The response to environmental and internal stimuli is one of the basic characteristics of living organisms. Inspired by this natural strategy and fast-developing nanotechnology and materials science, stimuli-responsive nanomedicine has emerged as an active and important field of nanomedicine. This book offers a fundamental and comprehensive overview of stimuli-responsive nanomedicine and compiles and details the recent cutting-edge findings and most impressive achievements in biomedical applications, from a pharmaceutical science perspective, making it the first book of its kind in this field. By providing readers a broad and in-depth coverage of endogenous and exogenous stimuli as well as their applicable nanomedicines, this book is valuable for students, researchers, and educators in biomedical sciences or anyone interested in this burgeoning field.

This comprehensive volume discusses approaches for a systematic selection of delivery systems for various classes of therapeutic agents including small molecule, protein, and nucleic acid drugs. Specific topics covered in this book include: * Solution, suspension, gel, nanoparticle, microparticle, and implant dosage forms* Refillable and microneedle devices* Intravitreal, suprachoroidal, intrascleral, transscleral, systemic, and topical routes of delivery* Physical methods including iontophoresis for drug delivery* Rational selection of routes of administration and delivery systems* Noninvasive and continuous drug monitoring * Regulatory path to drug product development* Clinical endpoints for drug product development* Emerging and existing drugs and drug targets Drug Product Development for the Back of the Eye is authored by renowned ocular drug delivery experts, representing academic, clinical, and industrial organizations and serves as indispensable resource for ophthalmic researchers, drug formulation scientists, drug delivery and drug disposition scientists, as well as clinicians involved in designing and developing novel therapeutics for the back of the eye diseases.This book is also relevant for students in various disciplines including ophthalmology, pharmaceutical sciences, drug delivery, and biomedical engineering. * Refillable and microneedle devices* Intravitreal, suprachoroidal, intrascleral, transscleral, systemic, and topical routes of delivery* Physical methods including iontophoresis for drug delivery* Rational selection of routes of administration and delivery systems* Noninvasive and continuous drug monitoring * Regulatory path to drug product development* Clinical endpoints for drug product development* Emerging and existing drugs and drug targets Drug Product Development for the Back of the Eye is authored by renowned ocular drug delivery experts, representing academic, clinical, and industrial organizations and serves as indispensable resource for ophthalmic researchers, drug formulation scientists, drug delivery and drug disposition scientists, as well as clinicians involved in designing and developing novel therapeutics for the back of the eye diseases. This book is also relevant for students in various disciplines including ophthalmology, pharmaceutical sciences, drug delivery, and biomedical engineering.* Refillable and microneedle devices* Intravitreal, suprachoroidal, intrascleral, transscleral, systemic, and topical routes of delivery* Physical methods including iontophoresis for drug delivery* Rational selection of routes of administration and delivery systems* Noninvasive and continuous drug monitoring * Regulatory path to drug product development* Clinical endpoints for drug product development* Emerging and existing drugs and drug targets Drug Product Development for the Back of the Eye is authored by renowned ocular drug delivery experts, representing academic, clinical, and industrial organizations and serves as indispensable resource for ophthalmic researchers, drug formulation scientists, drug delivery and drug disposition scientists, as well as clinicians involved in designing and developing novel therapeutics for the back of the eye diseases. This book is also relevant for students in various disciplines including ophthalmology, pharmaceutical sciences, drug delivery, and biomedical engineering.

Compatibility of Pharmaceutical Products and Contact Materials

Dennis Jenke

Important safety aspects of compatibility for therapeutic products and their manufacturing systems, delivery devices, and containers

"Compatibility of Pharmaceutical Products and Contact Materials" helps pharmaceutical, toxicology, analytical, and regulatory affairs professionals assess the safety of leachable and extractable chemicals associated with drug product packaging, manufacturing systems, and devices. The most comprehensive resource available, its coverage includes the strategies, tactics, and regulatory requirements for performing safety assessments, along with the means for interpreting results.

