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1.  Biologics: the role of delivery systems in improved therapy 
The beginning of the 21st century saw numerous protein and peptide therapeuticals both on the market and entering the final stages of clinical studies. They represent a new category of biologically originated drugs termed biologics or biologicals. Their main advantages over conventional drugs can be summarized by their high selectivity and potent therapeutic efficacy coupled with limited side effects. In addition, they exhibit more predictable behavior under in vivo conditions. However, up to now most of the formulations of biologics are designed and destined for the parenteral route of administration. As a consequence, many suffer from short plasma half-lives, resulting in their frequent administration and ultimately poor patient compliance. This review represents an attempt to address some of the challenges and promises in the product development of biologics both for parenteral and noninvasive administration. Some of the products currently in the pipeline of pharmaceutical development and corresponding perspectives are discussed in more detail.
PMCID: PMC3964020  PMID: 24672225
biologics; drug delivery systems; medical devices
2.  Targeted therapy for sarcomas 
Sarcomas are tumors of mesenchymal origin that make up approximately 1% of human cancers. They may arise as primary tumors in either bone or soft tissue, with approximately 11,280 soft tissue tumors and 2,650 bone tumors diagnosed each year in the United States. There are at least 50 different subtypes of soft tissue sarcoma, with new ones described with ever-increasing frequency. One way to look at sarcomas is to divide them into categories on the basis of their genetic make-up. One group of sarcomas has an identifiable, relatively simple genetic signature, such as the X:18 translocation seen in synovial sarcoma or the 11:22 translocation seen in Ewing’s sarcoma. These specific abnormalities often lead to the presence of fusion proteins, such as EWS-FLI1 in Ewing’s sarcoma, which are helpful as diagnostic tools and may become therapeutic targets in the future. Another group of sarcomas is characterized by complex genetic abnormalities as seen in leiomyosarcoma, osteosarcoma, and undifferentiated sarcoma. It is important to keep these distinctions in mind when contemplating the development of targeted agents for sarcomas. Different abnormalities in sarcoma could be divided by tumor subtype or by the molecular or pathway abnormality. However, some existing drugs or drugs in development may interfere with or alter more than one of the presented pathways.
PMCID: PMC3962319  PMID: 24669185
sarcoma; targeted agents; tyrosine kinase inhibitors; mTor inhibition
3.  Porcine dermis implants in soft-tissue reconstruction: current status 
Soft-tissue reconstruction for a variety of surgical conditions, such as abdominal wall hernia or pelvic organ prolapse, remains a challenge. There are numerous meshes available that may be simply categorized as either synthetic or biologic. Within biologic meshes, porcine dermal meshes have come to dominate the market. This review examines the current evidence for their use and the limitations of knowledge. Although there is increasing evidence to support their safety, long-term follow-up studies that support their efficacy are lacking. Numerous clinical trials that remain ongoing may help elucidate their precise role in soft-tissue reconstruction.
PMCID: PMC3956623  PMID: 24648721
hernia; mesh; xenograft; biologic
4.  A critical evaluation of the role of subcutaneous abatacept in the treatment of rheumatoid arthritis: patient considerations 
There are now more therapeutic options for the treatment of rheumatoid arthritis (RA) than ever before, involving a range of mechanisms of action and different routes of administration. The T-cell costimulation modulator abatacept is the first biologic therapy for RA to be available in both subcutaneous (SC) and intravenous (IV) formulations. This review evaluates the utility of SC abatacept, with a particular focus on patient-reported outcomes, including physical function, pain, fatigue, and quality of life. Practical questions relating to the clinical use of SC abatacept are also addressed, including the relevance of abatacept’s mechanism of action; whether IV and SC abatacept are comparable; if patients can easily switch from IV to SC abatacept; whether an IV loading dose is needed; and if temporary treatment interruptions or lack of concomitant methotrexate can affect efficacy or safety. Topics that are of particular concern to patients when using SC biologics, such as injection-site reactions, are also discussed. Observational data from registries and meta-analyses of clinical studies suggest comparable clinical efficacy between biologic disease-modifying antirheumatic drugs; however, such analyses rarely focus on key determinants of patient quality of life such as pain, fatigue, and physical function. The head-to-head AMPLE study is one of the first studies powered to directly compare two biologics in patients with RA. Patient-reported outcomes from year 1 of the ongoing study are evaluated, demonstrating comparable improvements in physical function, pain, fatigue, Short Form-36 Health Survey, and Routine Assessment of Patient Index Data 3 scores between SC abatacept and SC adalimumab when administered with concomitant methotrexate. In summary, the data presented herein show that the SC formulation of abatacept provides a valuable addition to the range of available therapy options for patients with RA, capable of significantly improving key patient considerations such as pain, disability, loss of function, fatigue, and quality of life.
