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This review highlights the discovery and development of chemotherapy at Eli Lilly & Company over the past 30 years from the Vinca alkaloids-vincristine, vinblastine, and vindesine-to targeted therapy. During the late 1970s, Lilly began an exploration of new synthetic compounds based on solid tumor screening models. Several novel antimetabolites with the potential to treat solid tumors were identified. Two such agents, gemcitabine and pemetrexed, underwent clinical development and are now among Lilly's portfolio of approved anticancer drugs. Gemcitabine, a pyrimidine nucleoside that has a profound effect on DNA synthesis, has been approved for the treatment of pancreatic, non-small cell lung, bladder, and most recently, breast, and ovarian cancer. Pemetrexed, a novel antifolate with potent cytotoxic effects, is distinguished from other antifolates by virtue of its ability to inhibit multiple folate-dependent enzymes. Pemetrexed, given in combination with cisplatin, has been recently approved for the treatment of malignant pleural mesothelioma and as second-line treatment for non-small cell lung cancer. Spurred by advances in the understanding of cancer as a disease process, Lilly's anticancer drug program began to transition to a more "targeted" approach during the 1990s. These efforts have recently culminated in the identification and development of enzastaurin, a PKCbeta inhibitor with potent anti-angiogenic properties. Enzastaurin has shown promising single-agent activity in patients with relapsed diffuse large B-cell lymphoma and recurrent glioblastoma multiforme, and is an excellent candidate for combination with cytotoxic agents.

Behiye Ozcan, Sebastian J C M M Neggers, Anne Reifel Miller, Hsiu-Chiung Yang, Virginia Lucaites, Thierry Abribat, Soraya Allas, Martin Huisman, Jenny A Visser, Axel P N Themmen, Eric J G Sijbrands, Patric J D Delhanty and Aart Jan van der Lely Department of Medicine, Erasmus University MC, 3000 CA, Rotterdam, The Netherlands, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA and Alize Pharma, 69 130 Ecully, France

Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA Departments of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, MO 63110, USA Scios, Inc., Sunnyvale, CA 94086, USA

For the past 25 years, I have devoted most of my research efforts to the application of molecular genetics to yield improvement and production of novel secondary metabolites in actinomycetes. My group at Lilly Research Laboratories worked with a variety of Streptomyces species and with strains of Amycolatopsis and Saccharopolyspora. We developed molecular genetic tools to manipulate actinomycete genes, and applied them to important secondary metabolites, including tylosin, daptomycin, vancomycin, chloroeremomycin, and spinosyns. In the early years, I helped establish recombinant DNA technology to manufacture mammalian proteins, and more recently, helped implement microbial genomics as a research tool for antibiotic discovery. In this paper, I review some highlights, primarily from the actinomycete work. Journal of Industrial Microbiology & Biotechnology (2000) 24, 79–88.

a Uni6ersity of California, San Diego, La Jolla, CA, USA b Emory Uni6ersity School of Medicine, 69 Butler Street, S.E., Atlanta, GA 30303, USA c Uni6ersity of California, San Francisco, San Francisco, CA, USA d Uni6ersity of Michigan, Ann Arbor, MI, USA e Royal Brompton Hospital and Imperial College, School of Medicine, London, UK f Uni6ersite Libre de Bruxelles, Brussels, Belgium g Lilly Research Laboratories, Indianapolis, IN, USA

Summary Background The discovery and clinical development of new drugs to treat cancer at Lilly Research Laboratories has undergone significant change during the past 15 years. During the early 1980s drug discovery relied heavily on a panel of syngeneic murine solid tumour models to identify new agents for clinical trial. New classes of oncolytic agents identified by this methodology include the difluoronucleoside antimetabolites, diarylsulfonylureas, and a series of folate-based enzyme inhibitors. Within the folate-based discovery programme at Lilly, a broad understanding of the structure activity relationships of folate antimetabolites and the biochemical basis of folate transport, processing, and enzyme inhibition has enabled a more rational approach for drug discovery. Current studies Folate receptor binding properties are being studied to predict tumour sensitivities and tissue toxicities. This information, together with knowledge of a compound's ability to undergo polyglutamation via the enzyme folylpolyglutamate syn-thase, assist in the more rational selection of agents with designed cellular selectivities. Ultimately, the complex metabolic pathways involving folate metabolism provide numerous targets for enzyme inhibition. Inhibitors of purine biosynthesis and thymidylate synthesis have demonstrated broad activity in preclinical models of disease including several human tumour xenografts, and are undergoing clinical testing. The folate-based drug discovery programme serves as a model for other biochemically based drug discovery programs including those based in drug resistance, signal transduction and cell cycle control.

