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Human Clinical Trials (human + clinical_trials)
Selected AbstractsCombination Nonviral Interleukin-2 Gene Immunotherapy For Head and Neck Cancer: From Bench Top to BedsideTHE LARYNGOSCOPE, Issue 3 2005Bert W. O'Malley Jr MD Abstract Objective/Hypothesis: Intralesional delivery of cytokine genes has emerged as a promising therapeutic strategy for the treatment of cancer. In addition to the therapeutic effect of the delivered cytokine gene, the components of the gene delivery system also have been shown to induce beneficial immune responses. On the basis of these principles, we hypothesized that a molecular therapy could be developed that would provide synergistic antitumor activity by way of intralesional expression of interleukin (IL)-2 from a recombinant plasmid combined with induction of endogenous interferon (IFN)-, and IL-12 cytokines by immunostimulatory DNA. Our objective in these studies was to create and optimize a novel formulation of cationic lipid and DNA that generates local production of IL-2 protein within a targeted tumor environment with concomitant induction of the antitumor cytokines IFN-, and IL-12. Study Design: Prospective laboratory drug development plan that would produce human clinical trials. Materials and Methods: Engineered bacterial plasmids containing a cytomegalovirus promoter (CMV)-IL-2 expression cassette were specifically formulated with cationic lipids and optimized for antitumor effect in a floor of mouth murine tumor model. The treated tumors were assayed for local expression of IL-2 and concurrent expression of secondary cytokines IFN-, and IL-12. Established tumors in C3H/HeJ mice were treated with various IL-2 gene formulations, and clinical and immunologic responses were evaluated. Immunologic studies were performed and included cytolytic T-cell assays and cytokine expression profiles. For human clinical trials, a phase I 10 patient formulated IL-2 gene therapy study was completed. Subsequently, two large scale, phase II multi-institutional and multi-international studies were initiated comparing non-viral IL-2 gene therapy to palliative methotrexate chemotherapy or in combination with cisplatin. Results: In the preclinical stage, maximum tumor inhibition in animal models was obtained using IL-2 plasmid formulated with 1,2-dioleyloxypropyl-3-trimethyl ammonium chloride (DOTMA):cholesterol (1:1 mol:mol) at a plasmid:lipid charge ratio of 1:0.5 (,/+). Cationic lipid formulated IL-2 plasmid significantly inhibited tumor growth compared with formulated control plasmid (P < .01) or vehicle (lactose; P < .01). Consistent with previously reported studies of the immunostimulatory activity of DNA of bacterial origin, treatment of tumors with control plasmid in cationic lipid formulation induced production of endogenous IFN-, and IL-12 but not IL-2. Treatment of tumors with formulated IL-2 plasmid produced IL-2 protein levels that were 5-fold over background and increased IFN-, by 32-fold (P < .001) and IL-12 by 5.5-fold (P < .001) compared with control plasmid formulations. The phase I human trial demonstrated dose escalation safety, which was its primary objective, and there was one anecdotal reduction in tumor size. The phase II studies have been initiated and focus on either comparing the novel nonviral IL-2 gene immunotherapy formulation alone to methotrexate or comparing IL-2 gene therapy in combination with cisplatin in recurrent or unresectable patients with head and neck squamous cell carcinoma. Conclusions: The preclinical data provided proof of principle for matching a delivered IL-2 transgene with an immunostimulatory nonviral formulation to enhance intralesional production of therapeutic cytokines for the maximization of antitumor response. Human clinical trials have demonstrated this novel therapy to be safe in the human clinical setting. Phase II trials have been initiated to assess efficacy and feasibility as a single or combination therapy for head and neck cancer. [source] Bifidobacterium longum lysate, a new ingredient for reactive skinEXPERIMENTAL DERMATOLOGY, Issue 8 2010Audrey Guéniche Please cite this paper as: Bifidobacterium longum lysate, a new ingredient for reactive skin. Experimental Dermatology 2010; 19: e1,e8. Abstract:, Reactive skin is characterized by marked sensitivity to physical (heat, cold, wind) or chemical (topically applied products) stimuli and by the impairment of the skin barrier's ability to repair itself. Several lines of evidence suggest that beyond their capacity to positively influence the composition of intestinal microbiota, some probiotic bacteria can modulate the immune system both at local and systemic levels, thereby improving immune defense mechanisms and/or down-regulating immune disorders such as allergies and intestinal inflammation. Several