PMCID: PMC3933241  PMID: 24600202
rheumatoid arthritis; abatacept; subcutaneous; biologic DMARD; patient-reported outcomes
5.  Update on the use of systemic biologic agents in the treatment of noninfectious uveitis 
Uveitis is one of the leading causes of blindness worldwide. Noninfectious uveitis may be associated with other systemic conditions, such as human leukocyte antigen B27-related spondyloarthropathies, inflammatory bowel disease, juvenile idiopathic arthritis, Behçet’s disease, and sarcoidosis. Conventional therapy with corticosteroids and immunosuppressive agents (such as methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine) may not be sufficient to control ocular inflammation or prevent non-ophthalmic complications in refractory patients. Off-label use of biologic response modifiers has been studied as primary and secondary therapeutic agents. They are very useful when conventional immunosuppressive therapy has failed or has been poorly tolerated, or to treat concomitant ophthalmic and systemic inflammation that might benefit from these medications. Biologic therapy, primarily infliximab, and adalimumab, have been shown to be rapidly effective for the treatment of various subtypes of refractory uveitis and retinal vasculitis, especially Behçet’s disease-related eye conditions and the uveitis associated with juvenile idiopathic arthritis. Other agents such as golimumab, abatacept, canakinumab, gevokizumab, tocilizumab, and alemtuzumab may have great future promise for the treatment of uveitis. It has been shown that with proper monitoring, biologic therapy can significantly improve quality of life in patients with uveitis, particularly those with concurrent systemic symptoms. However, given high cost as well as the limited long-term safety data, we do not routinely recommend biologics as first-line therapy for noninfectious uveitis in most patients. These agents should be used with caution by experienced clinicians. The present work aims to provide a broad and updated review of the current and in-development systemic biologic agents for the treatment of noninfectious uveitis.
PMCID: PMC3933243  PMID: 24600203
biologics; monoclonal antibody; eye
6.  Does the cis/trans configuration of peptide bonds in bioactive tripeptides play a role in ACE-1 enzyme inhibition? 
The milk casein-derived bioactive tripeptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP) have been shown to prevent development of hypertension in animal models and to lower blood pressure in moderately hypertensive subjects in most but not all clinical trials. Inhibition of angiotensin-converting enzyme 1 (ACE-1) has been suggested as the explanation for these antihypertensive and beneficial vascular effects. Previously, human umbilical vein endothelial cells (HUVEC) have not been used to test ACE-1 inhibiting properties of casein derived tripeptides in vasculature.
We focused on the cis/trans configurations of the peptide bonds in proline-containing tripeptides in order to discover whether the different structural properties of these peptides influence their activity in ACE-1 inhibition. We hypothesized that the configuration of proline-containing peptides plays a significant role in enzyme inhibition.
AutoDock 4.2 docking software was used to predict suitable peptide bond configurations of the tripeptides. Besides modeling studies, we completed ACE-1 activity measurements in vitro using HUVEC cultures.
In HUVEC cells, both IPP and VPP inhibited ACE-1. Based on molecular docking studies, we propose that in ACE-1 inhibition IPP and VPP share a similar cis configuration between the first aliphatic (isoleucine or valine) and the second (proline) amino acid residues and more different configurations between two proline residues. In vivo experiments are needed to validate the significance of the present findings.
