1,661 results match your criteria Current Opinion in Investigational Drugs[Journal]


Reporting disease control rates or clinical benefit rates in early clinical trials of anticancer agents: useful endpoint or hype?

Authors:
Mario Sznol

Curr Opin Investig Drugs 2010 Dec;11(12):1340-1

Disease Control Rate (DCR) and Clinical Benefit Rate (CBR) are defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents. DCR and CBR are commonly reported in many clinical trials in abstracts, papers, meeting presentations and media releases. The frequent use of these measures of drug activity presents the question of whether DCR and CBR are useful additional endpoints in early clinical trials, and if they can reasonably predict the success of an agent in subsequent, adequately powered, randomized trials. Read More

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December 2010
26 Reads

Antiretroviral drug development for HIV: challenges for the future.

Curr Opin Investig Drugs 2010 Aug;11(8):863-67

Boone Consulting Services LLC, 4801 Abercroft Place, Fuquay-Varina, NC, USA

The scarcity of new innovative drugs in the development pipeline for combating HIV replication may signal a change in direction for HIV researchers and drug developers. The model of introducing drugs with incremental improvements within existing drug classes is no longer commercially viable. While an argument can be made that drugs aimed at novel targets may have a greater impact, the list of such targets is limited and the scientific challenge of intervening at another stage in the HIV replication cycle is high. Read More

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August 2010
18 Reads

Abating progressive tissue injury and preserving function after CNS trauma: The role of inflammation modulatory therapies.

Curr Opin Investig Drugs 2010 Nov;11(11):1207-10

Brain and spinal cord injuries result in cognitive and/or sensorimotor impairments that can significantly diminish the quality of life for the patient and their carers, and result in healthcare system costs totaling in the billions. The current gold-standard of acute care for spinal cord injury is to administer high doses of glucocorticoids within 8 h of injury; administration after 8 h may be without effect or detrimental to the outcome of the patient. Therefore, improved pharmacological approaches for limiting the extent of tissue damage and neurological dysfunction in the acute injury setting are urgently needed. Read More

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November 2010
11 Reads

Teriflunomide, an inhibitor of dihydroorotate dehydrogenase for the potential oral treatment of multiple sclerosis.

Authors:
Alan M Palmer

Curr Opin Investig Drugs 2010 Nov;11(11):1313-23

MS Therapeutics Ltd, Beechey House, 87 Church Street, Crowthorne, Berkshire, RG45 7AW, UK.

Teriflunomide, being developed as a potential oral treatment for multiple sclerosis (MS) by sanofi-aventis, is the active metabolite of the rheumatoid arthritis drug leflunomide. Both teriflunomide and leflunomide are inhibitors of the mitochondrial enzyme dihydroorotate dehydrogenase, which is critically involved in pyrimidine synthesis. The production of activated T-cells largely depends on de novo pyrimidine synthesis, and thus pyrimidine depletion is thought to result in the inhibition of immune cell proliferation. Read More

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November 2010
8 Reads

Tralokinumab, an anti-IL-13 mAb for the potential treatment of asthma and COPD.

Authors:
Garry M Walsh

Curr Opin Investig Drugs 2010 Nov;11(11):1305-12

University of Aberdeen, Section of Immunology & Infection, Division of Applied Medicine, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, UK.

Biopharmaceutical approaches have been used to target key elements in the processes controlling airway inflammation in asthma and COPD. There is compelling evidence that IL-13 is a key mediator in the inflammatory processes in the asthmatic lung. Tralokinumab (CAT-354), under development by MedImmune, is an injectable, anti-IL-13 humanized mAb for the potential treatment of asthma and COPD. Read More

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November 2010
8 Reads

Vedolizumab, a humanized mAb against the α4β7 integrin for the potential treatment of ulcerative colitis and Crohn's disease.

Curr Opin Investig Drugs 2010 Nov;11(11):1295-304

Innsbruck Medical University, Christian Doppler Research Laboratory for Gut Inflammation, Anichstrasse 35, 6020 Innsbruck, Austria.

Advances in immunology and genetics have identified new therapeutic targets to control inflammation and symptoms in patients with inflammatory bowel diseases (IBD). Despite the success of anti-TNF therapies in the treatment of IBD, a considerable proportion of patients are refractory to treatment, highlighting an unmet medical need for new therapies. Molecules that direct the trafficking of inflammatory cells, such as the α4β7 integrin, are attractive targets for new drug candidates. Read More

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November 2010
9 Reads

Pitrakinra, a dual IL-4/IL-13 antagonist for the potential treatment of asthma and eczema.

Authors:
Sabina A Antoniu

Curr Opin Investig Drugs 2010 Nov;11(11):1286-94

University of Medicine and Pharmacy, 'Gr.T.Popa' Iasi, Faculty of Medicine, Department Medicine II - Pulmonary Disease, Pulmonary Disease University Hospital, 30 Dr I Cihac Street, Iasi 700115, Romania.

