alpha1-PI Levels Research Articles

Pharmacokinetic comparability of Prolastin®-C to Prolastin® in alpha1-antitrypsin deficiency: a randomized study

BackgroundAlpha1-antitrypsin (AAT) deficiency is characterized by low blood levels of alpha1-proteinase inhibitor (alpha1-PI) and may lead to emphysema. Alpha1-PI protects pulmonary tissue from damage caused by the action of proteolytic enzymes. Augmentation therapy with Prolastin® (Alpha1-Proteinase Inhibitor [Human]) to increase the levels of alpha1-PI has been used to treat individuals with AAT deficiency for over 20 years. Modifications to the Prolastin manufacturing process, incorporating additional purification and pathogen-reduction steps, have led to the development of an alpha1-PI product, designated Prolastin®-C (Alpha1-Proteinase inhibitor [Human]). The pharmacokinetic comparability of Prolastin-C to Prolastin was assessed in subjects with AAT deficiency.MethodsIn total, 24 subjects were randomized to receive 60 mg/kg of functionally active Prolastin-C or Prolastin by weekly intravenous infusion for 8 weeks before crossover to the alternate treatment for another 8 weeks. Pharmacokinetic plasma samples were drawn over 7 days following last dose in the first treatment period and over 10 days following the last dose in the second period. The primary end point for pharmacokinetic comparability was area under the plasma concentration versus time curve over 7 days post dose (AUC0-7 days) of alpha1-PI determined by potency (functional activity) assay. The crossover phase was followed by an 8-week open-label treatment phase with Prolastin-C only.ResultsMean AUC0-7 days was 155.9 versus 152.4 mg*h/mL for Prolastin-C and Prolastin, respectively. The geometric least squares mean ratio of AUC0-7 days for Prolastin-C versus Prolastin had a point estimate of 1.03 and a 90% confidence interval of 0.97-1.09, demonstrating pharmacokinetic equivalence between the 2 products. Adverse events were similar for both treatments and occurred at a rate of 0.117 and 0.078 per infusion for Prolastin-C (double-blind treatment phase only) and Prolastin, respectively (p = 0.744). There were no treatment-emergent viral infections in any subject for human immunodeficiency virus, hepatitis B or C, or parvovirus B19 during the course of the study.ConclusionProlastin-C demonstrated pharmacokinetic equivalence and a comparable safety profile to Prolastin.Trial RegistrationClinicalTrials.gov Identifier: NCT00295061

Impaired fibrinolytic potential related to elevated alpha1-proteinase inhibitor levels in patients with pulmonary thromboembolism.

The contribution of neutrophil leukocyte elastase (NE) to in vivo thrombolysis is still an open question. The present study examines the impact of variable levels of alpha1-proteinase inhibitor (alpha1-PI) (the major plasma inhibitor of NE) on fibrinolysis within the setting of thromboembolic diseases. Blood samples were taken from 56 patients with pulmonary thromboembolism prior to treatment. alpha1-PI and alpha1-PI-NE complex were measured in the serum and plasma with immunoturbidimetric and enzyme-linked immunosorbent assay (ELISA) methods, respectively. The fibrinolytic potential [spontaneous, tissue-type plasminogen activator (tPA) induced, and plasmin induced] of the plasma was evaluated in vitro with turbidimetric clot lysis assay. Correlation analysis (Pearson product-moment correlation coefficient, r) of the turbidimetric lysis parameters and the blood levels of alpha1-PI and alpha1-PI-NE complex was carried out. Fibrinolysis is slower in clots prepared from plasma containing elevated levels of alpha1-PI and alpha1-PI-NE complex. The maximal turbidity of the plasma clots shows significant correlation with the alpha1-PI level (r=0.39, p=0.003) and the correlation of the maximal turbidity and the tPA-induced lysis time is also significant (r=0.77, p<0.001). The lysis time correlates with the plasma level of alpha1-PI-NE complex, if fibrinolysis is induced with tPA (r=0.37, p=0.02), but not with plasmin (r=0.19, p=0.4). Our study shows that in pulmonary thromboembolism elevated levels of alpha1-PI are associated with suppressed plasma fibrinolytic potential. This effect can be at least partially explained by the coarse fibrin network structure and retarded plasminogen activator-dependent fibrinolysis.