recent human clinical trials clearly suggest that probiotic supplementation might be beneficial to the skin. Using a probiotic lysate, Bifidobacterium longum sp. extract (BL), we demonstrated first in vitro, and then in a clinical trial, that this non-replicating bacteria form applied to the skin was able to improve sensitive skin. The effect of BL were evaluated first on two different models. Using ex vivo human skin explant model we found a statistically significant improvement versus placebo in various parameters associated with inflammation such as a decrease in vasodilation, oedema, mast cell degranulation and TNF-alpha release. Moreover, using nerve cell cultures in vitro, we showed that after 6 h of incubation in culture medium (0.3,1%), the probiotic lysate significantly inhibited capsaicin-induced CGRP release by neurones. Then, a topical cream containing the active extract was tested in a randomized, double-blind, placebo-controlled trial. Sixty-six female volunteers with reactive skin were randomly given either the cream with the bacterial extract at 10% (n = 33) or the control cream (n = 33). The volunteers applied the cream to the face, arms and legs twice a day for two months. Skin sensitivity was assessed by stinging test (lactic acid) and skin barrier recovery was evaluated by measuring trans-epidermal water loss following barrier disruption induced by repeated tape-stripping at D1, D29 and D57. The results demonstrated that the volunteers who applied the cream with bacterial extract had a significant decrease in skin sensitivity at the end of the treatment. Moreover, the treatment led to increase skin resistance against physical and chemical aggression compared to the group of volunteers who applied the control cream. Notably, the number of strippings required to disrupt skin barrier function was significantly increased for volunteers treated with the active cream. Clinical and self-assessment scores revealed a significant decrease in skin dryness after 29 days for volunteers treated with the cream containing the 10% bacterial extract. Since in vitro studies demonstrated that, on one hand, isolate sensitive neurones release less CGRP under capsaicin stimulation in the presence of the bacterial extract and, on the other hand, increased skin resistance in volunteers applying the test cream, we speculate that this new ingredient may decrease skin sensitivity by reducing neurone reactivity and neurone accessibility. The results of this studies demonstrate that this specific bacterial extract has a beneficial effect on reactive skin. These findings suggest that new approaches, based on a bacteria lysate, could be developed for the treatment and/or prevention of symptoms related to reactive skin. [source] Developing live Shigella vaccines using , Red recombineeringFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 3 2006Ryan T. Ranallo Abstract Live attenuated Shigella vaccines have shown promise in inducing protective immune responses in human clinical trials and as carriers of heterologous antigens from other mucosal pathogens. In the past, construction of Shigella vaccine strains relied on classical allelic exchange systems to genetically engineer the bacterial genome. These systems require extensive in vitro engineering of long homologous sequences to create recombinant replication-defective plasmids or phage. Alternatively, the ,red recombination system from bacteriophage facilitates recombination with as little as 40 bp of homologous DNA. The process, referred to as recombineering, typically uses an inducible ,red operon on a temperature-sensitive plasmid and optimal transformation conditions to integrate linear antibiotic resistance cassettes flanked by homologous sequences into a bacterial genome. Recent advances in recombineering have enabled modification of genomic DNA from bacterial pathogens including Salmonella, Yersinia, enteropathogenic Escherichia coli, or enterohemorrhagic E. coli and Shigella. These advances in recombineering have been used to systematically delete virulence-associated genes from Shigella, creating a number of isogenic strains from multiple Shigella serotypes. These strains have been characterized for attenuation using both in vivo and in vitro assays. Based on this data, prototypic Shigella vaccine strains containing multiple deletions in virulence-associated genes have been generated. [source] Spending on new drug development,HEALTH ECONOMICS, Issue 2 2010Christopher Paul Adams Abstract This paper replicates DiMasi et al. (J. Health Econ. 2003; 22: 151,185; Drug Inf. J. 2004; 38: 211,223) estimates of expenditure on new drug development using publicly available data. The paper estimates that average expenditure on drugs in human clinical trials is around $27m per year, with $17m per year on drugs in Phase I, $34m on