Frontiers in Medicinal Chemistry

Volume: 1

Compound Optimization in Early and Late Phase Drug Discovery: Acceptable Pharmacokinetic Properties Utilizing Combined Physicochemical, In Vitro and In Vivo Screens

Author(s): Gary W. Caldwell

Pp: 607-618 (12)

DOI: 10.2174/978160805204210401010607

* (Excluding Mailing and Handling)

Abstract

New chemical entities (NCEs) are abandoned in development primarily because of insufficient efficacy, safety issues, and for economic reasons. Since efficacy and safety deficiencies are related in part to pharmacokinetics (PK), uncovering PK defects as early in drug discovery as possible would be highly valuable in reducing NCE failures in preclinical and clinical development. In this review, a strategy is put forth to integrate drug metabolism/pharmacokinetics and toxicology functions into drug discovery. Compound optimization in early and late phase drug discovery is covered emphasizing physicochemical properties, in vitro absorption, metabolism, and in vivo animal PK methodologies. The present study also illustrates the idea of sorting oral bioavailability data into high/intermediate/low categories based on combining high/low rank-ordered information from physicochemical properties and in vitro absorption, metabolism, and serum binding assays. It is shown that by combining the results from solubility, stability, absorption and metabolism assays the high/intermediate/low human oral bioavailability for a series of b- blockers can be approximately predicted. This method has a high sample throughput and should be useful in rank-ordering the predicted oral bioavailability of large collections of compounds at the lead optimization step of drug discovery. These results are useful for selecting compounds for future in vitro-in vivo correlation modeling or in vivo animal testing. This type of approach will improve the decision making process of compound selection in drug discovery.