Pulmonary function in children with homozygous alpha1-protease inhibitor deficiency.

Alpha1-protease inhibitor (alpha1-PI) deficiency is a well-recognized cause of emphysema in adults; however, the natural history of this disorder in children is unclear. Because of the paucity of data in the paediatric age group, we performed whole body plethysmography, spirometry, and diffusing capacity, in a cohort of 17 homozygous (PiZZ phenotype) children (9 females, 8 males; mean age +/- SEM 13.4 +/- 0.9, range 7-18 years) and in 17 normal schoolchildren (13.5 +/- 0.9, 7-18 years), using a matched-pair design. Blood was drawn for determination of serum alpha1-PI levels, PI phenotype, and standard biochemical tests of liver function. Among the PiZZ subjects, 12 were detected during diagnostic workup of prolonged neonatal icterus, and 5 by routine testing in paediatric patients. None had chronic respiratory symptoms except for an 18-year-old PiZZ girl with a history of recent onset of exertional dyspnoea. All were non-smokers. The Wilcoxon test was used for statistical analysis. As expected, serum alpha1-PI levels were lower in the PiZZ group (16% of the control value). A few patients had slight elevations of their liver enzymes. As for the pulmonary function parameters, differences between groups were not significant. Individual data showed no consistent abnormality in lung function except for signs of mild expiratory obstructive airway disease with hyperinflation (elevated TGV/TLC ratio) in the only symptomatic 18-year-old subject (0.63, control subject 0.49). This was unresponsive to bronchodilators. For her, augmentation therapy with intravenous infusion of alpha1-PI may be considered. Our study confirms the absence of pulmonary function abnormalities in the vast majority of children with homozygous alpha1-PI deficiency. Serial measurements of lung function may help to distinguish those individuals who require treatment with alpha1-PI from those who do not.

Elastase and α‐1‐Proteinase Inhibitor in Gingival Crevicular Fluid and Gingival Tissue in Adult and Juvenile Periodontitis

The presence and localization of PMN/neutrophil elastase and its endogenous inhibitor alpha 1-proteinase inhibitor (alpha 1 PI) were studied immunohistochemically in gingival tissue specimens collected from 9 adult periodontitis (AP) patients during flap surgery after the initial phase of periodontal therapy, and from 6 healthy controls with clinically-healthy periodontium upon surgical extraction of impacted third molars. In order to evaluate how periodontal tissue destructive events are reflected in gingival crevicular fluid (GCF), GCF samples were collected from the AP patients before any periodontal treatment and prior to flap surgery, from 5 localized juvenile periodontitis (LJP) patients, and from the controls. Elastase activity in the GCF was measured with the SAAVNA-assay and the molecular forms and amount of alpha 1PI by Western- and dot-blotting. Immunohistochemical staining for PMN elastase was strongly positive in the connective tissue, but not in the epithelium, of the AP patients' gingival tissue specimens. In the healthy gingival tissue specimens only a few elastase-positive cells were present. Both in AP and in control gingival specimens, alpha 1PI was detected in the connective tissue and in the keratinized layer of the epithelium, however, its amount was markedly lower in the control specimens. Elevated levels of alpha 1PI and PMN elastase were detected in the GCF of all periodontitis patients when compared to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

α1-Proteinase Inhibitor, Elastase Activity, and Lung Disease Severity in Cystic Fibrosis