On June 26, 2011, in San Diego, the Merrifield Award of the American Peptide Society was given to Richard DiMarchi of Indiana University. A day later, again in San Diego, the Outstanding Scientific Achievement Award of the American Diabetes Association was given to Matthias Tschop of the University of Cincinnati. Those attending both lectures might have witnessed many similarities; the Tschop and DiMarchi laboratories had been working as a single integrated unit across two universities for the last seven years, designing and optimizing new therapeutics for the treatment of diabetes and obesity (Figure ​(Figure1). 1). Figure 1 Richard DiMarchi (left) and Matthias Tschop. JCI: How did the two of you start collaborating? Tschop: We met at the Eli Lilly Research Laboratories, where Richard led drug discovery as a group vice president, while I was a postdoctoral fellow. Years later, when I had moved back to the US from Germany and Richard had left Lilly to be a chair of chemistry at Indiana University, we reconnected — our labs suddenly were just a two-hour drive apart. JCI: What avenue of research do you think has the greatest potential to improve the outlook for the obesity epidemic? Tschop: It seems increasingly clear that more than one neuroendocrine signal may have to be modulated at the same time in order to achieve beneficial metabolic effects with curative potential. Richard and I have been working on a series of approaches in which we are combining two or three gastrointestinal hormones into a single molecule. JCI: So are you both optimistic that we’ll find a drug-based cure for metabolic syndrome? DiMarchi: I am a perpetual optimist, supported by three decades of personal experiences. This kind of work requires steady progress made through contributions from many laboratories establishing a foundation for the discovery of transformative medicines. We believe that our work is contributing to the identification of a novel formula that might define a successful prescription for treatment. Tschop: More skeptical colleagues frequently point out to me that evolutionary pressures drove the development of redundant systems to efficiently ingest and store calories. My answer is always that reproduction is a pretty important requirement for the survival of the species too, but endocrinologists figured out how to interrupt it by tricking the brain into believing that there was already an ongoing pregnancy. We need to figure out how to trick the brain into believing that the stomach has been bypassed without actually cutting patients open. JCI: Your work at Lilly and now at Indiana University is largely based on macromolecules and, in particular, peptides — in spite of the limitation that peptide-based drugs almost always require injection. What are the advantages? DiMarchi: In many ways the peptides and proteins that have emerged as drugs are nature’s medicines. They have a high specificity of action with minimal off-target toxicity and natural routes of metabolic clearance. While injection is a limitation, the huge benefit is performance. However, it is important not to frame the question of drug discovery as an either/or option of conventional small molecules versus macromolecules. The combination of the two can deliver unprecedented efficacy with fewer adverse effects. JCI: Given that you moved from pharma to academe, you’re perhaps well positioned to answer the question of whether scientists will be successful in drug discovery outside of the pharmaceutical industry. DiMarchi: Large organizations may be required for cost-efficient drug development and production and marketing of drugs. However, it is individual scientists who deliver breakthrough discoveries. A laboratory composed of broadly trained chemists and pharmacologists can make a huge difference, if properly funded and appropriately nurtured. I am quite certain that Bruce Merrifield, the father of solid-phase chemical synthesis, could not have invented the concept if employed in a less supportive environment than an academic center like The Rockefeller University. JCI: You’re moving back to Germany this year. Will that be a challenge for your collaboration? Tschop: My wife and I are both from Munich, so when the Munich Hemholtz Centre together with the Technical University and the Ludwig Maximilians University Munich invited us to help build a new German Diabetes Center, it turned out to be an offer we couldn’t refuse. With our history of intense collaboration, Richard and I are both confident that the most fun is still ahead of us. And, Richard has a standing invitation for a sabbatical in the Bavarian Alps! JCI: How important have these collaborations been to shaping your science? Tschop: The most important lesson I have learned is that interdisciplinary and translational teamwork is — at least for us — key to every single breakthrough. It was painful at times, since we all speak different languages (literally and figuratively!) — but it always paid off.

