- Home
- A-Z Publications
- Annual Review of Medicine
- Previous Issues
- Volume 58, 2007
Annual Review of Medicine - Volume 58, 2007
Volume 58, 2007
-
-
The Drug Development Crisis: Efficiency and Safety
Vol. 58 (2007), pp. 1–16More LessDespite advancements in genetics, chemistry, and protein engineering, recent years have seen fewer approvals of new drugs, increases in development costs, and high-profile drug withdrawals. This article focuses on technologic methods for improving drug development efficiency. These technologies include high-content cell screening, expression profiling, mass spectroscopy, mouse models of disease, and a post-launch screening program that enables investigations of adverse drug effects. Implementation of these new technologies promises to improve performance in drug development and safety.
-
-
-
Idiosyncratic Toxicity: A Convergence of Risk Factors
Vol. 58 (2007), pp. 17–34More LessAbstractThe therapeutic margin for any drug is based on both toxicity and efficacy. Generally, toxicity is dose-dependent and is driven either by the therapeutic target or by an untoward target. However, idiosyncratic toxicities are usually not observed until a drug has been on the market and has gained broad exposure. Except in the case of pharmacokinetic interactions, these toxicities are not driven solely by drug exposure but rather depend on several drug- and patient-related risk factors. Drug-related risk factors include metabolism, bioactivation and covalent binding, and the inhibition of key cell functions. Patient-related risk factors include underlying disease, age, gender, comedications, nutritional status, activation of the innate immune system, physical activity, and genetic predispositions. Idiosyncratic toxicity can occur when a convergence of risk factors, including drug exposure, tips the risk-benefit balance away from benefit and toward risk.
-
-
-
Rethinking Electronic Health Records to Better Achieve Quality and Safety Goals
Vol. 58 (2007), pp. 35–47More LessAbstractHealth care information technology changes the ecosystem of a practice. Human roles, process work flow, and technology infrastructure are tightly interrelated. Medical errors may increase if a change in one is not accommodated by a change in the others. Introduction of information technology should be approached as an iterative process of care improvement rather than as a one-time insertion of an information system into established practice. Information technology supports a family of technological approaches, each with distinct mechanisms of action, benefits, and side effects. By matching technological approach to task and staging introduction into practice, initial benefit can be obtained more quickly, at reduced cost, while managing risk of a misfit. A staged approach to turning direct access by patients to their health information into more effective care is presented as an example of this strategy.
-
-
-
Schizophrenia: New Pathological Insights and Therapies
Vol. 58 (2007), pp. 49–61More LessAbstractThe neurodevelopmental hypothesis of schizophrenia posits an interaction between multiple susceptibility genes and one or more environmental insults in early life, resulting in altered brain development and the emergence of psychosis in early adulthood. Based on this framework, it has been argued that most neuropathological deficits observed in post mortem and neuroimaging studies of schizophrenia represent one or more lesions that originated in early life and remained static thereafter. However, recent longitudinal neuroimaging studies demonstrate a progressive component to the neuropathology of new-onset schizophrenia. This opens the possibility that the functional decline seen in many patients following the onset of illness may be halted or slowed. This review provides an update on developments in research on the neuropathology of schizophrenia and discusses recent advances in antipsychotic treatment and the potential impact on long-term outcomes.
-
-
-
Cardiac Resynchronization Treatment of Heart Failure
Vol. 58 (2007), pp. 63–74More LessAbstractCardiac resynchronization therapy (CRT) is well established as a treatment for patients with moderate to severe heart failure on optimal medical therapy. Early studies demonstrated improved functional capacity and evidence of reverse remodeling; more recently, CRT has been associated with a survival benefit in advanced heart failure both with and without a defibrillator. We review the eight landmark trials in CRT. To date, criteria have focused on electrical delay, but echocardiographic parameters emphasize the importance of mechanical delay or ventricular dyssynchrony. With the exponential rise in implants, new issues have emerged, such as optimal device programming, identifying appropriate candidates, and accounting for cases without clinical benefit from CRT.
