In patients with alpha 1-antitrypsin deficiency, the development of emphysema is believed to be caused by the unchecked action of proteases on lung tissue. We evaluated the feasibility, safety, and biochemical efficacy of intermittent infusions of alpha 1-antitrypsin in the treatment of patients with alpha 1-antitrypsin deficiency. Twenty-one patients were given 60 mg of active plasma-derived alpha 1-antitrypsin per kilogram of body weight, once a week for up to six months. After a steady state had been reached, the group had trough serum levels of alpha 1-antitrypsin of 126 +/- 1 mg per deciliter as compared with 30 +/- 1 mg per deciliter before treatment, and serum anti-neutrophil elastase capacities of 13.3 +/- 0.1 microM as compared with 5.4 +/- 0.1 microM. The alpha 1-antitrypsin level in the epithelial-lining fluid of the lungs was 0.46 +/- 0.16 microM before treatment, and the anti-neutrophil elastase capacity was 0.81 +/- 0.13 microM. Six days after infusion, alpha 1-antitrypsin levels (1.89 +/- 0.17 microM) and anti-neutrophil elastase capacities (1.65 +/- 0.13 microM) in the lining fluid were significantly increased (P less than 0.0001). Because of the chronicity of the disorder and the lack of sensitive measures of lung destruction, the clinical efficacy of this therapy could not be studied rigorously. No changes in lung function were observed in our patients over six months of treatment. The only important adverse reactions to the 507 infusions were four episodes of self-limited fever. This study demonstrates that infusions of alpha 1-antitrypsin derived from plasma are safe and can reverse the biochemical abnormalities in serum and lung fluid that characterize this disorder. Together with lifetime avoidance of cigarette smoking, replacement therapy with alpha 1-antitrypsin may be a logical approach to long-term medical treatment.
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Trotta, B. M., Stolin, A. V., Williams, M. B., Gay, S. B., Brody, A. S., Altes, T. A.
(2007). Characterization of the Relation Between CT Technical Parameters and Accuracy of Quantification of Lung Attenuation on Quantitative Chest CT. Am. J. Roentgenol.
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[Abstract][Full Text]
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[Abstract][Full Text]
Lewis, E. C., Shapiro, L., Bowers, O. J., Dinarello, C. A.
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[Abstract][Full Text]
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(2005). TLR-Induced Inflammation in Cystic Fibrosis and Non-Cystic Fibrosis Airway Epithelial Cells. J. Immunol.
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[Abstract][Full Text]
Ge, L., Shenoy, S. K., Lefkowitz, R. J., DeFea, K.
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[Abstract][Full Text]
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[Abstract][Full Text]
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(2002). The Effect of Augmentation Therapy on Bronchial Inflammation in {alpha}1-Antitrypsin Deficiency. Am. J. Respir. Crit. Care Med.
165: 1494-1498
[Abstract][Full Text]
Kropp, J., Wencker, M., Hotze, A., Banik, N., Hübner, G. E., Wunderlich, G., Ulbrich, E., Konietzko, N., Biersack, H.-J.
(2001). Inhalation of [123I]{{alpha}}1-Protease Inhibitor: Toward a New Therapeutic Concept of {{alpha}}1-Protease Inhibitor Deficiency?. JNM
42: 744-751
[Abstract][Full Text]
Crystal, R. G.
(2001). Research Opportunities and Advances in Lung Disease. JAMA
285: 612-618
[Abstract][Full Text]
Fahy, R. J., Diaz, P. T., Hart, J., Wewers, M. D.
(2001). BAL and Serum IgG Levels in Healthy Asymptomatic HIV-Infected Patients. Chest
119: 196-203
[Abstract][Full Text]
SHAPIRO, L., POTT, G. B., RALSTON, A. H.
(2001). Alpha-1-antitrypsin inhibits human immunodeficiency virus type 1. FASEB J.
15: 115-122
[Abstract][Full Text]
GOTTLIEB, D. J., LUISETTI, M., STONE, P. J., ALLEGRA, L., CANTEY-KISER, J. M., GRASSI, C., SNIDER, G. L., The American-Italian AATD Study&nbs,
(2000). Short-term Supplementation Therapy Does Not Affect Elastin Degradation in Severe {alpha}1-Antitrypsin Deficiency. Am. J. Respir. Crit. Care Med.
162: 2069-2072
[Abstract][Full Text]
Lieberman, J.
(2000). Augmentation Therapy Reduces Frequency of Lung Infections in Antitrypsin Deficiency : A New Hypothesis With Supporting Data. Chest
118: 1480-1485
[Abstract][Full Text]
MAYER, A. S., STOLLER, J. K., BARTELSON, B. B., JAMES RUTTENBER, A., SANDHAUS, R. A., NEWMAN, L. S.