In asthma, airway inflammation is driven by Th2-related cytokines, such as IL-4, IL-5 and IL-13. IL-4 and IL-13, in particular, have a major role in the development of airway hyperresponsiveness, allergen-specific IgE synthesis and airway remodeling because of their synergistic effects induced by binding to the IL-4Rα subunit. Pitrakinra (AER-001, BAY-16-9996), being developed by Aerovance, under license from Bayer, for the potential treatment of asthma and eczema, is an IL-4 mutein, which binds to the IL-4Rα subunit and prevents the inflammation induced by IL-4 and IL-13. Read More

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November 2010
62 Reads

Oligonucleotides: New therapeutic approaches for asthma and chronic obstructive pulmonary disease.

Curr Opin Investig Drugs 2010 Nov;11(11):1276-85

Topigen Pharmaceuticals Inc, 2901 Rachel Street East, Suite 13, Montreal, QC H1W 4A4, Canada.

Asthma and COPD are significant lung diseases for which anti-inflammatories, including inhaled corticosteroids and leukotriene- targeted drugs, represent a key element of current therapy. Oligonucleotides comprise a diverse family of emerging drug candidates for the treatment of these diseases. There is a commonality in the chemistry of oligonucleotide drug molecules but, importantly, individual candidates are distinct in their molecular targets and also possess different mechanisms of action. Read More

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November 2010
8 Reads

Resetting autoimmunity in the nervous system: The role of hematopoietic stem cell transplantation.

Curr Opin Investig Drugs 2010 Nov;11(11):1265-75

Imperial College London, Centre for Neurosciences, Department of Medicine, Burlington Danes Building, Room E415, 160 Du Cane Road, London, W12 0NN, UK.

According to current concepts for multiple sclerosis (MS), a fundamental pathogenic role is played by T- and B-cells that inappropriately recognize self antigens and initiate a cell-mediated or humoral inflammatory reaction that injures myelin and axons, and results in neural dysfunction and loss. Transplantation of bone marrow-derived hematopoietic stem cells following high-dose immunosuppression is being evaluated as an experimental treatment for severe forms of immune-mediated disorders, including MS. The primary goal of this therapeutic approach is to induce medication-free remission from new disease activity by correcting the immune aberrations that promote the attack against self tissue; this approach is termed 'immune repair'. Read More

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November 2010
31 Reads

Novel treatments for systemic lupus erythematosus.

Curr Opin Investig Drugs 2010 Nov;11(11):1256-64

Sandwell and West Birmingham Hospitals NHS Trust, Department of Rheumatology, City Hospital, Birmingham, B18 7QH, UK.

Systemic lupus erythematosus (SLE) is an autoimmune disease that is associated with the production of autoantibodies, and with considerable morbidity and mortality. There has been much interest in developing more specific therapies for this disease, which is currently managed with immunosuppressive drugs, predominantly corticosteroids, azathioprine, methotrexate and cyclophosphamide, in combination with hydroxychloroquine. Mycophenolate mofetil has been demonstrated to be as efficacious as cyclophosphamide in patients with lupus nephritis, and is being used increasingly in the clinic despite not being licensed for this indication. Read More

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November 2010
15 Reads

Function of NOD-like receptors in immunity and disease.

Curr Opin Investig Drugs 2010 Nov;11(11):1246-55

McGill University, Department of Biochemistry, 3775 University, Montréal, QC H3A 2B4, Canada.

Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are cytosolic pattern-recognition receptors that sense microbial invasion, cell stress and physiological perturbations, and elicit an inflammatory response to alert the system to the presence of danger. Most NLRs exert their functions by assembling inflammasomes that recruit and activate caspase-1, whereas a few engage the NFκB and MAPK pathways. In the past few years, significant insights have been gained into the regulatory mechanisms of these innate immunity effectors and their role in health and disease that, notably, have led to direct therapeutic applications in the clinic. Read More

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November 2010
7 Reads

Muscarinic receptors as targets for anti-inflammatory therapy.

Curr Opin Investig Drugs 2010 Nov;11(11):1239-45

Universidad de Buenos Aires, Segunda Cátedra de Farmacología, CEFYBO-CONICET, Paraguay 2155 piso 16, CP 1121ABG, Buenos Aires, Argentina.

ACh, the main neurotransmitter in the neuronal cholinergic system, is synthesized by pre-ganglionic fibers of the sympathetic and parasympathetic autonomic nervous system and by post-ganglionic parasympathetic fibers. There is increasing experimental evidence that ACh is widely expressed in prokaryotic and eukaryotic non-neuronal cells. The neuronal and non-neuronal cholinergic systems comprise ACh, choline acetyltransferase and cholinesterase, enzymes that synthesize and catabolize ACh, and the nicotinic and muscarinic ACh receptors (nAChRs and mAChRs, respectively), which are the targets for ACh action. Read More

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November 2010
7 Reads

Targeting Th2 cytokines in fibrotic diseases.

