Pharmaceutical &Health Technology Division   NEW DRUG DELIVERY                             TECHNOLOGIES                   ...
Table of ContentsBackground                                                                2-9Case Studies in MEDLINE & EM...
Background Drug Delivery = Dispensing mechanism/technology incorporated into apharmaceutical product that controls the pr...
 Gauging Commercial Potential Through Analysis of PatentsIn a Scrip Report on The Future of Pharmaceutical Innovation pub...
 Searching for information to support the development of new hybrid productsis challenging Drug delivery is an interdisc...
 U.S. regulatory definition of a “combination product” A product composed of two or more components, each of which is re...
Regulatory Jurisdiction Decision & Consequent Road to Market based on… Product’s Primary Mode of Action to achieve its pr...
FDA Centers and Approved Product Categories [continued]    Primary FDA       FDA Consulting Center        Examples    Appr...
Comparison Between Device and Drug/Biologic Product Regulatory Process [continued]     Post-approval reporting requirement...
Medical Device & Diagnostic Industry [magazine] Feature Articles…Sall, B; Lassoff, P; Babbitt, B. “Getting Started with a ...
Example #1: Biologic Drug - Device Combination with Orthopedic ApplicationsINFUSE Bone Graft – Delivers recombinant human ...
Descriptors:   *Absorbable Implants; *Bone Morphogenetic Proteins--administration and dosage--AD; *Intervertebral Disk Dis...
1/9/3DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.15536816   PMID: 12811263 A prospec...
1/9/4DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.12318614   PMID: 12679664 Is INFUSE...
Descriptors: *Bone Morphogenetic Proteins--administration and dosage--AD;*Bone Transplantation--methods--MT; *Lumbar Verte...
What analysis of initial search results revealed                    • Strategy = S INFUSE AND BONE()GRAFT                 ...
S2    4350 BONE MORPHOGENETIC PROTEINS? S S2 AND RECOMBINANT PROTEINS!          170383 RECOMBINANT PROTEINS!      S3      ...
MeSH scope noteFile   72:EMBASE 1993-2004/Sep W2        (c) 2004 Elsevier Science B.V.      Set Items Description      ---...
1/9/1DIALOG(R)File 72:EMBASE(c) 2004 Elsevier Science B.V. All rts. reserv.12755252      EMBASE No: 2004350984  The effect...
DIALOG(R)File 72:EMBASE(c) 2004 Elsevier Science B.V. All rts. reserv.12350876     EMBASE No: 2003469530 Collagen sponges ...
--clinical trial--ct; recombinant human bone morphogenetic protein 2--drugdevelopment--dv; recombinant human bone morphoge...
What analysis of initial search results reveals • For newer compounds, EMBASE drug   descriptors are typically more specif...
? RANK DE                            RANKing Descriptors enables analysis ofStarted processing RANK              indexing ...
? PDIALOG RANK Results--------------------RANK: S4/1-19   Field: /DE File(s): 72(Rank fields found in 19 records -- 495 un...
EMBASE strategies paralleling those shown earlier in MEDLINE…? S RECOMBINANT BONE MORPHOGENETIC PROTEIN 2      S2     285 ...
Example #2: Drug - Device Combination with Cardiac ApplicationsCYPHER Drug-Eluting Stent – Enables local delivery of an im...
1/9/15DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.16391936   PMID: 14981005 Randomiz...
4/6/216862576   PMID: 15057441 Drug-eluting stents for in-stent restenosis and acute myocardial infarction:present data fr...
The long-term clinical results of a platelet glycoprotein IIb/IIIa receptor blocker (Abciximab: Reopro) coated stent in pa...
File   72:EMBASE 1993-2004/Sep W2        (c) 2004 Elsevier Science B.V.          “Trial search” in EMBASE      Set Items D...
A.J. Carter, Providence Heart and Vasc. Institute, Providence St. Vincent  Med. Center, 9205 SW Barnes Road, 97225-5218, P...
Broader strategy to locate other drugs under investigation for stent delivery & restenosis reduction                      ...
Example #3: Drug Combination for Hepatitis C TherapyPEGASYS + RIBAVIRIN – Approved regimen involves separate administratio...
1/6/3DIALOG(R)File 154:(c) format only 2004 The Dialog Corp. All rts. reserv.16545348   PMID: 15225169 Pegylated interfero...
1/9/4DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.16349194   PMID: 15128353 Sudden he...
1/9/8DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.15676426   PMID: 14740531 [Treatmen...
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  1. 1. Pharmaceutical &Health Technology Division NEW DRUG DELIVERY TECHNOLOGIES ONLINE INFORMATION SOURCES Special Libraries & SEARCH STRATEGIES Association Bonnie Snow Director, Pharmaceutical Markets, Dialog Course Description Recent advances in drug delivery involve combinations of drugs or biologics with medical devices. Searching for information to support the development of new hybrid products and assessment of their business implications is challenging. This session will survey the broad spectrum of online databases typically needed, including bioengineering and biomaterials, clinical, and competitive intelligence information sources. Sample searches will also illustrate techniques for constructing effective keyword strategies for retrieving relevant data in a rapidly evolving discipline where little standardized indexing vocabulary is available. SLA Annual Conference – Toronto, June 2005 © Bonnie Snow, 2005
  2. 2. Table of ContentsBackground 2-9Case Studies in MEDLINE & EMBASE INFUSE Bone Graft 10 - 24 CYPHER Drug-Eluting Stent 25 - 31 PEGASYS – Drug Combination for Hepatitis C Therapy 32 - 40 Observations – Indexing Policies & Search Techniques 41Extending Your Reach: Other Biomedical Bibliographic Files Adis Clinical Trials Insight 42 - 47 BIOSIS Previews 48 - 49 Derwent Drug File 50 International Pharmaceutical Abstracts 51 - 52 Complementary Resources: SciSearch, CA Search, JICST, Pascal 52Extending Your Reach: Engineering Literature Resources EI Compendex 53 - 55 INSPEC 56 - 58 A Pertinent Dialindex/OneSearch Category 59 MEDITEC: Biomedical Engineering 59Drug Pipeline Databases: Will They Help in Identifying Products ThatIncorporate New Drug Delivery Technology? Introductory Overview 60 Pharmaprojects 61 - 66 IMS R&D Focus 67 - 72 Adis R&D Insight 73 - 76Full-Text Subject Specialty News Sources for Monitoring Drug DeliveryDevelopments PHIND 77-84 ESPICOM Pharmaceutical & Medical Device News 85 - 86 Prous Science Daily Essentials 87 FDA News 88 - 89 NewsRx Weekly Reports 90 Gale Group Newsletter Database 91 - 94Other Sources of Drug Delivery & Combination Product Information:Syndicated Market Research Reports & Investment Analysts’ Reports 95-97 Page 1
  3. 3. Background Drug Delivery = Dispensing mechanism/technology incorporated into apharmaceutical product that controls the precise anatomical location and timing of therelease of a therapeutic compound with the purpose of optimizing its safety and efficacy.  Familiar (widely accepted) applications – Oral controlled- or sustained-release formulations (e.g., enteric-coated tablets) – Topical preparations for localized delivery of medications to body site affected (e.g., antibacterial, cortisone sprays, ointments, or creams for skin conditions)  Emerging advanced applications – Transdermal patches – Inhalables – Long-acting depot injections – Needle-free injections – Nanotechnology Recent developments in drug delivery also involve, in increasing numbers,combinations of drugs + biologics, drugs + medical devices, or drugs + biologics +devices.  Examples of “hybrid” products: – Antibiotic bone cement – Bandage or wound dressing that incorporates a pain-reducing medication – Photodynamic therapy - Pharmacologically inactive agents administered topically or systemically are converted to active metabolites when exposed to a proprietary light source – Radioimmunotherapy - isotope-labeled monoclonal antibodies – Antimicrobial-coated catheters – Drug-eluting stents Impetus for increased interest in drug delivery technology development? Need to…  Administer new chemical entities consisting of insoluble small molecules or [sometimes unstable] macromolecules arising from biotechnology  Avoid or mitigate effects of metabolic process associated with oral ingestion of a medication (possible reduction in bioavailability, delayed onset of action, systemic side effects)  Improve dosing regimen for less frequent administration  Increase patient compliance & quality of life by introducing more “user-friendly” dosage forms (e.g., inhalable versus injectable insulin, transdermal patch administration in Parkinson’s disease, Alzheimer’s, arthritis)  Reduce healthcare costs (keep patients ambulatory, enable self-care, limit hospitalization and/or need for ongoing monitoring/tests, decrease risk of disease recurrence or severe adverse effects)  Prolong product life cycle, “rescue” drugs nearing patent expiration  Rejuvenate pipeline, re-examine previously investigated products where further development was suspended due to inadequate efficacy. Can delivery enhancement using emerging technology more fully exploit the compound’s potential benefits?  Block/delay competition by employing new modes of drug delivery that will make it more difficult and expensive for would-be generic competitors to achieve comparable bioavailability Page 2
  4. 4.  Gauging Commercial Potential Through Analysis of PatentsIn a Scrip Report on The Future of Pharmaceutical Innovation published in 2004, PJBdiscusses results of their analysis of U.S. patent data from January 2000 through June2003  Total number of patents granted that were directly related to pharmaceutical, biotech, or medical processes, products, or services = 69,823 – 1/3 of these were for devices, diagnostics, or equipment – Another 30% claimed formulations & therapeutic applications (outnumbering those granted for new chemical entities) Indicator of greater concentration on reformulations and extended indications than on new compound development? – 6.5% of patents issued over the 3.5-year period were directly related to drug delivery technology platforms (4,543 in all)  Source – Scrip-Online-Plus record in the Pharmaceutical & Healthcare Industry News Database - PHIND (T 00831852/9 in File 129 on Dialog) The Marketplace Drug delivery technologies increased from 9.6% of total worldwide pharmaceuticalsales in 1995 to 31% of total in 2002, when drug delivery revenue reached $38 billion. Ithas been estimated that drug delivery technology will account for 39% of pharmaceuticalsales by 2007.  Source – Drug Delivery 2003 report from Visiongain, highlighted in an M2 Presswire record in the Gale Group Newsletter Database (T 05574544/9 in File 636 on Dialog) Business Communications Company (BCC) estimated the U.S. market for advanceddrug delivery systems in 2003 at $43.7 billion, expected to rise at an average annualgrowth rate of 11.3% to reach $74.5 B by 2008.  Source – May 2004 Biotechnology Industry Review in BCC Market Research database (T 00239427/9 in File 764 on Dialog) SG Cowen Securities estimates that the U.S. drug-eluting stent market will grow to$3.315 billion in 2005 and $3.46B in 2006  Source – July 2004 report entitled Medical Supplies & Devices: The New World Order in Investext (Report Number 9773565, page 18) Sun Trust predicts that the worldwide market for drug-eluting stents will reach $5.26Bin 2005  Source – Aug 2003 report entitled Medical Devices - Drug-Eluting Stents: Place Your Bets Here! in Investext (Report Number 7572590, page 5) vFinance Investments (NY) predicts that the drug-eluting stent market in the U.S. willgrow to $6.3 billion by 2008  Source – “Drug-Eluting Stent Battle Picks Up Speed,” Hospital Materials Management, May 2004, in the Gale Group Newsletter Database (T 05794001/9 in File 636) Page 3