Structured around a logical framework for an extractables and leachables safety assessment and closely linked to the pharmaceutical product development process, "Compatibility of Pharmaceutical Products and Contact Materials" directly addresses the fundamental questions of "what activities need to be performed to completely, efficiently, and effectively address the issue of product safety from an extractables and leachables perspective?" and "when do the various required activities need to be performed?" Specifically, the chapters describe:

Pertinent regulations and practical ways to meet guidelines

Coordinating manufacturing, storage, and delivery systems development and qualification with therapeutic product development

Materials characterization and the materials screening process

Component and/or system qualification (illustrated by several case studies)

Performing validation/migration studies and interpreting and reporting the results

Creating a product registration dossier and putting it through regulatory review

Product maintenance (Change Control) from an extractables and leachables perspective

Likely future developments in extractables and leachables assessment

Additionally, the book's appendix provides a database, including CAS registry numbers, chemical formulas and molecular weights of extractable/leachable substances that have been reported in the chemical literature.

Detailing the interconnected roles played by analytical chemistry, biological science, toxicology, and regulatory science, "Compatibility of Pharmaceutical Products and Contact Materials" supplies a much-needed, comprehensive resource to all those in pharmaceutical product or medical device development.

Complied by an expert editorial team with noteworthy and remarkable experience, this book covers technological aspects related to probiotics, not only in terms of delivery modes but also in terms of protection technologies. It includes discussions of their therapeutic and physiologic implications and benefits, and provides a contemporary update and a holistic review of the topic. It focuses on the technological aspects of probiotic products, brings together the information needed for their successful development, and examines the international picture regarding regulatory issues.

Analytical chemists in the pharmaceutical industry are always looking for more-efficient techniques to meet the analytical challenges of today s pharmaceutical industry. One technique that has made steady advances in pharmaceutical analysis is supercritical fluid chromatography (SFC). SFC is meeting the chromatography needs of the industry by providing efficient and selective testing capabilities on the analytical and preparative scale. The supercritical fluid mobile phase, consisting mainly of CO2, facilitates cost reduction costs and helps the industry in meeting green chemistry standards. This book provides a comprehensive overview of the use of SFC in pharmaceutical analysis.

Supercritical Fluid Chromatography reviews the use of SFC in drug-discovery applications and describes its application in drug development. When a drug is developed and brought to market, it is tested many times for impurities and degradants, enantiomeric purity, and analytical and preparative isolations it is tested during discovery and development and for under-regulated and unregulated methodologies. The book describes the use of SFC for each of these applications and discusses more in-depth topics, such as the use of SFC in mass spectrometric and polarographic detection. The book also sheds light on the role of SFC in drug development from natural products and the advancement of SFC with new technologies and its use in pilot-scale operations as a chromatographic technique.

Pharmaceutical Biotechnology is a unique compilation of reviews addressing frontiers in biologicals as a rich source for innovative medicines. This book fulfills the needs of a broad community of scientists interested in biologicals from diverse perspectives basic research, biotechnology, protein engineering, protein delivery, medicines, pharmaceuticals and vaccinology. The diverse topics range from advanced biotechnologies aimed to introduce novel, potent engineered vaccines of unprecedented efficacy and safety for a wide scope of human diseases to natural products, small peptides and polypeptides engineered for discrete prophylaxis and therapeutic purposes. Modern biologicals promise to dramatically expand the scope of preventive medicine beyond the infectious disease arena into broad applications in immune and cancer treatment, as exemplified by anti-EGFR receptors antibodies for the treatment of breast cancer. The exponential growth in biologicals such as engineered proteins and vaccines has been boosted by unprecedented scientific breakthroughs made in the past decades culminating in an in-depth fundamental understanding of the scientific underpinnings of immune mechanisms together with knowledge of protein and peptide scaffolds that can be deliberately manipulated. This has in turn led to new strategies and processes. Deciphering the human, mammalian and numerous pathogens genomes provides opportunities that never before have been available identification of discrete antigens (genomes and antigenomes) that lend themselves to considerably improved antigens and monoclonal antibodies, which with more sophisticated engineered adjuvants and agonists of pattern recognition receptors present in immune cells, deliver unprecedented safety and efficacy. Technological development such a nanobiotechnologies (dendrimers, nanobodies and fullerenes), biological particles (viral-like particles and bacterial ghosts) and innovative vectors (replication-competent attenuated, replication-incompetent recombinant and defective helper-dependent vectors) fulfill a broad range of cutting-edge research, drug discovery and delivery applications. Most recent examples of breakthrough biologicals include the human papilloma virus vaccine (HPV, prevention of women genital cancer) and the multivalent Pneumoccocal vaccines, which has virtually eradicated in some populations a most prevalent bacterial ear infection (i.e., otitis media). It is expected that in the years to come similar success will be obtained in the development of vaccines for diseases which still represent major threats for human health, such as AIDS, as well as for the generation of improved vaccines against diseases like pandemic flu for which vaccines are currently available. Furthermore, advances in comparative immunology and innate immunity revealed opportunities for innovative strategies for ever smaller biologicals and vaccines derived from species such as llama and sharks, which carry tremendous potential for innovative biologicals already in development stages in many pharmaceutical companies. Such recent discoveries and knowledge exploitations hold the promise for breakthrough biologicals, with the coming decade. Finally, this book caters to individuals not directly engaged in the pharmaceutical drug discovery process via a chapter outlining discovery, preclinical development, clinical development and translational medicine issues that are critical the drug development process.