PMCID: PMC3930482  PMID: 24596454
ACE inhibition; Autodock modeling; Ile-Pro-Pro; Val-Pro-Pro; vascular function
7.  Therapeutic vaccines and cancer: focus on DPX-0907 
In an attempt to significantly enhance immunogenicity of peptide cancer vaccines, we developed a novel non-emulsion depot-forming vaccine platform called DepoVax™ (DPX). Human leukocyte antigen (HLA)-A2 restricted peptides naturally presented by cancer cells were used as antigens to create a therapeutic cancer vaccine, DPX-0907. In a phase I clinical study, the safety and immune-activating potential of DPX-0907 in advanced-stage breast, ovarian, and prostate cancer patients were examined, following encouraging results in HLA-A2 transgenic mice. The DPX-0907 vaccine was shown to be safe and well tolerated, with injection-site reactions being the most commonly reported adverse event. Vaccinated cancer patients exhibited a 61% immune response rate, with higher response rates in the breast and ovarian cancer patient cohorts. In keeping with the higher immune efficacy of this vaccine platform, antigen-specific responses were detected in 73% of immune responders after just one vaccination. In 83% of responders, peptide-specific T-cells were detected at two or more time points post-vaccination, with 64% of these patients showing evidence of immune persistence. Immune monitoring also demonstrated the generation of antigen-specific T-cell memory, with the ability to secrete multiple type 1 cytokines. The novel DPX formulation promotes multifunctional effector/memory responses to peptide-based tumor-associated antigens. The data support the capacity of DPX-0907 to elicit type-1 biased immune responses, warranting further clinical development of the vaccine. In this review, we discuss the rationale for developing DPX-based therapeutic cancer vaccine(s), with a focus on DPX-0907, aimed at inducing efficient anti-tumor immunity that may eventually be shown to prolong patient survival.
PMCID: PMC3930480  PMID: 24596453
immunotherapy; DepoVax™; cancer vaccine; DPX-0907
9.  Biologic targeting in the treatment of inflammatory bowel diseases [Retraction] 
PMCID: PMC3912050  PMID: 24501538
10.  Ziv-aflibercept in metastatic colorectal cancer 
The combination of cytotoxic chemotherapy and antiangiogenic agents has become a conventional treatment option for patients with metastatic colorectal cancer. Ziv-aflibercept is a fusion protein which acts as a decoy receptor for vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PlGF); it was approved in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing fluoropyrimidine-based regimen. Herein we review the role of tumor angiogenesis as the rationale for antiangiogenic therapy, the clinical data associated with ziv-aflibercept, and its current role as a treatment option compared to other antiangiogenic agents, such as bevacizumab and regorafenib.
PMCID: PMC3869833  PMID: 24368879
aflibercept; angiogenesis; colorectal cancer
11.  Non-tumor necrosis factor-based biologic therapies for rheumatoid arthritis: present, future, and insights into pathogenesis 
The way rheumatoid arthritis is treated has changed dramatically with the introduction of anti-tumor necrosis factor (anti-TNF) biologics. Nevertheless, many patients still have less than adequate control of their disease activity even with these therapeutic regimens, and current knowledge fails to explain all the data already gathered. There is now a wide range of drugs from different classes of biologic disease-modifying anti-rheumatic drugs available (and soon this number will increase significantly), that provides the opportunity to address each patient as a particular case and thereby optimize medical intervention. Currently available biologics for the treatment of rheumatoid arthritis apart from anti-TNF-based therapies are reviewed, along with an analysis of the new insights they provide into the pathogenesis of the disease and a discussion of future prospects in the area.
PMCID: PMC3861294  PMID: 24353404
rheumatoid arthritis; non-anti-tumor necrosis factor; treatment; pathogenesis
13.  Effects of 6 months of abatacept treatment on aortic stiffness in patients with rheumatoid arthritis 
Systemic inflammation plays an important role in the increased cardiac risk observed in rheumatoid arthritis (RA). Effective control of inflammation and disease activity may be of benefit in reducing cardiovascular risk in RA patients.
Our study was conducted in patients with active RA to investigate the effects of 24-week abatacept treatment on aortic stiffness measured by pulse wave velocity (PWV).
The study included 21 patients, of whom 17 were females, with a mean age of 65.2±13.7 years. Ten patients had positive rheumatoid factors, 16 positive anti-citrullinated protein antibodies, and 19 presented an erosive form of RA. Sixteen patients were nonresponders to anti-tumor necrosis factor-alpha treatments. After 6 months of abatacept treatment, there was a significant increase in PWV levels (9.8±2.9 versus 8.5±3.9 m/second; P=0.02). A nonsignificant increase in total cholesterol and low-density lipoprotein cholesterol was observed. There was also a significant increase in high-density lipoprotein cholesterol levels, which led to a nonsignificant decrease in atherogenic index. The improvement in disease activity was significant, and there was a decrease of systemic inflammatory parameters, but without reaching statistical significancy. Changes in PWV were significantly correlated with changes in Disease Activity Score on 28 joints based on erythrocyte sedimentation rate (r=0.46; P=0.035) and in high-density lipoprotein cholesterol (r=−0.38; P=0.046). No correlation was observed with changes in C-reactive protein and in other parameters of lipid profile or in steroid dose.