Barbara E. Laughon, H. S. Allaudeen,* Jeffrey M. Becker, William L. Current, Judith Feinberg,* Jacob K. Frenkel, Richard Hafner, Walter T. Hughes, Catherine A. Laughlin, Joel D. Meyers, Lewis K. Schrager, and Lowell S. Young Developmental Therapeutics Branch of the Basic Research and Development Program, Medical Branch of the Treatment Research Program, Epidemiology Branch of the Division of AIDS, and Antiviral Research Branch of the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland; Department of Microbiology, University of Tennessee, Knoxville, and Department of Infectious Diseases, St. Jude Children s Research Hospital, Memphis, Tennessee; Lilly Research Laboratories, Indianapolis, Indiana; Department of Pathology, University of Kansas Medical Center, Kansas City; Department of Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington; Kuzell Institute for Arthritis and Infectious Diseases, San Francisco, California

Background: Between 54%-85% of pediatric patients (pts) with ALL can be cured by definitive chemotherapy protocols. HSCT may be considered for high-risk pts after induction therapy or for refractory/relapsed pts. However, HSCT is recognized as a highly specialized, costly and resource intensive procedure requiring ongoing care over months to years. HSCT is associated with significant life-threatening complications with transplant related mortality of 20-30% and acute/chronic graft vs. host disease and infections. The objective of this study was to assess the economic burden up to 5 years of pediatric pts with ALL who received HSCT from the US commercial payers' perspective. Method: Pediatric pts ( Results: A total of 209 pediatric ALL pts were identified. Mean age was 10 years and 43.1% of pts were female. The median follow-up period after the index date was 1.3 years. During the 6 months prior to the index date, pts incurred average total healthcare costs of $287,001. The median duration of the initial hospitalization for the HSCT was 41 days (interquartile range 32-55). Over the five years following the index date, results showed substantial HRU and costs associated with the HSCT. The most intensive HRU and highest healthcare costs were observed within the first year following the index date; pts had an average of 49 days with outpatient (OP) visits, 29 days with OP laboratory services, and 68 inpatient (IP) days corresponding to 3.10 IP admissions (including the hospitalization for the first HSCT) and incurred mean total healthcare costs of $683,099 (median of $511,021) (Figure 1 and 2). Costs associated with the first HSCT hospitalization represented 62.4% of the total costs incurred during the first year. Although a decreasing trend was observed over time, HRU and costs remained high; 28.8% of pts had at least one IP admission at year 2, 19.6% at year 3, 20.0% at year 4, and 6.7% at year 5 (Figure 1). The number of days with OP visits and the number of days with laboratory services also remained high over time (Figure 1). The average total healthcare cost was $104,584 (median of $21,877) at year 2, $79,092 (median of $11,000) at year 3, $106,334 (median of $10,426) at year 4 and, and $38,291 (median of $10,082) at year 5 (Figure 2). Our results also showed high variation in healthcare costs across pediatric pts following the index date; 29.4% of the total costs (over the entire sample) in year 1 were incurred by the 10% pts with the highest costs. Starting from the second year, the 10% of pts with the highest costs accounted for 61.3 to 76.6% of the total costs for each year, suggesting that a small proportion of pts still incur very high costs several years after HSCT. Conclusions: Healthcare resource utilization and direct costs associated with allogeneic HSCT are substantial with the first year direct cost alone of $683,099 with substantial costs over the following years. Further studies are needed to understand the humanistic and financial burden of HSCT for pediatric pts and their caregivers. Figure 1. HRU after Index Date Figure 1. HRU after Index