Curr Opin Investig Drugs 2010 Nov;11(11):1229-38

University of Tsukuba, Graduate School of Human Comprehensive Sciences, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan.

Fibrosis is characterized by the excessive accumulation of extracellular matrix components, leading to tissue scarring. Fibrosis can occur in various tissue and organ systems, and is considered a leading cause of morbidity and mortality. Because of unsatisfactory results with currently available therapies for fibrotic diseases, the development of new therapies that target fibrosis directly is warranted. Read More

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November 2010
7 Reads

The growth receptors and their role in wound healing.

Curr Opin Investig Drugs 2010 Nov;11(11):1221-8

The Royal Free Hospital, Institute for Plastic Surgery Research and Education, Pond Street, Hampstead, London, NW3 2QG, UK.

Abnormal wound healing is a major problem in healthcare today, with both scarring and chronic wounds affecting large numbers of individuals worldwide. Wound healing is a complex process involving several variables, including growth factors and their receptors. Chronic wounds fail to complete the wound healing process, while scarring is considered to be an overzealous wound healing process. Read More

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November 2010
12 Reads

Targeting the IL-1 family members in skin inflammation.

Curr Opin Investig Drugs 2010 Nov;11(11):1211-20

Temple University School of Medicine, Department of Microbiology and Immunology, 1158 MERB, 3500 North Broad Street, Philadelphia, PA 19140-4106, USA.

The IL-1 family of cytokines comprises 11 proteins with pro- and anti-inflammatory functions that are mediated through an equally large group of receptors and coreceptors. Dysregulation of the IL-1 system may lead to diseases such as psoriasis, atopic dermatitis, contact dermatitis and cutaneous lupus erythematosus. These inflammatory skin conditions greatly affect quality of life and life expectancy, and their frequencies are increasing. Read More

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059231PMC
November 2010
19 Reads

Crizotinib, a small-molecule dual inhibitor of the c-Met and ALK receptor tyrosine kinases.

Curr Opin Investig Drugs 2010 Dec;11(12):1477-90

Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.

Crizotinib (PF-02341066), under development by Pfizer, is an orally bioavailable, ATP-competitive, small-molecule inhibitor of the receptor tyrosine kinases (RTKs) c-Met (also known as hepatocyte growth factor receptor) and anaplastic lymphoma kinase (ALK), for the potential treatment of cancers dependent on these oncogenic kinases for growth and survival. Since the first published characterizations of crizotinib only a few years ago, the drug has been extensively validated as a highly specific inhibitor of c-Met and ALK among > 120 different RTKs surveyed. In preclinical tumor xenograft studies, crizotinib inhibited the growth and survival of cell lines dependent upon c-Met or ALK enzymatic activity. Read More

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December 2010
135 Reads

STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer.

Curr Opin Investig Drugs 2010 Dec;11(12):1466-76

Center for Cancer Research, Medical Oncology Branch & Urologic Oncology Branch, National Cancer Institute/NIH, 10 Center Drive, Bethesda, MD 20892, USA.

STA-9090 is a second-generation Hsp90 inhibitor in clinical development by Synta Pharmaceuticals for the intravenous treatment of hematological and solid malignancies. It is a resorcinol-containing triazole compound, with a novel chemical structure that is unrelated to the geldanamycin class of Hsp90 inhibitors. STA-9090 binds to the ATP-binding domain at the N-terminus of Hsp90 and acts as a potent Hsp90 inhibitor by inducing degradation of multiple oncogenic Hsp90 client proteins including HER2/neu, mutated EGFR, Akt, c-Kit, IGF-1R, PDGFRα, Jak1, Jak2, STAT3, STAT5, HIF-1α, CDC2, c-Met, and Wilms' tumor 1. Read More

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December 2010
19 Reads
36 Citations

Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia.

Curr Opin Investig Drugs 2010 Dec;11(12):1450-65

Department of Leukemia, University of Texas-MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

Bafetinib (NS-187, INNO-406) is a second-generation tyrosine kinase inhibitor in development by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. It is a rationally developed tyrosine kinase inhibitor based on the chemical structure of imatinib, with modifications added to improve binding and potency against Bcr-Abl kinase. Besides Abl, bafetinib targets the Src family kinase Lyn, which has been associated with resistance to imatinib in CML. Read More

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December 2010
12 Reads

AT-9283, a small-molecule multi-targeted kinase inhibitor for the potential treatment of cancer.

Authors:
Shinya Kimura

Curr Opin Investig Drugs 2010 Dec;11(12):1442-9

Saga University, Division of Hematology, Respiratory Medicine and Oncology, Faculty of Medicine, Department of Internal Medicine, Saga University, 5-1-1 Nabeshima, Saga, Japan.