The authors and editors hope that this compilation of reviews will help readers rapidly and completely update knowledge and understanding of the frontiers in pharmaceutical biotechnologies."

Melville's Monumental Imagination explores the connection between the contested 19th century American monument tradition and one of the nation's most revered authors, Herman Melville (1819-1891). The book was written to fill a void in recent Melville scholarship. To date, there has not been a monograph that focuses exclusively on Melville's incorporation of monuments in his fictional world. The book charts the territory of Melville's novels in order to provide a trajectory of the monumental image in one particular literary form. This feature allows the reader to gradually see the monumental image as an important marker that sheds light into Melville's eventual abandonment of long fiction. Melville'sMonumental Imagination combines literary analysis and cultural criticism for a long neglected aspect of our nation's iconic development in statuary.

The use of honey can be traced back to the Stone Age. Evidence can be found for its nutritional and medicinal use beginning with prehistoric and ancient civilizations. Currently, there is a resurgence of scientific interest in natural medicinal products, such as honey, by researchers, the medical community, and even the general public. Honey in Traditional and Modern Medicine provides a detailed compendium on the medical uses of honey, presenting its enormous potential and its limitations. The book covers honey's ethnomedicinal uses, chemical composition, and physical properties. It discusses the healing properties of honey, including antimicrobial, anti-inflammatory, and antioxidant properties. It also examines the botanical origin of honey, a critical factor in relation to its medicinal use, along with the complex subject of the varying composition of honey. Honey's antibacterial qualities and other attributes are described in a chapter dedicated to Leptospermum, or Manuka honey, a unique honey with potential for novel therapeutic applications. Chapters explore a variety of medicinal uses for honey, including its healing properties and use in burn and wound management. They review honey's beneficial effects on medical conditions, such as gastrointestinal disorders, cardiovascular diseases, diabetic ulcers, and cancers as well as in pediatrics and animal health and wellness. The book also examines honey-based formulations, modern methods for chemical analysis of honey, and the history and reality of "mad honey." The final chapters cover honey in the food industry, as a nutrient, and for culinary use.

Recent reviews of respiratory-tract affections caused by M. pneumoniae under- score the benign and often subclinical course of the infection. Severe pneumonia with a reticular or acinar pattern is certainly unusual and a fatal outcome is rare, but the incidence of both is underestimated. Erythromycin and tetracyclines are the first-choice antibiotics. There is evidence indicating the importance of im- munopathogenic mechanism in provoking pneumonia and even respiratory failure. REFERENCES 1. Krech U, Price PC, Jung M: The laboratory diagnosis and epidemiology of mycoplasma pneumoniae in Switzerland. Infection 4:33, 1976. 2. Fischman RA, Marschall KE, Kislak JW: Adult respiratory distress syndrome caused by mycoplasma pneumoniae. Chest 74:471, 1978. 3. Reigner Ph, Domenighetti G, Feihl F, Bonjour JPh, Perret CI: Syndrome de detresse respiratoire aigu sur infection a mycoplasme. Sch Med W 110:220, 1980. 4. Kaufman JM, Cuvelier CA, Van der Straeten M: Mycoplasma pneumonia with fulminant evolution into diffuse interstitial fibrosis. Thorax 35:140, 1980. 5. Murray HW, Masur H, Senterfit L, Roberts R: The protean manifestations of mycoplasma pneumoniae infection in adults. Am J Med 58:229, 1975. 6. Levine DP, Lerner AM: The clinical spectrum of Mycoplasma pneumoniae infections. Med Clin N Am 62:961,1978. 7. Twomey JA, Espir ML: Neurological manifestations and Mycoplasma pneumoniae infection. BMJ 2:832, 1979. 8. Kingston JR, Chankock RM, Mufson MA, Hellman LP, James WD, Fox HH, Mankoma C, Boyers J: Eaton agent pneumonia. JAMA 176:118, 1961.

