Alpha 1-proteinase Inhibitor

(rINN)

💊 Chemical information

Chemical formula: Alpha1 Antitrypsin; alpha-1-Antitrypsinum; Antitrypsine alpha-1; Inhibidor de la1- proteinasa.
ATC — B02AB02.
ATC Vet — QB02AB02.

Pharmacopoeias.

In Eur..

Ph. Eur. 6.2

(Human α-1-Proteinase Inhibitor). A plasma protein fraction containing mainly human α-1-proteinase inhibitor. It is prepared from human plasma obtained from blood from healthy donors; the plasma is tested for the absence of hepatitis B surface antigen and antibodies against HIV-1 and HIV-2 and hepatitis C virus. The method of preparation includes a step or steps that have been shown to remove or inactivate known agents of infection. Other plasma proteins may be present. Freeze-dried products are hygroscopic, white or pale yellow or pale brown powders or friable solids; liquid products are clear or slightly opalescent, colourless or pale yellow or pale green or pale brown. pH of 6.5 to 7.8. Store in airtight and sterile containers at a temperature not exceeding 25°.

💊 Adverse Effects and Precautions

Adverse effects of intravenous alpha1-proteinase inhibitor include asthenia, chills, increase in cough, dizziness, dyspnoea, flu-like symptoms, headache, hypotension, pain at the injection site, paraesthesias, pharyngitis, pruritus, rashes, somnolence, and tachycardia. The infusion should be interrupted or the rate reduced if adverse effects occur and resumed at a more tolerable rate once the symptoms have subsided; the infusion should be stopped immediately in the event of anaphylactic or anaphylactoid reactions, and full supportive measures implemented. Preparations derived from pooled human plasma carry a risk of transmission of infection. The drug is contra-indicated in patients with selective IgA deficiencies who have known antibody against IgA since they are at risk of severe reactions to IgA that may be present in the product.

💊 Uses and Administration

Endogenous alpha1-proteinase inhibitor is a serum glycoprotein synthesised in the liver that acts as an elastase inhibitor, primarily inhibiting neutrophil elastase.

Alpha

1-proteinase inhibitor, prepared from pooled human plasma, is used as replacement therapy in patients with emphysema who have congenital alpha1 antitrypsin deficiency (see below). It is given in a dose of 60 mg/kg once a week by intravenous infusion at a rate of about 0.08 mL/kg per minute (usually corresponding to a 15 to 30 minute infusion). A recombinant form of alpha1-proteinase inhibitor is under investigation for nebulised delivery in congenital alpha1 antitrypsin deficiency and cystic fibrosis (see below).

Alpha

1-proteinase inhibitor has also been investigated for the prevention of bronchopulmonary dysplasia in preterm neonates.