AT-9283 has been identified and developed by Astex Therapeutics via structure-based optimization of a ligand-efficient pyrazole-benzimidazole fragment. AT-9283 inhibits several important kinases, including the Aurora kinase A, Aurora kinase B, Janus kinase (Jak)2, Jak3 and Abl kinase. Studies using multiple solid tumor and leukemia cell lines have demonstrated the ability of AT-9283 to inhibit growth and survival of tumor cells, and the direct inhibition of these kinases has been demonstrated in cell-based systems. Read More

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December 2010
8 Reads

Necitumumab, a fully human IgG1 mAb directed against the EGFR for the potential treatment of cancer.

Curr Opin Investig Drugs 2010 Dec;11(12):1434-41

Universitat Autònoma de Barcelona, Vall d'Hebron University Hospital, Medical Oncology Department, Passeig Vall d'Hebron 119-129, Barcelona, Spain.

Necitumumab (IMC-11F8), under development by ImClone Systems in collaboration with Bristol-Myers Squibb, is a fully human IgG1 mAb targeting the epidermal growth factor receptor (EGFR), for the potential intravenous treatment of cancer, in particular NSCLC. In vitro studies demonstrate that necitumumab inhibits downstream targets in the EGFR pathway (eg, MAPK), which are important for cellular proliferation, differentiation, invasion and metastasis. Furthermore, because necitumumab is an IgG1 construct, it has the potential to induce antibody-dependent cell-mediated cytotoxicity against tumor cells. Read More

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December 2010
8 Reads

EC-145, a folate-targeted Vinca alkaloid conjugate for the potential treatment of folate receptor-expressing cancers.

Curr Opin Investig Drugs 2010 Dec;11(12):1424-33

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, Turin, Italy.

EC-145, under development by Endocyte, is a conjugate composed of desacetylvinblastine monohydrazide linked through a peptide spacer to the targeting moiety folic acid, for the potential intravenous treatment of folate receptor-overexpressing tumors, in particular ovarian and lung cancers. In vitro studies demonstrated that EC-145 selectively binds to cells that overexpress the folate receptor, causing dose-dependent cytotoxicity. Furthermore, coincubation of the KB human nasopharyngeal carcinoma cell line with EC-145 and doxorubicin resulted in synergistic antitumor activity. Read More

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December 2010
40 Reads

The antifolates: evolution, new agents in the clinic, and how targeting delivery via specific membrane transporters is driving the development of a next generation of folate analogs.

Curr Opin Investig Drugs 2010 Dec;11(12):1409-23

Albert Einstein College of Medicine Cancer Center, Departments of Medicine and Molecular Pharmacology, Chanin Two, 1300 Morris Park Avenue, Bronx, NY 10803, USA.

More than 50 years after the introduction of the dihydrofolate reductase inhibitor, methotrexate, new antifolates have emerged and have been incorporated into the chemotherapeutic armamentarium. These include pralatrexate, with the same target as methotrexate, but with enhanced properties, and pemetrexed, with different enzyme targets and properties. Current synthetic efforts are focused on developing antifolates that are selectively delivered to cancer cells, but not to normal proliferating cells, exploiting the different properties of folate transporters. Read More

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December 2010
8 Reads

New approaches to the development of adenoviral dendritic cell vaccines in melanoma.

Curr Opin Investig Drugs 2010 Dec;11(12):1399-408

University of Pittsburgh, Cancer Institute, and Department of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.

Considerable research in the field of immunotherapy for melanoma has demonstrated that this tumor type can be responsive to therapeutic immune activation strategies. In early clinical trials, vaccine strategies using dendritic cells (DCs) and adenovirus (Ad) vectors (AdVs) were safe and immunogenic, and induced clinical responses in a minority of patients. Research from the past several years has yielded an improved mechanistic understanding of DC biology, AdV effects on DCs and the crosstalk that occurs between antigen-loaded DCs and specific lymphocyte subsets. Read More

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3758558PMC
December 2010
5 Reads

Agents targeting the Hedgehog pathway for pancreatic cancer treatment.

Curr Opin Investig Drugs 2010 Dec;11(12):1387-98

Department of Internal Medicine 3, Center of Integrated Oncology Cologne-Bonn, University of Bonn, Wilhelmstrasse 35-37, Bonn, Germany.

Recent evidence has demonstrated that aberrant reactivation of the Hedgehog signaling pathway contributes to tumor initiation and progression in various human malignancies, including pancreatic cancer; therefore, the Hedgehog pathway has emerged as a promising novel therapeutic target. Initial translational studies conducted using cyclopamine, a small-molecule inhibitor of the Smoothened (SMO) component of the Hedgehog pathway, demonstrated that pharmacological blockade of aberrant Hedgehog signaling has the potential to inhibit tumor initiation, progression and metastatic spread. This concept has been corroborated using different compounds in various preclinical models of pancreatic cancer and other malignancies; several of these studies suggest possible therapeutic synergisms of Hedgehog inhibitors with established antineoplastic agents. Read More

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December 2010
11 Reads

Anti-GITR antibodies--potential clinical applications for tumor immunotherapy.