In summary, there are many animal models that are useful in selecting new antiarrhythmic drugs. The selection of which model is most idea depends upon precisely what question is being asked. The large number of experimental models used to evaluate antiarrhythmic compounds points out the inability of anyone model to define the probability of antiarrhythmic efficacy in man. It has therefore become standard practice to utilize a batter of animal models for the evaluation of new antiarrhythmic agents. Each model has its own advantages and disadvantages and it is necessary to understand each model fully in oder to evaluate experimental findings and apply them to clinical settings. We believe that the availability of the chronic myocardial infarction ventricular tachyarrhythmia model provides 1) an excellent opportunity to more precisely understand arrhythmia mechanisms, 2) to develop new techniques such as signal averaging for evaluating late low level potentials identifying hearts at high risk of sudden death 3) to identify new antifibrillatory drugs versus drugs that are effective primarily against PVC's and ventricular tachycardia 4) to identify new surgical techniques to eliminate VT/VF, and 5) to evaluate new pacing modalities including implantable cardioverters. Although all animal models are wrong, many are very useful in furthering our knowledge directed at decreasing the distressingly high mortality from heart disease. NORMAL HtART TACHYCMDIA HtART , .. '" \ I I I I I I I I I .

Packed with real-world examples, this book illustrates the 12 principles of green chemistry. These diverse case studies demonstrate to scientists and students that beyond the theory, the challenges of green chemistry in pharmaceutical discovery and development remain an ongoing endeavor. By informing and welcoming additional practitioners to this mission, the negative environmental impact of pharmaceutical products will continue to be minimized. Green chemistry is the methodology by which chemical production in this industry can become more efficient, adding environmental stewardship to the noble mission of treating human disease.

Hypertension has certainly been one of the topics most fre quently discussed at symposia, meetings, and congresses during recent years. There may be several reasons for this; three of them are obvious: firstly, the fact that a large proportion of the world's population is suffering from various forms of hypertensive disease; secondly, increasing knowledge of the pathogenesis of hypertension and of the disturbances underlying it; and, thirdly, the marked progress which has been made in antihypertensive therapy over the past fifteen years. When plans for the present symposium were being drawn up, it was felt that it should not simply bring forth just another meeting on hypertension, but should place particular emphasis on those aspects which had not been adequately discussed at previous symposia of this kind. Curiously enough, the topic which appeared to have received least attention in the past was therapy, although from the practical point of view this is by far the most important. The choice of therapy as the main theme of the whole symposium also seemed to be warranted in view of the relatively long period that had elapsed since effective antihyper tensive treatment became available; the time had in fact come now to pass judgement on the benefits as well as the shortcomings of drug treatment as available today.

This Brief discusses key statistical concepts that facilitate the inferential analysis of data collected from a group of individuals participating in a pharmaceutical clinical trial, the estimation of their clinical significance in the general population of individuals likely to be prescribed the drug if approved, and the related decision-making that occurs at both the public health level (by regulatory agencies when deciding whether or not to approve a new drug for marketing) and the individual patient level (by physicians and their patients when deciding whether or not the patient should be prescribed a drug that is on the market). These concepts include drug safety and efficacy, statistical significance, clinical significance, and benefit-risk balance.

Cutting-edge researchers describe their efforts to design, synthesize, and evaluate the biological activities of farensyltransferase inhibitors (FTIs); geranylgeranyltransferase inhibitors (GGTIs) are also discussed as potential anticancer drugs. The authors survey in detail such inhibitors as CAAX box peptidomimetics, FPP mimics, and bisubstrate transition state analogs, and critically review their uses in combination with radiation and other cytotoxic agents, such as gemcitabine, cisplatin, and taxanes. Illuminating and richly detailed, Farnesyltransferase Inhibitors in Cancer Therapy constitutes today's standard reference for the pathbreaking use of FTIs and GGTIs in anticancer therapy and offers basic and clinical investigators a comprehensive treatment of the scientific and medical aspects of farnesyltransferase inhibitors.