The potential role of neutrophil elastase in exacerbating pulmonary infection and tissue damage in cystic fibrosis (CF) has led to proposals for treatment of lung disease in CF with the elastase inhibitor, alpha 1-proteinase inhibitor (alpha 1PI). Reports that alpha 1PI is inactivated in the CF lung suggest that the effectiveness of alpha 1PI therapy depends on the quantity of elastase present and the extent of alpha 1PI inactivation, both of which are expected to vary with disease severity. In this study we assessed the elastase-alpha 1PI profile in sputum and plasma from CF patients with various degrees of pulmonary involvement. Levels of active elastase in sputum samples increased with severity of pulmonary disease (F ratio = 5.63, p < 0.01), as did sputum levels of alpha 1PI (F ratio = 4.88, p < 0.01). A positive correlation was observed between sputum levels of active elastase and alpha 1PI (r = 0.68, p < 0.005). Plasma alpha 1PI levels were also elevated in CF patients compared with control subjects (p < 0.005), indicating a compensatory increase in plasma and sputum levels of alpha 1PI in response to increased elastase load. Molar levels of total immunogenic neutrophil elastase were, on average, 12 times higher than alpha 1PI in CF sputum. These results suggest that the major contributor to the elevated levels of active elastase observed in the CF lung is an increase in elastase release rather than inactivation of alpha 1PI.

Gingival crevicular fluid of patients with gingivitis or periodontal disease: evaluation of elastase-alpha 1 proteinase inhibitor complex.

Elastase-alpha 1 proteinase inhibitor (E alpha 1PI) concentrations were assessed in gingival crevicular fluids and evaluated in relation to the clinical signs of periodontal disease. 7 gingivitis patients (group G), 38 patients with adult periodontitis and clinically stable lesions (group AP), 21 patients with rapidly progressive periodontitis and clinically stable lesions (group RPP) and 11 patients with either adult periodontitis or rapidly progressive periodontitis and clinically progressive lesions (group Pr) were studied. 6 healthy subjects served as the control group (group H). Significantly differences were observed in the E alpha 1PI concentration between the healthy, gingivitis, clinically stable periodontitis and clinically progressive periodontitis group. In the control group, no E alpha 1PI was detected. Groups G, AP and RPP showed mean E alpha 1PI concentrations of 10.95 +/- 4.96 micrograms/ml, 35.55 +/- 18.64 micrograms/ml and 38.56 +/- 20.89 micrograms/ml, respectively. In these groups, high enzyme levels were correlated with clinical signs of inflammation. The highest E alpha 1PI levels were observed in the clinically progressive lesions. However, they were not necessarily associated with bleeding on probing or clinical evidence of inflammation. These data suggest that a significant increase in crevicular E alpha 1PI levels may be an early manifestation of a progressive or potentially progressive periodontal lesion.

Proteinase Inhibitors in the Gastrointestinal Tract, Pancreas and Liver during Fetal and Postnatal Development of the Pig

The occurrence and types of proteinase inhibitors were studied in the digestive system during the fetal and postnatal development of the pig. The protein concentration, the total trypsin-inhibiting capacity and the levels of the individual proteinase inhibitors, alpha 2-macroglobulin f (alpha 2Mf), alpha 2-macroglobulin s (alpha 2Ms), alpha 1-protease inhibitor (alpha 1PI) and alpha 2-antitrypsin (alpha 2AT) quantified by using electroimmunoassay, were assayed in stomach and intestinal contents, in homogenates of the stomach and intestinal mucosa, and in the pancreas and liver. The results showed that during porcine ontogeny high amounts of proteinase inhibitors are present in the digestive system. During the fetal period, the most outstanding characteristic was the high levels of alpha 1PI and alpha 2AT, in contrast to the low levels of the alpha 2-macroglobulins. Furthermore, the trypsin-inhibiting capacity and the levels of alpha 1PI and alpha 2AT showed in most cases a statistically significant decrease during the fetal period (12-36 cm crown-to-rump length). In the neonatal period, 0-96 h after birth, the levels of the individual inhibitors were rather constant, but a significant decrease to low levels of both trypsin inhibition and the individual inhibitors was observed in the adult pig. Trypsin activity was found in approximately half of the pancreas homogenates from the late fetal period and in newborn pigs before they began to suckle. The physiological function of the proteinase inhibitors observed in the digestive system during porcine ontogeny is probably to protect against precocious proteolytic degradation by the formation of inactive enzyme/inhibitor complexes.