-
-
-
New Approaches in the Therapy of Cardiomyopathy in Muscular Dystrophy
Vol. 58 (2007), pp. 75–88More LessAbstractCardiomyopathy is a frequent occurrence in muscular dystrophy, and heart disease in muscular dystrophy can contribute to both morbidity and mortality. A number of novel therapies are being developed for muscular dystrophy, and the efficacy of these therapies for heart disease is unknown. The most common X-linked recessive disease is Duchenne muscular dystrophy (DMD), which arises from defects in the dystrophin gene. Therapy specifically aimed at DMD is reviewed in the context of its projected effect on cardiomyopathy associated with DMD. Additionally, novel therapies are being pursued to treat specifically the cardiomyopathy of DMD. There is substantial genetic heterogeneity underlying the muscular dystrophies, and not all muscular dystrophy patients develop cardiomyopathy. A subset of muscular dystrophies may place patients at significantly greater risk of developing cardiomyopathy and cardiac rhythm disturbances. These disorders are discussed, highlighting recent studies and recommendations for therapy.
-
-
-
Acute Ischemic Stroke: Overview of Recent Therapeutic Developments
Vol. 58 (2007), pp. 89–106More LessAbstractStroke, a disorder encompassing all cerebrovascular accidents, is a public health problem of immense proportions across the globe. Therapeutic efforts are directed at three aspects: prevention, acute treatment, and rehabilitation. Preventative measures, which in many instances mirror those for cardiovascular disease, can achieve the greatest public health impact. Measures that enhance the recovery of neurologic function and reduce neurologic disability after stroke can also affect a large population of handicapped stroke survivors. In the past 10 years, the greatest changes have occurred in the field of acute stroke treatment. Ultra-early-stage therapies with the potential to dramatically reverse severe neurologic deficits, or halt their progression, have caused a restructuring of the emergency care of neurologic patients. The parallels with the evolution of emergency treatment of acute coronary syndromes after 1970 are striking. This review focuses on aspects of stroke therapy that are either just entering, or soon to enter, current practice.
-
-
-
Use of Stents to Treat Intracranial Cerebrovascular Disease
Vol. 58 (2007), pp. 107–122More LessAbstractIntracranial atherosclerosis is a common cause of stroke. Although it has been recognized for decades, the lack of successful treatment strategies has limited clinical interest until recently. We review the natural history and pathophysiology of intracranial atherosclerosis. Vascular biomechanics are important to define differences between cerebral arteries and extracranial vessels and partly explain the technical challenges facing cerebral artery revascularization as compared with revascularization of coronary arteries. Pharmacological interventions to prevent stroke have had limited success, but technological developments offer improved methods for endovascular revascularization of symptomatic and asymptomatic cerebral artery stenosis. Identification of appropriate candidates for treatment also remains a challenge, and our knowledge about the natural history of the disease is limited. At this time, patients with significant intracranial stenosis should receive information on the benefits and risks of revascularization therapy. Determining which patients should undergo revascularization procedures will require carefully planned, randomized clinical trials.
-
-
-
Kidney Disease and Cardiovascular Risk
Vol. 58 (2007), pp. 123–139More LessAbstractKidney failure and chronic kidney disease (CKD) are associated with accelerated cardiovascular disease, apparently because of a high burden of traditional vascular risk factors and possibly nontraditional risk factors such as inflammation, chronic volume overload, and abnormal calcium-phosphate metabolism. Although the burden of cardiovascular disease in CKD patients is well documented, potentially beneficial therapies appear to be underused in mild to moderate CKD and are relatively understudied in those with kidney failure. This review describes the epidemiology and pathophysiology of cardiovascular disease in CKD. We also discuss the clinical and public health implications of current knowledge and outline opportunities for further research.