The worsening of aortic stiffness found after 6 months of abatacept therapy might be due to an insufficient decrease in systemic inflammation.
PMCID: PMC3854916  PMID: 24324327
arterial stiffness; cardiovascular risk markers; systemic inflammation; atherogenic index
14.  Optimizing therapeutics in the management of patients with multiple sclerosis: a review of drug efficacy, dosing, and mechanisms of action 
Multiple sclerosis (MS) is a debilitating neurological disorder that affects nearly 2 million adults, mostly in the prime of their youth. An environmental trigger, such as a viral infection, is hypothesized to initiate the abnormal behavior of host immune cells: to attack and damage the myelin sheath surrounding the neurons of the central nervous system. While several other pathways and disease triggers are still being investigated, it is nonetheless clear that MS is a heterogeneous disease with multifactorial etiologies that works independently or synergistically to initiate the aberrant immune responses to myelin. Although there are still no definitive markers to diagnose the disease or to cure the disease per se, research on management of MS has improved many fold over the past decade. New disease-modifying therapeutics are poised to decrease immune inflammatory responses and consequently decelerate the progression of MS disease activity, reduce the exacerbations of MS symptoms, and stabilize the physical and mental status of individuals. In this review, we describe the mechanism of action, optimal dosing, drug administration, safety, and efficacy of the disease-modifying therapeutics that are currently approved for MS therapy. We also briefly touch upon the new drugs currently under investigation, and discuss the future of MS therapeutics.
PMCID: PMC3854923  PMID: 24324326
multiple sclerosis; immunomodulation; interferons; glatiramer acetate; monoclonal antibodies; dimethyl fumarate
15.  Lessons learned from peginesatide in the treatment of anemia associated with chronic kidney disease in patients on dialysis 
Peginesatide is the newest erythropoietin-stimulating agent (ESA) in the quest for the ideal treatment of anemia in chronic kidney disease (CKD) patients. Reduced frequency of administration along with a possibly lower cost as a result of simpler manufacturing techniques compared with other available agents makes peginesatide a highly desirable product in the competitive ESA market. Peginesatide is noninferior to the other ESAs, and has a good safety profile in patients on hemodialysis. The higher rates of adverse cardiovascular events reported in CKD patients not on dialysis in the recent Phase III studies require further, better planned, studies. Peginesatide had to be withdrawn from the market in the US after some reports of hypersensitivity reactions to the drug. This is a setback, but the scientific advances gained as a result of this product development can be used to develop other, newer products.
PMCID: PMC3848525  PMID: 24348017
anemia; hemodialysis; chronic kidney disease; peginesatide
16.  Immunization of rabbits with synthetic peptides derived from a highly conserved β-sheet epitope region underneath the receptor binding site of influenza A virus 
There is increasing concern about the speed with which health care providers can administer prophylaxis and treatment in an influenza pandemic. Generally, it takes several months to manufacture an influenza vaccine by propagation of the virus in chicken eggs or cultured cells. Newer, faster protocols for the production of vaccines that induce broad-spectrum immunity are therefore highly desirable. We previously developed human monoclonal antibody B-1 that shows broadly neutralizing activity against influenza A virus H3N2. B-1 recognizes an epitope region that includes an antiparallel β-sheet structure underneath the receptor binding site of influenza hemagglutinin (HA). In this study, the efficacy of a synthetic peptide vaccine derived from this epitope region against influenza A was evaluated.
Materials and methods
Two peptides were synthesized, the upper and lower peptides. These peptides comprise amino acid residues 167–187 and 225–241, respectively, of the B-1 epitope region of HA, which is involved in forming the β-sheet structure. Both peptides were then coupled to keyhole limpet hemocyanin, and the peptides, alone or in combination, were used to immunize rabbits. The resulting antibody responses were examined by enzyme-linked immunosorbent assay. The upper peptide, but not the lower peptide, elicited antibodies that were reactive to HA. Interestingly, the use of both peptides together could elicit antibodies with a higher reactivity to HA than either peptide alone. The antibodies were found to react to HA at the N-terminus of the upper peptide, which is exposed at the surface of trimeric HA on influenza virions.