Date Figure 2. Total Healthcare Costs after Index Date Figure 2. Total Healthcare Costs after Index Date Disclosures Maziarz: Athersys: Consultancy, Patents & Royalties, Research Funding; Novartis: Consultancy. Guerin:GlaxoSmithKline, Janssen Scientific Affairs, Janssen-Ortho, Inc., Merck & Co., Inc., Merck Frosst Canada, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ogilvy Renault, Ortho-Clinical Diagnostics, Inc., Otsuka America Pharmaceutical, Inc.,: Consultancy, Other: Annie Guerin is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations; Pfizer Canada, Inc., RX&D, Sanofi, Savient Pharmaceuticals, Inc., Shire Pharmaceuticals Inc., Sunovion Pharmaceuticals Inc., Takeda Global Research & Development Center, Inc., Takeda Pharmaceuticals U.S.A., Inc.: Consultancy, Other: Annie Guerin is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations; AbbVie Inc., Alcon Laboratories, Bayer Healthcare Pharmaceuticals, LLC, Celgene Corporation, Cempra Inc., Centocor Ortho Biotech, Cooley LLP, Cyberonics, Inc., DLA Piper, Eli Lilly & Company,Forest Laboratories, Inc., Genentech, Inc.,: Consultancy, Other: Annie Guerin is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations. Gauthier:AbbVie Inc., Celgene Corporation, Eli Lilly & Company, Genentech, Inc. ,GlaxoSmithKline, Janssen Scientific Affairs, LLC, Novartis Pharmaceuticals Corporation, Pfizer Canada, Inc., Sanofi, Savient Pharmaceuticals, Inc., Shire Pharmaceuticals Inc.,: Consultancy, Other: Genevieve Gauthier is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations; Sunovion Pharmaceuticals Inc.,Takeda Pharmaceuticals U.S.A., Inc.: Consultancy, Other: Genevieve Gauthier is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations. Heroux:AbbVie Inc., Alcon Laboratories, Celgene Corporation, Genentech, Inc., Merck Frosst Canada, Novartis Pharmaceuticals Corporation, Shire Pharmaceuticals Inc., Sunovion Pharmaceuticals Inc., Takeda Pharmaceuticals U.S.A., Inc.: Consultancy, Other: Julie Heroux is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations. Zhdanava:AbbVie Inc., Genentech, Inc., Merck Frosst Canada, Novartis Pharmaceuticals Corporation,Shire Pharmaceuticals Inc., Takeda Pharmaceuticals U.S.A., Inc.: Consultancy, Other: Maryia Zhdanava is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations. Wu:Molecular Insight Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Ortho McNeil Pharmaceuticals, Inc., Sanofi, Savient Pharmaceuticals, Inc., Shire Pharmaceuticals Inc.,: Consultancy, Other: Eric Q Wu is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations; Takeda Global Research & Development Center, Inc., Takeda Pharmaceuticals U.S.A., Inc., TAP Pharmaceutical Products, Inc., Vertex Pharmaceuticals Incorporated: Consultancy, Other: Eric Q Wu is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations; Janssen Pharmaceutica, Inc., Janssen Scientific Affairs, LLC, Lilly Research Laboratories, McNeil Consumer & Specialty Pharmaceuticals, MedImmune, LLC, Melinta Therapeutics, Inc., Millennium Pharmaceuticals, Inc.,: Consultancy, Other: Eric Q Wu is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations; Celgene Corporation, Centocor Ortho Biotech, Cephalon, Inc., ConvaTec Inc., Corus Pharma, Inc., Eli Lilly & Company, Eli Lilly & Company, Ethicon, Inc., Forest Laboratories, Inc., Genentech, Inc., GlaxoSmithKline, Janssen Global Services, LLC,: Consultancy, Other: Eric Q Wu is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations; AbbVie Inc., Alcon Laboratory, Astellas Pharma Inc., Astellas Pharma US, Inc., AstraZeneca, Barger & Wolen LLP, Bayer Healthcare Pharmaceuticals, LLC, Biosense Webster, Inc., Blue Cross Blue Shield Association, Boehringer Ingelheim, Bristol-Myers Squibb C: Consultancy, Other: Eric Q Wu is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations. Thomas:Novartis: Employment. Chen:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership, Other: Lei Chen is an employee of and owns stocks/options of Novartis Pharmaceuticals Corporation, the sponsor of this study.