  5. 5.  Searching for information to support the development of new hybrid productsis challenging Drug delivery is an interdisciplinary science, drawing on expertise in chemistry, biology,physics, mathematics, engineering, and electronics. Developments may be reported in the literature of any of these subject areas, requiring access to a broad cross-section of online resources—many of which represent “unfamiliar territory” for biomedical searchers Retrieving information on specific products is difficult, particularly when a medicaldevice is involved. Brand names for devices are not as well controlled as those for drugs, where regulatory authorities examine names for possible confusion from similarity with existing products. Many device brand names are ambiguous, especially when searched in non-biomedical sources (e.g. ENDEAVOR) Abbreviations commonly used in the literature are also non-exclusive and can lead toirrelevant retrieval (e.g., DES). The new breed of combination products typically employ proprietary technologyoriginating from several different companies, any of which may or may not be cited. – CYPHER drug-eluting stent includes a Johnson & Johnson (Cordis) BX VELOCITY stent modified to deliver a Wyeth drug, via a polymer coating for sustained elution developed by Surmodics. – INFUSE Bone Graft delivers a Wyeth biologic on Integra’s absorbable collagen sponge, embedded in a surgically implanted device produced by Medtronic.  Given this context, determining patent status/intellectual property protection can be arduous.  Monitoring licensing & partnership agreements, m&a activities is particularly important when assessing business implications and the competitive landscape As in any relatively new subject specialty, controlled (standardized & predictable)vocabulary is often unavailable in indexing provided by a given database. The concept of drug delivery and its specific components (chemical compounds, othermechanisms) is frequently overlooked in indexing. The term “combination product” can be misleading.Heretofore, it has been used to describe drugs with two or more active ingredients.The FDA’s recent decision to use the phrase for drug/biologic/device combinations doesnot change its meaning and application in extant database indexing. As a result, the situation is quite confusing (and annoying) from the searcher’s perspective, necessitating extra care in strategy formulation. Page 4
  6. 6.  U.S. regulatory definition of a “combination product” A product composed of two or more components, each of which is regulated by aseparate FDA Center (administrative division)  Drug + Device  Biologic + Device  Drug + Biologic  Drug + Device + Biologic The product’s components can be physically, chemically, or otherwise combined ormixed, e.g….. 1) produced as a single entity (monoclonal antibody + chemotherapy drug) 2) components remain separate, but are packaged together for administration as a unit (e.g., lumbar fusion device marketed with bone morphogenetic protein) 3) components packaged separately, but labeled for use only with another specified product, where both are required to achieve the intended purpose, indication, or effect, e.g., – diagnostic test designed for use with specific drug – Herceptin – branded biologic for concurrent use with drug to achieve synergistic therapeutic effect Note that this regulatory definition does not apply to combination drug-drug products Excludes CADUET (Pfizer’s combination of its lipid-lowering agent LIPITOR with an antihypertensive, NORVASC, for simultaneous treatment of high blood pressure and high cholesterol) or to drug delivery devices developed for administration of unspecified agents (syringes, infusion pumps) Key Regulatory Issue (Worldwide, not just in USA): Jurisdiction Traditionally, separate divisions (“Centers”) within government agencies areresponsible for marketing authorization of drugs, devices, or biologics.  When a hybrid product is proposed, regulatory jurisdiction is controversial. FDA’s Office of Combination Products (OCP) was established in December 2002 toassist in determining which Center will be responsible for premarket review of a productcandidate & its post-market surveillance, once approved. – OCP also tracks statistics related to the process, monitoring timeliness (published in an annual report to U.S. Congress) – Produces relevant Guidance documents for industry Page 5
  7. 7. Regulatory Jurisdiction Decision & Consequent Road to Market based on… Product’s Primary Mode of Action to achieve its principal therapeutic effect Relies on chemical action within or on the body, metabolism of agent administered?Example: biodegradable polymer wafer implanted for antineoplastic drug delivery – CDER (Center for Drug Evaluation & Research) or – CBER (Center for Biologics Evaluation & Research)  NDA or BLA submission required for marketing authorization  More & larger clinical trials, longer application review times, extensive post-marketing surveillance mandated, as well as higher user fees Primary intended purpose not dependent on metabolism or chemical action?Example: Coronary stent coated with a drug – CDRH (Center for Devices & Radiological Health)  PMA or 510(k) submission, depending on “class” (risk category) of device  One relatively small clinical trial, shorter review time, lower user fees, post-marketing surveillance focused on production process quality control If PMOA cannot be determined (too early in development process or dual action)… – Premarket review assigned to Center responsible for reviewing similar products in the past (historical precedents) – If no similar product heretofore, assigned to Center likely to have most expertise in reviewing the product’s component that poses more questions regarding safety & efficacy Example: Contact lens combined with glaucoma drug (CDER) Example: Powered catheter that uses ultrasound energy and thrombolytic agent to break up clots (CDRH) Source – Patterson, N. “Faster Approvals for Drug and Device Combination Products.” TheBBI Newsletter, Sept 2003, in Gale Group Newsletter Database (T 05636250/9 in File 636 onDialog). Extracts from this 7-page, 3,658-word article shown below…FDA Centers and Approved Product Categories Primary FDA FDA Consulting Center Examples Approval Center CDRH (device) CDER (drugs) Bone cement containing antimicrobial agent Cardiac pacemaker lead with steroid coated tip Condom or diaphragm with contraceptive or Antimicrobial agent Drug eluting stent Dental device with fluoride Page 6
  8. 8. FDA Centers and Approved Product Categories [continued] Primary FDA FDA Consulting Center Examples Approval Center CDRH (device) CBER (biologic) Spinal-fusion cage with recombinant human bone morphogenic protein Catheters that deliver angiogenesis gene to heart muscle CBER (biologic) CDRH (device) Plasmapheresis devices Blood banking equipment CDER (drug) CDRH (device) Photoactivated drugs with proprietary light source * Oxygen tank for therapy Prefilled syringe Transdermal patch CDRH (device) None Devices that calculate drug dosages Glucose monitor device/insulin pump combination Drug delivery pump and/or catheter infusion pump for implantation ** Iontophoreses device ** Nebulizer ** Small particle aerosol generator for ventilated patient Splitter block for mixing nitrous oxide and oxygen Syringe: jet injector; storage and dispensing equipment ** Ultrasound infusion catheters ** * Resulted in a new drug approval for the drug and several separate PMA approvalsfor the device ** Combination products requiring CDER/CBER consultation when prefilled or labeledfor a specific drugComparison Between Device and Drug/Biologic Product Regulatory Process Review Requirements Device Drug/Biologic Can use prototype in clinical trial Yes No Product life cycle Short Long Ease of in vitro assessment High Low Influence of physician technique on results High Low Ability to visualize performance after use High Low Number of full-scale clinical studies usually required 1 2 Number of regulatory classes 3 1 Extent of clinical data required Low High Average number patients in clinical trial Hundreds Thousands Average time to FDA approval once all required testing complete and submitted for review 510(k) 30-90 days PMA (Includes IDE study) 2 to 5 years NDA/BLA (pharmaceutical) 7 to 10 years (Includes IND studies) Page 7
  9. 9. Comparison Between Device and Drug/Biologic Product Regulatory Process [continued] Post-approval reporting requirements to the FDA 510(k) Low PMA Moderate to High NDA/BLA (pharmaceutical) High Approximate clinical trial costs 510(k) $300,000-$500,000 PMA $2 million-$4 million NDA/BLA (pharmaceutical) $200 million-$300 million Sources: Semih Oktay, PhD, president, CardioMed Device Consultants, Martha Feldman, president, Drug and Device Development Co.Regulatory Situation in European Union (2nd largest world market) No separate agency dedicated to determining jurisdiction Manufacturers/applicants can select least burdensome route to approval (if deviceinvolved: easier to obtain CE Mark than to complete the marketing authorization processfor drugs/biologics)CE Mark – Indicates that manufacturer has conformed with European regulatory requirements – Applicant selects one of more than 60 Notified Bodies to handle evaluation of safety/efficacy/quality control data. Certification by one constitutes authorization to market throughout the EU Source – Murphy, P. Understanding How Medical Devices are Approved in the U.S., Europeand Canada, RBC Capital Markets report issued January 2003. Fulltext available in Investext(Report Number 7440396) Source – Patterson, N. “Faster Approvals for Drug and Device Combination Products.” TheBBI Newsletter, Sept 2003, in Gale Group Newsletter Database (T 05636250/9 in File 636).Also cited previously as source of extracts shown above.Selected Web Resources for Additional Background InformationFDA Office of Combination Productshttp://www.fda.gov/oc/combination/Combination Products Primary Mode of Action. Proposed Rule: May 7, 2004, Federal Registerhttp://www.fda.gov/OHRMS/DOCKETS/98fr/04-10447.htmMX [magazine for medical device executives]Sumner, K. “Attitude Adjustment.” June 2003http://www.devicelink.com/MX/archive/03/05/sumner.html Page 8
