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  • 1
    Electronic Resource
    Electronic Resource
    The Pulmonary Absorption of Aerosolized and Intratracheally Instilled rhG-CSF and monoPEGylated rhG-CSF (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1343-1349 
    Details
    ISSN: 1573-904X
    Keywords: aerosols ; G-CSF ; lung ; drug delivery ; regulation ; proteins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The objective of this study was to highlight differences in the pulmonary absorption of a monoPEGylated rhG-CSF and rhG-CSF after intratracheal instillation and aerosol delivery. Methods. Male Sprague Dawley rats (250 g) were anesthetized and intratracheally instilled (IT) with protein solution or were endotracheally intubated and administered aerosol for 20 min via a Harvard small animal ventilator. A DeVilbiss “Aerosonic” nebulizer containing 5 ml of protein solution at ≈ 3 mg/ml was used to generate aerosol. The volume of protein solution deposited in the lung lobes was estimated to be ≈13 µl after delivery of Tc-99m HSA solutions. The PEGylated proteins consisted of a 6 kDa (P6) or 12 kDa PEG (PI2) linked to the N-terminus of rhG-CSF. rhG-CSF also was administered IT in buffers at pH 4 and pH 7 and in dosing volumes ranging from 100 to 400 µl. Blood samples were removed at intervals after dosing and the total white blood cell counts (WBC) were determined. Plasma was assayed for proteins by an enzyme immuno assay. Results. The plasma protein concentration v. time profiles were strikingly different for aerosol v. IT delivery. The C max values for rhG-CSF and P12 after aerosol delivery were greater than found after IT (Aerosol: 598 ± 135 (ng/ml) rhG-CSF; 182 ± 14 P12 v. IT: 105 ± 12 rhG-CSF; 65.9 ± 5 P12). Similarly, Tmax was reached much earlier after aerosol administration (Aerosol: 21.7 ± 4.8 (min) rhG-CSF; 168 ± 31 P12 v. IT: 100 ± 17 rhG-CSF; 310 ± 121 P12). Estimated bioavailabilities (Flung %) were significantly greater via aerosol delivery than those obtained after IT (Aerosol: 66 ± 14 rhG-CSF; 12.3 ± 1.9 P12 v. IT: 11.9 ± 1.5 rhG-CSF; 1.6 ± 0.1 P12). An increase in circulating WBC counts was induced by all proteins delivered to the lungs. The rate and extent of absorption of rhG-CSF was not influenced by the pH employed nor the instilled volume. Conclusions. Estimates of bioavailability are dependent upon the technique employed to administer drug to the lungs. Aerosol administration provides a better estimate of the systemic absorption of macromolecules.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016281925554
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Some Factors Associated with the Ultrasonic Nebulization of Proteins (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 53-59 
    Details
    ISSN: 1573-904X
    Keywords: aerosol ; lactate dehydrogenase ; nebulizers ; proteins ; ultrasonic nebulization ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Ultrasonic nebulization of lactate dehydrogenase (LDH) was investigated using a DeVilbiss “Aerosonic” nebulizer. The enzyme (8ml, 0.025mg/ml Na2HPO4, pH 7.0) was completely inactivated after 20 minutes of operation. However, the inactivation profile observed during ultrasonic nebulization was different from that previously observed using air-jet nebulization. At least two mechanisms are involved, one associated with heating and the other with aerosol production. By preventing heating of the nebulizer fluid during operation, the denaturation profile was dramatically altered. By additionally including 0.01% w/v Tween 80 or l%w/v PEG 8000, almost all activity was retained. Similar results were obtained by preventing aerosol production and heating. However, 100% of activity was lost when heating was allowed to occur without aerosol formation. The results demonstrate that cooling in conjunction with a surfactant is one approach that could be used to stabilize proteins to ultrasonic nebulization. However, cooling also significantly reduced solute output from the nebulizer. When operated at 10°C output was negligible. At 50°C the output was 5× greater than that found at room temperature. The median droplet size (µm) was not significantly influenced by the operating temperature of the nebulizer fluid (3.6 ± 0.4, 21°C; 3.9 ± 0.2, 50°C, p = NS (n = 6)) although the size distribution was noted to increase at the higher temperature.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016282502954
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Pulmonary Delivery of Powders and Solutions Containing Recombinant Human Granulocyte Colony-Stimulating Factor (rhG-CSF) to the Rabbit (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1101-1109 
    Details
    ISSN: 1573-904X
    Keywords: rhG-CSF ; intratracheal instillation ; lung ; pharmacokinetics ; pharmacodynamics ; pulmonary absorption ; Tc-99m
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Two powder formulations (MMAD 〈4 µm) containing rhG-CSF were insufflated (IF) via an endotracheal tube at doses of 5, 75 or 500 µg/kg to New Zealand white rabbits. Doses of 5 and 500 µg/kg of solutions were administered by intratracheal instillation (IT), subcutaneous (SC) injection in the thigh and intravenous injection (IV) via the marginal ear vein. Blood samples were removed at regular intervals from an indwelling jugular catheter. Blood was analyzed directly for total white blood cell counts (WBC). Plasma was assayed for rhG-CSF by a specific ELISA. The distribution of radioactive dose in lung tissue was found after administering Tc99m HSA in solution or when incorporated into powders. The pharmacokinetics and pharmacodynamics were determined for all routes of administration. High dose IV concentration vs. time profiles declined biexponentially (t1/2 α = 0.6 ± 0.2 hrs, t1/2 β = 4.6 ± 0.2 hrs, n = 8). Clearance was dose dependent (11.6 ± 2.6 [500 µg/kg, n = 8] vs. 21.8 ± 3.3 ml/hr/kg [5 µg/kg, n = 5]). A normal systemic response was obtained after IF, indicating that rhG-CSF retains activity in the solid state. Dissolution and absorption of rhG-CSF from the powders were not rate limiting. The plasma concentration vs. time profiles peaked at similar times to those after IT (Tmax 1 -2 hrs) but were earlier than obtained after SC (Tmax 6-10 hrs). Powders were less efficiently dosed to the lung lobes after insufflation compared with instillates (14.7 ± 10.5 vs. 60.1 ± 10.6%), resulting in bioavailabilities ranging from 5 to 33%. Bioavailability after SC was 11.0 ± 7.0% and 95.3 ± 7.9% (n = 6) for the low and high doses, respectively.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018924512928
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    Paper (German National Licenses)
    Fulltext
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