zum A1-PI-Mangel- Emphysem

Studien zum Alpha1-PI-Mangelemphysem

Wencker-M; Banik-N; Buhl-R; Seidel-R; Konietzko-N
Goethe Univ. Frankfurt, Ger.
Eur.Resp.J. ( 11, No.2, 428-33,1998 )

Long-term treatment of alphaI-antitrypsin deficiency-related pulmonary emphysema with human alpha1-antitrypsin.

This study was carried out in 443 patients with pulmonary emphysema secondary to hereditary alpha-I-antitrypsin deficiency to evaluate results of long-term i. v. alpha-1-antitrypsin (AT, Prolastin, Bayer) therapy. Side-effects included fever, chills, urticaria, nausea, vomiting, fatigue, anaphylaxis, worsening congestive heart failure and concornitant respiratory failure. Long-term treatment with i. v. AT in patients with alpha-1-antitrypsin deficiency was shown to be feasible and safe. METHODS: 443 Patients (292 male, mean age 47 yr) with severe alpha-1-antitrypsin deficiency and pulmonary emphysema receiving weekly i. v. infusions of 60 mg/kg AT in addition to their regular medication were studied. The progression of the disease was assessed by repeated lung function measurements, particularly the decline in forced expiratory volume in 1 sec (delta FEV1). RESULTS: The deltaFEV1 in 287 patients was 57.1 ml/yr. Stratified for baseline FEV1 the dec1ine was 35.6 ml in the 108 patients with an initial FEV 1 of 1ess than 30% and 64.0 ml in the 164 with FEV 1 30-65% of predicted normal. The remaining 15 patients had an initial FEV1 of 65% of predicted or more.
Tuschener Weg 40,45239 Essen, Germany. (N.K.).

Ward-A-C; Keogh-B-A LO: Dublin, Ire.
Ir.J.Med.Sci. ( 166, No. 1,7-9, 1997 )

Intravenous alpha-l-antitrypsin replacement therapy: case report after one year of treatment.

A case of advanced emphysema and progressive deterioration of lung function treated with i. v. alpha-1- antitrypsin (AT, Prolastin) replacement over 1 yr is reported. The patient was treated with i.v. infusion of AT and prednisolone. Inhaled bronchodilators, corticosteroids and antibiotics were given regularly before AT therapy. The AT therapy was encouraging with no side effects and stabilization of pulmonary function tests and symptomatic improvement. A 43 yr old man with a 7 yr history of progressive dyspnea, productive cough and intermittent wheeze who smoked 40 cigarettes daily had emphysematous chest configuration, normal breath sounds and 400 l/min PEFR upon examination. Arterial blood gases, FBC and liver profile were normal. He had hyperinflated lung fields and serum AT level was 25 mg/dl indicating severe deficiency. Phenotype was PIZZ. He stopped smoking and was treated with inhaled bronchodilators and maintenance corticosteroids. Over the next 4 yr he had multiple hospital admissions with lower respiratory tract infections, typically with bronchospasm and hypoxia as predominant features. He responded well to antibiotics, pulses of corticosteroids and nebulized bronchodilators. He suffered multiple rib fractures assumed to be related to corticosteroid therapy. Pulmonary function tests showed a gradual decline. AT therapy was started with i. v. infusion of Prolastin 60 mg/kg, followed by weekly (4 g) or fortnightly (8 g) infusions. The patient improved symptomatically and the maintenance daily prednisolone decreased from 15 to 7.5 mg. No adverse side effects occurred. The previous decline in FEV 1 did not continue after the start of A T therapy.
Consultant in Respiratory Medicine, Master Misericordiae Hospital, Eccles Street, Dublin 7, Ireland. (B.A. K.).

Schwaiblmair-M; Vogelmeier-C
Department of lnternal Medicine, Klinikum Grosshadem, University of Munich, Germany.
Drugs-Aging. 1998 Jun; 12(6): 429-40

Alpha 1-antitrypsin. Hope on the horizon for emphysema sufferers?