Because the increased prescriptions of antidepressants are correlated to increased medical visits, it is tempting to conclude, as Hockey did [1], that decreased suicides are a function of greater recognition of depression. It should be noted that the biggest cause of suicide is clinical major depression and increased visits do not treat that; antidepressants do. In a comprehensive review of the literature on the role of long-term antidepressant use to prevent relapse of major depression, Geddes et al. [2] reported that “data were pooled from 31 randomised trials (4410 participants). Continuing treatment with antidepressants reduced the odds of relapse by 70% (95% CI 62–78; 2p

LY333328 is a novel glycopeptide from Lilly Research Laboratories which is claimed to have activity both in vitro and in vivo against vancomycin-resistant enterococci. Information on this compound has been published at three recent meetings, the 7th European Congress of Clinical Microbiology and Infectious Diseases (March 26 - 30, Vienna, Austria); On the Frontier of Antibacterial Drug Discovery (April 27 - 28, Princeton, USA); and the 19th International Chemotherapy Congress (July 16 - 21, Montreal, Canada). This update draws together the published data and attempts to assess the potential therapeutic use of this interesting new compound.

With the intention of bringing together leading academic researchers, industry scientists, business development experts and scientific policy makers, the Society for Medicines Research (SMR) hosted a highly engaging and thought-provoking meeting entitled "Partnerships: Future Models for Drug Discovery" at the Lilly Research Centre in Windlesham, Surrey. With the challenges to discover and develop innovative and differentiated new medicines having never been greater and with many questions arising around the viability of current pharmaceutical business models, this meeting offered the opportunity to explore potential new ways to bring innovation and productivity to the drug discovery sector. Through a series of presentations from leading figures from across the public and private sector, the conference aimed to explore novel business models for research and development and to discuss on the changing dynamics around the interactions between traditional models for academia, industry and funders. Copyright © 2013 Prous Science, S.A.U. or its licensors. All rights reserved.

Jean Ferrieres [Orateur] (1), Guy Berkenboom (2), Zdenek Coufal (3), Stefan James (4), Attila MohaCsi (5), Gregory Pavlides (6), Kirsi Norrbacka (7), Magali Sartral (8), Marie-Ange Paget (8), Molly Tomlin (9), Uwe Zeymer (10) (1) CHU Rangueil, Cardiologie B, Toulouse, France – (2) ULB Erasme University Hospital, Department of Cardiology, Brussels, Belgium – (3) Batova Krajska Nemocnice Zlin, Department of Cardiology, Zlin, Republique Tcheque – (4) Uppsala University Hospital, Dept. of Cardiology and Uppsala Clinical Research Center, Uppsala, Suede – (5) Gottsegen Institute of Hungarian Cardiology, Budapest, Hungaria – (6) Onassis Cardiac Surgery Center, Kallithea, Grece – (7) Lilly Research Laboratories, Eli Lilly and Company, Vantaa, Finlande – (8) Lilly Research Laboratories, Eli Lilly and Company, Paris, France – (9) Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United-States – (10) Klinikum Ludwigshafen, Ludwigshafen, Allemagne

Atomoxetine (originally named tomoxetine), a new therapy for attention deficit hyperactivity disorder (ADHD) marketed by Eli Lilly, was compared to methylphenidate in a prospective, randomized, open-label study for 10 weeks duration, at the University of Nebraska Medical Center, Massachusetts General Hospital, Mount Sinai Medical Center, Carolinas Medical Center, and Lilly Research Laboratories.

G. Umpierrez, T. Blevins, J. Rosenstock, C. Cheng, E. Bastyr, J. Anderson 1 Emory University School of Medicine, Division of Endocrinology, Atlanta, USA 2 Texas Diabetes and Endocrinology, , Austin, USA 3 Dallas Diabetes and Endocrinology Center, , Dallas, USA 4 Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, USA 5 Eli lilly and Company, Lilly Research Laboratories, Indianapolis, USA