  10. 10. Medical Device & Diagnostic Industry [magazine] Feature Articles…Sall, B; Lassoff, P; Babbitt, B. “Getting Started with a Combination Product: Part I.” March 2003.http://www.devicelink.com/mddi/archive/03/03/018.html--------. “Getting Started with a Combination Product Part II: European Regulations.” April 2003.http://www.devicelink.com/mddi/archive/03/04/019.htmlSwain, E. “Blazing New Paths for Product Introductions.” Oct 2003.http://www.devicelink.com/mddi/archive/03/09/001.htmlLoob, W. “Combination Products Enhance Capabilities, Pose New Challenges.” (May 2000).http://www.devicelink.com/mddi/archive/00/05/009.htmlSpecial Libraries Association – Pharmaceutical & Health Technology DivisionPresentations…Rosenberg, B. “Breaking New Ground: Combination Products & Information Strategies.”http://www.sla.org/division/dpht/Annual2004/presentations2004/CombProducts_Rosenberg.pptWhite, B. “Breaking New Ground: Combination Products & Information Needs.”http://www.sla.org/division/dpht/Annual2004/presentations2004/CombProducts_White.pptMeisner, C and White, B. “Beyond Science Fiction: Medical Technology in the 21st Century.”http://www.sla.org/division/dpht/Annual2003/presentations2003/cindy_meisner.pptWhat’s Next? Three “case studies,” each focusing on an approved combination product,conducted to explore major biomedical database indexing characteristics andillustrate search strategy construction.Followed by… A survey of additional, complementary bibliographic resources in medicine &engineering. Detailed examination of drug pipeline database indexing of combination products &sample search strategies. A final section highlighting major full-text subject specialty news sources Page 9
  11. 11. Example #1: Biologic Drug - Device Combination with Orthopedic ApplicationsINFUSE Bone Graft – Delivers recombinant human bone morphogenetic protein-2 viaan absorbable collagen sponge embedded in a biodegradable medical device surgicallyimplanted at the body site where bone regeneration is needed. Currently approved in theU.S. for use with the LT-CAGE Lumbar Tapered Fusion Device as an alternative toautologous bone transplants (autografts) to achieve spinal fusion, enabling shorter post-operative recovery time.File 154:MEDLINE(R) 1990-2004/Sep W2 (c) format only 2004 The Dialog Corp. Set Items Description --- ----- ----------- 1st in a series of “test searches” for? S INFUSE AND BONE()GRAFT information on recently approved 394 INFUSE combination products, conducted to explore 281798 BONE database indexing characteristics and 106284 GRAFT illustrate strategy construction 4260 BONE(W)GRAFT S1 6 INFUSE AND BONE()GRAFT? T S1/9/1-6 1/9/1DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.16774640 PMID: 15198497 Lumbar interbody fusion after treatment with recombinant human bonemorphogenetic protein-2 added to poly(L-lactide-co-D,L-lactide) bioresorbableimplants. Lanman Todd H; Hopkins Thomas J DBA California Spine Group, and Century City Hospital, Los Angeles,California, USA. toddlanman@aol.com Neurosurg Focus (United States) Mar 15 2004, 16 (3) pE9, ISSN1092-0684 Journal Code: 100896471 Document type: Case Reports; Clinical Trial; Journal Article Languages: ENGLISH Record type: Completed Trial using a different implantable device Subfile: INDEX MEDICUS Object. To evaluate the effectiveness of recombinant human bonemorphogenetic protein-2 (rhBMP-2) combined with a bioresorbable implant, theauthors conducted a prospective study of 43 patients with degenerative lumbardisc disease who underwent transforaminal lumbar interbody fusion.Methods. The authors used Infuse bone graft, which consisted of rhBMP-2applied to an absorbable collagen sponge and contained within a HYDROSORBTelamon bioresorbable implant to perform the fusion. Multilevel fusions wereperformed in 30% of the 43 patients, for a total of 57 levels. At 6 monthspostoperatively, x-ray films and computerized tomography (CT) scansdemonstrated solid fusion in 98% of 41 patients. Improvement from the baselineOswestry Disability Rating was demonstrated at 6 months postoperatively in 68%of the patients, based on the Oswestry Disability Questionnaire. At 12 monthsall 11 patients in whom CT scans were obtained showed complete bridging ofbone; there were no device-related complications. Conclusions. Results in thisseries provide evidence of the feasibility of using HYDROSORB Telamonbioresorbable spacers in combination with Infuse bone graft for lumbar spinefusion. Tags: Female; Human; Male [record continues on next page] Page 10
  12. 12. Descriptors: *Absorbable Implants; *Bone Morphogenetic Proteins--administration and dosage--AD; *Intervertebral Disk Displacement--therapy--TH; *Lumbar Vertebrae--surgery--SU; *Polyesters--administration anddosage--AD; *Spinal Fusion--methods--MT; Adolescent; Adult; Aged; BoneTransplantation; Collagen--administration and dosage--AD; Follow-Up Studies;Intervertebral Disk--surgery--SU; Intervertebral Disk Displacement--diagnosis--DI; Intervertebral Disk Displacement--surgery--SU; Length ofStay; Materials Testing; Middle Aged; Orthopedic Fixation Devices;Osseointegration--drug effects--DE; Prospective Studies; RecombinantProteins CAS Registry No.: 0 (Bone Morphogenetic Proteins); 0 (Polyesters); 0 (Recombinant Proteins); 0 (bone morphogenetic protein 2); 26969-66-4 (poly(lactide)); 9007-34-5 (Collagen) Specific protein indexed under broad class Record Date Created: 20040616 terms. Delivery mechanisms & their major Record Date Completed: 20040826 chemical components identified. 1/9/2DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.16774637 PMID: 15198494 Early findings in a pilot study of anterior cervical interbody fusion in which recombinant human bone morphogenetic protein-2 was used with poly(L-lactide-co-D,L-lactide) bioabsorbable implants. Lanman Todd H; Hopkins Thomas J California Spine Group, Century City Hospital, Los Angeles, California, USA. Neurosurg Focus (United States) Mar 15 2004, 16 (3) pE6, ISSN1092-0684 Journal Code: 100896471 Document type: Evaluation Studies; Journal Article Languages: ENGLISH Record type: Completed Another study using an alternative device implant Subfile: INDEX MEDICUS OBJECT: The goal of this study was to assess the efficacy of bioabsorbableinterbody spacers in cervical spine fusion. METHODS: The authors report on aprospective examination of 20 patients with degenerative cervical disc diseasewho underwent anterior cervical fusion at 28 total levels. The authors usedInfuse bone graft (that is, recombinant human bone morphogenetic protein-2applied to an absorbable collagen sponge and contained within a Cornerstone-HSRbioabsorbable spacer. Multiple-level fusions were performed in 30% of thesepatients. At 3 months postfusion, radiographs and computerized tomography scansdemonstrated bridging bone in 100% of the patients. Improvement from baselinescores in physical functioning, mental health, and bodily pain was demonstratedat 3 months postoperatively according to results of the Short Form-36 Version2 health survey. There were no device-related complications. CONCLUSIONS: Theresults in this series indicate that the use of Cornerstone-HSR as abioabsorbable interbody spacer in combination with Infuse bone graft may be analternative treatment for cervical spine fusion. Tags: Female; Human; Male Descriptors: *Absorbable Implants; *Bone Morphogenetic Proteins--administration and dosage--AD; *Cervical Vertebrae--surgery--SU; *Polyesters--administration and dosage--AD; *Spinal Fusion--methods--MT; Adult; CervicalVertebrae--pathology--PA; Cervical Vertebrae--radiography--RA; Follow-UpStudies; Intervertebral Disk--surgery--SU; Intervertebral Disk Displacement--diagnosis--DI; Intervertebral Disk Displacement--surgery--SU; MaterialsTesting; Middle Aged; Orthopedic Fixation Devices; Osseointegration--drugeffects--DE; Pilot Projects; Prospective Studies; Recombinant Proteins CAS Registry No.: 0 (Bone Morphogenetic Proteins); 0 (Polyesters); 0 (Recombinant Proteins); 0 (bone morphogenetic protein 2); 26969-66-4 (poly(lactide)) Record Date Created: 20040616 Indexing omits reference to delivery vehicle (collagen) Record Date Completed: 20040826 Page 11
  13. 13. 1/9/3DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.15536816 PMID: 12811263 A prospective, randomized, controlled cervical fusion study using recombinanthuman bone morphogenetic protein-2 with the CORNERSTONE-SR allograft ring andthe ATLANTIS anterior cervical plate. Baskin David S; Ryan Patrick; Sonntag Volker; Westmark Richard; WidmayerMarsha A Department of Neurosurgery, Baylor College of Medicine, and VeteransAffairs Medical Center, Houston, Texas 77030, USA. dbaskin@tmh.tmc.edu Spine (United States) Jun 15 2003, 28 (12) p1219-25; discussion 1225,ISSN 1528-1159 Journal Code: 7610646 Document type: Clinical Trial; Journal Article; Randomized Controlled Trial Languages: ENGLISH Record type: Completed Subfile: INDEX MEDICUS STUDY DESIGN: A prospective, randomized, pilot clinical trial comparedrecombinant human bone morphogenetic protein-2 (rhBMP-2) with iliac crestautograft bone for the treatment of human cervical disc disease. OBJECTIVE:To examine the safety and effectiveness of using INFUSE Bone Graft (rhBMP-2applied to an absorbable collagen sponge), as compared with an autogenous iliaccrest bone graft placed inside the CORNERSTONE-SR fibular allograft, inanterior cervical discectomy and interbody fusion. SUMMARY OF BACKGROUNDDATA: Recombinant human bone morphogenetic protein-2 is an osteoinductiveprotein that induces a reliable fusion in the lumbar spine, but it has notbeen studied in patients with degenerative cervical disc disease. METHODS:For this study, 33 patients with degenerative cervical disc disease wererandomly assigned to investigational or control groups. The investigationalgroup received a fibular allograft (CORNERSTONE-SR Allograft Ring) with anrhBMP-2-laden collagen carrier inside the graft along with an ATLANTIS anteriorcervical plate. The control group received a fibular allograft with cancellousiliac crest autograft placed inside it, along with an ATLANTIS anteriorcervical plate. . . . Tags: Comparative Study; Female; Human; Male; Support, Non-U.S. Govt Descriptors: *Bone Morphogenetic Proteins--administration and dosage--AD;*Bone Transplantation--methods--MT; *Cervical Vertebrae--surgery--SU;*Ilium--transplantation--TR; *Spinal Diseases--surgery--SU; *Spinal Fusion--methods--MT; Cervical Vertebrae--radiography--RA; Diskectomy; Middle Aged;Osseointegration; Osteogenesis--drug effects--DE; Pilot Projects; ProspectiveStudies; Recombinant Proteins--administration and dosage--AD; Safety; SpinalDiseases--radiography--RA; Tomography, X-Ray Computed; Transplantation,Autologous; Treatment Outcome CAS Registry No.: 0 (Bone Morphogenetic Proteins); 0 (RecombinantProteins); 0 (bone morphogenetic protein 2) Record Date Created: 20030617 Record Date Completed: 20040129 Study focused on efficacy of biologic drug-induced osteogenesis versus bone transplantation (autograft). Delivery mechanism ignored in indexing. Page 12