The higher production of HA-reactive antibodies following immunization with both peptides suggests that the upper peptide forms the effective epitope structure in the binding state, and the lower peptide enhances the production of HA antibodies. This study could be the first step towards the development of pandemic viral vaccines that can be produced within short time periods.
PMCID: PMC3821756  PMID: 24235814
influenza A; hemagglutinin; epitope; synthetic peptide; rabbit
18.  Efficacy of intensity-modulated radiotherapy combined with chemotherapy or surgery in locally advanced squamous cell carcinoma of the head-and-neck 
Long-term locoregional control following intensity-modulated radiotherapy (IMRT) for locally advanced squamous cell carcinoma of the head-and-neck (SCCHN) remains challenging. This study aimed to assess the efficacy and toxicity of IMRT with and without chemotherapy or surgery in locally advanced SCCHN.
Materials and methods
Between January 2007 and January 2011, 61 patients with locally advanced SCCHN were treated with curative IMRT in the Department of Radiation Oncology, Xijing Hospital, Fourth Military Medical University; 28% underwent definitive IMRT and 72% postoperative IMRT, combined with simultaneous cisplatin-based chemotherapy in 58%. The mean doses of definitive and postoperative IMRT were 70.8 Gy (range, 66–74 Gy). Outcomes were analyzed using Kaplan–Meier curves. Acute and late toxicities were graded according to Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer radiation morbidity scoring criteria.
At a median follow-up of 35 months, 3-year local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were 83.8%, 86.1%, 82.4%, 53.2%, and 62%, respectively. Postoperative IMRT (n = 44, 72%) had significantly higher LRFS/OS/DMFS than definitive IMRT (n = 17, 28%; P < 0.05). IMRT combined with chemotherapy (n = 35, 58%) had significantly higher LRFS/OS/DMFS than IMRT alone (n = 26, 42%; P < 0.05). One year after radiotherapy, the incidence of xerostomia of grade 1, 2, or 3 was 13.1%, 19.7%, and 1.6%, respectively. No grade 4 acute or late toxicity was observed.
IMRT combined with surgery or chemotherapy achieved excellent long-term locoregional control and OS in locally advanced SCCHN, with acceptable early toxicity and late side-effects.
PMCID: PMC3804514  PMID: 24204121
SCCHN; IMRT; surgery; chemotherapy; prognosis analysis
19.  Everolimus in the treatment of subependymal giant cell astrocytomas, angiomyolipomas, and pulmonary and skin lesions associated with tuberous sclerosis complex 
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by inactivating mutations in either the TSC1 or TSC2 genes. It is characterized by the development of multiple, benign tumors in several organs throughout the body. Lesions occur in the brain, kidneys, heart, liver, lungs, and skin and result in seizures and epilepsy, mental retardation, autism, and renal and pulmonary organ system dysfunction, as well as other complications. Elucidation of the molecular pathways and etiological factors responsible for causing TSC has led to a paradigm shift in the management and treatment of the disease. TSC1 or TSC2 mutations lead to constitutive upregulation of the mammalian target of rapamycin pathway, which affects many cellular processes involved in tumor growth. By targeting mammalian target of rapamycin with everolimus, an orally active rapamycin derivative, clinically meaningful and statistically significant reductions in tumor burden have been achieved for the main brain (subependymal giant cell astrocytoma) and renal manifestations (angiomyolipoma) associated with TSC. This review provides an overview of TSC, everolimus, and the clinical trials that led to its approval for the treatment of TSC-associated subependymal giant cell astrocytoma and renal angiomyolipoma.