Curr Opin Investig Drugs 2010 Dec;11(12):1378-86

Memorial Sloan-Kettering Cancer Center, Department of Medicine, 1275 York Avenue, New York, NY 10065, USA.

Since the development of the first vaccines, modern medicine has been consistently aiming to improve the efficacy of immune responses. Traditionally, adjuvants have been used as non-specific immune modulators to enhance recognition and activation against a desired antigen. By providing 'danger' signals to the immune system, adjuvants activate innate immunity, which enhances the development of protective and therapeutic adaptive immune responses. Read More

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December 2010
45 Reads

Intracellular amino acid sensing and mTORC1-regulated growth: new ways to block an old target?

Curr Opin Investig Drugs 2010 Dec;11(12):1360-7

Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK.

Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a multicomponent, nutrient-sensitive protein that is implicated in a wide range of major human diseases. mTORC1 responds to both growth factors and changes in local amino acid levels. Until recently, the intracellular amino acid-sensing mechanism that regulates mTORC1 had remained unexplored. Read More

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044466PMC
December 2010
11 Reads

Clinical development of mAbs to block the PD1 pathway as an immunotherapy for cancer.

Curr Opin Investig Drugs 2010 Dec;11(12):1354-9

University of Chicago, Department of Medicine and Pathology, Section of Hematology/Oncology, 5841 South Maryland Avenue, Chicago, IL 60637, USA.

Tumor antigen-specific T-cell function is regulated by both positive and negative costimulatory signals, which are received in the secondary lymphoid organs and within the tumor microenvironment. Tumor-induced T-cell dysfunction results from a lack of positive costimulatory signals, combined with a predominance of negative immunoregulatory mechanisms. The engagement of the protein programmed death 1 (PD1), expressed on activated T-cells, by programmed death ligand 1 (PD-L1)/B7H1 within tumor cells or other host-derived cells results in the downregulation of T-cell function, and represents an important negative regulatory pathway. Read More

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December 2010
8 Reads

Pharmacological inhibition of TGFβ as a strategy to augment the antitumor immune response.

Curr Opin Investig Drugs 2010 Dec;11(12):1342-53

Department of Internal Medicine, Division of Hematology and Oncology, Duke University Medical Center, 450 Research Drive, Durham, NC 27708, USA.

There is considerable evidence suggesting that a variety of malignancies utilize the TGFβ cytokine to evade immune surveillance mechanisms to facilitate tumor growth and metastatic progression. The recently developed large- and small-molecule TGFβ inhibitors have demonstrated antitumor efficacy in several preclinical tumor models. Further investigation has revealed these agents to be critically dependent upon the host's immune system, suggesting that the inhibition of TGFβ may overcome the immunosuppressive tumor microenvironment and, ultimately, augment the antitumor immune response. Read More

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December 2010
3 Reads

Mutations in the melanocortin-3 receptor (MC3R) gene: Impact on human obesity or adiposity.

Authors:
Ya-Xiong Tao

Curr Opin Investig Drugs 2010 Oct;11(10):1092-6

Auburn University, Department of Anatomy, Physiology and Pharmacology, AL 36849-5519, USA.

The melanocortin-3 receptor (MC3R), together with the related melanocortin-4 receptor (MC4R), are important regulators of energy homeostasis. Rodent studies have demonstrated that the two receptors have non-redundant roles in regulating energy balance. However, while mutations for the MC4R have been established as a cause of monogenic obesity, mutations in the MC3R gene remain controversially associated with human obesity pathogenesis. Read More

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October 2010
3 Reads

BI-10773, a sodium-glucose cotransporter 2 inhibitor for the potential oral treatment of type 2 diabetes mellitus.

Curr Opin Investig Drugs 2010 Oct;11(10):1182-90

New University of Lisbon, Department of Genetics, Lisbon, Portugal.

BI-10773, being developed by Boehringer Ingelheim Corp, is a sodium-glucose cotransporter (SGLT)2 inhibitor for the oral treatment of type 2 diabetes mellitus (T2DM). Preclinical and clinical research has demonstrated that inhibition of SGLT2, the major pathway of renal glucose reabsorption, leads to increased urinary glucose excretion with concomitant reductions in fasting and postprandial plasma glucose levels, HbA1c levels and body mass. In phase I clinical trials in patients with T2DM, once-daily BI-10773 increased urinary glucose excretion resulting in dose-proportional reductions in fasting plasma glucose and mean daily glucose levels. Read More

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October 2010
14 Reads

Eliglustat tartrate, an orally active glucocerebroside synthase inhibitor for the potential treatment of Gaucher disease and other lysosomal storage diseases.

