk of bias was assessed appropriately according to study methodology. RESULTS In all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved Alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation). Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments. Computed tomography (CT) density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide, health status, and exacerbation rates were frequently used as outcomes. Meta-analyses were only possible for RCTs of intravenous augmentation, which slowed progression of emphysema measured by CT density change, 0.79 g/L/year versus placebo (P=0.002), and associated with a small increase in exacerbations 0.29/year (P=0.02). Mortality following lung transplant was comparable between AATD- and non-AATD-related COPD. Surgical reduction of lung volume demonstrated inferior outcomes compared with non-AATD-related emphysema. CONCLUSION Intravenous augmentation remains the only disease-specific therapy in AATD and there is evidence that this slows decline in emphysema determined by CT density. There is paucity of data around other treatments in AATD. Treatments for usual COPD may not be as efficacious in AATD, and further studies may be required for this disease group.
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p58 a comparison between the clinical features of pisz and pizz patients with Alpha 1 antitrypsin Deficiency
Thorax, 2014Co-Authors: Sushanth Vayalapra, Robert A Stockley, Ross Edgar, D Griffiths, Alice M TurnerAbstract:Introduction Alpha-1 antitrypsin Deficiency (AATD) is a hereditary disorder affecting about 1 in 3000 people in the UK commonly associated with early-onset emphysema. There are two common Deficiency alleles - PiS and PiZ. PiZZ patients have severe AATD, with levels of 10–15% normal. PiSZ patients have less severe Deficiency (≈ 40% normal) and are generally thought to have a minimal risk. We hypothesised that if PiSZ patients were at lower risk of COPD than PiZZ, and their lung disease would be more characteristic of usual COPD than that of PiZZ patients. Method 104 PiSZ patients and 638 PiZZ patients from the UK AATD registry (ADAPT) were compared for their demographics, lung function, risk factors for COPD (e.g. smoking, occupation), co-morbidities associated with COPD, index status (i.e. if diagnosed due to lung disease or family screening) and CT densitometry (where available). Outcome in terms of lung function decline and mortality was also assessed. Univariate statistics were used to guide subsequent regression analyses. Results Emphysema was more likely in PiZZ than PiSZ patients (OR 11.0 (5.7–21.3); p Conclusion PiSZ patients have a milder form of AATD associated with better lung function. The data suggests the pattern of emphysema is closer to usual COPD than classical AATD. Further analyses comparing PiSZ to PiMM are now ongoing.
Charlie Strange - One of the best experts on this subject based on the ideXlab platform.
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rationale and design of the genomic research in Alpha 1 antitrypsin Deficiency and sarcoidosis study Alpha 1 protocol
Annals of the American Thoracic Society, 2015Co-Authors: Charlie Strange, Alison Morris, Robert M, Frank C Sciurba, Scott M Oneal, Stephen R Wisniewski, Russell P Bowler, Harry Hochheiser, Michael J Becich, Yingze ZhangAbstract:Severe Deficiency of Alpha-1 antitrypsin has a highly variable clinical presentation. The Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis α1 Study is a prospective, multicenter, cross-sectional study of adults older than age 35 years with PiZZ or PiMZ Alpha-1 antitrypsin genotypes. It is designed to better understand if microbial factors influence this heterogeneity. Clinical symptoms, pulmonary function testing, computed chest tomography, exercise capacity, and bronchoalveolar lavage (BAL) will be used to define chronic obstructive pulmonary disease (COPD) phenotypes that can be studied with an integrated systems biology approach that includes plasma proteomics; mouth, BAL, and stool microbiome and virome analysis; and blood microRNA and blood mononuclear cell RNA and DNA profiling. We will rely on global genome, transcriptome, proteome, and metabolome datasets. Matched cohorts of PiZZ participants on or off Alpha-1 antitrypsin augmentation therapy, PiMZ participants not on augmentation therapy, and control participants from the Subpopulations and Intermediate Outcome Measures in COPD Study who match on FEV1 and age will be compared. In the primary analysis, we will determine if the PiZZ individuals on augmentation therapy have a difference in lower respiratory tract microbes identified compared with matched PiZZ individuals who are not on augmentation therapy. By characterizing the microbiome in Alpha-1 antitrypsin Deficiency (AATD), we hope to define new phenotypes of COPD that explain some of the diversity of clinical presentations. As a unique genetic cause of COPD, AATD may inform typical COPD pathogenesis, and better understanding of it may illuminate the complex interplay between environment and genetics. Although the biologic approaches are hypothesis generating, the results may lead to development of novel biomarkers, better understanding of COPD phenotypes, and development of novel diagnostic and therapeutic trials in AATD and COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01832220).
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social impact identified in and by the Alpha 1 antitrypsin Deficiency community
Rare Diseases and Orphan Drugs, 2014Co-Authors: Charlie Strange, Sara Wienke, Deirdre Walker, Marvin Sineath, James Quill, Barbara Warner, Lucinda Shore, Susan Flavin, Pamela Holtzclaw WilliamsAbstract:Alpha-1 antitrypsin Deficiency (AATD) is a rare genetic cause for two common chronic conditions, emphysema and liver disease. The social impact of living with this rare genetic disease has been incompletely defined. The paper describes thematic analysis of qualitative data. The goal of this project was to identify the social burdens of this rare genetic disease that occur independent of symptoms. Through two pilot studies, transcripts from focus groups and interviews with 42 patients and caregivers living with AATD were collected. Nvivo10 software was used to synthesize qualitative and thematic overarching domains. Two domains with three respective subdomains each emerged: Rarity and Genetic Etiology. Combining these data with existing literature, a model was developed to explain the social impacts in this rare genetic disease. This model will inform the development of tools to measure and improve clinical practice and research for patients living with other rare inherited conditions.Domains of social burden associated with a genetic diagnosis inform healthcare providers of areas where best practices in clinical care, support and future research require future development. In addition, domains support future development of psychometric instrumentation to measure the social burden of rare disease with a genetic etiology.