Hyung Ki Choi, Je Jong Kim, Sae-Chul Kim, JunKyu Suh, Yoon Kyu Park, Seong Choi, Woong Hee Lee, Ki Hak Moon, Hae Young Park, Jong Kwan Park, Wei Christine Wang, Vladimir Kopernicky From the Department of Urology, Yongdong Severance Hospital, Seoul, Korea University Ansan Hospital, Ansan, Chungang University Hospital, Seoul, Inha University Hospital, Incheon, Kyungpook University Hospital, Daegu, Kosin University Hospital, Busan, Dong Seoul Hospital, Seoul, Yeungnam University Hospital, Daegu, Hanyang University Hospital, Seoul, Chonbuk National University Hospital, Jeonju, Korea, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA, Lilly Area Medical Center, Vienna, Austria

This is the first special topic volume, collected from articles within Progress and Drug Research dealing with new antiviral agents. The editors have chosen an important range of topics – concentrating on only one aspect of HIV (a good idea given the breadth of antivirals for HIV), and agents for influenza, hepatitis C, hepatitis B, herpesviruses and picornaviruses. Although the range of topics is broad, most of the authors come from pharmaceutical companies, particularly the Lilly Research Laboratories at Eli-Lilly in Indianapolis. In fact, authors of four of the six chapters are members of the Eli-Lilly Research Laboratories, one is from the Roche Research Laboratories in Hertfordshire, and one from the University of Southern California. The reviews all tend towards academic discussion of the pharmacologic uses of drugs. Further, all the authors approach the subject from the point of view of drug design and use, rather than from a clinical standpoint with drug design based upon response to clinical needs. This is not a criticism of the authors' approach, but readers need to be aware that emphasis is more on biochemical rather than clinical drug design. In general, the chapters deal with important issues, and have brief summaries of the virology at the start, followed by more detailed discussion of different types of drug classes, and individual representatives of these classes. Who would find this book useful? The book is very much aimed at a specialist reader with knowledge of pharmacology, rather than a clinical audience. The discussion of HIV protease inhibitors is good, although the rapid change in HIV therapy means any book chapter will be rapidly out-of-date. The chapter on influenza drugs was excellent, although more discussion of the use of these agents in pandemic situations (such as arose with H5 influenza in Hong Kong during 1997) would be of interest. The discussion of hepatitis C was useful, although the evolution of treatment of hepatitis C means multi drug therapy is now standard, and it would be useful to have further discussion of what may be next. Furthermore, recent developments in the treatment of acute HCV infection, and new indicators of response to treatment, mean this chapter lacked discussion of some evolving and important areas. The chapter on herpesviruses dealt with the basic issues well, although several areas of treatment such as the use of valganciclovir, intravitreal ganciclovir, and animal models for testing of herpesviruses were deficient. It was disappointing not to see some discussion of vaccines as there has been considerable literature regarding vaccination, particularly for HSV infection, particularly in the last three years. The picornavirus chapter was adequate, although there was less discussion of drugs such as pleconaril (which is now in limited clinical use) than would be useful to the general reader. Overall, the specialist pharmacologist, or a clinician interested in a particular area of antiviral research, would do well to start with one of these chapters relating to their area of interest. The major weakness of the book is the rapid rate of advance in antiviral therapy – particularly for HIV, hepatitis C and the herpesviruses. This will be a weakness of any book, although the provision of addenda immediately prior to publication can be of use in reducing this problem. What I liked about this book was the excellent overall structure, dealing with the most important antivirals available in 2001. Selection of one area of HIV therapy for more detailed discussion was a wise choice, and utilization of review style articles to make up the book, made for in-depth reading. The problems with this book were that in many areas it was incomplete (such as for anti viral agents for herpesviruses), the lack of any significant reference to vaccination, and the dense nature of the material. The book would benefit from more summary tables for occasional readers. It was striking that new vaccines for influenza (adjuvanted, intranasal, and others), HSV, and HIV were not mentioned. The referencing style, where article titles were not given was also annoying, given that a target audience for this book may well look to the references for further information about particular areas that they find of interest within each chapter. Overall, Antiviral Agents: Advances and Problems is a reasonable book in a difficult field. The information is readable, the authors provide significant detail in the areas they cover, and the references are in general inclusive. It would be a useful book for the reader looking for a succinct introduction to one of the six major areas covered in the chapters, or looking for further information about the pharmacology of these antiviral agents.