  14. 14. 1/9/4DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.12318614 PMID: 12679664 Is INFUSE bone graft superior to autograft bone? An integrated analysis of clinical trials using the LT-CAGE lumbar tapered fusion device. Burkus J Kenneth; Heim Stephen E; Gornet Matthew F; Zdeblick Thomas A Spine Service, The Hughston Clinic, Columbus, Georgia, USA.JKB66@knology.net Journal of spinal disorders & techniques (United States) Apr 2003, 16 (2)p113-22, ISSN 1536-0652 Journal Code: 101140323 Document type: Journal Article; Meta-Analysis Languages: ENGLISH Record type: Completed Subfile: INDEX MEDICUS Multicenter human clinical studies of patients undergoing anterior lumbarfusion have been conducted using recombinant bone morphogenetic protein orrhBMP-2 on an absorbable collagen sponge, marketed as INFUSE Bone Graft, orautograft implanted in the LT-CAGE Lumbar Tapered Fusion device. An integratedanalysis of multiple clinical studies was performed … . . . Tags: Comparative Study; Female; Human; Male Descriptors: *Bone Substitutes; *Bone Transplantation--statistics andnumerical data--SN; *Spinal Diseases--epidemiology--EP; *Spinal Fusion--statistics and numerical data--SN; *Transplantation, Autologous--statisticsand numerical data--SN; Analysis of Variance; Bone Substitutes--therapeuticuse--TU; Bone Transplantation--methods--MT; Clinical Trials--statistics andnumerical data--SN; Collagen--therapeutic use--TU; Spinal Diseases--surgery--SU; Spinal Fusion--instrumentation--IS; Spinal Fusion--methods--MT;Transplantation, Autologous--methods--MT CAS Registry No.: 0 (Bone Substitutes); 9007-34-5 (Collagen) Record Date Created: 20030407 Indexing fails to identify composition of Record Date Completed: 20030604 bone substitute (recombinant protein). 1/9/5DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.12110870 PMID: 12438990 Clinical and radiographic outcomes of anterior lumbar interbody fusion usingrecombinant human bone morphogenetic protein-2. Burkus J Kenneth; Transfeldt Ensor E; Kitchel Scott H; Watkins Robert G;Balderston Richard A Hughston Spine Service, The Hughston Clinic, Columbus, Georgia31908-9517, USA. jkb66@knology.net Spine (United States) Nov 1 2002, 27 (21) p2396-408, ISSN 1528-1159Journal Code: 7610646 Document type: Clinical Trial; Journal Article; Multicenter Study;Randomized Controlled Trial Languages: ENGLISH Record type: Completed Subfile: INDEX MEDICUS STUDY DESIGN: A prospective, nonblinded, multicenter study of outcomes inpatients undergoing single-level anterior lumbar discectomy and interbodyfusion with InFUSE Bone Graft. OBJECTIVE: To determine the safety andeffectiveness of InFUSE Bone Graft applied to an absorbable collagen spongein anterior lumbar interbody fusion with threaded cortical allografts. [remainder of abstract omitted here. Indexing shown on next page] Page 13
  15. 15. Descriptors: *Bone Morphogenetic Proteins--administration and dosage--AD;*Bone Transplantation--methods--MT; *Lumbar Vertebrae--drug effects--DE;*Lumbar Vertebrae--surgery--SU; *Osteogenesis--drug effects--DE; *SpinalFusion--methods--MT; Adult; Aged; Bone Morphogenetic Proteins--adverseeffects--AE; Collagen--administration and dosage--AD; Diskectomy; Drug Carriers--administration and dosage--AD; Drug Implants--administration anddosage--AD; Ilium--transplantation--TR; Intervertebral Disk Displacement--complications--CO; Intervertebral Disk Displacement--surgery--SU; Low BackPain--etiology--ET; Low Back Pain--surgery--SU; Lumbar Vertebrae--radiography--RA; Middle Aged; Prospective Studies; Recombinant Proteins--administration anddosage--AD; Recombinant Proteins--adverse effects--AE; Spinal Fusion--adverseeffects--AE; Spinal Fusion--instrumentation--IS; Tomography, X-Ray Computed;Treatment Outcome CAS Registry No.: 0 (Bone Morphogenetic Proteins); 0 (Drug Carriers);0 (Drug Implants); 0 (Recombinant Proteins); 0 (bone morphogenetic protein2); 9007-34-5 (Collagen) Record Date Created: 20021119 Record Date Completed: 20030113 1/9/6DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.12082246 PMID: 12408742 BMP 2--Genetics Institute/Medtronic-Sofamor Danek/Integra. Bone morphogeneticprotein 2--Genetics Institute/Medtronic-Sofamor Danek/Integra, INFUSE BoneGraft, recombinant human bone morphogenetic protein 2--Genetics Institute/Medtronic-Sofamor Danek/Integra, RhBMP 2--Genetics Institute/Medtronic-SofamorDanek/Integra. BioDrugs - clinical immunotherapeutics, biopharmaceuticals and genetherapy (New Zealand) 2002, 16 (5) p376-7, ISSN 1173-8804Journal Code: 9705305 Document type: Journal Article Languages: ENGLISH Genetics Institute (Wyeth) is collaborating with Medtronic-Sofamor Danek(which specialises in spinal reconstruction) and Integra Life Sciences todevelop a BMP 2 product [INFUSE Bone Graft] for use in spinal reconstructionin North America. The INFUSE Bone Graft product has been approved for use inlumbar interbody spinal fusion procedures in the USA and is in phase III trialsfor use in lumbar posterolateral spinal fusion procedures. During theprocedure, damaged disc is replaced with a collagen sponge (IntegrasAbsorbable Collagen Sponge) soaked with BMP 2, which is held in place within animplanted cage device (LT-CAGE Lumbar Tapered Fusion Device); the fusionprocess subsequently requires several months to complete. However, the patientis able to leave hospital the day after the operation, whereas in conventionalspinal surgery a longer recovery time is required. The procedure supersedes theuse of autograft bone as it uses a recombinant human bone morphogenic protein,rhBMP-2, which induces the body to grow its own bone where required. GeneticsInstitute has cloned and expressed bone morphogenic proteins 1-7 andestablished manufacturing processes by recombinant DNA technology. Bonemorphogenic proteins may be useful in the treatment of osteoporosis andorthopaedic trauma. BMP 2 is also being developed for bone regeneration as animplanted device and as an injectable formulation. Genetics Institute is alsocollaborating with Integra LifeSciences to develop a formulation of BMP 2 withIntegras absorbable collagen-based structures for fracture treatment, which isawaiting approval in the USA. Tags: Human Descriptors: *Bone Morphogenetic Proteins--therapeutic use--TU; *DrugIndustry--trends--TD; Clinical Trials--statistics and numerical data--SN;Musculoskeletal Diseases--drug therapy--DT; Musculoskeletal Diseases--metabolism--ME Indexing very general—but highly informative abstract. Demonstrates utility of brand name inclusion in online strategies—augmented with preferred MeSH terms, as shown on next page. Page 14
  16. 16. What analysis of initial search results revealed • Strategy = S INFUSE AND BONE()GRAFT – Only 6 records retrieved – small enough sample to survey all – Note: Potential ambiguity of brand name • Brand names are accessible in MEDLINE only if included in original title and abstract (if latter provided online) • Viewing records in full format – rather than just format 8 (title & indexing only) – assists in identifying “natural language” terms & their synonyms that may be needed to improve the strategy when Descriptors do not “tell the whole story” Information to Change the World Results on Page 10-14 What analysis of initial search results revealed • Specific protein indexed under broad “class” or category MeSH descriptors – “Bone Morphogenetic Proteins” + “Recombinant Proteins” in record #1-3,5 – Only “Bone Morphogenetic Proteins” in record #6 – “Bone Substitutes” in record #4 – Conclusion? • Will need to combine MeSH descriptors with results of a “free text” search for terms identifying the specific protein (RHBMP2 & variants) Information to Change the World Results on Page 10-14 What analysis of initial search results revealed • Delivery mechanism & its composition indexed in 4 out of 6 records, but terms varied – Absorbable Implants – 2 records – Polyesters – 2 records – Collagen – 3 records – Drug Implants – 1 record – Drug Carriers – 1 record – Conclusion? • OR together terms, accepting records containing any or all of them. Search COLLAGEN without field qualification to locate occurrences beyond /DE • Application/indication indexing more consistent – Spinal Fusion in 5 out of 6 records – Conclusion? Okay to use without embellishment Information to Change the World Results on Page 10-14? S BONE MORPHOGENETIC PROTEINS Page 15
  17. 17. S2 4350 BONE MORPHOGENETIC PROTEINS? S S2 AND RECOMBINANT PROTEINS! 170383 RECOMBINANT PROTEINS! S3 847 S2 AND RECOMBINANT PROTEINS!? S S3 AND SPINAL FUSION 6662 SPINAL FUSION S4 63 S3 AND SPINAL FUSION? S S4 AND (COLLAGEN OR DRUG CARRIERS OR DRUG IMPLANTS OR ABSORBABLE IMPLANTS) 71758 COLLAGEN 7979 DRUG CARRIERS 4126 DRUG IMPLANTS 1349 ABSORBABLE IMPLANTS S5 35 S4 AND (COLLAGEN OR DRUG CARRIERS OR DRUG IMPLANTS OR ABSORBABLE IMPLANTS)? S S5 NOT S1 S6 31 S5 NOT S1? S RHBMP2 OR RHBMP()2 OR RECOMBINANT()HUMAN()BONE()MORPHOGENETIC()PROTEIN()2 11 RHBMP2 440 RHBMP 2382742 2 411 RHBMP(W)2 336 RECOMBINANT(W)HUMAN(W)BONE(W)MORPHOGENETIC(W)PROTEIN(W)2 S7 494 RHBMP2 OR RHBMP()2 OR RECOMBINANT()HUMAN()BONE()MORPHOGENETIC()PROTEIN()2? S S6 AND S7 S8 23 S6 AND S7? T S8/6/1-6 8/6/116228877 PMID: 15069140 Recombinant human bone morphogenetic protein-2 enhances anterior spinal fusion in a thoracoscopically instrumented animal model.Apr 2004 8/6/216172389 PMID: 14623404 Collagen sponges for bone regeneration with rhBMP-2.Nov 28 2003 8/6/315935452 PMID: 12973141 Lumbar spinal fusion with a mineralized collagen matrix and rhBMP-2 in a rabbit model.Sep 1 2003 8/6/415682262 PMID: 12897477 Bone morphogenetic proteins and spinal surgery.Aug 1 2003 8/6/514529309 PMID: 10528370 Lumbar spinal fusion using recombinant human bone morphogenetic protein in the canine. A comparison of three dosages and two carriers.Oct 1 1999 8/6/614516722 PMID: 10515009 Experimental spinal fusion using sintered bovine bone coated with type I collagen and recombinant human bone morphogenetic protein-2.Sep 15 1999 Page 16