drugs in Phase II and $27m per year on drugs in Phase III of the human clinical trials. The paper's estimated expenditure on new drug development is somewhat greater than suggested by the survey results presented in DiMasi et al. (J. Health Econ. 2003; 22: 151,185; Drug Inf. J. 2004; 38: 211,223). The paper combines a 12-year panel of research and development expenditure for 183 publicly traded firms in the pharmaceutical industry with panel of drugs in human clinical trials for each firm over the same period. The paper estimates drug expenditure by estimating the relationship between research and development expenditure and the number of drugs in development for 1682 company/years (183 firms multiplied by the number of years for which we have financial and drug development information). The paper also estimates expenditure on drugs in various therapeutic categories. Copyright © 2009 John Wiley & Sons, Ltd. [source] Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeuticsIMMUNOLOGICAL REVIEWS, Issue 1 2008Marc Feldmann Summary: Advances in cDNA and monoclonal antibody technology in the 1980s fuelled the discovery and characterization of the properties of cytokines. It became apparent that because cytokines were expressed in tissues derived from autoimmune diseases, they were likely to be of fundamental importance in disease pathogenesis and developing a new class of biological therapeutics. In this review, we describe the history of bench to bedside translation of work that led to the identification of tumor necrosis factor (TNF) as a key regulator of the loss of homeostatic immune-inflammatory responses in rheumatoid arthritis (RA) and a good therapeutic target. First in human clinical trials in collaboration with a biotechnology company, the safety and efficacy of TNF blockade with a chimeric monoclonal antibody was substantiated in patients refractory to standard anti-rheumatoid drugs. Abnormal immune-inflammatory responses after therapy showed improvement and remain a focus of ongoing research in many laboratories. Longer term multi-center studies that followed with several anti-TNF biologicals have demonstrated the augmented efficacy, including inducing clinical remission, of low dose methotrexate and anti-TNF therapy co-therapy, but serious infections and lymphomas in a low frequency have been observed. In the course of the past decades, three ,blockbuster' anti-TNF biologicals are in the clinic. Over a million patients with RA and other immune-mediated diseases have been successfully treated, and a better perspective on the risk of harm and its management has become part of good clinical practice. This success has encouraged a burgeoning industry of biologicals for chronic diseases. [source] New Devices for Chronic Ventricular SupportJOURNAL OF CARDIAC SURGERY, Issue 3 2001F.A.C.S., F.C.C.P., Kenneth L. Franco M.D. Congestive heart failure affects 5 million people in the United States with 500,000 new cases diagnosed each year. Medical and surgical therapy have helped many patients but when these options fail, heart transplantation remains the only other treatment available to help improve their condition. Heart transplantation suffers from the lack of a sufficient number of suitable donor organs, the complications of chronic immunosuppression, and many patients die while on the waiting list. A number of pulsatile and nonpulsatile cardiac assist devices are being developed to provide chronic support for patients with heart failure and to be an alternative to heart transplantation. It is estimated that as many as 60,000 patients with heart failure could be helped by mechanical devices used for chronic support. For these devices to be effective they must provide sufficient cardiac output to allow patients to perform their daily activities, have a low risk of thromboemboli, be fully implantable thereby reducing the risk of infection, and have a low incidence of device malfunction requiring part or all of the device to be replaced. In this article, we will review several new devices which have been developed over the past 5 years or so and will be in human clinical trials in the United States soon, either as a bridge or as an alternative to heart transplantation. [source] Airway gene therapy and cystic fibrosisJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 3 2005DW Parsons Abstract:, Airway disease in cystic fibrosis (CF) is the major cause of death and is presently inadequately treatable, but genetic therapies offer the hope that such life-long disease will be curable, or at least satisfactorily treated. Normal pathogen defences that have evolved on airway surfaces also prevent the various gene vectors now available from producing effective gene transfer. Nevertheless, findings from basic research and human clinical trials are revealing how these barriers might