PMCID: PMC3797614  PMID: 24143074
everolimus; subependymal giant cell astrocytoma; angiomyolipomas; lymphangioleiomyomatosis; facial angiofibromas; tuberous sclerosis complex
20.  Clinical utility of asthma biomarkers: from bench to bedside 
Asthma is a chronic disease characterized by airway inflammation, bronchial hyperresponsiveness, and recurrent episodes of reversible airway obstruction. The disease is very heterogeneous in onset, course, and response to treatment, and seems to encompass a broad collection of heterogeneous disease subtypes with different underlying pathophysiological mechanisms. There is a strong need for easily interpreted clinical biomarkers to assess the nature and severity of the disease. Currently available biomarkers for clinical practice – for example markers in bronchial lavage, bronchial biopsies, sputum, or fraction of exhaled nitric oxide (FeNO) – are limited due to invasiveness or lack of specificity. The assessment of markers in peripheral blood might be a good alternative to study airway inflammation more specifically, compared to FeNO, and in a less invasive manner, compared to bronchoalveolar lavage, biopsies, or sputum induction. In addition, promising novel biomarkers are discovered in the field of breath metabolomics (eg, volatile organic compounds) and (pharmaco)genomics. Biomarker research in asthma is increasingly shifting from the assessment of the value of single biomarkers to multidimensional approaches in which the clinical value of a combination of various markers is studied. This could eventually lead to the development of a clinically applicable algorithm composed of various markers and clinical features to phenotype asthma and improve diagnosis and asthma management.
PMCID: PMC3762671  PMID: 24009412
asthma; airway inflammation; biological markers; pharmacogenomics; metabolomics
21.  Treatment and management of myelofibrosis in the era of JAK inhibitors 
Myelofibrosis (MF) can present as a primary disorder or evolve from polycythemia vera (PV) or essential thrombocythemia (ET) to post-PV MF or post-ET MF, respectively. MF is characterized by bone marrow fibrosis, splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, and a collection of debilitating symptoms. Until recently, the therapeutic options for patients with MF consisted of allogeneic hematopoietic stem cell transplant (alloHSCT), the use of cytoreductive agents (ie, hydroxyurea), splenectomy and splenic irradiation for treatment of splenomegaly, and management of anemia with transfusions, erythropoiesis-stimulating agents (ESAs), androgens, and immunomodulatory agents. However, with increased understanding of the pathogenesis of MF resulting from dysregulated Janus kinase (JAK) signaling, new targeted JAK inhibitor therapies, such as ruxolitinib, are now available. The purpose of this article is to review the clinical features of MF, discuss the use and future of JAK inhibitors, reassess when and how to use conventional MF treatments in the context of JAK inhibitors, and provide a perspective on the future of MF treatment.
PMCID: PMC3753053  PMID: 23990704
myelofibrosis; ruxolitinib; JAK inhibitor
22.  Cross-reactivity of human monoclonal antibodies generated with peripheral blood lymphocytes from dengue patients with Japanese encephalitis virus 
Hybridomas that produce human monoclonal antibodies (HuMAbs) against Dengue virus (DV) had been prepared previously using peripheral blood lymphocytes from patients with DV during the acute and convalescent phases of a secondary infection. Anti-DV envelope glycoprotein (E) 99 clones, anti-DV premembrane protein (prM) 8 clones, and anti-DV nonstructural protein 1 (NS1) 4 clones were derived from four acute-phase patients, and anti-DV E 2 clones, anti-DV prM 2 clones, and anti-DV NS1 8 clones were derived from five convalescent-phase patients.
Methods and results
In the present study, we examined whether these clones cross-reacted with Japanese encephalitis virus (JEV), which belongs to the same virus family. Forty-six of the above-described 99 (46/99) anti-E, 0/8 anti-prM, and 2/4 anti-NS1 HuMAbs from acute-phase, and 0/2 anti-E, 0/2 anti-prM, and 5/8 anti-NS1 HuMAbs from convalescent-phase showed neutralizing activity against JEV. Thus, most of the anti-E and anti-NS1 (but not the anti-prM) antibodies cross-reacted with JEV and neutralized this virus. Interestingly, 3/46 anti-E HuMAbs derived from acute-phase patients and 3/5 anti-NS1 HuMAbs from convalescent-phase patients showed particularly high neutralizing activity against JEV. Consequently, the HuMAbs showing neutralization against JEV mostly consisted of two populations: one was HuMAbs recognizing DV E and showing neutralization activity against all four DV serotypes (complex-type) and the other was HuMAbs recognizing DV NS1 and showing subcomplex-type cross-reaction with DV.
Anti-DV E from acute phase (46/99) and anti-DV NS1 (7/12) indicate neutralizing activity against JEV. In particular, three of 46 anti-DV E clones from acute phase and three of five anti-NS1 clones from convalescent phase showed strong neutralizing activity against JEV.
