Pharmacokinetics and Optimal Dosing of Levofloxacin in Children for Drug-Resistant Tuberculosis: An Individual Patient Data Meta-Analysis
Abstract Background Each year 25 000–32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet...
Uloženo v:
| Vydáno v: | Clinical infectious diseases Ročník 78; číslo 3; s. 756 - 764 |
|---|---|
| Hlavní autoři: | , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
US
Oxford University Press
20.03.2024
|
| Témata: | |
| ISSN: | 1058-4838, 1537-6591, 1537-6591 |
| On-line přístup: | Získat plný text |
| Tagy: |
Přidat tag
Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!
|
| Abstract | Abstract
Background
Each year 25 000–32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children.
Methods
Levofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)–recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses.
Results
Data from 242 children (2.8 years [0.2–16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing <24 kg and under <10 years, resulting in approximately half of the exposure in adults. Model-informed doses of 16–33 mg/kg for dispersible tablets or 16–50 mg/kg for nondispersible tablets were required to meet the AUC target without significantly exceeding the median adult Cmax.
Conclusions
Revised weight-band dosing guidelines with doses of >20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses.
Most children receiving levofloxacin for the treatment or prevention of rifampicin- and multidrug-resistant tuberculosis at currently recommended doses will not achieve adult-matched exposures. New guidelines with increased levofloxacin doses for children weighing <24 kg are proposed to ensure adequate exposure. |
|---|---|
| AbstractList | Each year 25 000-32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children.BACKGROUNDEach year 25 000-32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children.Levofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)-recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses.METHODSLevofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)-recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses.Data from 242 children (2.8 years [0.2-16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing <24 kg and under <10 years, resulting in approximately half of the exposure in adults. Model-informed doses of 16-33 mg/kg for dispersible tablets or 16-50 mg/kg for nondispersible tablets were required to meet the AUC target without significantly exceeding the median adult Cmax.RESULTSData from 242 children (2.8 years [0.2-16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing <24 kg and under <10 years, resulting in approximately half of the exposure in adults. Model-informed doses of 16-33 mg/kg for dispersible tablets or 16-50 mg/kg for nondispersible tablets were required to meet the AUC target without significantly exceeding the median adult Cmax.Revised weight-band dosing guidelines with doses of >20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses.CONCLUSIONSRevised weight-band dosing guidelines with doses of >20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses. Abstract Background Each year 25 000–32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children. Methods Levofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)–recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses. Results Data from 242 children (2.8 years [0.2–16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing <24 kg and under <10 years, resulting in approximately half of the exposure in adults. Model-informed doses of 16–33 mg/kg for dispersible tablets or 16–50 mg/kg for nondispersible tablets were required to meet the AUC target without significantly exceeding the median adult Cmax. Conclusions Revised weight-band dosing guidelines with doses of >20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses. Most children receiving levofloxacin for the treatment or prevention of rifampicin- and multidrug-resistant tuberculosis at currently recommended doses will not achieve adult-matched exposures. New guidelines with increased levofloxacin doses for children weighing <24 kg are proposed to ensure adequate exposure. Each year 25 000-32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children. Levofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)-recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses. Data from 242 children (2.8 years [0.2-16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing <24 kg and under <10 years, resulting in approximately half of the exposure in adults. Model-informed doses of 16-33 mg/kg for dispersible tablets or 16-50 mg/kg for nondispersible tablets were required to meet the AUC target without significantly exceeding the median adult Cmax. Revised weight-band dosing guidelines with doses of >20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses. |
| Author | Denti, Paolo Garcia-Prats, Anthony J Hesseling, Anneke C Schaaf, H Simon Savic, Radojka M van der Laan, Louvina E Vonasek, Bryan White, Yasmine N Malik, Amyn A Solans, Belen P Hussain, Hamidah Draper, Heather R |
| Author_xml | – sequence: 1 givenname: Yasmine N surname: White fullname: White, Yasmine N – sequence: 2 givenname: Belen P orcidid: 0000-0003-4621-5480 surname: Solans fullname: Solans, Belen P – sequence: 3 givenname: Paolo surname: Denti fullname: Denti, Paolo – sequence: 4 givenname: Louvina E surname: van der Laan fullname: van der Laan, Louvina E – sequence: 5 givenname: H Simon surname: Schaaf fullname: Schaaf, H Simon – sequence: 6 givenname: Bryan surname: Vonasek fullname: Vonasek, Bryan – sequence: 7 givenname: Amyn A surname: Malik fullname: Malik, Amyn A – sequence: 8 givenname: Heather R surname: Draper fullname: Draper, Heather R – sequence: 9 givenname: Hamidah surname: Hussain fullname: Hussain, Hamidah – sequence: 10 givenname: Anneke C surname: Hesseling fullname: Hesseling, Anneke C – sequence: 11 givenname: Anthony J surname: Garcia-Prats fullname: Garcia-Prats, Anthony J email: garciaprats@wisc.edu – sequence: 12 givenname: Radojka M surname: Savic fullname: Savic, Radojka M email: rada.savic@ucsf.edu |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/38340060$$D View this record in MEDLINE/PubMed |
| BookMark | eNo9kU1LxDAQhoMofp-8S07ipZo0Sdv1tuz6BSuK6LnMJhONdpO1SUV_gv_aiKswwwzMM-_hfXfIug8eCTng7ISzkTjVzuQGZKVcI9tcibqo1Iiv552pppCNaLbITowvjHHeMLVJtkQjJGMV2yZfd8_QL0CHV-cxOR0peENvl8ktoKPTEJ1_osHSGb4H24UP0M7TXJNn15kePbWhp9N-eCruMbqYwCf6MMyx10OXn-MZHXt67Y17d2bIineQHGZmCgnoDSYoxh66z0zukQ0LXcT91dwljxfnD5OrYnZ7eT0ZzwotuUiFQSlra6paG2SitLVmwGFupa2FlfWcgUVljeBNpdAIzbmCRqG2pQClJYpdcvyru-zD24AxtQsXNXYdeAxDbMtRqVi2qmoyerhCh_kCTbvssyv9Z_tnXwaOfoEwLP-vnLU_ubQ5l3aVi_gGIdeDUA |
| CitedBy_id | crossref_primary_10_1016_j_mmifmc_2025_04_368 crossref_primary_10_1016_j_seppur_2024_130350 crossref_primary_10_1093_jac_dkae311 crossref_primary_10_1016_j_prrv_2024_08_002 crossref_primary_10_1016_S1473_3099_25_00157_4 crossref_primary_10_1093_infdis_jiaf401 crossref_primary_10_1016_j_idnow_2025_105062 |
