Frontiers in Drug Design and Discovery

Volume: 4

Role of Inflammatory Biomarkers in Establishing PK/PD Relationships and Target Organ Toxicity

Author(s): Sivaram Pillarisetti and Ish Khanna

Pp: 81-96 (16)

DOI: 10.2174/978160805202810904010081

* (Excluding Mailing and Handling)

Abstract

High levels of inflammatory cytokines and adhesion molecules are associated with many inflammatory disorders [e.g. rheumatoid arthritis, inflammatory bowel disease and lupus] as well as metabolic and cardiovascular diseases including diabetes and obesity. Examples of such markers include tumor necrosis factor [TNFα], interleukins [IL-1, IL-6, IL-8 and IL-18], vascular cell adhesion molecules and markers of macrophage inflammation [e.g. MMPs]. In many preclinical disease models, levels of these markers are significantly elevated relative to normal animals. Modulation of these biomarkers with pharmaceutical agents in preclinical and clinical studies can be effectively used for concept validation, effective dose selection, and establishing good pharmacokinetics/pharcodynamics correlation. On the other hand, elevation of these markers in normal animals, following treatment with an agent, could indicate safety concerns leading to potential tissue damage. Monitoring of inflammatory markers in normal animals can be diagnostic and of high value in evaluating safety or efficacy of new molecules. The levels of biomarkers can be monitored either by high throughput microarrays/proteomics or by specific ELISA based assays. Since many of the biomarkers appear in systemic circulation, these can be monitored in blood/plasma without interference with tissues. This makes the approach particularly attractive for clinical studies. An overview of the biomarkers, potential applications and case histories linking biomarkers to PK/PD correlation from preclinical and clinical studies are discussed.