PMCID: PMC3747787  PMID: 23983454
Dengue virus; Japanese encephalitis virus; viral neutralization; human monoclonal antibody; envelope; nonstructural protein 1
23.  Erythropoiesis stimulating agents: approaches to modulate activity 
Recombinant human erythropoietin (rHuEPO), such as the approved agents epoetin alfa and epoetin beta, has been used successfully for over 20 years to treat anemia in millions of patients. However, due to the relatively short half-life of the molecule (approximately 8 hours), frequent dosing may be required to achieve required hemoglobin levels. Therefore, a need was identified in some anemic patient populations for erythropoiesis stimulating agents with longer half-lives that required less frequent dosing. This need led to the development of second generation molecules which are modified versions of rHuEPO with improved pharma-cokinetic and pharmacodynamic properties such as darbepoetin alfa, a hyperglycosylated analog of rHuEPO, and pegzyrepoetin, a pegylated rHuEPO. Third generation molecules, such as peginesatide, which are peptide mimetics that have no sequence homology to rHuEPO have also recently been developed. The various molecular, pharmacokinetic, and pharmacodynamic properties of these and other erythropoiesis stimulating agents will be discussed in this review.
PMCID: PMC3704234  PMID: 23847411
darbepoetin alfa; erythropoiesis; erythropoietin; glycosylation; pharmacokinetics; pharmacology; polyethylene glycols
24.  A novel platinum chromium everolimus-eluting stent for the treatment of coronary artery disease 
The development of coronary stents represents a major step forward in the treatment of obstructive coronary artery disease since the introduction of percutaneous coronary intervention. The initial enthusiasm for bare metal stents was, however, tempered by a significant incidence of in-stent restenosis, the manifestation of excessive neointima hyperplasia within the stented vessel segment, ultimately leading to target vessel revascularization. Later, drug-eluting stents, with controlled local release of antiproliferative agents, consistently reduced this need for repeat revascularization. In turn, the long-term safety of first-generation drug-eluting stents was brought into question with the observation of an increased incidence of late stent thrombosis, often presenting as myocardial infarction or sudden death. Since then, new drugs, polymers, and platforms for drug elution have been developed to improve stent safety and preserve efficacy. Development of a novel platinum chromium alloy with high radial strength and high radiopacity has enabled the design of a new, thin-strut, flexible, and highly trackable stent platform, while simultaneously improving stent visibility. Significant advances in polymer coating, serving as a drug carrier on the stent surface, and in antiproliferative agent technology have further improved the safety and clinical performance of newer-generation drug-eluting stents. This review will provide an overview of the novel platinum chromium everolimus-eluting stents that are currently available. The clinical data from major clinical trials with these devices will be summarized and put into perspective.
PMCID: PMC3692344  PMID: 23818756
drug-eluting stent; restenosis; Promus Element; Synergy
25.  Tivozanib in the treatment of renal cell carcinoma 
Renal cell carcinoma (RCC) is an aggressive malignancy compared to other urological malignancies and has been associated with poor responses to conventional cytotoxic chemotherapy. Interferon-α and interleukin-2 were previously utilized in a limited number of patients with good performance status due to toxicity and safety issues. Over the last decade, through advances in the understanding of the biology and pathology of RCC, the important role of vascular endothelial growth factor (VEGF) in RCC has been identified. Data from randomized trials have led to the approval of first-generation tyrosine kinase inhibitors (TKIs) sorafenib, sunitinib, and pazopanib; however, these agents inhibit a wide variety of kinase targets and are associated with a range of adverse effects. More recently, a new generation TKI, axitinib, has been approved by the US Food and Drug Administration. Tivozanib is a novel TKI, which is a potent inhibitor of VEGF-1, VEGF-2, VEGF-3, c-kit, and PDGR kinases, with a more restricted target spectrum. Phase II and III studies have demonstrated significant activity and a favorable safety profile as an initial targeted treatment for advanced RCC. This review examines the emerging data with tivozanib for the treatment of advanced RCC. Preclinical investigations as well as Phase I, II, and III data are examined; data on the comparative benefits of tivozanib are reviewed. Finally, we discuss the future potential of tivozanib in combination, biomarkers associated with tivozanib response, and acquisition of resistance and nonkidney cancer indications.
PMCID: PMC3684142  PMID: 23788831
targeted therapy; renal cell cancer; tyrosine kinase inhibitor; tivozanib

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