  18. 18. MeSH scope noteFile 72:EMBASE 1993-2004/Sep W2 (c) 2004 Elsevier Science B.V. Set Items Description --- ----- -----------? S INFUSE AND BONE()GRAFT Note higher recall from brand name 237 INFUSE strategy in EMBASE, compared to 187285 BONE MEDLINE (19 versus 6). 103696 GRAFT 6719 BONE(W)GRAFT S1 19 INFUSE AND BONE()GRAFT? T S1/6/ALL 1/6/112755252 EMBASE No: 2004350984 The effectiveness of rhBMP-2 in replacing autograft: An integrated analysis of three human spine studies 1/6/212727550 EMBASE No: 2004319349 Tissue engineering: The current status of this futuristic modality in head neck reconstruction . . 1/6/612350876 EMBASE No: 2003469530 Collagen sponges for bone regeneration with rhBMP-2 1/6/712219518 EMBASE No: 2003321207 Clinical applications of recombinant human BMPs: Early experience and future development . .After browsing titles, full display of a few sample records enables exploration of EMBASEindexing characteristics… Page 17
  19. 19. 1/9/1DIALOG(R)File 72:EMBASE(c) 2004 Elsevier Science B.V. All rts. reserv.12755252 EMBASE No: 2004350984 The effectiveness of rhBMP-2 in replacing autograft: An integrated analysis of three human spine studies Burkus J.K.; Heim S.E.; Gornet M.F.; Zdeblick T.A. Dr. J.K. Burkus, The Hughston Clinic, 6262 Veterans Pkwy., Columbus, GA 31908-9517 United States Orthopedics ( ORTHOPEDICS ) (United States) 2004, 27/7 (723-728) LANGUAGE: ENGLISH NUMBER OF REFERENCES: 17BRAND NAME/MANUFACTURER NAME: infuse bone graft/Medtronic Sofamor Danek/United StatesMANUFACTURER NAMES: Wyeth/United States; Medtronic Sofamor Danek/UnitedStatesDEVICE BRAND NAME/MANUFACTURER NAME: LT-CAGE Lumbar Tapered Fusion Device/Medtronic Sofamor Danek/United StatesDEVICE MANUFACTURER NAMES: Medtronic Sofamor Danek/United StatesDRUG DESCRIPTORS:*bone morphogenetic protein 2--clinical trial--ct; *bone morphogeneticprotein 2--drug therapy--dt; *bone morphogenetic protein 2--pharmaceutics--pr; *bone morphogenetic protein 2--pharmacology—pd; recombinant protein--clinical trial--ct; recombinant protein--drug therapy--dt; recombinant protein--pharmaceutics--pr; recombinant protein--pharmacology--pd; collagen; drugcarrier; antiinflammatory agent—drug therapy--dtMEDICAL DESCRIPTORS:*bone graft; *anterior spine fusion; drug efficacy; lumbar spine; drug deliverysystem; statistical analysis; treatment outcome; intermethod comparison;autograft; spine disease--diagnosis--di; spine disease--drug therapy--dt; spinedisease--surgery--su; spine disease--therapy--th; degenerative disease--diagnosis--di; degenerative disease--drug therapy--dt; degenerative disease--surgery--su; degenerative disease--therapy--th; computer assisted tomography;operation duration; bleeding; hospitalization; work capacity; low back pain—drug therapy--dt; low back pain--surgery--su; low back pain--therapy--th;physiotherapy; drug mechanism; human; male; female; major clinical study;clinical trial; controlled study; aged; adult; articleDRUG TERMS (UNCONTROLLED): infuse bone graftCAS REGISTRY NO.: 9007-34-5 (collagen)SECTION HEADINGS: 027 Biophysics, Bioengineering and Medical Instrumentation 030 Clinical and Experimental Pharmacology 033 Orthopedic Surgery 037 Drug Literature Index 039 Pharmacy What analysis of initial search results reveals • EMBASE identifies drug & device brand names & manufacturers cited in the full text of the original source – whether or not they also appear in the title and/or abstract – However, not always in TN, MN field (see record #12 on p. 20) – Conclusion? Search brand names without field qualification 1/9/6 Page 18
  20. 20. DIALOG(R)File 72:EMBASE(c) 2004 Elsevier Science B.V. All rts. reserv.12350876 EMBASE No: 2003469530 Collagen sponges for bone regeneration with rhBMP-2 Geiger M.; Li R.H.; Friess W. M. Geiger, Drug Product Development, Wyeth BioPharma, One Burtt Road, Andover, MA 01810 United States AUTHOR EMAIL: mgeiger@wyeth.com Advanced Drug Delivery Reviews ( ADV. DRUG DELIV. REV. ) (Netherlands)28 NOV 2003, 55/12 (1613-1629) CODEN: ADDRE ISSN: 0169-409X DOCUMENT TYPE: Journal ; Review LANGUAGE: ENGLISH SUMMARY LANGUAGE: ENGLISH NUMBER OF REFERENCES: 108 In the US alone, approximately 500,000 patients annually undergo surgicalprocedures to treat bone fractures, alleviate severe back pain throughspinal fusion procedures, or promote healing of non-unions. Many of theseprocedures involve the use of bone graft substitutes. An alternative tobone grafts are the bone morphogenetic proteins (BMPs), which have beenshown to induce bone formation. For optimal effect, BMPs must be combinedwith an adequate matrix, which serves to prolong the residence time of theprotein and, in some instances, as support for the invading osteoprogenitorcells. Several factors involved in the preparation of adequate matrices,specifically collagen sponges, were investigated in order to test theperformance in a new role as an implant providing local delivery of anosteoinductive differentiation factor. Another focus of this review is thecurrent system consisting of a combination of recombinant human BMP-2(rhBMP-2) and an absorbable collagen sponge (ACS). The efficacy and safetyof the combination has been clearly proven in both animal and human trials.(c) 2003 Elsevier B.V. All rights reserved.DEVICE BRAND NAME/MANUFACTURER NAME: Osigraft/Howmedica/Ireland; InFuse/medronic sofamor danek/United States; InductOs/Wyeth/United Kingdom;NeOsteo/Sulzer/United StatesDEVICE MANUFACTURER NAMES: Howmedica/Ireland; medtronic sofamor danek/UnitedStates; Wyeth/United Kingdom; Sulzer/United StatesDRUG DESCRIPTORS:*collagen--clinical trial--ct; *collagen--pharmaceutics--pr; *bonemorphogenetic protein 2--clinical trial--ct; *bone morphogenetic protein 2--drug development--dv; *bone morphogenetic protein 2--drug therapy--dt; *bone morphogenetic protein 2--pharmaceutics--pr; *bone morphogeneticprotein 2--pharmacology—pd; formaldehyde; osteogenic protein 1--drug therapy--dt; osteogenic protein 1--pharmaceutics--pr; drug carrier--clinical trial--ct;drug carrier--pharmaceutics--pr; collagen type 1--pharmaceutics--pr; collagentype 4--pharmaceutics--pr; calcium phosphate--pharmaceutics--pr; hydroxyapatite--pharmaceutics--pr; chondroitin 6 sulfate--pharmaceutics--pr; roseolicacid--pharmaceutics--pr; carboxymethylcellulose--pharmaceutics--pr;titanium--pharmaceutics--pr; unclassified drugMEDICAL DESCRIPTORS:*bone regeneration sponge (Porifera); surgical patient; surgical technique;fracture—drug therapy--dt; fracture--surgery--su; backache--drug therapy--dt;backache--surgery--su; spine fusion; fracture healing; bone graft;ossification; drug effect; bone matrix; cell invasion; precursor cell; bonecell; performance; absorption; drug efficacy; drug safety; drug deliverysystem; cross linking; vapor; thermodynamics; heat treatment; instrumentsterilization; gamma radiation; beta radiation; plastic surgery; toothimplantation; craniofacial morphology; bone transplantation; morphogenesis;biocompatibility; drug mechanism; in vitro study; in vivo study; diseasemodel; treatment outcome; human; nonhuman; clinical trial; review; priorityjournalDRUG TERMS (UNCONTROLLED): recombinant human bone morphogenetic protein 2 Page 19
  21. 21. --clinical trial--ct; recombinant human bone morphogenetic protein 2--drugdevelopment--dv; recombinant human bone morphogenetic protein 2--drugtherapy--dt; recombinant human bone morphogenetic protein 2--pharmaceutics--pr; recombinant human bone morphogenetic protein 2--pharmacology--pd;poly(alpha hydroxy acid)--pharmaceutics--prCAS REGISTRY NO.: 9007-34-5 (collagen); 50-00-0 (formaldehyde); 10103-46-5, 13767-12-9, 14358-97-5, 7758-87-4 (calcium phosphate); 1306-06-5, 51198-94-8 (hydroxyapatite); 25322-46-7 (chondroitin 6 sulfate); 11052-94-1, 603-45-2 (roseolic acid); 8050-38-2, 9000-11-7, 9004-32-4, 9050-04-8 (carboxymethylcellulose); 7440-32-6 (titanium)SECTION HEADINGS: 027 Biophysics, Bioengineering and Medical Instrumentation 030 Clinical and Experimental Pharmacology Concept of “recombinant” may be 033 Orthopedic Surgery identified in the abstract and 037 Drug Literature Index “uncontrolled” indexing, rather than in 039 Pharmacy the Descriptor field 1/9/12DIALOG(R)File 72:EMBASE(c) 2004 Elsevier Science B.V. All rts. reserv.12032153 EMBASE No: 2003144118 Is INFUSE Bone Graft superior to autograft bone? An integrated analysis of clinical trials using the LT-CAGE Lumbar Tapered Fusion device Burkus J.K.; Heim S.E.; Gornet M.F.; Zdeblick T.A. Dr. J.K. Burkus, Hughston Clinic, 6262 Veterans Parkway, Columbus, GA 31908-9517 United States AUTHOR EMAIL: JKB66@knology.net Journal of Spinal Disorders and Techniques ( J. SPINAL DISORD. TECH. ) ( United States) 2003, 16/2 (113-122) CODEN: JSDTB ISSN: 1536-0652 DOCUMENT TYPE: Journal ; Article LANGUAGE: ENGLISH SUMMARY LANGUAGE: ENGLISH NUMBER OF REFERENCES: 15 Multicenter human clinical studies of patients undergoing anterior lumbarfusion have been conducted using recombinant bone morphogenetic protein orrhBMP-2 on an absorbable collagen sponge, marketed as INFUSE Bone Graft, orautograft implanted in the LT-CAGE Lumbar Tapered Fusion device. Anintegrated analysis of multiple clinical studies was performed using ananalysis of covariance to adjust for preoperative variables in a total of679 patients. Of these patients, 277 had their cages implanted with rhBMP-2on an absorbable collagen sponge and 402 received autograft transferredfrom the iliac crest. The patients treated with rhBMP-2 had statisticallysuperior outcomes with regard to length of surgery, blood loss, hospitalstay, reoperation rate, median time to return to work, and fusion rates at6, 12, and 24 months. Oswestry Disability Index scores and the PhysicalComponent Scores and Pain Index of the SF-36 scale at 3, 6, 12, and 24months showed statistically superior outcomes in the rhBMP-2 group.DEVICE MANUFACTURER NAMES: Medtronic Sofamor Danek/United StatesDRUG DESCRIPTORS: Cited drug/device brand names*recombinant bone morphogenetic protein 2 omitted in indexing.MEDICAL DESCRIPTORS:*bone graft; *autograft; *anterior spine fusion; *intervertebral diskdegeneration--surgery—su; biodegradable implant; iliac crest; treatmentoutcome; operation duration; bleeding; hospitalization; reoperation; workresumption; disability; pain assessment; follow up; surgical technique;comparative study; device; human; male; female; major clinical study; clinicaltrial; randomized controlled trial; multicenter study; controlled study; adult;article; priority journal [remainder of record omitted here] Page 20