Related Journals
Related Books
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version175msRequest Duration26MBMemory UsageGET chapter/{id}/{param?}Route
  • warninglog[23:19:44] LOG.warning: Optional parameter $id declared before required parameter $request is implic...
  • Booting (92.05ms)time
  • Application (82.71ms)time
  • 1 x Booting (52.67%)
    92.05ms
    1 x Application (47.33%)
    82.71ms
    12 templates were rendered
    • ebook.chapter_detailschapter_details.blade.php#?blade
    • layouts.chapter_header_sectionchapter_header_section.blade.php#?blade
    • ebook.chapter_top_bannerchapter_top_banner.blade.php#?blade
    • ebook.chapter_bottom_bannerchapter_bottom_banner.blade.php#?blade
    • ebook.ebook_right_bannerebook_right_banner.blade.php#?blade
    • includes.inc_related_journalsinc_related_journals.blade.php#?blade
    • includes.inc_related_ebooksinc_related_ebooks.blade.php#?blade
    • layouts.appapp.blade.php#?blade
    • layouts._login_access_login_access.blade.php#?blade
    • layouts._header_header.blade.php#?blade
    • layouts._main_menu_main_menu.blade.php#?blade
    • layouts._footer_menu_footer_menu.blade.php#?blade
    uri
    GET chapter/{id}/{param?}
    middleware
    web, check_user_access
    controller
    App\Http\Controllers\ChapterController@GetChapterDetails
    namespace
    App\Http\Controllers
    where
    as
    chapter
    file
    app/Http/Controllers/ChapterController.php:1350-1704
    19 statements were executed29.17ms
    • Connection Establishedalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 9. middleware::check_user_access:24
      • 10. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 11. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address (ip_address,visitor_agent,visitor_count, created_on,updated_on) VALUES ('221938058','',1,1739834384,1739834384) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1739834384
      950μsalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 11. middleware::check_user_access:24
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address_detail (ip_address,visitor_url,visitor_count, created_on,updated_on) VALUES ('221938058','/chapter/2291',1,1739834384,1739834384)
      140μsalphaeurekaselec_live_10_06_2022UserAccessCheck.php#27
      Backtrace
      • 11. middleware::check_user_access:27
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_trail WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_corporate WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_token WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_trail WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_corporate WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_token WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 221938058 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221938058) limit 1
      17.83msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 221938058
      • 1: 221938058
      • 2: 221938058
      • 3: 221938058
      • 4: 221938058
      • 5: 221938058
      • 6: 221938058
      • 7: 221938058
      • 8: 221938058
      • 9: 221938058
      • 10: 221938058
      • 11: 221938058
      • 12: 221938058
      • 13: 221938058
      • 14: 221938058
      • 15: 221938058
      Backtrace
      • 14. app/Models/UserAccess/UserAccess.php:784
      • 15. middleware::check_user_access:114
      • 16. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 18. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
    • select * from `chapter` where `chapter_id` = '2291' limit 1
      320μsalphaeurekaselec_live_10_06_2022ChapterController.php#1406
      Bindings
      • 0: 2291
      Backtrace
      • 16. app/Http/Controllers/ChapterController.php:1406