Authors:
Timothy M Cox

Curr Opin Investig Drugs 2010 Oct;11(10):1169-81

University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.

Eliglustat tartrate (Genz-112638), currently under development by Genzyme Corp, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Gaucher disease is an inherited defect of lysosomal functions caused by mutations in the GBA1 gene leading to accumulation of glucocerebroside, primarily in macrophages. Gaucher disease is characterized by visceromegaly and skeletal complications, including osteoporosis and painful episodes of osteonecrosis. Read More

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October 2010
13 Reads

Sirtuin-targeting drugs: Mechanisms of action and potential therapeutic applications.

Curr Opin Investig Drugs 2010 Oct;11(10):1158-68

Long Island University, Department of Biomedical Sciences, Brookville, NY 11548, USA.

The sirtuins are NAD+-dependent histone/protein deacetylases that are similar to Saccharomyces cerevisiae silent information regulator 2 (Sir2). Sirtuins regulate various normal and abnormal cellular and metabolic processes, including tumorigenesis, neurodegeneration, and processes associated with type 2 diabetes and obesity. Several age-related diseases, such as Alzheimer's disease, and longevity have also been linked to the functions of sirtuins. Read More

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October 2010
8 Reads

The mechanism of action for oxyntomodulin in the regulation of obesity.

Curr Opin Investig Drugs 2010 Oct;11(10):1151-7

Imperial College London, Department of Metabolic Medicine, Hammersmith Hospital, UK.

Oxyntomodulin, a product of the proglucagon gene, is released from the enteroendocrine L-cells of the gastrointestinal tract after the digestion of food, and acts via glucagon-like peptide 1 receptors in the arcuate nucleus to induce satiety. The administration of oxyntomodulin to animals and humans causes weight loss by reducing food intake in combination with increasing energy expenditure. Thus, the development of potent and long-acting analogs of oxyntomodulin is an exciting new therapeutic avenue for addressing the global obesity epidemic. Read More

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October 2010
40 Reads

Growth hormone-releasing factor agonists for the treatment of HIV-associated lipodystrophy.

Curr Opin Investig Drugs 2010 Oct;11(10):1143-50

The Chinese University of Hong Kong, Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.

HIV-associated lipodystrophy characterized by body composition changes and associated metabolic abnormalities, including dyslipidemia and insulin resistance, is a major challenge in the treatment of HIV infection. Growth hormone-releasing factor (GRF) analogs with greater stability than the natural hormone can induce growth hormone secretion in a physiological manner, and appear to be promising candidate therapies for these conditions. The most promising GRF agonist in development is tesamorelin (EMD Serono/Theratechnologies), which has exhibited efficacy for the treatment of excess visceral adipose tissue in patients with HIV infection in two recent phase III, randomized, placebo-controlled clinical trials. Read More

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October 2010
3 Reads

Thyroid hormone receptor and lipid regulation.

Authors:
Paul Webb

Curr Opin Investig Drugs 2010 Oct;11(10):1135-42

The Methodist Hospital Research Institute, Center for Diabetes Research, Houston, TX 77030, USA.

The concept of thyroid hormone (TH) analogs that retain the beneficial effects of TH excess on lipid lowering and fat metabolism, while avoiding any harmful effects on the heart, muscle, bone and other tissues, has interested scientists and physicians for several decades. While there have been many attempts to develop selective TH receptor (TR) modulators (STRMs) for safe lipid lowering, these approaches have failed consistently. This review details recent advances in the development of TRβ subtype- and liver-selective STRM analogs, and presents the results of preliminary clinical trials with one of these compounds, eprotirome (KB-2115; Karo Bio AB). Read More

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October 2010
11 Reads

S-Nitrosothiol biology and therapeutic potential in metabolic disease.

Curr Opin Investig Drugs 2010 Oct;11(10):1127-34

Louisiana State University Health Sciences Center, Department of Pathology, Shreveport, LA 71130, USA.

S-Nitrosothiols (RSNOs) have been used widely as experimental nitric oxide (NO) donors, but the clinical use of these agents remains limited. Recent data support a role for endogenous RSNOs as mediators of NO signaling via the post-translational modification of proteins. This review discusses the increased understanding of the role of RSNOs in NO signaling, as well as emerging insights into NO donor-dependent and -independent mechanisms of action of RSNOs, in the context of emerging and potential therapeutics that target endogenous RSNOs or use synthetic RSNOs to stimulate NO signaling. Read More

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677214PMC
October 2010
3 Reads

Testosterone therapy in women with androgen deficiency: Its time has come.

Curr Opin Investig Drugs 2010 Oct;11(10):1116-26

Lahey Clinic Northshore, Center for Sexual Function/Endocrinology, Peabody, MA 01960, USA.

