Anticoagulative effects of the inhaled low molecular weight heparin certoparin in healthy subjects.
Inhalation of heparin results in local antiinflammatory and antifibrotic effects and an inhibition of blood coagulation. A number of experimental and clinical studies demonstrated that inhalant administration of heparin or low molecular weight heparin (LMWH) is a feasible and save tool for anticoagulative treatment. However, heparin and LMWH differ in respect to their molecular weight, pulmonary absorption, and principle of their anticoagulative pattern. In our study we investigated the anticoagulative effect of different doses of the LMWH certoparin after inhalation (3000 IU-9000 IU) and subcutaneous injection (3000 IU) in healthy individuals in a cross-over design. Inhalations were performed using a new device allowing inhalations with optimized and standardized breathing patterns. The anticoagulative effect was determined by measurement of the anti-factor-Xa (anti-FXa) activity. Lung function parameters were measured before and after drug inhalation. Analysis of the anti-FXa activity as a function of the time after administration revealed values of the area under the curve (AUC) of 5.70+/-1.58 U.hour/ml and 8.43+/-1.31 U.hour/ml (mean+/-SD) with interindividual coefficients of variation of 28% and 13% after injection of 3000 IU and inhalation of 9000 IU, respectively. The AUC after inhalation of 9000 IU was significantly higher (P=0.0007) compared with subcutaneous injection of 3000 IU. In consequence, in order to obtain plasma anti-FXa activities of above 0.2 U/ml, which is considered sufficient for prophylaxis of venous thrombosis, 9000 IU LMWH have to be inhaled. Compared with the subcutaneous administration, the action of certoparin is longer after inhalation than after injection. Apparently, the drug is released rapidly according to a two-compartment kinetics, and its anticoagulant activity lasts over a long time without a marked plasma peak after administration. In detail, an elevation of plasma anti-FXa activity is achieved for 12 hours to 24 hours without a distinct peak shortly after inhalation. Inhalation of LMWH does not result in any changes in lung function or other side effects. The administration of LMWH by inhalation bears the following: the non-invasive route of drug application, the low interindividual variability of the anticoagulative effect, and a long-time pharmacological effect. These properties suggest that controlled inhalation of heparin is an attractive alternative to subcutaneous administration.
Scheuch
G
G
Activaero GmbH, Gemuenden/Wohra, Germany.
Brand
P
P
Meyer
T
T
Herpich
C
C
Müllinger
B
B
Brom
J
J
Weidinger
G
G
Kohlhäufl
M
M
Häussinger
K
K
Spannagl
M
M
Schramm
W
W
Siekmeier
R
R
D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D019540:Area Under Curve; D001777:Blood Coagulation / Q000187:drug effects; D018592:Cross-Over Studies; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D015951:Factor Xa / Q000032:analysis; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D012129:Respiratory Function Tests
D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D015951:Factor Xa; C403769:certoparin