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT(au.last_name, IFNULL(CONCAT(' ', au.initials), ''), ' ', au.first_name) AS authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs, CONCAT_WS(' ',au.first_name, IFNULL(CONCAT(' ', au.initials), ''), IFNULL(CONCAT(' ', au.last_name), '')) as authorsmodal , `au`.*, `af`.`ror_id`, `af`.`institution`, `af`.`department`, `af`.`country`, `af`.`city`, `af`.`address`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.institution,','),''), ifnull(concat(af.department,','),''), ifnull(concat(af.address,','),''), ifnull(concat(af.city,','),''), ifnull(concat(af.country,','),''), ifnull(concat(af.postal_code,','),''), ifnull(concat(af.phone,','),''), ifnull(concat(af.fax,','),''))) SEPARATOR '|')) as `author_affiliation`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.web_view,','),''))) SEPARATOR '|')) as `web_view` from `author` as `au` left join `author_affiliation` as `af` on `au`.`author_id` = `af`.`author_id` where `au`.`chapter_id` = '2291' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      790μsalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 2291
      Backtrace
      • 13. app/Models/Author.php:86
      • 14. app/Http/Controllers/ChapterController.php:1411
      • 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 * from `keywords` where `chapter_id` = '2291'
      250μsalphaeurekaselec_live_10_06_2022ChapterController.php#1415
      Bindings
      • 0: 2291
      Backtrace
      • 15. app/Http/Controllers/ChapterController.php:1415
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select * from `ebook` where `ebook_id` = 157 limit 1
      270μsalphaeurekaselec_live_10_06_2022ChapterController.php#1430
      Bindings
      • 0: 157
      Backtrace
      • 16. app/Http/Controllers/ChapterController.php:1430
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select count(*) as aggregate from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `e`.`ebook_id` where subject_id IN (select subject_id FROM subject_ebook WHERE ebook_id=157) and se.ebook_id!=157 and v.ebook_status='1'
      1.64msalphaeurekaselec_live_10_06_2022Subject.php#238
      Backtrace
      • 16. app/Models/Subject.php:238
      • 17. app/Http/Controllers/ChapterController.php:1434
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 19. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select distinct v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `e`.`ebook_id` where subject_id IN (select subject_id FROM subject_ebook WHERE ebook_id=157) and se.ebook_id!=157 and v.ebook_status='1' limit 10 offset 0
      930μsalphaeurekaselec_live_10_06_2022Subject.php#238
      Backtrace
      • 14. app/Models/Subject.php:238
      • 15. app/Http/Controllers/ChapterController.php:1434
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as aggregate from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where subject_id IN (select subject_id FROM subject_ebook WHERE ebook_id=157)
      490μsalphaeurekaselec_live_10_06_2022Subject.php#255
      Backtrace
      • 16. app/Models/Subject.php:255
      • 17. app/Http/Controllers/ChapterController.php:1435
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 19. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select distinct j.nid as journal_nid,j.title,j.subtitle,j.issn,j.eissn,j.keyword,sj.journal_id,j.image_file_name,j.flyer_link from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where subject_id IN (select subject_id FROM subject_ebook WHERE ebook_id=157) limit 10 offset 0
      570μsalphaeurekaselec_live_10_06_2022Subject.php#255
      Backtrace
      • 14. app/Models/Subject.php:255
      • 15. app/Http/Controllers/ChapterController.php:1435
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `e`.*, `a`.*, `y`.`year`, `e`.`ebook_volume_id` as `ebook_volume_id`, `a`.`ebook_volume_id` as `ebk_vol_id`, `e`.`ebook_id` as `ebk_ebook_id` from `ebook_volume` as `e` left join `author` as `a` on `e`.`ebook_volume_id` = `a`.`ebook_volume_id` left join `year` as `y` on `y`.`id` = `e`.`year_id` where `e`.`ebook_volume_id` = 948 and `e`.`is_uploaded` = 1