-
-
-
Cardiovascular Risks of Antiretroviral Therapies
Kristin Mondy, and Pablo TebasVol. 58 (2007), pp. 141–155More LessAbstractThe use of highly active antiretroviral therapy (HAART) has resulted in sustained reductions in mortality from HIV infection. In recent years, HAART has also been associated with metabolic complications that may increase patients’ cardiovascular disease risk. Recent studies have begun to support a more complex interaction between HAART, HIV infection itself, and other traditional social and immunologic factors that may predispose patients to premature cardiovascular disease. Substantial progress has been made in the development of newer antiretroviral therapies that have a better metabolic profile with respect to dyslipidemia, hyperglycemia, and lipodystrophy. Optimal selection of metabolically neutral antiretroviral therapies, together with aggressive management of other modifiable coronary risk factors, may improve cardiovascular disease risk in the long term.
-
-
-
Airway Surface Dehydration in Cystic Fibrosis: Pathogenesis and Therapy
Vol. 58 (2007), pp. 157–170More LessAbstractCystic fibrosis (CF) lung disease reflects the failure of airways defense against chronic bacterial infection. Studies of CF cultures, transgenic mice, and CF patients suggest that the initiating event in CF airways disease pathogenesis is reduced airway surface liquid (ASL) volume, i.e., dehydration. CF ASL volume regulation depends on a single extracellular signaling system, ATP, which renders CF airways more vulnerable to disease-causing insults (e.g., viruses) than are normal airways, which regulate ASL volume by dual ATP and adenosine signaling pathways. Clinical studies have explored the hypothesis that treating the dehydration of CF airways will be therapeutically beneficial. Inhaled hypertonic saline osmotically draws water onto airway surfaces, improves mucus clearance and pulmonary function, and reduces acute exacerbations in CF patients. Thus, rehydration therapies may slow the progression of CF lung disease in patients with established bacterial infection and may prevent the onset of CF lung disease if initiated early in life.
-
-
-
Toward a Comprehensive Set of Asthma Susceptibility Genes
Vol. 58 (2007), pp. 171–184More LessAbstractEpidemiological and twin studies have demonstrated that asthma is under genetic and environmental influences. Numerous candidate gene association studies as well as genome-wide linkage scans have followed, aiming to elucidate the genetic architecture underlying this complex disease. Several promising asthma susceptibility genes were identified, and a comprehensive catalogue of these genes seems a realistic goal within 5 to 10 years. However, a key challenge is to understand the combination of genes and environmental factors that gives rise to the disease in a specific individual. Currently, most of the reports of asthma susceptibility genes are either preliminary or controversial, with little knowledge about the genetic mechanisms leading to abnormal function of the gene that promotes the development of asthma. Replications of published associations are relatively few. Many factors, including the inherent complexity of asthma as well as methodological issues, can explain these inconsistencies. Promising genetic tools are emerging with the completion of the International HapMap Project that will increase the scope of gene-discovery investigations. It is hoped that these tools, combined with validation studies in additional populations, will enable the creation of a comprehensive catalogue of susceptibility genes for asthma. Notwithstanding the difficulties in making sense of the vast amount of new genetic data, we already see the emergence of new biological pathways of atopy, airway remodeling, and asthma that may lead to novel therapeutic approaches.
-
-
-
Does Anti-IgE Therapy Help in Asthma? Efficacy and Controversies
Vol. 58 (2007), pp. 185–203More LessOmalizumab, a humanized monoclonal antibody against IgE, is clinically efficacious when it neutralizes almost all free IgE and reduces IgE receptors on basophils and mast cells. Asthmatic subjects on inhaled corticosteroids who are treated with omalizumab as an add-on therapy experience only modest benefits in symptoms and perhaps in quality of life, but the most significant effects are reductions in airway inflammation and in exacerbation rate. Airway obstruction and hyperresponsiveness do not change significantly. Although the magnitude of the beneficial effects is small, they are observed even in the most severe cases, particularly the reduction in exacerbation rate. The safety profile of omalizumab is very encouraging, although phase IV studies are ongoing to clarify the incidence of neoplasias. Because of its cost, omalizumab therapy may be most cost-effective in patients with severe and refractory asthma, particularly those with frequent exacerbations requiring hospital care. Further clinical studies are now evaluating the best place for omalizumab in the algorithm of asthma management.