be overcome or circumvented, with benefits to therapeutic efficacy and patient safety. Though progress is slower than expected or desired, the therapeutic rewards will be great when safe and effective gene therapy for CF airway disease becomes a clinical reality. [source] HIV-1 integrase inhibitors: 2005,2006 updateMEDICINAL RESEARCH REVIEWS, Issue 1 2008Raveendra Dayam Abstract HIV-1 integrase (IN) catalyzes the integration of proviral DNA into the host genome, an essential step for viral replication. Inhibition of IN catalytic activity provides an attractive strategy for antiretroviral drug design. Currently two IN inhibitors, MK-0518 and GS-9137, are in advanced stages of human clinical trials. The IN inhibitors in clinical evaluation demonstrate excellent antiretroviral efficacy alone or in combination regimens as compared to previously used clinical antiretroviral agents in naive and treatment-experienced HIV-1 infected patients. However, the emergence of viral strains resistant to clinically studied IN inhibitors and the dynamic nature of the HIV-1 genome demand a continued effort toward the discovery of novel inhibitors to keep a therapeutic advantage over the virus. Continued efforts in the field have resulted in the discovery of compounds from diverse chemical classes. In this review, we provide a comprehensive report of all IN inhibitors discovered in the years 2005 and 2006. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 1, 118,154, 2008 [source] Linaclotide , a secretagogue and antihyperalgesic agent , what next?NEUROGASTROENTEROLOGY & MOTILITY, Issue 3 2010A. E. Bharucha Abstract Ongoing clinical trials suggest that linaclotide, a first-in-class, 14-amino acid peptide guanylate cyclase-C (GC-C) receptor agonist and intestinal secretagogue is an effective treatment for chronic constipation. A study in this issue of the Journal suggests that linaclotide also has antihyperalgesic effects in three common rat models of inflammation- and stress-induced hypersensitivity (i.e., acute trinitrobenzene sulfonic acid colitis, water avoidance stress [WAS], and restraint-induced stress) but not in naïve animals. In mice, linaclotide at least partly reduces hyperalgesia via GC-C receptors. Dose,effect relationships of linaclotide were complicated and non-linear. This viewpoint discusses human clinical trials with linaclotide and the results of this study. Potential mechanisms and clinical significance of these findings are explored. Collectively, these data suggest that GC-C receptors exert other, as yet poorly understood, effects on gastrointestinal sensitivity in conditions associated with inflammation and/or stress-induced increased intestinal permeability. However, the data need to be confirmed in humans and in long-term animal models. Further studies are also necessary to elucidate the mechanisms as these effects cannot be explained by linaclotide's known effects on epithelial GC-C receptors. [source] Functional foods: An Australian perspectiveNUTRITION & DIETETICS, Issue 2008Linda TAPSELL Abstract There are many definitions of functional foods, although with a common element of providing some functional advantage to consumers, and they are almost universally associated with food innovation. In Australia, the National Centre of Excellence in Functional Foods (NCEFF) was established with five-year federal innovation funding to help build capability in functional food research and development. This review sets the context for the NCEFF science program, by first outlining global concepts of functional foods and the nature of the scientific enterprise associated with it. The review provides a working definition of functional foods, describes the types of research reported in Medline in the last year and compares this with the NCEFF program of research. The ,working space' for functional foods was found to relate to the nutritional and food sciences, regulatory conditions, consumer/market and health concerns and industry opportunity. The term is appearing increasingly in Medline, mostly under review articles, but also with respect to in vitro and animal model studies, human clinical trials and consumer research. The spectrum of research undertaken in the NCEFF science program was consistent with this pattern. The review found that Australian researchers and practitioners have the capacity to deliver on major fronts in the functional foods domain and to be part of the challenges for food and nutrition research that have been exposed through the functional food phenomenon. [source] Better Regulation of Industry-Sponsored Clinical Trials Is Long OverdueTHE JOURNAL OF LAW, MEDICINE & ETHICS, Issue 3 2009Matthew Wynia Regulating clinical trials for testing new drugs is fraught with risk. Misregulation can slow development of innovative and useful new drugs, but in other ways