The concept that women may have a testosterone deficiency is controversial, as is the possibility of testosterone replacement therapy for women. It has been stated that androgen deficiency is a new concept; however, women have been treated off-label for more than 50 years. A number of objections to such therapy in women have been reviewed and discussed, including the lack of a normal age-related concentration range for androgens, the lack of randomized, placebo-controlled clinical trials, and the possibility of chronic adverse effects, particularly the risk of cardiovascular disease and breast cancer. Read More

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October 2010
6 Reads

Plant-derived therapeutics for the treatment of metabolic syndrome.

Curr Opin Investig Drugs 2010 Oct;11(10):1107-15

Rutgers University, SEBS, New Brunswick, NJ 08901, USA.

Metabolic syndrome is defined as a set of coexisting metabolic disorders that increase an individual's likelihood of developing type 2 diabetes, cardiovascular disease and stroke. Medicinal plants, some of which have been used for thousands of years, serve as an excellent source of bioactive compounds for the treatment of metabolic syndrome because they contain a wide range of phytochemicals with diverse metabolic effects. In order for botanicals to be effectively used against metabolic syndrome, however, botanical preparations must be characterized and standardized through the identification of their active compounds and respective modes of action, followed by validation in controlled clinical trials with clearly defined endpoints. Read More

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755736PMC
October 2010
7 Reads

Appetite- and volume-regulating neuropeptides: Role in treating alcohol dependence.

Curr Opin Investig Drugs 2010 Oct;11(10):1097-106

Center for Addiction Research, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover, Germany.

Recent studies have demonstrated a role for appetite- and volume-regulating neuropeptides in alcohol dependence, particularly in association with alcohol craving. The peptides leptin, ghrelin, adiponectin, vasopressin and the atrial natriuretic peptide (ANP) have been of particular interest because of their central effects on various brain circuits, including the hypothalamic-pituitary-adrenocortical (HPA) axis. In addition, pro-opiomelanocortin (POMC) plays an important role in linking appetite regulation with the HPA axis. Read More

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October 2010
6 Reads

Macitentan, a tissue-targeting endothelin receptor antagonist for the potential oral treatment of pulmonary arterial hypertension and idiopathic pulmonary fibrosis.

Authors:
Shahzad G Raja

Curr Opin Investig Drugs 2010 Sep;11(9):1066-73

Harefield Hospital, Department of Cardiothoracic Surgery, Royal Brompton & Harefield NHS Trust, Hill End Road, Harefield, London, UB9 6JH, UK.

Macitentan (ACT-064992), under development by Actelion Ltd in collaboration with Japanese licensee Nippon Shinyaku Co Ltd, is an orally active, non-peptide dual endothelin (ET)(A) and ET(B) receptor antagonist for the potential treatment of idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). Scientific evidence suggests that the ET system may play an important role in the pathobiology of several cardiovascular diseases. A major therapeutic advance for the treatment of patients with PAH and IPF has been the pharmacological control of the activated ET system with ET receptor antagonists. Read More

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September 2010
48 Reads

M-118, a novel, low-molecular-weight heparin for the potential treatment of cardiovascular disorders.

Curr Opin Investig Drugs 2010 Sep;11(9):1059-65

University of Michigan, Division of Cardiovascular Medicine, 2A394, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5853, USA.

Safe inhibition of thrombosis is a key therapeutic strategy in modern cardiovascular medicine, and both unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are commonly used in clinical practice. However, both have several drawbacks, such as the unpredictable pharmacokinetics of UFH and the non-reversibility of LMWH. M-118, being developed by Momenta Pharmaceuticals Inc, is a novel LMWH that has been engineered to overcome the drawbacks of UFH and currently available LMWHs, while maintaining their beneficial attributes. Read More

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September 2010
5 Reads

Vernakalant, a mixed sodium and potassium ion channel antagonist that blocks K(v)1.5 channels, for the potential treatment of atrial fibrillation.

Authors:
George E Billman

Curr Opin Investig Drugs 2010 Sep;11(9):1048-58

Department of Physiology and Cell Biology, The Ohio State University, Columbus OH 43210-1218, USA.

Despite being the most common arrhythmia currently treated by cardiologists, safe and effective treatments for atrial fibrillation (AF) remain elusive. To address this issue, Astellas Pharma Inc, Merck & Co Inc and Cardiome Pharma Corp are developing vernakalant (RSD-1235), a drug which dose-dependently inhibits sodium channels and several potassium repolarizing currents. Of particular note, vernakalant inhibits I(Kur) (K(v)1. Read More

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September 2010
16 Reads

Cinaciguat, a soluble guanylate cyclase activator for the potential treatment of acute heart failure.

Curr Opin Investig Drugs 2010 Sep;11(9):1039-47

Universidad Complutense de Madrid, School of Medicine, Department of Pharmacology, Ciudad Universitaria, 28040 Madrid, Spain.