-
-
-
Advances in the Treatment of Prostate Cancer
Vol. 58 (2007), pp. 205–220More LessSeveral recent advances have been made in the management of prostate cancer. Active surveillance is an increasingly attractive and reasonable approach for those with low-volume, low-risk disease. For locally advanced or localized high-risk disease, neoadjuvant and adjuvant therapies are emerging as the standard of care. Innovative uses of traditional hormonal treatments can potentially limit common side effects. Recent data also support the utility of second-line hormonal therapy. For the first time, a survival advantage with the use of chemotherapy has been established. Much work is under way to augment its efficacy with novel agents such as targeted therapeutics and tumor vaccines. Recent scientific breakthroughs suggest additional strategies in treating prostate cancer.
-
-
-
Immunotoxin Treatment of Cancer*
Vol. 58 (2007), pp. 221–237More LessAbstractImmunotoxins are proteins used to treat cancer that are composed of an antibody fragment linked to a toxin. The immunotoxin binds to a surface antigen on a cancer cell, enters the cell by endocytosis, and kills it. The most potent immunotoxins are made from bacterial and plant toxins. Refinements over many years have produced recombinant immunotoxins; these therapeutic proteins are made using protein engineering. Individual immunotoxins are designed to treat specific cancers. To date, most success has been achieved treating hematologic tumors. Obstacles to successful treatment of solid tumors include poor penetration into tumor masses and the immune response to the toxin component of the immunotoxin, which limits the number of cycles that can be given. Strategies to overcome these limitations are being pursued.
-
-
-
NSAIDs and Cancer Prevention: Targets Downstream of COX-2
Vol. 58 (2007), pp. 239–252More LessPreclinical and clinical studies have clearly shown a benefit of nonsteroidal anti-inflammatory drug (NSAID) use in reducing cancer risk. However, the adverse gastrointestinal and cardiovascular side effects associated with NSAIDs and COX-2 selective inhibitors (coxibs) have provoked more scrutiny of the precise role of specific downstream mediators in the prostaglandin (PG) signaling cascade. NSAIDs and coxibs inhibit PG biosynthesis. One of the PGs produced at high levels in the tumor microenvironment is PGE2, which is thought to play a major role in cancer progression. Thus, a better understanding of PGE2 signaling could enable identification of novel and safer therapeutic targets downstream of the cyclooxygenase enzymes. We review the emerging molecular mechanisms by which COX-2–derived PGE2 is involved in cancer progression and delineate potential opportunities for development of novel pharmacologic approaches utilizing this pathway.
-
-
-
The Multiple Endocrine Neoplasia Syndromes
Vol. 58 (2007), pp. 253–265More LessAbstractMultiple endocrine neoplasia (MEN) type 1 and type 2 exhibit an autosomal dominant pattern of inheritance. In the past two decades the germline mutations that cause these inherited syndromes have been identified. The large majority of patients with MEN1 have mutations in the menin gene. Mutations in the REarranged during Transfection (RET) gene cause MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). Specific codon mutations within RET correlate with disease phenotype and severity. Also, children from families with MEN2A, MEN2B, or FMTC, who are found to have inherited a mutated RET allele, can be managed by prophylactic thyroidectomy, thus preventing the development of medullary thyroid carcinoma (MTC), the dominant endocrinopathy in patients with these hereditary syndromes. New insights into the molecular pathway of RET signal transduction are leading to novel targeted therapies in patients with locally advanced or metastatic hereditary MTC.