  22. 22. What analysis of initial search results reveals • For newer compounds, EMBASE drug descriptors are typically more specific than indexing provided in MEDLINE – Precoordinated term available: “Recombinant Bone Morphogenetic Protein 2” (record #12) – “Bone Morphogenetic Protein 2” + “Recombinant Protein” (record #1) – Or “Bone Morphogenetic Protein 2” + “recombinant” in abstract or “uncontrolled” indexing (record #6) – Conclusion? Take advantage of the precoordinated term, but augment retrieval with “free text” termsWhat analysis of initial search results reveals• “Drug delivery” concept appears to be more systematically identified in EMBASE records, although a variety of Descriptors are used – “Drug Delivery System” – “Drug Carrier” – “Biodegradable Implant” – “Collagen”• Two alternative Descriptors used for the indication – “Anterior Spine Fusion” – “Spine Fusion”• Conclusion? Need to assess term occurrence in a larger sample of results Page 21
  23. 23. ? RANK DE RANKing Descriptors enables analysis ofStarted processing RANK indexing beyond what can be accomplishedCompleted Ranking 19 records through selective browsing.DIALOG RANK Results--------------------RANK: S1/1-19 Field: /DE File(s): 72(Rank fields found in 19 records -- 495 unique terms) Page 1 of 62RANK No. Items Term-------- ----- ---- 1 18 HUMAN 2 16 RECOMBINANT BONE MORPHOGENETIC PROTEIN 2 3 15 BONE GRAFT 4 13 CLINICAL TRIAL Item counts assist users in gauging the 5 12 PRIORITY JOURNAL relative reliability of descriptors when used 6 12 SU in follow-up searches. 7 12 SURGERY 8 10 AUTOGRAFTP = next page Pn = Jump to page nP- = previous page M = More Options Exit = Leave RANKTo view records from RANK, enter VIEW followed by RANK number,format, and item(s) to display, e.g., VIEW 2/9/ALL.Enter desired option(s) or enter RANK number(s) to save terms.? PDIALOG RANK Results--------------------RANK: S4/1-19 Field: /DE File(s): 72(Rank fields found in 19 records -- 495 unique terms) Page 2 of 62RANK No. Items Term-------- ----- ---- 9 10 COLLAGEN 10 10 NONHUMAN 11 9 CT 12 9 REVIEW 13 8 CONTROLLED STUDY 14 8 SURGICAL TECHNIQUE 15 7 ARTICLE 16 7 CALCIUM PHOSPHATEP = next page Pn = Jump to page nP- = previous page M = More Options Exit = Leave RANK? PDIALOG RANK Results--------------------RANK: S4/1-19 Field: /DE File(s): 72(Rank fields found in 19 records -- 495 unique terms) Page 3 of 62RANK No. Items Term-------- ----- ---- 17 7 PD 18 7 PHARMACOLOGY 19 7 RECOMBINANT BONE MORPHOGENETIC PROTEIN 2 --CLI 20 7 SPINE FUSION 21 6 ADULT 22 6 DRUG THERAPY 23 6 DT 24 5 ANTERIOR SPINE FUSIONP = next page Pn = Jump to page nP- = previous page M = More Options Exit = Leave RANK Page 22
  24. 24. ? PDIALOG RANK Results--------------------RANK: S4/1-19 Field: /DE File(s): 72(Rank fields found in 19 records -- 495 unique terms) Page 4 of 62RANK No. Items Term-------- ----- ---- 25 5 BONE MORPHOGENETIC PROTEIN 26 5 DRUG DELIVERY SYSTEM 27 5 DRUG EFFICACY 28 5 FEMALE 29 5 LUMBAR SPINE 30 5 MALE 31 5 OSTEOGENIC PROTEIN 1 32 5 RECOMBINANT BONE MORPHOGENETIC PROTEIN 2 –PHA . . . 33 5 TITANIUM 34 5 TREATMENT OUTCOME 35 4 BONE MATRIX 36 4 BONE MORPHOGENETIC PROTEIN 2 37 4 BONE TRANSPLANTATION 38 4 CALCIUM SULFATE 39 4 CO 40 4 COMPLICATION 41 4 COMPUTER ASSISTED TOMOGRAPHY 42 4 DRUG CARRIER 43 4 FIBROBLAST GROWTH FACTOR 44 4 INTERVERTEBRAL DISK DEGENERATION --SURGERY --S 45 4 INTERVERTEBRAL DISK DEGENERATION 46 4 MAJOR CLINICAL STUDY 47 4 PHARMACEUTICS 48 4 PR 49 4 SPINE DISEASE 50 4 TRANSFORMING GROWTH FACTOR BETA 51 3 ADVERSE DRUG REACTION 52 3 AE 53 3 BIODEGRADABLE IMPLANT 54 3 BIOMECHANICS 55 3 BONE CONDUCTION 56 3 BONE MORPHOGENETIC PROTEIN --CLINICAL TRIAL --P = next page Pn = Jump to page nP- = previous page M = More Options Exit = Leave RANKTo view records from RANK, enter VIEW followed by RANK number,format, and item(s) to display, e.g., VIEW 2/9/ALL.Enter desired option(s) or enter RANK number(s) to save terms.? EXITRANK results will be erased; have you saved all the terms of interest?(YES/NO)? YExiting rank... (no terms were saved) Page 23
  25. 25. EMBASE strategies paralleling those shown earlier in MEDLINE…? S RECOMBINANT BONE MORPHOGENETIC PROTEIN 2 S2 285 RECOMBINANT BONE MORPHOGENETIC PROTEIN 2? S BONE MORPHOGENETIC PROTEIN 2 AND (RECOMBINANT OR RHBMP2 OR RHBMP()2) Augments retrieval from the precoordinated term (set 2) by 1144 BONE MORPHOGENETIC PROTEIN 2 anticipating assignment of an 114659 RECOMBINANT 7 RHBMP2 alternative descriptor, 330 RHBMP supplemented here with “free text” 1497758 2 keywords 308 RHBMP(W)2 S3 258 BONE MORPHOGENETIC PROTEIN 2 AND (RECOMBINANT OR RHBMP2 OR RHBMP()2)? S S2 OR S3 S4 501 S2 OR S3 Insertion of the proximity? S S4 AND SPINE()FUSION/DE operator ( ) ensures retrieval 31817 SPINE/DE of both “spine fusion” and 15091 FUSION/DE “anterior spine fusion”. 3862 SPINE/DE(W)FUSION/DE S5 83 S4 AND SPINE()FUSION/DE? S COLLAGEN OR DRUG CARRIER OR DRUG DELIVERY SYSTEM OR BIODEGRADABLE IMPLANT 44903 COLLAGEN 3292 DRUG CARRIER 19163 DRUG DELIVERY SYSTEM 612 BIODEGRADABLE IMPLANT S6 66235 COLLAGEN OR DRUG CARRIER OR DRUG DELIVERY SYSTEM OR BIODEGRADABLE IMPLANT? S S5 AND S6 S7 45 S5 AND S6 Retrieves additional references to? S S7 NOT S1 technology pertinent to the product S8 36 S7 NOT S1 that do not cite the brand nameSample titles…? T S8/6/1-8Spinal fusion using bone morphogenetic proteinsRecombinant Human Bone Morphogenetic Protein-2 Enhances Anterior Spinal Fusion in a Thoracoscopically Instrumented Animal ModelSpine fusion by gene therapyEffect of nano-hydroxyapatite/collagen composite and bone morphogenetic protein-2 on lumbar intertransverse fusion in rabbitsFusion Biology and Contemporary Graft OptionsA cost analysis of bone morphogenetic protein versus autogenous iliac crest bone graft in single-level anterior lumbar fusionEffect of regional gene therapy with bone morphogenetic protein-2-producing bone marrow cells on spinal fusion in ratsSimple carrier matrix modifications can enhance delivery of recombinant human bone morphogenetic protein-2 for posterolateral spine fusion Page 24
  26. 26. Example #2: Drug - Device Combination with Cardiac ApplicationsCYPHER Drug-Eluting Stent – Enables local delivery of an immunosuppressive drug atthe site of the surgically implanted medical device to reduce the incidence of restenosis.The approved product includes a Cordis (Johnson & Johnson) BX-Velocity stent coatedwith a sirolimus/synthetic polymer blend for slow release, targeted drug delivery to inhibitproliferation of muscle cells in the artery wall. Because only minimal amounts of the drugenter the bloodstream, systemic adverse effects are avoided.File 154:MEDLINE(R) 1990-2004/Sep W2 (c) format only 2004 The Dialog Corp. Set Items Description --- ----- -----------? S CYPHER AND STENT 46 CYPHER 15036 STENT S1 25 CYPHER AND STENT? T S1/9/1,15 1/9/1DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.16415064 PMID: 15085373 "Real life" use of sirolimus-eluting coronary stents in Germany. Results fromthe prospective multi-centre German Cypher Registry. Zahn R; Hamm C W; Zeymer U; Schneider S; Nienaber C A; Richardt G; Kelm M; Levenson B; Bonzel T; Tebbe U; Schobel W A; Sabin G; Senges J Herzzentrum Ludwigshafen, Kardiologie, Bremserstrasse 79, 67063Ludwigshafen, Germany. erzahn@aol.com Zeitschrift fur Kardiologie (Germany) Apr 2004, 93 (4) p287-94,ISSN 0300-5860 Journal Code: 0360430 Document type: Clinical Trial; Journal Article; Multicenter Study Languages: ENGLISH Subfile: INDEX MEDICUS BACKGROUND: Drug eluting stents (DES) are currently judged to be a"break-through" technology for the prevention of restenosis after percutaneouscoronary interventions (PCI). However, experience is limited to randomisedcontrolled clinical trials (RCT) in selected lesions and the currentlyavailable DES are more expensive compared to conventional "bare" stents.Therefore, actual clinical practice may be very different to RCT.METHODS: We analysed the data of the German Cypher trade mark Registry, anationwide registry which was initiated in parallel to the launch of the firstDES, the Cypher trade mark sirolimus-eluting coronary stent, in April 2002.RESULTS: From April 2002 until March 2003, 1638 procedures at 88 hospitalswere included in the German Cypher trade mark Registry. . . . Tags: Female; Human; Male Descriptors: *Blood Vessel Prosthesis--utilization--UT; *Coronary Disease--epidemiology--EP; *Coronary Disease--surgery--SU; *Coronary Restenosis--epidemiology--EP; *Coronary Restenosis--prevention and control--PC;*Registries; *Sirolimus--administration and dosage--AD; *Stents--utilization--UT; Comorbidity; Coronary Restenosis--drug therapy--DT; Drug Delivery Systems--utilization--UT; Germany--epidemiology--EP; Middle Aged CAS Registry No.: 53123-88-9 (Sirolimus) Record Date Created: 20040415 Record Date Completed: 20040630 Page 25
  27. 27. 1/9/15DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.16391936 PMID: 14981005 Randomized study to evaluate sirolimus-eluting stents implanted at coronarybifurcation lesions. Colombo Antonio; Moses Jeffrey W; Morice Marie Claude; Ludwig Josef;Holmes David R; Spanos Vassilis; Louvard Yves; Desmedt Benny; Di MarioCarlo; Leon Martin B EMO Centro Cuore Columbus, Milan, Italy. Circulation (United States) Mar 16 2004, 109 (10) p1244-9, ISSN1524-4539 Journal Code: 0147763 Document type: Clinical Trial; Journal Article; Randomized Controlled Trial Languages: ENGLISH Record type: Completed Subfile: AIM; INDEX MEDICUS BACKGROUND: A sirolimus-eluting stent (Cypher, Cordis Corp) has beenreported to markedly decrease restenosis in selected lesions; higher-risklesions, including coronary bifurcations, have not been studied. METHODS ANDRESULTS: This prospective study evaluated the safety and efficacy ofsirolimus-eluting stents for treatment of coronary bifurcation lesions. . . . Tags: Comparative Study; Female; Human; Male; Support, Non-U.S. Govt Descriptors: *Coronary Restenosis--prevention and control--PC; *CoronaryStenosis--surgery--SU; *Sirolimus--therapeutic use--TU; *Stents; *Ticlopidine--analogs and derivatives--AA; Aged; Anticoagulants--therapeutic use--TU;Aspirin--therapeutic use--TU; Balloon Dilatation; Combined Modality Therapy;Comorbidity; Coronary Angiography; Coronary Restenosis--radiography--RA;Coronary Stenosis--drug therapy--DT; Coronary Thrombosis--etiology--ET;Coronary Vessels--pathology--PA; Death, Sudden; Diabetes Mellitus--epidemiology--EP; Disease-Free Survival; Drug Implants; Follow-Up Studies; LifeTables; Middle Aged; Pilot Projects; Postoperative Complications--etiology--ET;Prospective Studies; Safety; Sirolimus--administration and dosage--AD; SurvivalAnalysis; Ticlopidine--therapeutic use--TU; Treatment Outcome CAS Registry No.: 0 (Anticoagulants); 0 (Drug Implants); 50-78-2 (Aspirin);53123-88-9 (Sirolimus); 55142-85-3 (Ticlopidine); 90055-48-4 (clopidogrel) Record Date Created: 20040316 Record Date Completed: 20040628 Date of Electronic Publication: 20040223? S SIROLIMUS/DE AND STENTS/DE AND CORONARY RESTENOSIS 2682 SIROLIMUS/DE 18301 STENTS/DE 1404 CORONARY RESTENOSIS S2 135 SIROLIMUS/DE AND STENTS/DE AND CORONARY RESTENOSIS? S S2 NOT S1 S3 129 S2 NOT S1? S S3/HUMAN AND PY=2004 Strategy to retrieve additional references to 127 S3/HUMAN the drug-device combination that do not cite 401807 PY=2004 the product’s brand name in the original S4 40 S3/HUMAN AND PY=2004 source? T S4/6/1-5 4/6/116862577 PMID: 15057442 [Do drug-eluting stents influence the spectrum of coronary artery bypasssurgery?] Beeinflussen Drug-eluting Stents das Spektrum der Koronarchirurgie? Page 26