Alpha 1-Antitrypsin (alpha 1AT) deficiency is the most common genetic cause of liver disease in children and emphysema in adults. Therapy for pulmonary disease attributable to alpha 1 A T deficiency includes alpha 1AT augmentation therapy along with supportive measures. The alpha 1AT preparation that is current1y used for therapy is derived from fractionated plasma. The resu1ts of c1inical trials suggest that augmentation therapy with alpha lAT slows the progression of emphysema and causes few adverse events. Patients with plasma levels of alpha 1AT that are < 11 mumol/L and who have airway obstruction should be considered for augmentation therapy. Novel approaches include the administration of aerosolised alpha 1 AT, recombinant alpha 1 A T, gene therapy and synthetic elastase inhibitors.

Lomas-D-A; Elliott-P-R; Carrell-R-W CA: Univ.Cambridge LO: Cambridge, U.K.
Eur.Resp.J. ( 10, No.3, 672-75,1997 )

Commercial plasma alpha-antitrypsin (Prolastin) contains a conformationally inactive, latent component.

Native alphaI-antitrypsin was purified plasma and commercial antitrypsin (Prolastin, Bayer) was shown to migrate as 2 bands using Western blot analysis of transverse urea gradient gels. 1 Band was with an unfolding profile of native antitrypsin and the other band with a profile of latent antitrypsin. The latent fraction was separated from the native antitrpysin in Prolastin by Q-Sepharose anion exchange chromatography. Refolding of the inactive latent fraction of antitrypsin from Prolastin produced an increase in specific activity against bovine alpha-chymotrypsin. The results show that commercial antitrpysin contains a latent component but the significance is unknown in-vivo although Prolastin has been shown to have few adverse effects in long-term therapy. METHODS: Native antitrypsin was purified from plasma. Commercial antitrypsin was used for replacement therapy. Native antitrypsin (25 mg) was induced to form loop-sheet polymers. RESULTS: Commercial Prolastin was resuspended in water and the antitrypsin concentration was 32 mglml and the preparation was 66% active as an inhibitor of alpha-chymotrypsin. The upper protein on the SDS-P AGE was identified as antitrypsin and there was a minor band with electrophoretic mobility similar to reactive center loop cleaved antitrypsin. Transverse urea gradient gel electrophoresis followed by Western blot analysis identified a constituent if Prolastin that was resistant to unfolding urea 8 M which was characteristic of latent and cleaved antitrypsin. The latent and cleaved components were separated by heating commercial Prolastin at 2 mg/ml at 60 deg and the components were separated from the polymers by Q-Sepharose anion exchange chromatography. The heat-resistant peak was 8% of the total Prolastin and was 1.6% active as an inhibitor of bovine alpha-chymotrypsin. Refolding of the inactive fraction of antitrypsin from Prolastin produced an increase in specific activity against bovine alpha-chymotrypsin from 1% to 2% to approximately 50% over 3 hr.
Dept of Haematology, University of Cambridge, MRC Centre, Hills Road, Cambridge CB2 2QH, England.

Schwaiblmair-M; Vogelmeier-C; Fruhmann-G
Abteilung f™r Pneumologie, Klinikum Grosshadern, Ludwig-Maximilians-UniversitØt, M™nchen, Deutschland.
Respiration. 1997; 64(1 ): 10-5

Long-term augmentation therapy in twenty patients with severe alpha-1-antitrypsin deficiency--three-year follow-up.

The purpose of this uncontrolled, prospective study was to eva1uate the inf1uence of long-term augmentation therapy with plasma-derived alpha 1-antitrypsin (AAT) on lung function parameters in patients with severe emphysema caused by AAT deficiency. Twenty patients (mean age 48 years) received AA T infusions once weekly for up to 36 months. No adverse effects were observed. At the beginning of the study, mean (+/- SEM) FEV1 was 1.35 +/- 0.121iters and mean TLCO was 54 +/- 4% of predicted. After 36 months of treatment, mean FEV1 was 1.25 +/- 0.121iters (p = n.s) and the TLCO was 52 +/- 4% predicted (p = n.s). Similar values were obtained before and after therapy for FVC (2.79 +/- 0.23 vs. 2.82 +/- 0.211iters), MEF50 (0.72 +/- 0.09 vs. 0.68 +/- 0.08 liters/s), RV (4.60 +/00.44 vs 4.45 +/- 0.311) and TLC (7.72 +/- 0.49 vs. 7.38 +/- 0.421). The calculated annua11oss of FEV1 (35.6 ml/ year) was smaller than in historical untreated patients with AAT deficiency.