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      • 13. app/Models/UserAccess/UserAccess.php:1266
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      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316567616 and j.to_ip >=316567616 )) and ((j.from_date <= 1740497154 and j.to_date >= 1740497154 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2202) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316567616 and j.to_ip >=316567616 )) and ((j.from_date <= 1740497154 and j.to_date >= 1740497154 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2202) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316567616 and j.to_ip >=316567616 )) and ((j.from_date <= 1740497154 and j.to_date >= 1740497154 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2202)
      580μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 945 and `b`.`banner_from_date` <= 1740497154 and `b`.`banner_to_date` >= 1740497154 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.03msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 945
      • 3: 1740497154
      • 4: 1740497154
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='44c9f0479885f329efd3a05663de402c'
      200μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        Kp6n74h5t4dXLm9vJ6Uph5uI2ewvJKOxZemQHrph
        uc_cart_id
        44c9f0479885f329efd3a05663de402c
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/2202" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/2202
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:17 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6Ijh0RzgvNXJKNW43QmFxb2l6VGdBdEE9PSIsInZhbHVlIjoiK3V4UlZhVVphSmtwTHBFbzREMnRPWWFERHViL1p4UStQUEhnZ1FnUnFnWT0iLCJtYWMiOiIyOGUwYWNlYWYxMzRlODExNGNkYjdhMTBkZjQ5MTcxZDE5M2I2ZWFiMjlhNjE0M2NkNjc4MmE3OTEwMzVhMjdmIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6Ijh0RzgvNXJKNW43QmFxb2l6VGdBdEE9PSIsInZhbHVlIjoiK3V4UlZhVVphSmtwTHBFbzREMnRPWWFERHViL1p4UStQUEhnZ1FnUnFnWT0iLCJtYWMiOiIyOGUwYWNlYWYxMzRl" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 15:25:54 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IkJlSkxYN1BOcHVBNHZDNjJHQzhKckE9PSIsInZhbHVlIjoiV1J4Zld0bVNIMHd3VENaZitkMUxsVmNBWkF4c3RlZWRFbytYcU0yZmZSZERGVmN6YWI3cEdZbnp1M08zbDkvdW9DcUJzVkw3WWdweVRBUUEzV2x3MjBTVFo2K3YxRXZzWm5KRWc0dGZGRDBZU1NrNlRmOWxsZjBmMjl0cll5eHIiLCJtYWMiOiI0YWRmM2RlNjFhYzlhNWM3NGRjNGFhOGU2N2NjMWZlNzUyYWU4MjZhODZiMjc1NWFjNzFlZWIzNTBiNWVjY2Q2IiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 03:25:54 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IkJlSkxYN1BOcHVBNHZDNjJHQzhKckE9PSIsInZhbHVlIjoiV1J4Zld0bVNIMHd3VENaZitkMUxsVmNBWkF4c3RlZWRFbytYcU0yZmZSZERGVmN6YWI3cEdZbnp1M08zbDkvdW9DcUJzV" 1 => "alphaeurekaselectnet_session=eyJpdiI6IlRVQWZQbGlJSkVpbVBVR3hERXg5MHc9PSIsInZhbHVlIjoiM09YK0JPUm9FM3h5L2E2UGNjZ3FtRXFNRTRnV1FmWk9TYjN0RFNYTjF1QWFtUDBDdldtSjRsR1orTjVkeXNHY3VFc0hoREZLMjJXWWZ1Y1hNL1kvR2F5M1NQWjE3ZXZpdERWSkhVSTBTSGE0RVg3TVhIck50VXNsbS9CK0t5cTYiLCJtYWMiOiJmNjQ3ZmZkNjI3NzA0ZTRlNzM1ZmVkN2JjN2RkNTNjN2RlYjE3ZDIxYjY2MTVjNjE0MTgwNWJiMjhiOGI1N2IyIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IlRVQWZQbGlJSkVpbVBVR3hERXg5MHc9PSIsInZhbHVlIjoiM09YK0JPUm9FM3h5L2E2UGNjZ3FtRXFNRTRnV1FmWk9TYjN0RFNYTjF1QWFtUDBDdldtSjRsR1o" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IkJlSkxYN1BOcHVBNHZDNjJHQzhKckE9PSIsInZhbHVlIjoiV1J4Zld0bVNIMHd3VENaZitkMUxsVmNBWkF4c3RlZWRFbytYcU0yZmZSZERGVmN6YWI3cEdZbnp1M08zbDkvdW9DcUJzVkw3WWdweVRBUUEzV2x3MjBTVFo2K3YxRXZzWm5KRWc0dGZGRDBZU1NrNlRmOWxsZjBmMjl0cll5eHIiLCJtYWMiOiI0YWRmM2RlNjFhYzlhNWM3NGRjNGFhOGU2N2NjMWZlNzUyYWU4MjZhODZiMjc1NWFjNzFlZWIzNTBiNWVjY2Q2IiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 03:25:54 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IkJlSkxYN1BOcHVBNHZDNjJHQzhKckE9PSIsInZhbHVlIjoiV1J4Zld0bVNIMHd3VENaZitkMUxsVmNBWkF4c3RlZWRFbytYcU0yZmZSZERGVmN6YWI3cEdZbnp1M08zbDkvdW9DcUJzV" 1 => "alphaeurekaselectnet_session=eyJpdiI6IlRVQWZQbGlJSkVpbVBVR3hERXg5MHc9PSIsInZhbHVlIjoiM09YK0JPUm9FM3h5L2E2UGNjZ3FtRXFNRTRnV1FmWk9TYjN0RFNYTjF1QWFtUDBDdldtSjRsR1orTjVkeXNHY3VFc0hoREZLMjJXWWZ1Y1hNL1kvR2F5M1NQWjE3ZXZpdERWSkhVSTBTSGE0RVg3TVhIck50VXNsbS9CK0t5cTYiLCJtYWMiOiJmNjQ3ZmZkNjI3NzA0ZTRlNzM1ZmVkN2JjN2RkNTNjN2RlYjE3ZDIxYjY2MTVjNjE0MTgwNWJiMjhiOGI1N2IyIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IlRVQWZQbGlJSkVpbVBVR3hERXg5MHc9PSIsInZhbHVlIjoiM09YK0JPUm9FM3h5L2E2UGNjZ3FtRXFNRTRnV1FmWk9TYjN0RFNYTjF1QWFtUDBDdldtSjRsR1o" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "Kp6n74h5t4dXLm9vJ6Uph5uI2ewvJKOxZemQHrph" "uc_cart_id" => "44c9f0479885f329efd3a05663de402c" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/2202" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 15:25:54GET/chapter/2202112192