-
-
-
Cancer Stem Cells: Models and Concepts
Vol. 58 (2007), pp. 267–284More LessAbstractAlthough monoclonal in origin, most tumors appear to contain a heterogeneous population of cancer cells. This observation is traditionally explained by postulating variations in tumor microenvironment and coexistence of multiple genetic subclones, created by progressive and divergent accumulation of independent somatic mutations. An additional explanation, however, envisages human tumors not as mere monoclonal expansions of transformed cells, but rather as complex tridimensional tissues where cancer cells become functionally heterogeneous as a result of differentiation. According to this second scenario, tumors act as caricatures of their corresponding normal tissues and are sustained in their growth by a pathological counterpart of normal adult stem cells, cancer stem cells. This model, first developed in human myeloid leukemias, is today being extended to solid tumors, such as breast and brain cancer. We review the biological basis and the therapeutic implications of the stem cell model of cancer.
-
-
-
Stem Cells and Chronic Lung Disease
Vol. 58 (2007), pp. 285–298More LessAbstractStem cells have been shown to contribute to the repair and regeneration of injured lungs. These stem cells are resident in specific protected niches in the lung, or they can be mobilized from the bone marrow and recruited from the circulation in the setting of severe injury. Normal repair of the airway involves regeneration of the airway epithelium by stem cells in both the proximal airway and distal airspace, whereas aberrant repair of the lung may result from stem cells that lead to fibrosis. The stem cell niche in the lung is probably critical in determining whether “good” or “bad” stem cells are involved in local repair, and therefore whether fibrosis predominates. There is much excitement about the possibility of harnessing stem cells for repair and regeneration of the lungs. This review highlights current knowledge of this area and identifies gaps in our understanding of this complicated process.
-
-
-
Progress and Potential for Regenerative Medicine
Vol. 58 (2007), pp. 299–312More LessAbstractRegenerative medicine focuses on new therapies to replace or restore lost, damaged, or aging cells in the human body to restore function. This goal is being realized by collaborative efforts in nonmammalian and human development, stem cell biology, genetics, materials science, bioengineering, and tissue engineering. At present, understanding existing reparative processes in humans and exploring the latent ability to regenerate tissue remains the focus in this field. This review covers recent work in limb regeneration, fetal wound healing, stem cell biology, somatic nuclear transfer, and tissue engineering as a foundation for developing new clinical therapies to augment and stimulate human regeneration.
-
-
-
The Leading Edge of Stem Cell Therapeutics
Vol. 58 (2007), pp. 313–328More LessAbstractStem cells, by virtue of their defining property of self-renewal, represent an unlimited source of potentially functional human cells for basic research and regenerative medicine. Having validated the feasibility of cell-based therapeutic strategies over the past decade, mostly through the use of rodent cells, the stem cell field has now embarked upon a detailed characterization of human cells. Recent progress has included improved cell culture conditions, long-term propagation, directed differentiation, and transplantation of both human embryonic and somatic stem cells. Continued progress in understanding basic human stem cell biology, combined with a better handle on the fundamental pathophysiology of human diseases one wishes to target (including the use of human stem cells in primate and other large animal models of human disease), should help to move this technology closer to clinical application.
-
-
-
New Reagents on the Horizon for Immune Tolerance
Vol. 58 (2007), pp. 329–346More LessAbstractRecent advances in immunology and a growing arsenal of new drugs are bringing the focus of tolerance research from animal models into the clinical setting. The conceptual framework for therapeutic tolerance induction has shifted from a “sledgehammer” approach that relies solely on cellular depletion and cytokine targeting, to a strategy directed toward restoring a functional balance across the immune system, namely the different populations of naive cells, effector and memory cells, and regulatory cells. Unlocking the key to tolerance induction in the future will likely depend on our ability to harness the functions of T regulatory cells. Also, dendritic cells are strategically positioned at the interface between innate and adaptive immunity and may be subject to deliberate medical intervention in a way that can control a chronic inflammatory response. Many reagents with tolerance-inducing potential are currently undergoing clinical testing in transplantation, autoimmune diseases, and allergic diseases, and even more that are on the horizon promise to offer enormous benefits to human health.