Stoessel-U; Braendli-O LO: Faltigberg, Switz.
Schweiz.Rundsch.Med.Prax. (80, No.48, 1344-48,1991)

Substitution Therapy in alphaI-Antiprotease Deficiency. (Ger.).

Substitution therapy with i. v. human alpha-I protease inhibitor (API, Prolastin) in alpha-I-antiproteinase deficiency is reviewed with reference to a case in a female with emphysema. Therapy improved lung function and diffusion capacity. Early diagnosis, stopping smoking and substitution therapy of the phenotypes at risk should help to slow the rapid progression of lung darnage in such patients. EX: A 51-yr-old woman had a chronic progressive cough for 11 yr despite stopping smoking 7 yr previously. X - ray and laboratory tests revealed signs of ernphyserna with hypoxemia and poor lung function. Serum alphaI protease inhibitor was 0.35 g/l. Electrophoresis showed her to be a ZZ homozygote. Lung function and diffusion capacity improved following treatment with API at 4 g/wk at first then 12 g/mth. Alpha-I protease inhibitor deficiency is caused by a dominant autosomally inherited error of metabolism which manifests itself in 30-40-yr-olds causing a progressive dyspnea. It can be diagnosed by radiology which shows destruction of the lung tissues but for early diagnosis lung function tests, chest x-rays and CT-scans are necessary. Electrophoresis has revealed 3 alleles, M, Z and S which control this disease, the ZZ and null homozygotes being worst affected the others being at little risk of developing ernphysema. There is a relationship between alphaI protease inhibitor deficiency and liver disorders in children who are ZZ homozygotes. The heterozygotes MZ have an increased risk of chronic hepatitis and liver cirrhosis. API concentrate given combined with abstinence from smoking can improve lung function in ZZ, Z-null and null-null patients.
(Substitutionstherapie bei AlphaI-Proteaseinhibitor-MangeI ('I AlphaI-Antitrypsin-Mangel").) Zuercher Hoehenklinik Wald, 8639 Faltigberg, Switzerland. (O.B.)

Stiskal-J-A; Dunn-M-S; Shennan-A-T; O'-Brien-K-K-E; Kelly-E-N; Koppel-R-I CA: Univ.Toronto
Pediatrics ( 101, No.1, Pt. 1,89-94,1998 )

Alpha1-proteinase inhibitor therapy for the prevention of chronic lung disease of prematurity: a randomized, controlled trial.

The effects of alpha1-proteinase inhibitor (A1PI; alpha1-antitrypsin; Prolastin; Bayer) infusion were assessed in 106 premature neonates with chronic lung disease (CLD) in a randomized, placebo-control1ed, double-blind study. The incidence of CLD in survivors was lower in the treated group and this beneficial trend persisted at 36 wk corrected gestational age. A1PI was well tolerated. It was concluded that A1PI therapy may impede the development of CLD and appears to reduce the incidence of pulmonary hemorrhage in some neonates born prematurely. METHODS: 53 Infants (mean age 26.1 wk) received A1PI 60 mg/kg infused over 5 min and 53 infants (mean age 26.5 wk) received placebo. RESULTS: There were 9 deaths before the 28-day evaluated point, 5 in the treatment group and 4 in the placebo group. Oxygen dependence at 36 wk corrected gestational age was lower in the treated group. The group of infants receiving AIPI were extuvated 1 day earlier, weaned to room air 11 days earlier, and free from the need for respiratory support 10 days earlier than infants in the placebo group. Although 31 infants in each group met the predeterrnined steroid criteria, only 20 of the A1PI-treated infants compared with 28 of the placebo-treated infants were treated with dexamethasone. Fewer infants in the treated group were prescribed inhaled steroids (budesonide) and bronchodilators (salbutamol). Almost all of the infants in both groups received caffeine and very few infants received chronic diuretic therapy. Electrocardiograms on infants who received active and placebo treatment noted right ventricular hypertrophy in 12 vs. 6 and ischemia in 13 vs. 17. The incidence of pulmonary hemorrhage was lower in the A1PI group. There were 6 cases of necrotizing enterocolitis in the treatment group. 3 Infants died in the A1PI group after day 28 but before hospital discharge. Tracheal colonization with ureaplasma urealyticum was present in 38% of the A1PI-treated infants and 30% of those who received placebo.
Service of Neonatology, Bryn Mawr Hospital, 130 S Bryn Mawr Ave, Bryn Mawr, PA 19010, U.S.A.