  28. 28. 4/6/216862576 PMID: 15057441 Drug-eluting stents for in-stent restenosis and acute myocardial infarction:present data from nonrandomized studies.Mar 2004 4/6/316862575 PMID: 15057440 Classification and current treatment options of in-stent restenosis. Presentstatus and future perspectives.Mar 2004 4/6/416862572 PMID: 15057437 Polymer-sirolimus-eluting stents in de novo lesions.Mar 2004 4/6/516862555 PMID: 15054588 Rapamycin analogs for stent-based local drug delivery. Everolimus- andtacrolimus-eluting stents.Mar 2004Results include references to other drugs under investigation for stent delivery. How canthe strategy be modified to retrieve additional bibliography on this topic? One approach…. Updated results reflect recallSet Items Description as of May 2005S1 39 CYPHER AND STENTS2 236 STENTS/DE AND SIROLIMUS/DE AND CORONARY RESTENOSISS3 223 S2 NOT S1S4 131 S3/HUMAN AND PY=2004:2005? S STENTS/DE AND CORONARY RESTENOSIS 20194 STENTS/DE 1850 CORONARY RESTENOSIS S5 1250 STENTS/DE AND CORONARY RESTENOSIS? S S5 AND (ELUTING OR COATED) Note: Strategy avoids 2522 ELUTING specifying word order or 31152 COATED proximity S6 400 S5 AND (ELUTING OR COATED)? S S6 NOT S2 S7 202 S6 NOT S2 Optional: Use of “free- floating” subheadings and “delivery methodology” MeSH terms in an attempt to focus results on drugs.? S S7 AND (AD OR TU OR DRUG DELIVERY SYSTEMS OR DRUG IMPLANTS)/DE 449265 AD/DE 658344 TU/DE 9466 DRUG DELIVERY SYSTEMS/DE 3762 DRUG IMPLANTS/DE S8 145 S7 AND (AD OR TU OR DRUG DELIVERY SYSTEMS OR DRUG IMPLANTS)/DESample titles retrieved…Paclitaxel-eluting stents: current clinical experience.2004 Page 27
  29. 29. The long-term clinical results of a platelet glycoprotein IIb/IIIa receptor blocker (Abciximab: Reopro) coated stent in patients with coronary artery disease.Dec 2004High-dose 7-hexanoyltaxol-eluting stent with polymer sleeves for coronary revascularization: one-year results from the SCORE randomized trial.Oct 6 2004Actinomycin-eluting stent for coronary revascularization: a randomized feasibility and safety study: the ACTION trial.Oct 6 2004Dexamethasone-eluting stent: an anti-inflammatory approach to inhibit coronary restenosis.Sep 2004Advanced c-myc antisense (AVI-4126)-eluting phosphorylcholine-coated stent implantation is associated with complete vascular healing and reduced neointimal formation in the porcine coronary restenosis model.Apr 2004Methotrexate eluting stents: to modify or cure?Feb 2004A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease.Jan 15 2004Comparison of initial efficacy and long-term follow-up of heparin-coated Jostent with conventional NIR stent.Nov 2003Study of antirestenosis with the BiodivYsio dexamethasone-eluting stent(STRIDE): a first-in-human multicenter pilot trial.Oct 2003 . . . Page 28
  30. 30. File 72:EMBASE 1993-2004/Sep W2 (c) 2004 Elsevier Science B.V. “Trial search” in EMBASE Set Items Description --- ----- -----------? S CYPHER AND STENT 136 CYPHER 20723 STENT S1 122 CYPHER AND STENT? T S1/9/1,5 1/9/1DIALOG(R)File 72:EMBASE(c) 2004 Elsevier Science B.V. All rts. reserv.12777834 EMBASE No: 2004373942 Implantation of sirolimus-eluting stents in patients with higher risk ofrestenosis. One-year follow-up of 100 patients IMPLANTACJA STENTOW WYDZIELAJACYCH RAPAMYCYNE (SIROLIMUS) U CHORYCH ZEZWIEKSZONYM RYZYKIEM RESTENOZY. ROCZNA OBSERWACJA 100 PACJENTOW Lesiak M.; Rzezniczak J.; Baszko A.M.; Pyda M.A.; Grajek S.; Mularek T.;Skorupski W.; Mitkowski P.; Grygier M.; Prech M.; Cieslinski A. Dr. M. Lesiak, I Klinika Kardiologii, ul. Dl(stroke)uga 1/2, 61-848 Poznan Poland AUTHOR EMAIL: maciej.lesiak@sk1.am.poznan.pl Folia Cardiologica ( FOLIA CARDIOL. ) (Poland) 2004, 11/7 (505-511) CODEN: FCGPB ISSN: 1507-4145 DOCUMENT TYPE: Journal ; Article LANGUAGE: POLISH SUMMARY LANGUAGE: ENGLISH; POLISH NUMBER OF REFERENCES: 15 Background: In-stent restenosis is still one of the main limitations ofpercutaneous coronary revascularization. The novel drug-eluting stents seem toreduce the risk of restenosis substantially. We conducted this study todetermine the short- and long-term results of sirolimus-eluting stentimplantation in patients with higher risk of restenosis. Material and methods:Coronary angioplasty with Cypher(TM) (Cordis, Johnson & Johnson) stent . . .DEVICE BRAND NAME/MANUFACTURER NAME: Cypher/Cordis Johnson and JohnsonDEVICE MANUFACTURER NAMES: Cordis Johnson and JohnsonDRUG DESCRIPTORS:*rapamycin--drug therapy--dt; *rapamycin--pharmaceutics—pr; pyridinederivative--drug therapy--dtMEDICAL DESCRIPTORS:*restenosis--complication--co; *restenosis--diagnosis--di; *restenosis--drug therapy--dt; *drug eluting stent; drug implantation; follow up; highrisk patient; transluminal coronary angioplasty; stable angina pectoris--drugtherapy--dt; … [remainder of record omitted here] EMBASE added “drug eluting stent” to its 1/9/5 controlled vocabulary in June 2003DIALOG(R)File 72:EMBASE(c) 2004 Elsevier Science B.V. All rts. reserv.12754051 EMBASE No: 2004349236 Long-term effects of polymer-based, slow-release, sirolimus-eluting stents ina porcine coronary model Carter A.J.; Aggarwal M.; Kopia G.A.; Tio F.; Tsao P.S.; Kolata R.; YeungA.C.; Llanos G.; Dooley J.; Falotico R. Page 29
  31. 31. A.J. Carter, Providence Heart and Vasc. Institute, Providence St. Vincent Med. Center, 9205 SW Barnes Road, 97225-5218, Portland, OR United States AUTHOR EMAIL: acarter@providence.org Cardiovascular Research ( CARDIOVASC. RES. ) (Netherlands) 01 SEP 2004, 63/4(617-624) CODEN: CVREA ISSN: 0008-6363 PUBLISHER ITEM IDENTIFIER: S0008636304002019 DOCUMENT TYPE: Journal ; Article LANGUAGE: ENGLISH SUMMARY LANGUAGE: ENGLISH NUMBER OF REFERENCES: 15 Background: Stent-based delivery of sirolimus (SRL) has shown reduction inneointimal hyperplasia and restenosis. The purpose of this study was toevaluate the chronic vascular response and the expression of cell cycleregulators after SRL-eluting stent implantation in a porcine coronary model. . . .BRAND NAME/MANUFACTURER NAME: cypher/CordisMANUFACTURER NAMES: Wyeth Ayerst/United States; CordisDEVICE BRAND NAME/MANUFACTURER NAME: BX Velocity/Cordis/United StatesDEVICE MANUFACTURER NAMES: Cordis/United StatesDRUG DESCRIPTORS:*rapamycin--drug therapy--dt; *rapamycin--pharmaceutics--pr; *rapamycin--pharmacology—pd; polymer--pharmaceutics--pr; cycline; protein p27; CD45antigen; monocyte chemotactic protein 1; interleukin 2; interleukin 6;lymphotoxin; cyclin dependent kinase; drug carrier--pharmaceutics--prMEDICAL DESCRIPTORS:*coronary artery; long term care; drug effect; drug eluting stent; biologicalmodel; evaluation; blood vessel reactivity; implantation; swine; histology;Western blotting; thrombus; protein expression; blood vessel wall;modulation; artery intima proliferation--drug therapy--dt; artery intimaproliferation--surgery--su; cell proliferation; postoperative complication;postoperative thrombosis--complication--co; nonhuman; animal experiment;animal model; controlled study; animal tissue; article; priority journalDRUG TERMS (UNCONTROLLED): cypherCAS REGISTRY NO.: 53123-88-9 (rapamycin); 85898-30-2 (interleukin 2); 150428-23-2 (cyclin dependent kinase) [remainder of record omitted here]? E (RAPAMYCIN) Verifying that RAPAMYCIN is an alternative nonproprietary name for SIROLIMUSRef Items Type RT Index-termR1 5802 7 *RAPAMYCINR2 136528 DC=D24.440.445 (IMMUNOSUPPRESSIVE AGENT)R3 17973 B 90 IMMUNOSUPPRESSIVE AGENTR4 11 S 1 AY 22989R5 0 S 1 AY22989 Strategy to retrieve references to theR6 297 S 1 RAPAMUNE drug-device combination that do notR7 1030 S 1 SIROLIMUS cite the product’s brand nameR8 5269 S 1 RN=53123-88-9? S RAPAMYCIN/DE AND RESTENOSIS/DE AND DRUG ELUTING STENT 5480 RAPAMYCIN/DE 6233 RESTENOSIS/DE 304 DRUG ELUTING STENT S2 120 RAPAMYCIN/DE AND RESTENOSIS/DE AND DRUG ELUTING STENT? S S2 NOT S1 S3 84 S2 NOT S1 Page 30
  32. 32. Broader strategy to locate other drugs under investigation for stent delivery & restenosis reduction Updated results reflect recallSet Items Description as of May 2005S1 210 CYPHER AND STENTS2 280 RAPAMYCIN/DE AND RESTENOSIS/DE AND DRUG ELUTING STENTS3 192 S2 NOT S1S4 157 S3/HUMAN AND PY=2004:2005? S DRUG ELUTING STENT AND RESTENOSIS/DE 676 DRUG ELUTING STENT 6917 RESTENOSIS/DE S5 437 DRUG ELUTING STENT AND RESTENOSIS/DE? S S5 NOT S2 S6 157 S5 NOT S2? S S6 AND (AD OR PR OR DRUG CARRIER OR DRUG IMPLANTATION OR POLYMER?)/DE 89890 AD/DE 82181 PR/DE 3591 DRUG CARRIER/DE 314 DRUG IMPLANTATION/DE 211420 POLYMER?/DE S8 44 S6 AND (AD OR PR OR DRUG CARRIER OR DRUG IMPLANTATION OR POLYMER?)/DESample of citation titles retrieved…Evaluation of a high-dose Dexamethasone-eluting stent 15 JUL 2004Local gene transfer of phVEGF-2 plasmid by gene-eluting stents: An alternative strategy for inhibition of restenosis 06 JUL 2004Intracoronary brachytherapy may be cost-effective for in-stent restenosis in the long term 2003Stent-based controlled release of intravascular angiostatin to limit plaque progression and in-stent restenosis 2004Molecular responses of vascular smooth muscle cells and phagocytes to curcumin-eluting bioresorbable stent materials 2004First human experience with the 17-beta-estradiol-eluting stent: The estrogen and stents to eliminate restenosis (EASTER) trial 17 MAR 2004In-Stent Restenosis Limitation with Stent-based Controlled-Release NitricOxide: Initial Results in Rabbits 2004Science to Practice Why Coat a Stent with Polymer? 2004In vitro evaluation of vascular endothelial growth factor (VEGF)-eluting stents 2003 Page 31