-
-
-
T Cell Costimulation: A Rational Target in the Therapeutic Armamentarium for Autoimmune Diseases and Transplantation
Vol. 58 (2007), pp. 347–358More LessAbstractT cells are central mediators of adaptive immunity. As such, they are involved in both normal immune responses (e.g., rejection of a transplanted organ) and abnormal ones (e.g., rheumatoid arthritis). T cells require both antigen-specific and costimulatory signals for their full activation. Advances in protein engineering and an increased understanding of the immune response have culminated in the evolution and creation of protein therapeutics that target specific costimulatory molecules. The selective costimulation modulator abatacept (CTLA-4Ig) binds to CD80 and CD86, blocking interaction with CD28, and is approved for the treatment of moderate to severe rheumatoid arthritis. Belatacept, currently enrolling phase III trials in renal transplantation, was rationally designed from abatacept to bind with more avidity to CD86, providing the more potent immunosuppressive properties required for immunosuppression in transplantation. This review describes the relevant immunology and summarizes recent clinical findings on these two molecules. Although both inhibit the CD28 costimulatory pathway, they are tailored for specific disease states—abatacept for autoimmune diseases and belatacept for transplantation.
-
-
-
A Human Monoclonal Antibody Cocktail as a Novel Component of Rabies Postexposure Prophylaxis*
Vol. 58 (2007), pp. 359–368More LessAbstractThe currently recommended treatment for individuals exposed to rabies virus is the combined administration of rabies vaccine and rabies immune globulin (RIG). This review sets out the criteria used to guide development of a cocktail of human monoclonal antibodies as a replacement for RIG. Using this process as a model, the general requirements for development of safe and efficacious monoclonal antibody alternatives to currently used polyclonal serum products are discussed.
-
-
-
Why Hasn't Eliminating Acute Rejection Improved Graft Survival?*
Vol. 58 (2007), pp. 369–385More LessAbstractAlthough patients with end-stage renal disease can be maintained with dialysis therapy, the superiority of patient survival with renal transplantation makes transplantation the preferred method of renal replacement. Potent immunosuppressive therapies, particularly calcineurin inhibitors, have greatly reduced the incidence of acute rejection. However, long-term allograft survival remains limited. We discuss the impact of acute rejection on long-term allograft survival and discuss other factors leading to late allograft loss, including calcineurin inhibitor toxicity, chronic allograft nephropathy, and BK virus nephropathy, as well as donor and recipient factors associated with long-term allograft loss.
-
-
-
End-Stage Renal Disease Measures of Quality
Vol. 58 (2007), pp. 387–399More LessAbstractDuring the past 35 years, there has been a geometric expansion of the population of patients receiving chronic dialysis therapy in the United States. As the size and associated costs of the dialysis population have grown, there has been a consistent and evolving emphasis on measuring and improving the quality of dialysis care. These efforts, aided by robust data collection vehicles, have translated into defined clinical performance measures; nevertheless, morbidity and mortality rates remain high for the dialysis population. Recently, attention has focused on whether improved outcomes could be obtained by paying physicians and dialysis providers on the basis of quality metrics. The feasibility, value, pitfalls, and appropriate quality metrics in a “payment-for-quality” program for dialysis care are currently under vigorous discussion.
-
-
-
Inflammatory Bowel Disease Genetics: Nod2
Judy H. Cho, and Clara AbrahamVol. 58 (2007), pp. 401–416More LessAbstractThe inflammatory bowel diseases (IBD) are comprised of two major subphenotypes, Crohn's disease (CD) and ulcerative colitis (UC). A significant role for genetic factors in IBD was established from epidemiologic studies and, more recently, the identification of well-established disease associations, notably the association of Nod2 (CARD15) polymorphisms with CD. The mapping to CD of Nod2 variants that alter protein function represents one of the earliest, most well-established, associations in complex genetic disorders. Since the initial discovery, genotype-phenotype correlations, definition of Nod2 expression and signaling pathways, association studies in other, related disorders, and features of Nod2 deficiency in murine models have been reported. Taken together, the Nod2 association to CD provides an illustrative model of the role of single gene variants in disease pathogenesis for common, complex multigenic disorders. Here we review general aspects of IBD genetics with particular focus on the role of Nod2 in CD.