Macromolecular (specifically peptide-based) drugs could potentially be highly effective medicines. However they have a relatively short duration of action and variable therapeutic index. An example of such a peptide is Glucagon-like Peptide I which could potentially be used as a revolutionary drug for diabetes. This is because it stimulates insulin only when the blood glucose level is high thereby reducing the risk of hypoglycemia (a significant disadvantage of using insulin is that an insulin overdose is the single most potent cause of life-threatening hypoglycemia). However it's short duration of action (half-life of 2 minutes in plasma) precludes its therapeutic use. In this volume, the use of novel therapeutics like GLP1 as an alternative to tradition insulin-based drugs in diabetes is described. Application of Peptide-Based Prodrug Chemistry in Drug Development elucidates the traditional concept of prodrugs as "specialized non-toxic protective groups used in a transient manner to alter or to eliminate certain limiting properties in the parent small molecule" (IUPAC definition). It goes on to provide insight into how prodrugs of peptides (with GLP1 as an example) could be appropriately used to extend the biological half life, broaden the therapeutic index of macromolecules and improve the pharmacodynamics of such drugs. Author explains the logic behind designing peptide prodrugs, synthetic procedures and bioassays to examine the conversion of the prodrug to the drug under therapeutic conditions. The prodrugs described slowly convert to the parent drug at physiological conditions of 37C and pH 7.2 driven by their inherent chemical instability without the need of any enzymatic cleavage. The diketopiperazine and diketomorpholine (DKP and DMP) strategies for prodrug conversion are demonstrated in detail with special emphasis on the chemical flexibility that it offers to develop prodrugs with variable time actions. This book will be of useful to chemists, biochemists, medicinal chemists, biologists and people in the medical profession (doctors). It may be used in undergraduate classes but will certainly help post-graduate students and advanced professionals. The author is grateful to Prof. Richard DiMarchi (Standiford H. Cox Professor of Chemistry and the Linda & Jack Gill Chair in Biomolecular Sciences at Indiana University) for valuable suggestions. The foreword for the book has been written by Prof. Jean Martinez, (Legion d'Honneur awarded by the French Republic; Professor of Chemistry and Medicinal Chemistry of the University of Montpellier, France; and Chairman of European Peptide Society, 2002-2010).

to Cyclic glucans are polysaccharides that are predominantly produced by "Agrobacterium, Bradyrhizobium" and "Rhizobium "sp. and widely used in the pharmaceutical and food industries. In this book, the applications, properties, analytical tools, production and genes of four main cyclic -glucans from microorganisms are highlighted and critically evaluated. As biocompatible and biodegradable renewable resources, they have an immense potential for future applications, which has not yet been fully exploited. This concise review will help to bridge this gap."

An increasing number of pharmaceuticals in human and veterinary medicine are being developed using advanced genetic and other methods that focus on modification of somatic and embryonic cells. These methods, in the setting of drug manufacture, call for new processes that go beyond the traditional unit processes of chemical and biological production, such as batch submerged culture.

This book is the first to describe in detail these advanced biological processes and show how they are applied to the production of biopharmaceuticals, from product generation and purification to fill-finish operations.

The work explains how technologies developed in the last decade function similarly to unit operations for producing advanced biopharmaceuticals, such as hormones, cytokines, therapeutic enzymes, modified proteins, and transgenic products - to name a few. From large-scale animal cell bioreactors to patient-customized products, this volume describes the effects of new technologies on biopharmaceutical processes and guides users on how to apply new technologies in process development.