misregulation can foster trials that are inefficient and unethical, driven by commercial rather than scientific ends, and that can harm patients. In this paper, we argue not for more but for better regulation, based on the goal of rapidly producing innovative and safe products that represent significant advances in medical care. Data on industry-funded, late-stage clinical trials demonstrate an urgent need for dramatic changes in how these trials are designed, conducted, and analyzed. On the one hand, current patent rules can dissuade development of innovative new products with smaller markets and press trial designers to create positive results too rapidly. But at the same time, numerous studies show that when the pharmaceutical industry sponsors clinical trials, the results are systematically biased in favor of the sponsor's product, often to the detriment of patients and the public. The reasons for this bias are both complex and unavoidable, and the ways in which clinical trial design, conduct, and reporting can be inappropriately influenced are so varied and nuanced, that efforts to manage this conflict of interest and prevent harms are inevitably unsuccessful. Instead, we conclude such conflict should be avoided and a strong firewall should exist between drug developers and the final stages of clinical testing in humans. All financial support for phase III clinical trials should pass through a public-private partnership organization , perhaps tied to a broader clinical effectiveness research enterprise , which would be charged with designing, funding, and monitoring late-stage human clinical trials of new pharmaceutical products. [source] Combination Nonviral Interleukin-2 Gene Immunotherapy For Head and Neck Cancer: From Bench Top to BedsideTHE LARYNGOSCOPE, Issue 3 2005Bert W. O'Malley Jr MD Abstract Objective/Hypothesis: Intralesional delivery of cytokine genes has emerged as a promising therapeutic strategy for the treatment of cancer. In addition to the therapeutic effect of the delivered cytokine gene, the components of the gene delivery system also have been shown to induce beneficial immune responses. On the basis of these principles, we hypothesized that a molecular therapy could be developed that would provide synergistic antitumor activity by way of intralesional expression of interleukin (IL)-2 from a recombinant plasmid combined with induction of endogenous interferon (IFN)-, and IL-12 cytokines by immunostimulatory DNA. Our objective in these studies was to create and optimize a novel formulation of cationic lipid and DNA that generates local production of IL-2 protein within a targeted tumor environment with concomitant induction of the antitumor cytokines IFN-, and IL-12. Study Design: Prospective laboratory drug development plan that would produce human clinical trials. Materials and Methods: Engineered bacterial plasmids containing a cytomegalovirus promoter (CMV)-IL-2 expression cassette were specifically formulated with cationic lipids and optimized for antitumor effect in a floor of mouth murine tumor model. The treated tumors were assayed for local expression of IL-2 and concurrent expression of secondary cytokines IFN-, and IL-12. Established tumors in C3H/HeJ mice were treated with various IL-2 gene formulations, and clinical and immunologic responses were evaluated. Immunologic studies were performed and included cytolytic T-cell assays and cytokine expression profiles. For human clinical trials, a phase I 10 patient formulated IL-2 gene therapy study was completed. Subsequently, two large scale, phase II multi-institutional and multi-international studies were initiated comparing non-viral IL-2 gene therapy to palliative methotrexate chemotherapy or in combination with cisplatin. Results: In the preclinical stage, maximum tumor inhibition in animal models was obtained using IL-2 plasmid formulated with 1,2-dioleyloxypropyl-3-trimethyl ammonium chloride (DOTMA):cholesterol (1:1 mol:mol) at a plasmid:lipid charge ratio of 1:0.5 (,/+). Cationic lipid formulated IL-2 plasmid significantly inhibited tumor growth compared with formulated control plasmid (P < .01) or vehicle (lactose; P < .01). Consistent with previously reported studies of the immunostimulatory activity of DNA of bacterial origin, treatment of tumors with control plasmid in cationic lipid formulation induced production of endogenous IFN-, and IL-12 but not IL-2. Treatment of tumors with formulated IL-2 plasmid produced IL-2 protein levels that were 5-fold over background and increased IFN-, by 32-fold (P < .001) and IL-12 by 5.5-fold (P < .001) compared with control plasmid formulations. The phase I human trial demonstrated dose escalation safety, which was its primary objective, and there was one anecdotal reduction in tumor size. The phase II studies have been initiated and focus