The vinca alkaloids were discovered independently in two separate laboratories by a combinat ion of serendipity and what we have called rational broad spectrum tumor screening. In the first case, R. L. Noble and his colleagues in the Collip Labora tory at the University of Western Ontar io were examining extracts ofCatharanthus roseus G. Don ( Vinca rosea Linn.) for their effects on blood glucose because of unconfirmed reports in various parts of the world that the plant was being used for the treatment of diabetes. These investigators (4) found by chance observation that the extracts produced profound leukopenia in the rat, and they isolated an alkaloid which demonstrated such activity as a crystalline sulfate, which they named vincaleukoblastine (VLB). They speculated that it might have potential chemotherapeutic properties. This is the drug which is currently marketed as Velban ~'~ (vinblastine sulfate, Lilly). Unknown to the Canadian group, a group of investigators in the Lilly Research Laboratories had observed profound activity in extracts from the same plant against the P-1534 lymphocytic leukemia in DBA/2 mice and had isolated a second alkaloid with antileukemic activity which they named leurosine (3). We were also able to show that after VLB and leurosine were removed from the extracts that there were components remaining with profound ant i tumor activity. These were eventually identified as leurocristine (Oncovin, vincristine sulphate, Lilly) and leurosidine (12). The discovery in the Lilly Research Laboratories resulted from a privately funded ant i tumor screening program mounted in response to a national effort to increase the detection and development of new anticancer drugs through what was then the Cancer Chemotherapy National Service Center (CCNSC). We had long felt that harnessing the major pharmaceutical laboratories to a single set of tests or test systems would have been an error. It had been the experience of most such laboratories that, as new systems, tests, techniques, etc., are devised, a new class of agent was frequently found. The more varied the system in use, the greater the probability of different kinds of materials being detected. In the nationally organized program, the screening philosophy appeared to be based upon the concept of using as few detection systems as possible that would detect the largest number of drugs currently considered as having clinical activity. This was clearly an at tempt at a cost-effective approach. Our concern was that cancer was a heterogenous family of proliferative diseases, and that just as cancer drugs had tumor spectra, experimental neoplasms also had drug spectra. I f this were true, continuous use of a few or even single murine neoplasms for cancer screening might not be expected to detect new or novel drugs, much less predict for activity against a broad spectrum of neoplasms and histological types. While performing well in terms of detecting novel structures, our system did not predict

In the early autumn of 1924 we were invited by Professor A. A. Noyes, director of the Gates Chemical Laboratory of the California Institute of Technology, Pasadena, California, to investigate the chemical and other properties of insulin in his laboratory under a grant from the Carnegie Foundation. Commercial insulin as prepared by the Lilly Research Laboratories of Eli Lilly and Company, Indianapolis, Indiana, has served as the material for our investigation. Two forms of commercial insulin have been used by us; one a dry powder evaluated at approximately 8 rabbit units per milligram; the second a highly concentrated aqueous solution (2.44 per cent. solids) containing approximately 300 rabbit units per cubic centimeter, and with 120 milligrams of hydrochloric acid per 100 cubic centimeters.

SINCE PHENYLKETONURIA, a metabolic anomaly associated with mental retardation, can now often be beneficially treated with a phenylalanine-free diet, it has become desirable to detect its presence as early as possible, since the diet loses its efficacy as the child grows older. At the suggestion of one of us (J.W.) both the Lilly Research Laboratories of Indianapolis, Ind., and later the Ames Company, Inc., of Elkhart, Ind., developed test papers for the detection of phenylketonuria. These small strips of prepared paper may be used by immersion in a fresh urine specimen or by simple pressure against a wet diaper. The Lilly test paper* was released as RT 974 for clinical trial purposes only. The Ames reagent strips are being marketed under the name of Phenistix. The work reported in this paper was done with the Lilly material, but the Phenistix are almost identical in application. With the Lilly test paper the presence of phenylpyruvic acid in the urine produces a color change from the original yellowish white to a blue of varying density, depending on the amount of phenylpyruvic acid present. Amounts as small as 15-20 mg per 100 cc of urine are detectable by this method. The test is not, however, specific for phenylketone; the following substances may also induce color changes as follows: phenol, blue; pyruvic acid