-
-
-
New Therapeutic Approaches for Multiple Sclerosis
Vol. 58 (2007), pp. 417–432More LessAbstractAlthough several therapies exist for multiple sclerosis (MS), the most common inflammatory demyelinating disease of the central nervous system (CNS), there remains a large unmet clinical need for more effective immunomodulatory treatments in this category of diseases and for interventions that address their neurodegenerative component, which is currently untreated. Progress in our understanding of the immunology of MS over the past 30 years has recently synergized with novel computational methods and emerging high-throughput technologies that characterize variations in DNA, RNA, proteins, and metabolites to usher in a period of intense pathophysiologic investigation. These efforts are beginning to define subsets of patients with different forms of demyelinating disease. This partitioning of patients will prove valuable as we begin to tailor immunotherapy to the underlying pathophysiologic processes of individual patients using current therapies, emerging treatments, and rational combinations of all of these treatments. Preventing the entry of lymphocytes into the CNS and modifying the nature of the immune response are treatment approaches that work in the inflammatory component of MS but have little or no effect on neurodegeneration. Two challenges confront us: to develop cocktails of therapies that shift the immune homeostasis of patients with MS toward a healthy profile, and to identify and modulate the activity of targets within the neurodegenerative component of MS.
-
-
-
Cytokine Therapy for Crohn's Disease: Advances in Translational Research
Vol. 58 (2007), pp. 433–444More LessAbstractCrohn's disease (CD) and ulcerative colitis (UC), the two idiopathic inflammatory bowel diseases (IBDs), affect almost two million individuals in North America and several million worldwide. Cytokines are important in the pathogenesis of CD, and their manipulation has successfully reduced disease severity and maintained remission. Following the discovery of novel cytokines and the role they may play in gut mucosal immunity, as well as the emergence of new concepts and changing paradigms in CD pathogenesis, the roles of several cytokines have been elucidated and tested in both preclinical animal models and clinical trials of patients with IBD. Complementary to this, proof of concept for new cytokine targets is rapidly developing, with the possibility of future cytokine-based therapies that may offer greater specificity and decreased toxicity for the treatment of CD. This review discusses novel concepts in CD pathogenesis and the roles of cytokines in the initiation and perpetuation of disease. In addition, we review applications of cytokine-based therapies in human clinical trials and preclinical animal studies. Finally, we discuss novel cytokine targets not yet investigated in vivo and describe their potential contribution to CD pathogenesis.
-
-
-
Chemokine Antagonists as Therapeutics: Focus on HIV-1
Vol. 58 (2007), pp. 445–459More LessAbstractHuman immunodeficiency virus type 1 (HIV-1) entry into target cells is a multistep process involving the interaction of viral envelope proteins with cell surface receptors. Binding to CD4 is followed by engagement of specific chemokine receptors (CCR5 or CXCR4), triggering molecular rearrangements in the envelope transmembrane subunit that result in membrane fusion. Chemokine receptor antagonists that block the interaction of the HIV-1 envelope with CCR5 or CXCR4 potently inhibit HIV-1 in vitro. Pilot studies of orally bioavailable small-molecule CCR5 inhibitors in HIV-1-infected subjects have provided proof of concept for this novel drug class; phase III safety and efficacy trials are under way.
-
-
-
Current Concepts in AIDS Pathogenesis: Insights from the SIV/Macaque Model
Vol. 58 (2007), pp. 461–476More LessAbstractThe pathogenesis of AIDS has proven to be quite complex and dynamic, with most of the critical events (e.g., transmission, CD4+ T cell destruction) occurring in tissues that are not easily accessible for analysis. In addition, although the disease can progress over years, many critical events happen within the first few weeks of infection, when most patients are unaware that they are infected. The nonhuman primate model of AIDS has been used extensively to fill these gaps in our understanding of AIDS pathogenesis.