on either comparing the novel nonviral IL-2 gene immunotherapy formulation alone to methotrexate or comparing IL-2 gene therapy in combination with cisplatin in recurrent or unresectable patients with head and neck squamous cell carcinoma. Conclusions: The preclinical data provided proof of principle for matching a delivered IL-2 transgene with an immunostimulatory nonviral formulation to enhance intralesional production of therapeutic cytokines for the maximization of antitumor response. Human clinical trials have demonstrated this novel therapy to be safe in the human clinical setting. Phase II trials have been initiated to assess efficacy and feasibility as a single or combination therapy for head and neck cancer. [source] 4D11: The Second Mouse?AMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009A. D. Kirk The non-human primate experience with the human CD40-specific human monoclonal antibody 4D11 reported in this issue holds promise that this agent will be suitable for human clinical trials, provided that we remember the lessons learned from previous agents acting on this mechanism. See Article by Aoyagi et al on page 1732,1741. [source] West Nile virus neuroinvasive diseaseANNALS OF NEUROLOGY, Issue 3 2006Larry E. Davis MD Since 1999, there have been nearly 20,000 cases of confirmed symptomatic West Nile virus (WNV) infection in the United States, and it is likely that more than 1 million people have been infected by the virus. WNV is now the most common cause of epidemic viral encephalitis in the United States, and it will likely remain an important cause of neurological disease for the foreseeable future. Clinical syndromes produced by WNV infection include asymptomatic infection, West Nile Fever, and West Nile neuroinvasive disease (WNND). WNND includes syndromes of meningitis, encephalitis, and acute flaccid paralysis/poliomyelitis. The clinical, laboratory, and diagnostic features of these syndromes are reviewed here. Many patients with WNND have normal neuroimaging studies, but abnormalities may be present in areas including the basal ganglia, thalamus, cerebellum, and brainstem. Cerebrospinal fluid invariably shows a pleocytosis, with a predominance of neutrophils in up to half the patients. Diagnosis of WNND depends predominantly on demonstration of WNV-specific IgM antibodies in cerebrospinal fluid. Recent studies suggest that some WNV-infected patients have persistent WNV IgM serum and/or cerebrospinal fluid antibody responses, and this may require revision of current serodiagnostic criteria. Although there is no proven therapy for WNND, several vaccines and antiviral therapy with antibodies, antisense oligonucleotides, and interferon preparations are currently undergoing human clinical trials. Recovery from neurological sequelae of WNV infection including cognitive deficits and weakness may be prolonged and incomplete. Ann Neurol 2006;60:286,300 [source] Minocycline and doxycycline are not beneficial in a model of Huntington's diseaseANNALS OF NEUROLOGY, Issue 2 2003Donna L. Smith BSc Huntington's Disease (HD) is an inherited neurological disorder causing movement impairment, personality changes, dementia, and premature death, for which there is currently no effective therapy. The modified tetracycline antibiotic, minocycline, has been reported to ameliorate the disease phenotype in the R6/2 mouse model of HD. Because the tetracyclines have also been reported to inhibit aggregation in other amyloid disorders, we have investigated their ability to inhibit huntingtin aggregation and further explored their efficacy in preclinical mouse trials. We show that tetracyclines are potent inhibitors of huntingtin aggregation in a hippocampal slice culture model of HD at an effective concentration of 30,M. However, despite achieving tissue levels approaching this concentration by oral treatment of R6/2 mice with minocycline, we observed no clear difference in their behavioral abnormalities, or in aggregate load postmortem. In the light of these new data, we would advise that caution be exercised in proceeding into human clinical trials of minocycline. Ann Neurol 2003 [source] Human Clinical Fitting Study of the DexAide Right Ventricular Assist DeviceARTIFICIAL ORGANS, Issue 7 2009Yoshio Ootaki Abstract The DexAide right ventricular assist device (RVAD) has been developed as an implantable RVAD. The purpose of this study was to determine the final design and optimal anatomical placement of the DexAide RVAD when implanted simultaneously with either of two commercially available left ventricular assist devices (LVADs) in patients. A mock-up DexAide RVAD was used to assess configuration with each of two types of commercially available LVADs at the time of LVAD implantation in three human clinical cases. The pump body of the DexAide RVAD was placed either in the