      660μsalphaeurekaselec_live_10_06_2022EbookVolume.php#271
      Bindings
      • 0: 948
      • 1: 1
      Backtrace
      • 13. app/Models/EbookVolume.php:271
      • 14. app/Http/Controllers/ChapterController.php:1438
      • 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 count(*) rcd from `ebook_volume` where `ebook_id` = 157 and ebook_volume_id <> 948 limit 1
      310μsalphaeurekaselec_live_10_06_2022EbookVolume.php#999
      Bindings
      • 0: 157
      Backtrace
      • 14. app/Models/EbookVolume.php:999
      • 15. app/Http/Controllers/ChapterController.php:1462
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from ebook_access where content_type_id = '2291' and content_type = 'c' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      360μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ChapterController.php:1465
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from ebook_access where content_type_id = '948' and content_type = 'v' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      360μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ChapterController.php:1478
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. 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,"ebook_volume" as access_level,"" as chapter_id from `user_access_ebook_volume_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 221938058 and j.to_ip >=221938058 )) and ((j.from_date <= 1739834384 and j.to_date >= 1739834384 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 948) 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,"ebook_volume" as access_level,"" as chapter_id from `user_access_ebook_volume_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 221938058 and j.to_ip >=221938058 )) and ((j.from_date <= 1739834384 and j.to_date >= 1739834384 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 948) 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,"ebook_volume" as access_level,"" as chapter_id from `user_access_ebook_volume_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 221938058 and j.to_ip >=221938058 )) and ((j.from_date <= 1739834384 and j.to_date >= 1739834384 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 948)
      800μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1518
      • 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 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 <= 221938058 and j.to_ip >=221938058 )) and ((j.from_date <= 1739834384 and j.to_date >= 1739834384 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2291) 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 <= 221938058 and j.to_ip >=221938058 )) and ((j.from_date <= 1739834384 and j.to_date >= 1739834384 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2291) 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 <= 221938058 and j.to_ip >=221938058 )) and ((j.from_date <= 1739834384 and j.to_date >= 1739834384 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2291)
      840μsalphaeurekaselec_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` = 948 and `b`.`banner_from_date` <= 1739834384 and `b`.`banner_to_date` >= 1739834384 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.45msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 948
      • 3: 1739834384
      • 4: 1739834384
      • 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='944e7fbe7c6d2eef2a3d826adbe74156'
      210μsalphaeurekaselec_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
        fAym6F5dY1V72zH07UIKzKZpXpdzMs2pavFX3yV9
        uc_cart_id
        944e7fbe7c6d2eef2a3d826adbe74156
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/2291" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/2291