Wiedemann-HP; Stoller-JK
Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, OH 44195, USA.
Curr-Opin-Pulm-Med. 1996 Mar; 2(2): 155-60

Lung disease due to alpha 1-antitrypsin deficiency.

The association between alpha l-antitrypsin deficiency and heritable emphysema was discovered in 1963. Subsequent epidemiologic evidence suggested that a serum alpha l-antitrypsin level of 11 mumoll L (about 80 mg/dL by the still-used "commercial standard"), which is about 35% of the normal level, represents a 'threshold" value, below which the risk of developing emphysema is increased and above which the emphysema risk is not increased. Recently, the ability to isolate and purify the alpha 1-antitrypsin protein >from human blood has made "specific" augmentation therapy possible. Intravenous infusion of alpha l-antitrypsin raises serum and alveolar levels above the putative thresholds, but clinical efficacy (i.e., decreased rate of decline in lung function and/or improved survival) remains presumptive. Based on available evidence, the American Thoracic Society recommends augmentation therapy for individuals with both a documented severe deficiency of alpha l-antitrypsin and fixed airflow obstruction.

Stahl-E; Buhl-R; Kardos-P; Gebardt-T; Rust-M; Loercher-U LO: Frankfurt, Ger.
Pneumologie ( 46, Suppl. 1, 426, 1992)

Lung Emphysema in Hereditary Alpha-l-Antitrypsin Deficiency: Lung Function Parameters after Replacement Therapy with Alpha-I-Antitrypsin. (Ger.).

Long-term replacement therapy with i. v. alpha-I-antitrypsin (AT , Prolastin) did not lead to an improvement of lung function in 11 patients with hereditary AT deficiency and emphysema, although AT serum levels were raised to normal levels. No side-effects were observed during treatment. (congress abstract). METHODS: 11 Patients (6 male, mean age 47 yr) with AT deficiency (10 homozygous, 1 heterozygous Z phenotype) received i.v. AT (60 mg/kg) once weekly for 15 mth. All were ex-smokers. RESULTS: AT levels increased to more than 80 mg/dl. Severe emphysema present in all patients at the start of the study did not improve; FVC, FEVl , specific airway resistance, functional reserve and CO diffusion capacity, and p02 remained unchanged. 1 Tab. (K90/MM) (Lungenemphysem bei hereditaerem alphaI-Antitrypsin-Mangel: Lungenfunktionsparameter unter Substitution mit AlphaI-Antitrypsin.)
Abteilung fuer Pneumologie, Klinikum der J.W. Goethe-Universitaet, Frankfurt

Gastroenterol-Nurs. 1991 Dec; 14(3): 138-41

Alpha 1-antitrypsin deficiency

alpha 1-Antitrypsin (AAT) is a polymorphic protein with many variants collectively known as the Pi system. The most common alleles are the M, S and Z, which are co-dominantly inherited. Infants with PiZZ have approximately 16% of the normal AAT serum concentration. alpha 1-Antitrypsin deficiency ( AATD) is an inborn error of metabo1ism which is principally associated with liver disease in children and emphysema in young adulthood. Individuals with AATD produce an abnormal protein which accumulates in the liver, resulting in decreased serum levels. Affected individuals cannot protect their lungs from digestion by elastase. Smoking is a significant risk factor for the early development of emphysema. Prolastin, human alpha 1-protease inhibitor, is now available as replacement therapy. Weekly intravenous administration, with the goal of maintaining the serum AAT greater than 80 mg/dl, appears to arrest pulmonary darnage. Its effect on liver disease is unknown at this time. A recombinant alpha 1-protease inhibitor is being tested in aerosol form with promising ear1y results.