-
-
-
Macular Degeneration
Vol. 58 (2007), pp. 477–490More LessAbstractMacular degeneration is a term that describes a large group of conditions that are collectively the most common cause of irreversible vision loss in the developed world. Approximately one in three people will be affected to some degree by the time they reach 75 years of age. Many forms of macular degeneration have a significant genetic component, and a large amount of progress has recently been made in understanding the genes involved. In the future, genetic testing may allow specific preventive treatments to be delivered to individuals at risk, decades before the disease would ordinarily become manifest.
-
-
-
Targeting VEGF-A to Treat Cancer and Age-Related Macular Degeneration
Vol. 58 (2007), pp. 491–504More LessAbstractInhibiting angiogenesis is a promising strategy to treat cancer and several other disorders, including intraocular neovascular syndromes. The identification of vascular endothelial growth factor (VEGF)-A as a major regulator of normal and pathological angiogenesis has enabled significant progress toward effective treatments for such disorders. Several VEGF inhibitors have been recently approved by the U.S. Food and Drug Administration for the treatment of cancer and the neovascular form of age-related macular degeneration. This review summarizes the basic biology of VEGF-A and illustrates the clinical progress in targeting this molecule.
-
Previous Volumes
-
Volume 75 (2024)
-
Volume 74 (2023)
-
Volume 73 (2022)
-
Volume 72 (2021)
-
Volume 71 (2020)
-
Volume 70 (2019)
-
Volume 69 (2018)
-
Volume 68 (2017)
-
Volume 67 (2016)
-
Volume 66 (2015)
-
Volume 65 (2014)
-
Volume 64 (2013)
-
Volume 63 (2012)
-
Volume 62 (2011)
-
Volume 61 (2010)
-
Volume 60 (2009)
-
Volume 59 (2008)
-
Volume 58 (2007)
-
Volume 57 (2006)
-
Volume 56 (2005)
-
Volume 55 (2004)
-
Volume 54 (2003)
-
Volume 53 (2002)
-
Volume 52 (2001)
-
Volume 51 (2000)
-
Volume 50 (1999)
-
Volume 49 (1998)
-
Volume 48 (1997)
-
Volume 47 (1996)
-
Volume 46 (1995)
-
Volume 45 (1994)
-
Volume 44 (1993)
-
Volume 43 (1992)
-
Volume 42 (1991)
-
Volume 41 (1990)
-
Volume 40 (1989)
-
Volume 39 (1988)
-
Volume 38 (1987)
-
Volume 37 (1986)
-
Volume 36 (1985)
-
Volume 35 (1984)
-
Volume 34 (1983)
-
Volume 33 (1982)
-
Volume 32 (1981)
-
Volume 31 (1980)
-
Volume 30 (1979)
-
Volume 29 (1978)
-
Volume 28 (1977)
-
Volume 27 (1976)
-
Volume 26 (1975)
-
Volume 25 (1974)
-
Volume 24 (1973)
-
Volume 23 (1972)
-
Volume 22 (1971)
-
Volume 21 (1970)
-
Volume 20 (1969)
-
Volume 19 (1968)
-
Volume 18 (1967)
-
Volume 17 (1966)
-
Volume 16 (1965)
-
Volume 15 (1964)
-
Volume 14 (1963)
-
Volume 13 (1962)
-
Volume 12 (1961)
-
Volume 11 (1960)
-
Volume 10 (1959)
-
Volume 9 (1958)
-
Volume 8 (1957)
-
Volume 7 (1956)
-
Volume 6 (1955)
-
Volume 5 (1954)
-
Volume 4 (1953)
-
Volume 3 (1952)
-
Volume 2 (1951)
-
Volume 1 (1950)
-
Volume 0 (1932)