Severity: Warning
Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Filename: helpers/my_audit_helper.php
Line Number: 143
Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 143
Function: file_get_contents
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 209
Function: simplexml_load_file_from_url
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 994
Function: getPubMedXML
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3134
Function: GetPubMedArticleOutput_2016
File: /var/www/html/application/controllers/Detail.php
Line: 574
Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
Line: 488
Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
Line: 316
Function: require_once
The assessment and prediction of lung absorption and disposition are an increasingly essential preclinical task for successful discovery and product development of inhaled drugs for both local and systemic delivery. Hence, in vitro, ex vivo and in vivo preclinical methods of lung absorption continue to evolve with several technical, methodological and analytical refinements. As in vitro lung epithelial cell monolayer models, the air-liquid interface (ALI)-cultured Calu-3 cells have most frequently been used, but the NCI-H441 and hAELVi cells have now been proposed as the first immortalized human alveolar epithelial cells capable of forming highly-restricted monolayers. The primary ALI-cultured three-dimensional (3D) human lung cell barriers have also become available; efforts to incorporate aerosol drug deposition into the in vitro lung cell models continue; and stem cell-derived lung epithelial cells and "lung-on-a-chip" technology are emerging. The ex vivo isolated perfused rat lung (IPRL) methods have increasing been used, as they enable the kinetic determination of tissue/organ-level diffusive and membrane protein-mediated absorption and competing non-absorptive loss; the assessment of "pre-epithelial" aerosol biopharmaceutical events in the lung, such as dissolution and release; and the ex vivo-to-in vivo extrapolation and prediction. Even so, in vivo small rodent-based methods have been of mainstay use, while large animal-based methods find an additional opportunity to study region-dependent lung absorption and disposition. It is also exciting that human pharmacokinetic (PK) profiles and systemic exposures for inhaled drugs/molecules may be able to be predicted from these in vivo rodent PK data following lung delivery using kinetic modeling approach with allometric scaling. Overall, the value of these preclinical assessments appears to have shifted more to their translational capability of predicting local lung and systemic exposure in humans, in addition to rationalizing optimal inhaled dosage form and delivery system for drugs/molecules in question. It is critically important therefore to make appropriate selection and timely exploitation of the best models at each stage of drug discovery and development program for efficient progress toward product approval and clinical use.
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Source |
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http://dx.doi.org/10.1016/j.addr.2020.07.025 | DOI Listing |
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