Dirksen-A; Dijkman-JH; Madsen-F; Stoel-B; Hutchison-DC; Ulrik-CS; Skovgaard-LT; Kok-Jensen-A; Rudolphus-A; Seersholm-N; Vrooman-HA; Reiber-JH; Hansen-NC; Heckscher-T; Viskum-K; Stolk-J
Department ofRespiratory Medicine, The Rigshospital, Copenhagen, Denmark.
Am-J-Respir-Crit-Care-Med. 1999 Nov; 160(5 Pt 1): 1468-72

A randomized clinical trial of alpha(I)-antitrypsin augmentation therapy.

We have investigated whether restoration of the balance between neutrophil elastase and its inhibitor, alpha(l)-antitrypsin, can prevent the progression of pulmonary emphysema in patients with alpha(l)- antitrypsin deficiency. Twenty-six Danish and 30 Dutch ex-smokers with alpha(I)-antitrypsin deficiency of PI*ZZ phenotype and moderate emphysema (FEV(I) between 30% and 80% of predicted) participated in a double-blind trial of alpha(l )- antitrypsin augmentation therapy. The patients were randomized to either alpha(l)- antitrypsin (250 mglkg) or albumin (625 mglkg) infusions at 4-wk intervals for at least 3 yr. Self-administered spirometry performed every moming and evening at horne showed no significant difference in decline of FEV(l) between treatment and placebo. Each year, the degree of emphysema was quantified by the 15th percentile point of the lung density histogram derived from computed tomography (CT). The loss of lung tissue measured by CT (mean +1- SEM) was 2.6 +1- 0.41 g/L/yr for placebo as compared with 1.5 +1- 0.41 g/L/yr for alpha(l)-antitrypsin infusion (p = 0.07). Power analysis showed that this protective effect would be significant in a similar trial with 130 patients. This is in contrast to calculations based on annual decline of FEV(l) showing that 550 patients would be needed to show a 50% reduction of annual decline. We conclude that lung density measurements by CT may facilitate future randomized clinical trials of investigational drugs for a disease in which little progress in therapy has been made in the past 30 yr.

Am-Rev-Respir-Dis. 1983 Feb; 127(2): S47-53

Can alpha-l-protease inhibitor be used in replacement therapy?

We propose that alpha-l-protease inhibitor (alpha 1 PI) can assume a major and beneficial role in preventing emphysema in alpha 1 PI-deficient individuals, and may also prove of value in the treatment of adult respiratory distress syndrome (ARDS). alpha 1 PI has a single, unusual disulfide bond that consists of a cysteine residue in the peptide chain covalently bound to a free amino acid cysteine. The linkage can be broken by reductants without adversely affecting the stability or the inhibitory activities of the protein. As a result of this property, alpha 1 PI can be effectively separated in solution from many other plasma proteins by salting out the contaminants in the presence of strong reductants. We have applied the technique of reductive-salting out, coupled with more conventional DEAE-anion exchange chromatography to isolate alpha 1 PI from Cohn Fraction IV -1, a relatively unused side product in the worldwide production of albumin and immunoglobulins. Furthermore, we have demonstrated that the product can be effectively pasteurized in the presence of various stabilizing additives. The necessary ingredients now exist for extensive clinical studies in the years ahead.

Wewers-MD; Caso1aro-MA; Sel1ers-SE; Swayze-SC; McPhaul-KM; Wittes-JT; Crysta1-RG
N-Eng1-J-Med. 1987 Apr 23; 316(17): 1055-62

Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema.

In patients with alpha 1-antitrypsin deficiency, the deve1opment of emphysema is believed to be caused by the unchecked action of proteases on lung tissue. We eva1uated the feasibility, safety, and biochemica1 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 deci1iter as compared with 30 +/- 1 mg per deci1iter before treatment, and serum anti-neutrophi1 elastase capacities of 13.3 +/- 0.1 microM as compared with 5.4 +/- 0.1 microM. The alpha 1-antitrypsin leve1 in the epithelial-1ining fluid of the 1ungs was 0.46 +/- 0.16 microM before treatment, and the anti-neutrophi1 elastase capacity was 0.81 +/- 0.13 microM. Six days after infusion, alpha 1-antitrypsin levels (1.89 +/- 0.17 microM) and anti-neutrophi1 elastase capacities (1.65 +/- 0.13 microM) in the 1ining fluid were significant1y increased (P 1ess than 0.0001). Because of the chronicity of the disorder and the lack of sensitive measures of 1ung 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.