(2000). Occupational Exposure Risks in Individuals with PI*Z alpha 1-Antitrypsin Deficiency. Am. J. Respir. Crit. Care Med.
162: 553-558
[Abstract][Full Text]
Stockley, R A
(2000). Alpha-1-antitrypsin deficiency: what next?. Thorax
55: 614-618
[Full Text]
Alkins, S. A., O’Malley, P.
(2000). Should Health-Care Systems Pay for Replacement Therapy in Patients With {alpha}1-Antitrypsin Deficiency?: A Critical Review and Cost-Effectiveness Analysis. Chest
117: 875-880
[Abstract][Full Text]
SCHLUCHTER, M. D., STOLLER, J. K., BARKER, A. F., SONIA BUIST, A., CRYSTAL, R. G., DONOHUE, J. F., FALLAT, R. J., TURINO, G. M., VREIM, C. E., WU, M. C.
(2000). Feasibility of a Clinical Trial of Augmentation Therapy for alpha 1-Antitrypsin Deficiency. Am. J. Respir. Crit. Care Med.
161: 796-801
[Abstract][Full Text]
STOLLER, J K
(1998). Augmentation therapy for severe alpha 1-antitrypsin deficiency: is the jury still out on a trial?. Thorax
53: 1007-1009
[Full Text]
Song, S., Morgan, M., Ellis, T., Poirier, A., Chesnut, K., Wang, J., Brantly, M., Muzyczka, N., Byrne, B. J., Atkinson, M., Flotte, T. R.
(1998). Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors. Proc. Natl. Acad. Sci. USA
95: 14384-14388
[Abstract][Full Text]
WEWERS, M. D., DIAZ, P. T., WEWERS, M. E., LOWE, M. P., NAGARAJA, H. N., CLANTON, T. L.
(1998). Cigarette Smoking in HIV Infection Induces a Suppressive Inflammatory Environment in the Lung. Am. J. Respir. Crit. Care Med.
158: 1543-1549
[Abstract][Full Text]
The Alpha-1-Antitrypsin Deficiency Registry Study ,
(1998). Survival and FEV1 Decline in Individuals with Severe Deficiency of alpha 1-Antitrypsin. Am. J. Respir. Crit. Care Med.
158: 49-59
[Abstract][Full Text]
Mahadeva, R., Lomas, D. A
(1998). Genetics and respiratory disease bullet 2: Alpha1-antitrypsin deficiency, cirrhosis and emphysema. Thorax
53: 501-505
[Full Text]
Ferkol, T., Mularo, F., Hilliard, J., Lodish, S., Perales, J. C., Ziady, A., Konstan, M.
(1998). Transfer of the Human Alpha1-Antitrypsin Gene into Pulmonary Macrophages In Vivo. Am. J. Respir. Cell Mol. Bio.
18: 591-601
[Abstract][Full Text]
MASON, R. J., CRYSTAL, R. G.
(1998). Pulmonary Cell Biology. Am. J. Respir. Crit. Care Med.
157: S72-S81
[Full Text]
EDEN, E., MITCHELL, D., MEHLMAN, B., KHOULI, H., NEJAT, M., GRIECO, M. H., TURINO, G. M.
(1997). Atopy, Asthma, and Emphysema in Patients with Severe alpha -1-Antitrypysin Deficiency. Am. J. Respir. Crit. Care Med.
156: 68-74
[Abstract][Full Text]
Weinberger, S. E.
(1993). Recent Advances in Pulmonary Medicine- First of Two Parts. NEJM
328: 1389-1397
[Full Text]
Ferguson, G. T., Cherniack, R. M.
(1993). Management of Chronic Obstructive Pulmonary Disease. NEJM
328: 1017-1022
[Full Text]
DeYoung, G. R., Vetter, P. L., Kradjan, W. A.
(1992). The Pharmacological Treatment of Ambulatory Chronic Obstructive Pulmonary Disease Patients. Journal of Pharmacy Practice
5: 204-216
[Abstract]
Rosenfeld, M., Siegfried, W, Yoshimura, K, Yoneyama, K, Fukayama, M, Stier, L., Paakko, P., Gilardi, P, Stratford-Perricaudet, L., Perricaudet, M, et, al.
(1991). Adenovirus-mediated transfer of a recombinant alpha 1-antitrypsin gene to the lung epithelium in vivo. Science
252: 431-434
[Abstract]
Taggart, C., Cervantes-Laurean, D., Kim, G., McElvaney, N. G., Wehr, N., Moss, J., Levine, R. L.
(2000). Oxidation of either Methionine 351 or Methionine 358 in alpha 1-Antitrypsin Causes Loss of Anti-neutrophil Elastase Activity. J. Biol. Chem.
275: 27258-27265
[Abstract][Full Text]
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