| ContentType | Journal Article |
| Copyright | The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. 2024 The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. |
| Copyright_xml | – notice: The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. 2024 – notice: The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. |
| DBID | TOX CGR CUY CVF ECM EIF NPM 7X8 |
| DOI | 10.1093/cid/ciae024 |
| DatabaseName | Oxford Journals Open Access Collection Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic |
| DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic |
| DatabaseTitleList | MEDLINE - Academic MEDLINE |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: TOX name: Oxford Journals Open Access Collection url: https://academic.oup.com/journals/ sourceTypes: Publisher – sequence: 3 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database |
| DeliveryMethod | fulltext_linktorsrc |
| Discipline | Medicine |
| EISSN | 1537-6591 |
| EndPage | 764 |
| ExternalDocumentID | 38340060 10.1093/cid/ciae024 |
| Genre | Meta-Analysis Research Support, Non-U.S. Gov't Journal Article Research Support, N.I.H., Extramural |
| GrantInformation_xml | – fundername: NIH HHS grantid: T32GM007546 – fundername: NIGMS NIH HHS grantid: T32 GM007546 |
| GroupedDBID | --- ..I .2P .GJ .I3 .ZR 08P 0R~ 1KJ 1TH 29B 2AX 2WC 36B 3O- 4.4 48X 53G 5GY 5RE 5VS 5WD 6J9 70D AABZA AACGO AACZT AAJKP AAJQQ AAMVS AANCE AAOGV AAPGJ AAPNW AAPQZ AAPXW AAQQT AARHZ AAUAY AAUQX AAVAP AAWDT AAYOK ABBHK ABDFA ABEJV ABEUO ABGNP ABIXL ABJNI ABKDP ABLJU ABNGD ABNHQ ABNKS ABOCM ABPLY ABPQP ABPTD ABQLI ABQNK ABSMQ ABTLG ABVGC ABWST ABXSQ ABXVV ABZBJ ACFRR ACGFO ACGFS ACHIC ACPQN ACPRK ACUFI ACUKT ACUTJ ACUTO ACVCV ACYHN ACZBC ADBBV ADEYI ADGZP ADHKW ADHZD ADIPN ADMTO ADNBA ADOCK ADQBN ADQXQ ADRTK ADULT ADVEK ADYVW ADZXQ AEGPL AEGXH AEJOX AEKPW AEKSI AEMDU AEMQT AENEX AENZO AEPUE AETBJ AEUPB AEWNT AEXZC AFFNX AFFQV AFFZL AFIYH AFOFC AFRAH AFSHK AFXAL AFYAG AGINJ AGKEF AGKRT AGMDO AGQXC AGSYK AGUTN AHMBA AHMMS AHXPO AI. AIAGR AIJHB AJDVS AJEEA AJNCP ALMA_UNASSIGNED_HOLDINGS ALUQC ALXQX APIBT APJGH APWMN AQDSO AQKUS AQVQM ASPBG ATGXG AVNTJ AVWKF AXUDD AZFZN BAWUL BAYMD BCRHZ BEYMZ BHONS BTRTY BVRKM BZKNY C1A C45 CDBKE CS3 CZ4 DAKXR DCCCD DIK DILTD DU5 D~K E3Z EBS EE~ EIHJH EJD EMOBN ENERS F5P F9B FECEO FEDTE FLUFQ FOEOM FOTVD FQBLK GAUVT GJXCC H13 H5~ HAR HQ3 HTVGU HVGLF HW0 HZ~ IOX IPSME J21 J5H JAAYA JBMMH JENOY JHFFW JKQEH JLS JLXEF JPM JSG JST JXSIZ KAQDR KBUDW KOP KSI KSN L7B M49 MBLQV MHKGH MJL ML0 N4W N9A NGC NOMLY NOYVH NU- NVLIB O0~ O9- OAUYM OAWHX OBFPC OCZFY ODMLO ODZKP OJQWA OJZSN OK1 OPAEJ OVD OWPYF O~Y P2P P6G PAFKI PB- PEELM PQQKQ Q1. Q5Y QBD RD5 ROX ROZ RUSNO RW1 RXO SA0 SJN TCURE TEORI TJX TMA TOX TR2 VH1 W8F X7H Y6R YAYTL YKOAZ YXANX ZGI ~91 ~S- AGORE AHGBF AJBYB CGR CUY CVF ECM EIF NPM 7X8 |
| ID | FETCH-LOGICAL-c413t-de447fd67cde032f7c0a1abf4f73f47b0afe5fd31865ed3c115a85ecf23a5c4e3 |
| IEDL.DBID | TOX |
| ISICitedReferencesCount | 6 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=001160735500001&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 1058-4838 1537-6591 |
| IngestDate | Wed Oct 01 11:12:17 EDT 2025 Mon Jul 21 06:07:06 EDT 2025 Wed Apr 02 07:06:43 EDT 2025 |
| IsDoiOpenAccess | true |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 3 |
| Keywords | pharmacokinetics levofloxacin drug-resistant tuberculosis pediatrics |
| Language | English |