The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine-3',5'-monophosphate (cGMP) pathway plays an important role in cardiovascular regulation by producing vasodilation and inhibiting platelet aggregation and vascular smooth muscle proliferation. The NO/SGC/cGMP pathway is disrupted in patients with heart failure as a result of a decrease in NO bioavailability and an increase in NO-insensitive forms of sGC, resulting in insufficient vasodilation. Drugs that activate sGC in a NO-independent manner may provide considerable therapeutic advantages in treating these patients. Read More

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September 2010
8 Reads

Chronic kidney disease-associated anemia: new remedies.

Curr Opin Investig Drugs 2010 Sep;11(9):1030-8

A Manzoni Hospital, Department of Nephrology, Dialysis and Renal Transplant, Via dell'Eremo 9, 23900 Lecco, Italy.

Erythropoiesis stimulating agents (ESAs) are effective drugs that correct anemia in patients with chronic kidney disease (CKD). Recombinant human erythropoietin (EPO), the first ESA that became available more than 20 years ago, is similar to the naturally occurring molecule. In subsequent years, pharmacological research focused on the development of new agents with improved characteristics, with the creation of high molecular weight ESAs having been the first approach. Read More

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September 2010
7 Reads

Primate models for cardiovascular drug research and development.

Authors:
You-Tang Shen

Curr Opin Investig Drugs 2010 Sep;11(9):1025-9

University of Pennsylvania, Department of Medicine, Glenolden Research Laboratories, 500 South Ridgeway Avenue, Glenolden, PA 19036, USA.

One of the primary impediments to successful drug R&D is the frequent failure of successfully translating positive results obtained in animal models to human disease. To a large degree, this discrepancy is secondary to the substantial biological differences between species. Non-human primate models have the advantage of significant physiological, metabolic, biochemical and genetic similarity to humans. Read More

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September 2010
5 Reads

The utility of cardiovascular drugs in the treatment of cerebrovascular disease.

Curr Opin Investig Drugs 2010 Sep;11(9):1015-24

University Hospital Heidelberg, Department of Neurology, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany.

Cardiovascular and cerebrovascular diseases share many pathophysiological traits, often impact one another and share several risk factors, though not always to the same magnitude. Therefore, it is not surprising that many classes of cardiovascular drugs have demonstrated effectiveness in the primary prevention, acute treatment and secondary prevention of stroke. Important advances have been made since 2007 in the use of antiplatelets, anticoagulants, antihypertensives, antiarrhythmics and statins for the treatment of stroke. Read More

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September 2010
19 Reads

The use of vasopressin receptor antagonists in hyponatremia.

Curr Opin Investig Drugs 2010 Sep;11(9):1007-14

SUNY Upstate Medical University, Department of Medicine, 750 East Adams Street, Syracuse, NY 13210, USA.

Hyponatremia is the most prevalent electrolyte disorder in hospitalized patients. Vasopressin plays an important role in the pathogenesis of this disorder through its action on the vasopressin type 2 receptor (V(2)R), leading to electrolyte-free water reabsorption. Multiple vasopressin receptor antagonists have recently been developed that differ in their specificity for V(2)R and V(1)R. Read More

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September 2010
6 Reads

Targeting hyaluronan of the endothelial glycocalyx for therapeutic intervention.

Curr Opin Investig Drugs 2010 Sep;11(9):997-1006

Royal Veterinary College, Department of Veterinary Basic Sciences, Royal College Street, London, NW1 0TU, UK.

The endothelial glycocalyx (EG) is an extracellular matrix (ECM) coating the luminal surface of the vascular endothelium. Hyaluronan (HA), a glycosaminoglycan, is an important constituent of the EG that regulates inflammation and repair. By providing a direct link between the endothelium and its ECM, HA contributes to maintaining glycocalyx integrity; emerging evidence indicates a close association between EG deterioration, concomitant loss of HA and the onset of endothelial dysfunction, a phenomenon that is involved in many disorders, including atherosclerosis, diabetes, hypertension and dyslipidemia. Read More

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September 2010
19 Reads

Apolipoprotein A-I and its mimetics for the treatment of atherosclerosis.

Authors:
Jonathan D Smith

Curr Opin Investig Drugs 2010 Sep;11(9):989-96

Cleveland Clinic, Department of Cell Biology, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

Although statin treatment leads consistently to a reduction in major adverse coronary events and death in clinical trials, approximately 60 to 70% residual risk of these outcomes still remains. One frontier of investigational drug research is treatment to increase HDL, the 'good cholesterol' that is associated with a reduced risk of coronary artery disease. HDL and its major protein apolipoprotein A-I (apoAI) are protective against atherosclerosis through several mechanisms, including the ability to mediate reverse cholesterol transport. Read More

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074469PMC
September 2010
3 Reads