Alpha1 antitrypsin deficiency.Alpha

1 antitrypsin deficiency (alpha1-proteinase inhibitor deficiency) is characterised by chronic obstructive pulmonary disease (COPD) and chronic liver disease associated with a lack of alpha1-proteinase inhibitor.1This inhibitor is produced in the liver but exerts its main effects in the lungs as an inhibitor of neutrophil elastase, an enzyme released in response to inflammation. Congenital deficiency of the inhibitor thus leaves the lungs vulnerable to destruction by elastase, leading to the development of emphysema (see Chronic Obstructive Pulmonary Disease1112), usually in the third or fourth decade of life. Hepatic manifestations of deficiency include hepatitis, cirrhosis, and hepatoma. Panniculitis and vasculitis may also occur less frequently in some phenotypes.2,3 Management of COPD associated with the deficiency involves avoidance of factors (mainly cigarette smoking) that cause pulmonary inflammation, and supportive treatment with bronchodilators and oxygen as appropriate. Augmentation therapy with alpha1-proteinase inhibitor to raise serum concentrations above the protective threshold is also of benefit in some patients.2,4 Intravenous infusion of the drug has been shown to correct the biochemical abnormality5 and has been recommended in those patients with some deterioration of lung function.2,6 In a short-term study7 serum and secretion concentrations of alpha1-proteinase inhibitor as well as markers of neutrophilic inflammation were monitored in 12 patients receiving augmentation therapy over 4 weeks. Results demonstrated a rise in serum levels of alpha1-proteinase inhibitor to above the protective threshold, and reduction in elastase activity and levels of leukotriene B4 levels (thought to be important in producing airway inflammation in alpha1 antitrypsin deficiency). A small placebo-controlled study8 found that the rate of decline of FEV1 was not affected in patients treated for at least 3 years. Data9 from a large registry of patients also suggested that, overall, treatment did not affect the rate of decline of FEV1, but that it decreased mortality, although this may be influenced by other factors. Evaluation6 of 2 of these studies8,9 and one other concluded that replacement therapy might reduce the progression of disease in selected patients, but that further randomised placebo-controlled studies were required to provide conclusive evidence for overall clinical efficacy. The Canadian Thoracic Society10 recommends that replacement therapy should be reserved for patients with an FEV1 between 35 and 65% predicted who are no longer smoking and on optimal medical therapy but continuing to show a rapid decline in FEV1. In a retrospective cohort study11 in 96 patients followed up for a minimum of 12 months, results indicated that the rate of progression of pulmonary emphysema was reduced during the time that the patients received augmentation therapy, and patients with wellmaintained lung function and a rapid decline in FEV1 benefited most from therapy. These authors recommended early diagnosis to identify patients at risk and to start augmentation even if lung function is greater than 65% predicted. Liver involvement does not respond to treatment with alpha1proteinase inhibitor and is managed symptomatically.2 Several new approaches to treatment of alpha1 antitrypsin deficiency are under investigation:2,3,12 plasma-derived and recombinant forms of alpha1-proteinase inhibitor for inhalation; synthetic elastase inhibitors for oral use; synthetic chaperones to block intrahepatic polymerisation of the inhibitor and other methods to improve serum concentrations; retinoids; inhaled hyaluronic acid; and gene therapy.
1. Köhnlein T, Welte T. Alpha-1 antitrypsin deficiency: pathogenesis, clinical presentation, diagnosis, and treatment. Am J Med 2008; 121: 3–9
2. American Thoracic Society/European Respiratory Society. Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2003; 168: 818–900. Also available at: http://www.thoracic.org/ sections/publications/statements/pages/respiratory-disease-adults/ alpha1.html (accessed 14/07/06
3. Stoller JK, Aboussouan LS.
α -Antitrypsin deficiency. Lancet
2005; 365: 2225–36
4. Juvelekian GS, Stoller JK. Augmentation therapy for α -antitrypsin deficiency. Drugs 2004; 64: 1743–56
5. Coakley RJ, et al. α1-Antitrypsin deficiency: biological answers to clinical questions. Am J Med Sci 2001; 321: 33–41
6. Abboud RT, et al. Alpha -antitrypsin deficiency: a position statement of the Canadian Thoracic Society. Can Respir J 2001; 8: 81–8
7. Stockley RA, et al. The effect of augmentation therapy on bronchial inflammation in α1-antitrypsin deficiency. Am J Respir Crit Care Med 2002; 165: 1494–8
8. Dirksen A, et al. A randomized clinical trial of α -antitrypsin augmentation therapy. Am J Respir Crit Care Med 1999; 160: 1468–72
9. The Alpha-1-Antitrypsin Deficiency Registry Study Group. Survival and FEV decline in individuals with severe deficiency of α -antitrypsin. Am J Respir Crit Care Med 1998; 158: 49–59
10. O’Donnell DE, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease – 2007 update. Can Respir J 2007; 14 (suppl B): 5B–32B
11. Wencker M, et al. Longitudinal follow-up of patients with α protease inhibitor deficiency before and during therapy with IV
α -protease inhibitor. Chest 2001; 119: 737–44.
12. Sandhaus RA. α -Antitrypsin deficiency 6: new and emerging treatments for α -antitrypsin deficiency. Thorax 2004; 59: 904–9.

Cystic fibrosis.

Some of the inflammatory damage that occurs in the lungs of patients with cystic fibrosis is thought to be caused by excessive amounts of elastase released locally.

Alpha

1-proteinase inhibitor given by nebuliser is therefore under investigation1-3 in patients with cystic fibrosis.
1. Martin SL, et al. Safety and efficacy of recombinant alpha -antitrypsin therapy in cystic fibrosis. Pediatr Pulmonol 2006; 41:177–83
2. Cantin AM, et al. Prolastin aerosol therapy and sputum taurine in cystic fibrosis. Clin Invest Med 2006; 29: 201–7
3. Griese M, et al. α -Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients. Eur Respir J 2007; 29: 240–50.

💊 Preparations

Proprietary Preparations

Austria: Prolastin; Canad.: Prolastin; Cz.: Trypsone; Fr.: Alfalastin; Ger.: Prolastin; Ital.: Prolastina; Port.: Prolastin; Spain: Prolastina; Trypsone; USA: Aralast; Prolastin; Zemaira.
Published December 01, 2018.