Konietzko-N; Becker-M; Schmidt-EW; Rasche-B; Ulmer-WT; Ferlinz-R; Lorenz-J
Zentrum f™r Pneumologie und Thoraxchirurgie, Medizinische UniversitØtsklinik, Krankenhaus Bergmannsheil, Bochum.
Dtsch-Med-Wochenschr. 1988 Mar 11; 113(10): 369-73

Substitution therapy with a1pha-1-Pi in patients with alpha-1-Pi deficiency and progressive pulmonary Substitutionstherapie mit Alpha-1-Pi bei Patienten mit Alpha-l-Pi-Mangel und progredientem Lungenemphysem.

In a multi-centre study 20 patients with severe congenital alpha-l-Pi deficiency and progressive pulmonary emphysema received infusions of alpha-l-Pi concentrate from human plasma once weekly for six months, at an initial dosage of 60 mg/kg body-weight, in some instances slightly increased to achieve a minimum serum level above 70 mg/100 mI. The immunologically measured serum level of alpha-l-Pi rose 30 min after start ofthe infusion by a mean of 130% of normal, at an initial level of 13%. An exponential fall followed this rise. The lowest level occurred at the end of the first week, immediately before the next infusion, to 35% of normal, a serum level which is assumed still to provide an effective protection against elastases in the lung. There was also a definite increase of free inhibitors against both trypsin and leucocyte-elastase in serum of all patients, with a minimal level which for both was many times that of the initial value. There were no side-effects in more than 500 infusions and no dose reduction was necessary .During the entire course there were no significant changes in haematological, coagulation and biochemical test results, and lung function means remained constant. No antibodies against alpha-l-Pi were demonstrated, nor transmission of hepatitis B.

Hubbard-RC; Crystal-RG
Pulmonary Branch, National Heart, Lung and Blood Institute, Bethesda, Maryland 20892.
Am-J-Med. 1988 Jun 24; 84(6A): 52-62

Alpha-I-antitrypsin augmentation therapy for alpha-I-antitrypsin deticiency.

Alpha-I-antitrypsin (AIAT) deficiency is a genetic disorder characterized by low serum levels of AIAT and a high risk for the development of emphysema. AIAT is the principal inhibitor of neutrophil elastase, such that a deficiency of AIAT results in insufficient anti-elastase protection in the lower respiratory tract, thus allowing neutrophil elastase to destroy alveolar structures. The goal of AIAT augmentation therapy in AlAT deficiency is to raise lung AIAT levels and anti-neutrophil elastase capacity to levels that will provide adequate protection against neutrophil elastase, thereby preventing the lung from further elastase-mediated degradation. Studies with intravenous administration of human AIAT (60 mg/kg at weekly intervals) demonstrate that serum AIAT levels increased from an average 33 +1- 8 mg/dl pre-infusion to a steady-state trough level of 117 +1- 4 mg/dl, well above the projected threshold protective serum level of AIAT. The infused AIAT diffused into the lung and significantly augmented the epithelial lining fluid AIAT levels, rising from an average 0.44 +1- 0.16 microM (pre- infusion) to 2.62 +1- 1.29 microM at the nadir level just prior to the next infusion. Of critical importance is the fact that the AIAT that diffused into the lung was active as an inhibitor or neutrophil elastase, resulting in significant augmentation of epithelial lining fluid anti-neutrophil elastase capacity and normalization of the lung anti-elastase protection.1n the over 800 weekly infusions administered, no significant adverse reactions have occurred. These findings demonstrate that long-term augmentation therapy with weekly infusions of AlAT is a rational, safe, and biochemically effective therapy for AIAT deficiency.

Hubbard-RC; Sellers-S; C zerski-D; Stephens-L; Crystal-RG
Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, MD 20892.
JAMA. 1988 Sep 2; 260(9): 1259-64

Biochemical efficacy and safety of monthly augmentation therapy for alpha l-antitrypsin deficiency.