  33. 33. Example #3: Drug Combination for Hepatitis C TherapyPEGASYS + RIBAVIRIN – Approved regimen involves separate administration, on afixed schedule, of the antiviral drug ribavirin (COPEGUS) and an immunostimulantproduced via biotechnology, pegylated (PEG) recombinant human interferon alpha-2A(PEGASYS). PEG (polyethylene glycol) modification of the interferon represents asignificant advance in pharmaceutical technology. Attachment of an inert syntheticpolymer to the molecule encircles the protein, effectively “disguising” it from the humanmetabolic system. In consequence, pegylation has enhanced clinical efficacy bylengthening the interferon’s half-life, enabling longer sustained delivery and reduction ofdose frequency to once weekly (versus 3 x week for non-PEG version). When used incombination, PEGASYS and ribavirin have demonstrated dramatic improvement in long-term virological response compared to monotherapy using either agent. MEDLINE Indexing of This Topic • Concept of pegylation is not precoordinated with interferon: two separate index terms, the 2nd of which is not consistently assigned (must be augmented with “free text” terms) – Interferon Alfa-2a – Polyethylene Glycols • The specific interferon is sometimes incorrectly indexed (see record #7,8,10) – Also, incorrect (or missing) CAS RNs (see record #2, 9) • “Drug Therapy, Combination” is infrequently used (assigned to only 5 out of 26 records citing PEGASYS)File 154:MEDLINE(R) 1990-2004/Sep W2 (c) format only 2004 The Dialog Corp. Set Items Description --- ----- -----------? S PEGASYS S1 26 PEGASYS? T S1/6/1-5 1/6/1DIALOG(R)File 154:(c) format only 2004 The Dialog Corp. All rts. reserv.16782845 PMID: 15313671 Impact of virus genotype on interferon treatment of patients with chronichepatitis C: a multicenter controlled study.Aug 2004 1/6/2DIALOG(R)File 154:(c) format only 2004 The Dialog Corp. All rts. reserv.16631058 PMID: 14569259 Improved biological and transcriptional activity of monopegylated interferon-alpha-2a isomers. Page 32
  34. 34. 1/6/3DIALOG(R)File 154:(c) format only 2004 The Dialog Corp. All rts. reserv.16545348 PMID: 15225169 Pegylated interferon-alpha2a kinetics during experimental haemodialysis:impact of permeability and pore size of dialysers.Jul 1 2004 1/6/4DIALOG(R)File 154:(c) format only 2004 The Dialog Corp. All rts. reserv.16349194 PMID: 15128353 Sudden hearing loss in patients with chronic hepatitis C treated withpegylated interferon/ribavirin.May 2004 1/6/5DIALOG(R)File 154:(c) format only 2004 The Dialog Corp. All rts. reserv.16278379 PMID: 15096276 Pegasys: software for executing and integrating analyses of biologicalsequences. Note that PEGASYS in also a brand name forApr 19 2004 computer software? T S1/9/2,4,7-10 1/9/2DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.16631058 PMID: 14569259 Improved biological and transcriptional activity of monopegylated interferon-alpha-2a isomers. Foser S; Weyer K; Huber W; Certa U Department of Pharma Technical Operations Biotechnology, F Hoffmann LaRoche Ltd, Basel, Switzerland. pharmacogenomics journal (United States) 2003, 3 (6) p312-9, ISSN1470-269X Journal Code: 101083949 Document type: Journal Article Languages: ENGLISH Record type: Completed Subfile: INDEX MEDICUS The addition of polyethyleneglycol (PEG) side chains to interferon alpha-2aimproves the serum stability and clinical efficacy. Current commercial PEG-INFformulations such as PEGASYS are heterogeneous and contain multiplemonopegylated isomers. We have analyzed the activity of nine, purifiedmonopegylated variants ………………………………………………………………………………………………………………………………………………….The possible clinical implications are discussed, which might guide thedevelopment of pegylated interferons with improved pharmacological properties. Tags: Comparative Study; Human Descriptors: *Antiviral Agents--pharmacology--PD; *Interferon Alfa-2a--pharmacology--PD; *Polyethylene Glycols--pharmacology--PD; *Transcription,Genetic--drug effects--DE; Animals; Antiviral Agents--chemistry--CH; Cattle;Cell Line; Dogs; Interferon Alfa-2a--chemistry--CH; Polyethylene Glycols--chemistry--CH; Stereoisomerism; Transcription, Genetic--physiology--PH CAS Registry No.: 0 (Antiviral Agents); 0 (Polyethylene Glycols);76543-88-9 (Interferon Alfa-2a) Because the concept of pegylation is not Record Date Created: 20031211 precoordinated with interferon in controlled Record Date Completed: 20040809 indexing, the CAS RN for only the non-PEG compound is provided. Page 33
  35. 35. 1/9/4DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.16349194 PMID: 15128353 Sudden hearing loss in patients with chronic hepatitis C treated withpegylated interferon/ribavirin. Formann Elisabeth; Stauber Rudolf; Denk Doris-Maria; Jessner Wolfgang;Zollner Gernot; Munda-Steindl Petra; Gangl Alfred; Ferenci Peter Department of Internal Medicine IV, Gastroenterology and Hepatology,University of Vienna, Austria. American journal of gastroenterology (United States) May 2004, 99 (5) p873-7, ISSN 0002-9270 Journal Code: 0421030 Document type: Journal Article Languages: ENGLISH Record type: Completed Subfile: INDEX MEDICUS BACKGROUND: Sudden hearing loss has been reported on standard interferon(IFN)-alpha2 therapy. This is the first report on the occurrence of suddenhearing loss in six cases of chronic hepatitis C in temporal relation totreatment with pegylated (PEG)-IFN alfa2a or b/ribavirin combination therapy.Three patients were treated in an ongoing randomized placebo-controlled trialcomparing the addition of 200 mg amantadine or placebo to the combination of180 microg PEG-IFN alpha2a (PEGASYS, Roche, Basel, CH)/wk and 1-1.2 gribavirin/d (COPEGUS, Roche, Nutley, USA) in de novo patients infected withHCV genotype 1. Sudden hearing loss and tinnitus developed on day 1 and after4, 23, 25, 36, and 40 wk of treatment, respectively. … Tags: Comparative Study; Female; Human; Male Descriptors: *Amantadine--adverse effects--AE; *Hearing Loss, Sudden--chemically induced--CI; *Hepatitis C, Chronic--drug therapy--DT; *InterferonAlfa-2a--adverse effects--AE; *Interferon Alfa-2b--adverse effects--AE;*Ribavirin--adverse effects--AE; Adult; Amantadine--administration and dosage--AD; Audiometry; Dose-Response Relationship, Drug; Drug Administration Schedule;Drug Therapy, Combination; Hearing Loss, Sudden--diagnosis--DI; Hepatitis C,Chronic--diagnosis--DI; Interferon Alfa-2a--administration and dosage--AD;Interferon Alfa-2b--administration and dosage--AD; Middle Aged; Prognosis;RNA, Viral--analysis--AN; Ribavirin--administration and dosage--AD; RiskAssessment; Sampling Studies; Severity of Illness Index CAS Registry No.: 0 (RNA, Viral); 36791-04-5 (Ribavirin); 76543-88-9(Interferon Alfa-2a); 768-94-5 (Amantadine); 99210-65-8 (Interferon Alfa-2b) Pegylation may be noted in the abstract, but not be identified in indexing of MEDLINE records. 1/9/7DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.16144091 PMID: 15116695 Pegasys-Copegus combination treats both HIV and hepatitis C. AIDS reader (United States) Apr 2004, 14 (4) p164, ISSN 1053-0894Journal Code: 9206753 Document type: News Interferon in PEGASYS is incorrectly indexed in this Languages: ENGLISH example. The source of the error may be imprecise Record type: Completed identification in the primary source? Subfile: AIDS/HIV Tags: Human Descriptors: *Antiviral Agents--therapeutic use--TU; *HIV Infections--drug therapy--DT; *Hepatitis C--drug therapy--DT; *Interferon Alfa-2b--therapeutic use--TU; *Ribavirin—therapeutic use--TU; Drug Combinations CAS Registry No.: 0 (Antiviral Agents); 0 (Drug Combinations); 0(polyethylene glycol-interferon alfa-2b); 36791-04-5 (Ribavirin); 99210-65-8(Interferon Alfa-2b) Page 34
  36. 36. 1/9/8DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.15676426 PMID: 14740531 [Treatment of chronic hepatitis C with PEG-interferon] Lecenje hronicnog hepatitisa C peg-interferonom. Fabri Milotka; Bozic Milena; Delic Dragan; Jesic Rada; Nozic Darko Klinicki centar Novi Sad, Klinika za infektivne bolesti, 21000 Novi Sad,Hajduk Veljkova 1-7. Medicinski pregled (Yugoslavia) Sep-Oct 2003, 56 (9-10) p427-30,ISSN 0025-8105 Journal Code: 2985249R Document type: Clinical Trial; Journal Article ; English Abstract Languages: SERBIAN Record type: Completed Subfile: INDEX MEDICUS INTRODUCTION: Since the discovery of the hepatitis C virus, the etiology ofchronic liver diseases has been revealed in great number of patients. However,the treatment of hepatitis C viral infection still hasnt been completelyresolved. Antiviral and immunomodulatory effects of interferon, and antiviraleffect on the nucleoside analogs were efficient only in small number ofpatients. Discovery of pegylated interferon brings progress in therapeuticsuccess rates. MATERIAL AND METHODS: Combined therapy with peginterferonalfa-2a (Pegasys) 180 mg once a week plus Ribavirin 800 mg a day . Another example of incorrect indexing—despite accurate . compound identification in the original source abstract. . Note that pegylation may be cited in non-MeSH chemical indexing, although, in this case, it’s attributed to another form of interferon. Tags: Female; Human; Male Descriptors: *Antiviral Agents--administration and dosage--AD; *Hepatitis C,Chronic--drug therapy--DT; *Interferon Alfa-2b--administration and dosage--AD;Adult; Aged; Antiviral Agents--adverse effects--AE; Drug Therapy, Combination;Interferon Alfa-2b--adverse effects--AE; Middle Aged; Ribavirin--administrationand dosage--AD CAS Registry No.: 0 (Antiviral Agents); 0 (polyethylene glycol-interferonalfa-2b); 36791-04-5 (Ribavirin); 99210-65-8 (Interferon Alfa-2b) 1/9/9DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.15660416 PMID: 12934164 Pegylation of interferon alfa: structural and pharmacokinetic properties. Pedder Simon C J Shearwater Corporation, a Division of Inhale Therapeutics, Charlotte,North Carolina 28227, USA. thepedders@yahoo.com Seminars in liver disease (United States) 2003, 23 Suppl 1 p19-22,ISSN 0272-8087 Journal Code: 8110297 Document type: Journal Article; Review; Review, Tutorial Languages: ENGLISH Record type: Completed Subfile: INDEX MEDICUS The attachment of a polyethylene glycol(PEG) polymer to a protein or peptideis becoming increasingly common within the pharmaceutical industry as a way ofaltering the activity of the parent molecule. Significant improvements inbiological activity with PEG molecules have been seen with several licenseddrugs, allowing for product life cycle management, as well as with experimentalcompounds in development that have pharmaceutical properties making themsuitable candidates for pegylation. Among the various disease states that havebeen targeted for the study of drugs incorporating pegylation technology, the Page 35

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