Vitamin C may offer significant therapeutic benefits in the treatment of cancer. This book includes chapters by a group of leading scientific researchers documenting the ways cancer can be affected by high doses of ascorbate. After an initial chapter providing a historical perspective, subsequent chapters focus on cancer cell death, reprogramming of somatic cells, recent case studies, and other ways vitamin C can improve outcomes of therapy. Features Includes chapters from a team of leading international scholars Reviews the history of beneficial uses of vitamin C in the treatment of cancer Summarizes recent case studies Discusses how vitamin C may synergistically affect other cancer treatment methods

A comprehensive treatise on the hot working of aluminum and its alloys, Hot Deformation and Processing of Aluminum Alloys details the possible microstructural developments that can occur with hot deformation of various alloys, as well as the kind of mechanical properties that can be anticipated. The authors take great care to explain and differentiate hot working in the context of other elevated temperature phenomena, such as creep, superplasticity, cold working, and annealing. They also pay particular attention to the fundamental mechanisms of aluminum plasticity at hot working temperatures. Using extensive analysis derived from polarized light optical microscopy (POM), transmission electron microscopy (TEM), x-ray diffraction (XRD) scanning electron-microscopy with electron backscatter imaging (SEM-EBSD), and orientation imaging microscopy (OIM), the authors examine those microstructures that evolve in torsion, compression, extrusion, and rolling. Further microstructural analysis leads to detailed explanations of dynamic recovery (DRV), static recovery (SRV), discontinuous dynamic recrystallization (dDRX), discontinuous static recrystallization (dSRX), grain defining dynamic recovery (gDRV) (formerly geometric dynamic recrystallization, or gDRX), and continuous dynamic recrystallization involving both a single phase (cDRX/1-phase) and multiple phases (cDRX/2-phase). A companion to other works that focus on modeling, manufacturing involving plastic and superplastic deformation, and control of texture and phase transformations, this book provides thorough explanations of microstructural development to lay the foundation for further study of the mechanisms of thermomechanical processes and their application.

Liposome Technology, Volume III: Interactions of Liposomes with the Biological Milieu, Third Edition, is a comprehensively updated and expanded new edition of a classic text in the field. Including step-by-step technical details, Volume III describes technologies for yielding liposomes that can function in a targeted fashion, and highlights methods for studying the interaction of liposomes within the biological environment to be applied in the detection, therapy, or prevention of disease. This source also offers critical discussions of the methodologies of each technology described so that readers can examine the benefits and limitations and compare it to other approaches.

One of the biggest computer validation challenges facing pharmaceutical manufacturers is the large corporate system. This book provides practical information and advice on good IT practice and validation principles. Written by experts, it includes case studies on EDMSs, EAM systems, LIMSs, and MRP II systems.

Biotechnology: Quality Assurance and Validation provides a practical, detailed discussion of what issues Quality Assurance and Quality Control need to identify for effective control in the preparation of biotechnology products. The book presents a series of topics that define some of the unique challenges facing biotechnology companies in producing biopharmaceutical products. The topics selected address quality and validation issues, starting with the cryopreservation of cell lines through the filling and finishing of the product. It includes a validation guide, a clear presentation of how to use filtration effectively, a synoptic view of cleaning procedures, and much more.

Designed with academic vaccine researchers in mind, this book presents a road map of how a vaccine develops from an idea in a researcher's imagination, to the lab bench, through preclinical evaluation, and into the clinic for safety and immunogenicity. The result of the editors' own efforts to glean practical information on the steps necessary to manufacture, bottle, and test their vaccines for clinical trials, this book provides answers to researcher questions such as: How do I identify antigens that would produce effective vaccines? Can I produce a clinical lot of vaccine in my laboratory? How should a vaccine be bottled? Which FDA expectations must I meet? What is an IND application and how do I file it? Which CFRs apply to production of a vaccine?

Due to a worldwide need for lower cost drug therapy, use of generic and multi-source drug products have been increasing. To meet international patent and trade agreements, the development and sale of these products must conform to national and international laws, and generic products must prove that they are of the same quality and are therapeutically equivalent to the brand name alternative. However, many countries have limited resources to inspect and verify the quality of all drug products for sale in their country. This title discusses the worldwide legislative and regulatory requirements for the registration of generic and multi-source drug products.

Gathering information of critical importance for professionals in the pharmaceutical and medical device industries, this guide provides a comprehensive overview of key resources, such as databases, on-line directories, reports, and periodicals-providing at-a-glance guidance and collection development tools for information professionals in this field. Each chapter corresponds to a key stage or component of the drug development processin a typical pharmaceutical company and covers the types of information typically required at that particular phase.