The hereditary disorder alpha l-antitrypsin (alpha lAT) deficiency results in the development of emphysema due to a diminished anti-neutrophil elastase screen of the lower respiratory tract. Specific therapy for this disorder is available in the form of weekly intravenous infusions of human plasma alpha IAT, which effectively reconstitute the anti-elastase screen of the lung in these individuals. In an attempt to reduce the frequency of therapy we evaluated the ability of monthly infusions of alpha 1 A T to provide equivalent lower respiratory tract protection against neutrophil elastase. Intravenous infusion of 250 mg/kg of alpha lAT at 28-day intervals to nine individuals with alpha lAT deficiency and emphysema was carried out for 12 months. Serum alpha lAT levels exceeded the protective threshold for an average of 25 days after each dose of alpha lAT was administered. Furthermore, the postinfusion level of alpha lAT in the nadir lung epithelial lining fluid was fivefold greater than the preinfusion level, and the anti-neutrophil elastase capacity of the nadir epithelial lining fluid also was elevated significantly, nearly threefold above the preinfusion level. These results indicate that monthly administration of human alpha 1 A T is fully capable of adequately augmenting serum and lung alpha lAT levels and anti-elastase capacity and is therefore a rational alternative to weekly therapy.

Braun-J; Welle-S; van-Wees-J; Winterhoff-R; Wood-WG; Dalhoff-K; Wiessmann-KJ
Klinik f™r Innere Medizin, Medizinische UniversitØt L™beck.
Dtsch-Med-Wochenschr.1990Jun8; 115(23): 889-94

Long-term substitution in homozygous alpha 1-antitrypsin deficiency. Effect oft he proteinase-antiproteinase equilibriurn in plasma and sputum Dauersubstitution bei homozygotem alpha 1-Antitrypsin-Mangel. Einfluss auf das Proteinasen-Antiproteinasen-Gleichgewicht in Plasma und Sputum

Long-term replacement with human alpha 1-antitrypsin (60 mg/kg once a week intravenously) was carried out in seven patients with homozygous alpha 1-antitrypsin deficiency (7 males, mean age 50.8 ( 40-59) years) and progressive pulmonary ernphysema for an average of 16 (13-20) weeks. After at least 12 weeks therapy the concentrations of alpha 1-antitrypsin, elastase-alpha 1-antitrypsin complex, alpha 2-rnacroglobulin, lactoferrin and elastase inhibition capacity in plasma and sputum were assayed, these assays being performed before starting the alpha 1-antitrypsin infusion and at various times during the fo1lowing week. After the infusion the plasma concentration of alpha 1-antitrypsin rose from a depressed initial level (median 1.22 g/l) to a level approximately five times higher (median after 1 hour: 5.96 g/l, P less than 0.001), and then declined exponentially, though it never fell below the threshold of 35% of normal which is regarded as the protective level. Elastase inhibition capacity displayed similar changes ( r = 0.85). The sputum concentration of alpha 1-antitrypsin rose more slowly than the plasma concentration; from the initial level (median 8 mg/l) it reached a maximum about four times higher after 24 hours (median 36 mg/l; P 1ess than 0.02). Elastase inhibition capacity rose from 151 mIU/m1 (median) before the alpha 1-antitrypsin infusion to 450 mIU/m1 at 24 hours. These findings suggest that alpha 1-antitrypsin replacement will have beneficial effects on proteinase-antiproteinase equilibrium. Determination of elastase inhibition capacity in the sputum is suitable for monitoring dosage during replacement therapy.

Swedish Hospital, Denver, CO.
Agents-Actions-Suppl. 1993; 42: 97-102

Alpha 1-antitrypsin augmentation therapy.

Alpha 1-proteinase inhibitor (also known as alpha 1-antitrypsin) derived from pooled human serum ( Prolastin, Miles Biologicals) has been available in the United States since 1988. Although no formal controlled prospective study has been performed to prove its efficacy, intravenous administration of Prolastin has been the accepted treatment for individuals with pulmonary emphysema due to alpha l-antitrypsin deficiency. In addition, Prolastin has been used experimentally by inhalation for the treatment of cystic fibrosis. It has been administered with some success to treat the panniculitis associated with alpha l-antitrypsin deficiency. As a greater number of severely impaired alpha l-antitrypsin deficient patients receive lung transplantation, the role of Prolastin in the post-transplant therapy of these patients will need evaluation. Newer antiproteases may render Prolastin obsolete with respect to its route of administration and its pricing, however, the safety record of this drug has been impressive.

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