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safety and pharmacokinetics of 120 mg kg versus 60 mg kg weekly intravenous infusions of Alpha 1 proteinase inhibitor in Alpha 1 antitrypsin Deficiency a multicenter randomized double blind crossover study spark
COPD: Journal of Chronic Obstructive Pulmonary Disease, 2013Co-Authors: Michael A Campos, James M Stocks, Charlie Strange, Friedrich Kueppers, Junliang Chen, Rhonda Griffin, Laurene Wangsmith, Mark L BrantlyAbstract:Augmentation therapy with the approved dose of 60 mg/kg weekly intravenous (IV) Alpha-1 proteinase inhibitor (Alpha1-PI), achieves a trough serum level of 11 μM in individuals with Alpha-1 antitrypsin Deficiency (AATD), yet this is still below the level observed in healthy individuals. This study assessed the safety and pharmacokinetic profile of weekly infusions of a 120 mg/kg dose of Alpha1-PI in 30 adults with AATD. Subjects with symptomatic, genetically determined (genotypes PI*ZZ, PI*Z(null), PI*(null)(null) or PI*(Z)Mmalton) AATD were randomly assigned to weekly infusions of 60 or 120 mg/kg Alpha1-PI (Prolastin-C®) for 8 weeks before crossing over to the alternate dose for 8 weeks. Adverse events (AEs) (including exacerbations), vital signs, pulmonary function tests, and laboratory assessments were recorded. Pharmacokinetic measurements included AUC0-7days, Cmax, trough, tmax, and t1/2, based on serum Alpha1-PI concentrations. In total for both treatments, 112 AEs were reported, with exacerbation of COPD being the most frequent, consistent with the subjects' diagnoses. Mean steady-state serum Alpha1-PI concentrations following 120 mg/kg weekly IV Alpha1-PI were higher than with the 60 mg/kg dose and mean trough concentrations were 27.7 versus 17.3 μM, respectively. Dose proportionality was demonstrated for AUC0-7days and Cmax, with low inter-subject variability. The 120 mg/kg Alpha1-PI weekly dose was considered to be safe and well tolerated, and provided more favorable physiologic Alpha1-PI serum levels than the currently recommended 60 mg/kg dose. The effect of this dosing regimen on slowing and/or preventing emphysema progression in subjects with AATD warrants further investigation.
Amparo Escribano - One of the best experts on this subject based on the ideXlab platform.
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Alpha 1 antitrypsin Deficiency outstanding questions and future directions
Orphanet Journal of Rare Diseases, 2018Co-Authors: Maria Torresduran, Marc Miravitlles, Jose Luis Lopezcampos, Miriam Barrecheguren, Beatriz Martinezdelgado, Silvia Castillo, Amparo Escribano, Adolfo Baloira, Maria Mercedes NavarrogarciaAbstract:Alpha-1 antitrypsin Deficiency (AATD) is a rare hereditary condition that leads to decreased circulating Alpha-1 antitrypsin (AAT) levels, significantly increasing the risk of serious lung and/or liver disease in children and adults, in which some aspects remain unresolved. In this review, we summarise and update current knowledge on Alpha-1 antitrypsin Deficiency in order to identify and discuss areas of controversy and formulate questions that need further research. 1) AATD is a highly underdiagnosed condition. Over 120,000 European individuals are estimated to have severe AATD and more than 90% of them are underdiagnosed. 2) Several clinical and etiological aspects of the disease are yet to be resolved. New strategies for early detection and biomarkers for patient outcome prediction are needed to reduce morbidity and mortality in these patients; 3) Augmentation therapy is the only specific approved therapy that has shown clinical efficacy in delaying the progression of emphysema. Regrettably, some countries reject registration and reimbursement for this treatment because of the lack of larger randomised, placebo-controlled trials. 4) Alternative strategies are currently being investigated, including the use of gene therapy or induced pluripotent stem cells, and non-augmentation strategies to prevent AAT polymerisation inside hepatocytes.
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low catalase activity contributes to oxidative stress in patients with Alpha 1 antitrypsin Deficiency
European Respiratory Journal, 2014Co-Authors: Amparo Escribano, Silvia Castillo, Monica Amor, Francisco Sanz, Sara Pastor, Pilar Codonerfranch, Francisco DasiAbstract:Background: Alpha-1 antitrypsin Deficiency (AATD) is a hereditary condition that leads to decreased circulating AAT levels, significantly increasing the risk of serious lung and liver disease in children and adults. Oxidative stress has been shown to be a contributing factor in the development of liver and lung damage in animal models of AAT Deficiency. Rationale and aims : We have previously demonstrated that oxidative stress is increased in serum of children with AATD. However, the mechanisms leading to the oxidative stress observed in these patients are currently unknown. Methods : Fifty-one children diagnosed with AATD were prospectively included in the study. Patients were classified in three risk groups of developing lung disease: low (MM; MS; SS phenotypes), intermediate (MZ; SZ) and high risk (ZZ). The activity of enzymes involved in oxidative stress metabolism, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GRd), were determined in serum of AATD patients and controls using ELISA. Results : Our results show that, when compared to the control group, intermediate and high-risk groups showed significantly increased GPx activity and decreased CAT activity whereas no differences were observed with the low-risk group. No significant differences were observed in SOD and GRd activities. Conclusions : Low CAT activity is responsible for the oxidative stress observed in these patients. Funding Sources : Supported by SVN, GVA AP-096/11, ISCIII PI11/02884 grants.