| License | This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c413t-de447fd67cde032f7c0a1abf4f73f47b0afe5fd31865ed3c115a85ecf23a5c4e3 |
| Notes | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
| ORCID | 0000-0003-4621-5480 |
| OpenAccessLink | https://dx.doi.org/10.1093/cid/ciae024 |
| PMID | 38340060 |
| PQID | 2925000168 |
| PQPubID | 23479 |
| PageCount | 9 |
| ParticipantIDs | proquest_miscellaneous_2925000168 pubmed_primary_38340060 oup_primary_10_1093_cid_ciae024 |
| PublicationCentury | 2000 |
| PublicationDate | 2024-03-20 |
| PublicationDateYYYYMMDD | 2024-03-20 |
| PublicationDate_xml | – month: 03 year: 2024 text: 2024-03-20 day: 20 |
| PublicationDecade | 2020 |
| PublicationPlace | US |
| PublicationPlace_xml | – name: US – name: United States |
| PublicationTitle | Clinical infectious diseases |
| PublicationTitleAlternate | Clin Infect Dis |
| PublicationYear | 2024 |
| Publisher | Oxford University Press |
| Publisher_xml | – name: Oxford University Press |
| SSID | ssj0011805 |
| Score | 2.4892678 |
| SecondaryResourceType | review_article |
| Snippet | Abstract
Background
Each year 25 000–32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive... Each year 25 000-32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin... |
| SourceID | proquest pubmed oup |
| SourceType | Aggregation Database Index Database Publisher |
| StartPage | 756 |
| SubjectTerms | Adult Antitubercular Agents Child Humans Infant Infant, Newborn Levofloxacin Rifampin - pharmacokinetics Rifampin - therapeutic use Tablets - therapeutic use Tuberculosis, Multidrug-Resistant - drug therapy Tuberculosis, Multidrug-Resistant - prevention & control |
| Title | Pharmacokinetics and Optimal Dosing of Levofloxacin in Children for Drug-Resistant Tuberculosis: An Individual Patient Data Meta-Analysis |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/38340060 https://www.proquest.com/docview/2925000168 |
| Volume | 78 |
| WOSCitedRecordID | wos001160735500001&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | 1 |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwjV1bS8MwFA46RHzxfpnXCL4Wu15T38bmUHBzyJS9leT0RMTZytoO_4L_2tOLe5iCQmnJwzmEfGnOl5xLGLsQGAgPPNcgrg2G42vLkAAOEbkgQilcDWV69NOdPxiI8TgY1gGy6S8u_MC-BEKF-olkTWipbbmimM6j-_HcWdASZaQiMYXybEzUaXgLsgsZbD-IZGlQehv_7comW68pI29XGG-xJYy32Wq_dorvsM9hXX76lZpF1WUu44jf01rwRmLdpDgN4InmdzhL9CT5kCTG6enUedyceCvvTvNn4wHTgk7GGR_lCqeQT0g4veLtmN_OE7f4sCrFyrsyk7yPmTS-K5vsssfe9ahzY9Q3LBhAxiszInQInsjzIULTtrQPpmxJpR3t29rxlSk1ujqi_95zMbKB6CPhh6AtW7rgoL3HGnES4wHjplBA1BHQVeB4SknSpr1A2ZJ2YDJQTXZGwx--VzU0wsr3bYfFxcH1iDbZ-Tc0Ic3xwnEhY0zyNLQCyy3JqWiy_QqzuSLaYTtFUZnDP_UfsTWLPkUAmWUes0Y2zfGErcAse0mnp2zZHwt6D4b903J6fQHSGM1w |
| linkProvider | Oxford University Press |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Pharmacokinetics+and+Optimal+Dosing+of+Levofloxacin+in+Children+for+Drug-Resistant+Tuberculosis%3A+An+Individual+Patient+Data+Meta-Analysis&rft.jtitle=Clinical+infectious+diseases&rft.au=White%2C+Yasmine+N&rft.au=Solans%2C+Belen+P&rft.au=Denti%2C+Paolo&rft.au=van+der+Laan%2C+Louvina+E&rft.date=2024-03-20&rft.pub=Oxford+University+Press&rft.issn=1058-4838&rft.eissn=1537-6591&rft.volume=78&rft.issue=3&rft.spage=756&rft.epage=764&rft_id=info:doi/10.1093%2Fcid%2Fciae024&rft.externalDocID=10.1093%2Fcid%2Fciae024 |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1058-4838&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1058-4838&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1058-4838&client=summon |