preperitoneal space or in the right thoracic cavity. The DexAide RVAD placed into the right thoracic cavity is suitable for use with the Novacor or HeartMate II LVADs. The results of this study will guide the finalization of the inflow cannula and optimal placement of the DexAide RVAD for human clinical trials. [source] Knowledge of Treatment Group Does Not Bias Assessment of Time to Seizure in an Animal Model of Cocaine PoisoningACADEMIC EMERGENCY MEDICINE, Issue 7 2010Kennon J. Heard MD ACADEMIC EMERGENCY MEDICINE 2010; 17:E75,E77 © 2010 by the Society for Academic Emergency Medicine Abstract Objectives:, Blinded outcome assessment decreases bias in human clinical trials. The necessity of blinded outcome assessment on animal studies is unknown. The authors determined the effect of knowledge of treatment group on assessment of time to seizure in an animal model of cocaine poisoning. Methods:, Four subjects observed 20 animal experiments where all animals were administered a high dose of cocaine and placebo. For each experiment, two of the observers were told the animal had been treated with placebo and two were told the animal had been treated with a medication expected to delay the onset of seizures. Each observer recorded the time from cocaine administration to onset of seizure. The median time to seizure was compared between observers told the animal received placebo and those told the animal received active treatment. Results:, Seizures were reported by all subjects in 12 animals and by no subjects in five animals, and there was disagreement in three animals. The reported median time to seizure was similar for observers told that the animals were treated with placebo and those told they were treated with study medication. Conclusions:, It is feasible to determine whether unblinded assessments are biased in an animal study. Knowledge of treatment group did not bias the assessment of time to seizure in this animal model. [source] 2211: The utility of a rabbit model of adenovirus ocular infectionACTA OPHTHALMOLOGICA, Issue 2010E ROMANOWSKI Acute adenovirus ocular infections are the most common ocular viral infections worldwide and are associated with community and medical facility epidemics. While not permanently blinding, ocular adenoviral infections are associated with significant patient morbidity, including symptomatic distress with visual disturbances which can last years, and loss of time from school or work. Currently, the treatment of these acute infections is symptomatic due to the lack of an approved antiviral. This symptomatic treatment presents a controversy of whether to treat these viral infections with immunomodulating agents (e.g. topical corticosteroids, NSAIDs, cyclosporine A), which are contraindicated for use in the treatment of the other major external ocular viral infection, HSV-1 epithelial keratitis. The adenovirus type 5 (Ad5)/New Zealand White (NZW) rabbit ocular model has provided data for potential clinical guidelines for the use of immunomodulating agents in the treatment of adenovirus ocular infections. Moreover, this model has been used extensively to evaluate promising candidate antivirals for adenovirus. Multiple candidate antivirals have been evaluated in vivo using this model, and several have proceeded to human clinical trials. The current presentation will discuss the potential clinical guidelines for the use of immunomodulating agents, present data on potential new topical antiviral agents, discuss the potential combination therapy of an antiviral and immunomodulatory agent in the treatment of adenovirus ocular infections as well as the limitations of the model. Commercial interest [source] Small-Molecule Inhibitors of the Hedgehog Signaling Pathway as Cancer TherapeuticsCHEMMEDCHEM, Issue 4 2010Stefan Peukert Dr. Abstract Inhibitors of the Hedgehog (Hh) molecular signaling pathway have emerged in recent years as a promising new class of potential therapeutics for cancer treatment. Numerous drug discovery efforts have resulted in the identification of a wide variety of small molecules that target different members of this pathway, including Smoothened (Smo), Sonic hedgehog protein (Shh), and Gli1. Several Smo inhibitors have now entered human clinical trials, and successful proof-of-concept studies have been carried out in patients with defined genetic mutations in the Hh pathway. This review provides a general overview of three main topics in this rapidly expanding area: 1),the various types of biological assays and in,vivo models that have been employed for the identification and optimization of Hh pathway inhibitors; 2),Smo inhibitors reported to date, including recent clinical results where available; and 3),efforts toward the identification and characterization of inhibitors of other members of the Hh pathway. [source] | |||||||||||||