        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=eyJpdiI6IjFXaURVQytUNDBxY3hXaS9WbXhQanc9PSIsInZhbHVlIjoiTEg2aXdBZWE0bndHczVwSSt2UGYxbUcxK2c1T3JsVEZwTGxNdjlHcytFQT0iLCJtYWMiOiI5OTQ1ZmJmYWY4OTEwM2JjYjIyNmQ2ZWQ5NTg5NTNjNjMyOWI3N2M3ZWQxMWY4YjNkM2VhMGFhMDk5NjIwOWE4IiwidGFnIjoiIn0%3D; XSRF-TOKEN=eyJpdiI6IlZTUlh4QzJmK1I5NWxkaytiQ2dEWFE9PSIsInZhbHVlIjoieG4zZ1hmREdrVi9yekhPQ2J3ZjRsUU05ZzNYdXZoOTQrZkR2eTZIWERLLysyWWFFNzFwUi9qNXd4THk5cTFBRXVCYUFmRDRYZTJhajQrRWtrZnc4aysyWlVmcS9IZTI2RS9vMGhUK09vL0JLbVFpTHNjeW56bW1UMVhZYWFLVTgiLCJtYWMiOiIzMGZjYzgzYzZhNjMwMTBkNDM3ZTY4ODQ4NWNkZjVhNGNmNDBhZjI5OTU4YzEyZjUxNjE4NjE0NDk0OGZhOWQ3IiwidGFnIjoiIn0%3D; alphaeurekaselectnet_session=eyJpdiI6IjRTZjN6VzhucWRPbjhrdUhLdGZpM3c9PSIsInZhbHVlIjoieitPOUNKR1BGZDVnSWtrV2t6U2VSY2pxbThUdStsc3FsTTFILzBIb1hYNHZ6UDhhaWVMZDl5bDZadDVsbEhPWk9YNEd2c1hIb1YyYklmektsNHArSE5XT1F6RGlQQkdoTC9rK0tCWWVyaUprelV4K3A5WHdpNG9IdnVSSGZiY0IiLCJtYWMiOiJmMmJlMWRjN2ZhYTA4MjUyYTQ2MjZjMWUwMWFlNTQyNjkyNzY5MDFlMmQ2MjAxYWE3NGNmZmNlZjczNTFkNjZhIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6IjFXaURVQytUNDBxY3hXaS9WbXhQanc9PSIsInZhbHVlIjoiTEg2aXdBZWE0bndHczVwSSt2UGYxbUcxK2c1T3JsVEZwTGxNdjlHcytFQT0iLCJtYWMiOiI5OTQ1ZmJmYWY4OTEw" ] "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:3 [ "wayfindertarget" => null "XSRF-TOKEN" => "fAym6F5dY1V72zH07UIKzKZpXpdzMs2pavFX3yV9" "alphaeurekaselectnet_session" => "xu51NuKULdo1RAEdUXJK7l9qER33zThgkT8F9K0e" ]
        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 => "Mon, 17 Feb 2025 23:19:44 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6InF4NjdCVVZzQ2xtRDRvMUVEeW5GU3c9PSIsInZhbHVlIjoiVFNjeVZxR3pMRmk4Qm1Dd3FkRUpsSGlsbGhhKzdJSmZpTFVPY1ZvWU8vbm00clpXRFp1QW01bWZpMFlDTjBQRlA2Smh5R0k2M0xBdzJaalEvdWNmVlNpRDhBeGZKNDRzaVVuZm5wZUVldnFUNDF2OG13VHZtczUzTHpwbWFOMnEiLCJtYWMiOiI4NTc3YWQ0NGQ5MmE3ZmRjMGM1ZmU1Mzg2YmRlN2E2MDMxMzIzNjJmOTQ1MjY3OTgzZTA5NGNhNzU1ZDEyY2VkIiwidGFnIjoiIn0%3D; expires=Thu, 20 Feb 2025 11:19:44 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6InF4NjdCVVZzQ2xtRDRvMUVEeW5GU3c9PSIsInZhbHVlIjoiVFNjeVZxR3pMRmk4Qm1Dd3FkRUpsSGlsbGhhKzdJSmZpTFVPY1ZvWU8vbm00clpXRFp1QW01bWZpMFlDTjBQRlA2Smh5R" 1 => "alphaeurekaselectnet_session=eyJpdiI6IkdGVUgzOTVhKzMxWlN0dHV0MUhkOFE9PSIsInZhbHVlIjoiaHVydXFOV1ZtUkNVcXBYUys0Znk2VDVqZ3A4aEJuS0JSZDgvK2E0VFVOMEEyQmZyNDNLbmdTZ2txOFYrOVljdGpQeDVkVkpacUxIL1RIZ2s3UkI2Z0hWNlB1SC9pc1B1QTFRNzR1MHAxTW9Nb09ENFo5Qm8wc3FaSXlwRXNxNWIiLCJtYWMiOiI2ZTg0MjE2ZGM2YTQ3NjVjMDYxMWZiMmVjY2ZhZTg1ZjllNmU4MDJhMDEwZTZlMDY4NDUyODdhZDgwYzk2Y2Q0IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IkdGVUgzOTVhKzMxWlN0dHV0MUhkOFE9PSIsInZhbHVlIjoiaHVydXFOV1ZtUkNVcXBYUys0Znk2VDVqZ3A4aEJuS0JSZDgvK2E0VFVOMEEyQmZyNDNLbmdTZ2t" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6InF4NjdCVVZzQ2xtRDRvMUVEeW5GU3c9PSIsInZhbHVlIjoiVFNjeVZxR3pMRmk4Qm1Dd3FkRUpsSGlsbGhhKzdJSmZpTFVPY1ZvWU8vbm00clpXRFp1QW01bWZpMFlDTjBQRlA2Smh5R0k2M0xBdzJaalEvdWNmVlNpRDhBeGZKNDRzaVVuZm5wZUVldnFUNDF2OG13VHZtczUzTHpwbWFOMnEiLCJtYWMiOiI4NTc3YWQ0NGQ5MmE3ZmRjMGM1ZmU1Mzg2YmRlN2E2MDMxMzIzNjJmOTQ1MjY3OTgzZTA5NGNhNzU1ZDEyY2VkIiwidGFnIjoiIn0%3D; expires=Thu, 20-Feb-2025 11:19:44 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6InF4NjdCVVZzQ2xtRDRvMUVEeW5GU3c9PSIsInZhbHVlIjoiVFNjeVZxR3pMRmk4Qm1Dd3FkRUpsSGlsbGhhKzdJSmZpTFVPY1ZvWU8vbm00clpXRFp1QW01bWZpMFlDTjBQRlA2Smh5R" 1 => "alphaeurekaselectnet_session=eyJpdiI6IkdGVUgzOTVhKzMxWlN0dHV0MUhkOFE9PSIsInZhbHVlIjoiaHVydXFOV1ZtUkNVcXBYUys0Znk2VDVqZ3A4aEJuS0JSZDgvK2E0VFVOMEEyQmZyNDNLbmdTZ2txOFYrOVljdGpQeDVkVkpacUxIL1RIZ2s3UkI2Z0hWNlB1SC9pc1B1QTFRNzR1MHAxTW9Nb09ENFo5Qm8wc3FaSXlwRXNxNWIiLCJtYWMiOiI2ZTg0MjE2ZGM2YTQ3NjVjMDYxMWZiMmVjY2ZhZTg1ZjllNmU4MDJhMDEwZTZlMDY4NDUyODdhZDgwYzk2Y2Q0IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IkdGVUgzOTVhKzMxWlN0dHV0MUhkOFE9PSIsInZhbHVlIjoiaHVydXFOV1ZtUkNVcXBYUys0Znk2VDVqZ3A4aEJuS0JSZDgvK2E0VFVOMEEyQmZyNDNLbmdTZ2t" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "fAym6F5dY1V72zH07UIKzKZpXpdzMs2pavFX3yV9" "uc_cart_id" => "944e7fbe7c6d2eef2a3d826adbe74156" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/2291" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-17 23:19:44GET/chapter/2291112192