Relational memory and self-efficacy measures reveal distinct profiles of subjective memory concerns in older adults.

PubMed

Lucas, Heather D; Monti, Jim M; McAuley, Edward; Watson, Patrick D; Kramer, Arthur F; Cohen, Neal J

2016-07-01

Subjective memory concerns (SMCs) in healthy older adults are associated with future decline and can indicate preclinical dementia. However, SMCs may be multiply determined, and often correlate with affective or psychosocial variables rather than with performance on memory tests. Our objective was to identify sensitive and selective methods to disentangle the underlying causes of SMCs. Because preclinical dementia pathology targets the hippocampus, we hypothesized that performance on hippocampally dependent relational memory tests would correlate with SMCs. We thus administered a series of memory tasks with varying dependence on relational memory processing to 91 older adults, along with questionnaires assessing depression, anxiety, and memory self-efficacy. We used correlational, regression, and mediation analyses to compare the variance in SMCs accounted for by these measures. Performance on the task most dependent on relational memory processing showed a stronger negative association with SMCs than did other memory performance metrics. SMCs were also negatively associated with memory self-efficacy. These 2 measures, along with age and education, accounted for 40% of the variance in SMCs. Self-efficacy and relational memory were uncorrelated and independent predictors of SMCs. Moreover, self-efficacy statistically mediated the relationship between SMCs and depression and anxiety, which can be detrimental to cognitive aging. These data identify multiple mechanisms that can contribute to SMCs, and suggest that SMCs can both cause and be caused by age-related cognitive decline. Relational memory measures may be effective assays of objective memory difficulties, while assessing self-efficacy could identify detrimental affective responses to cognitive aging. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Tissue Engineering of the Urethra: A Systematic Review and Meta-analysis of Preclinical and Clinical Studies.

PubMed

Versteegden, Luuk R M; de Jonge, Paul K J D; IntHout, Joanna; van Kuppevelt, Toin H; Oosterwijk, Egbert; Feitz, Wout F J; de Vries, Rob B M; Daamen, Willeke F

2017-10-01

Urethra repair by tissue engineering has been extensively studied in laboratory animals and patients, but is not routinely used in clinical practice. To systematically investigate preclinical and clinical evidence of the efficacy of tissue engineering for urethra repair in order to stimulate translation of preclinical studies to the clinic. A systematic search strategy was applied in PubMed and EMBASE. Studies were independently screened for relevance by two reviewers, resulting in 80 preclinical and 23 clinical studies of which 63 and 13 were selected for meta-analysis to assess side effects, functionality, and study completion. Analyses for preclinical and clinical studies were performed separately. Full circumferential and inlay procedures were assessed independently. Evaluated parameters included seeding of cells and type of biomaterial. Meta-analysis revealed that cell seeding significantly reduced the probability of encountering side effects in preclinical studies. Remarkably though, cells were only sparsely used in the clinic (4/23 studies) and showed no significant reduction of side effects. ln 21 out of 23 clinical studies, decellularized templates were used, while in preclinical studies other biomaterials showed promising outcomes as well. No direct comparison to current clinical practice could be made due to the limited number of randomized controlled studies. Due to a lack of controlled (pre)clinical studies, the efficacy of tissue engineering for urethra repair could not be determined. Meta-analysis outcome measures were similar to current treatment options described in literature. Surprisingly, it appeared that favorable preclinical results, that is inclusion of cells, were not translated to the clinic. Improved (pre)clinical study designs may enhance clinical translation. We reviewed all available literature on urethral tissue engineering to assess the efficacy in preclinical and clinical studies. We show that improvements to (pre)clinical study design is required to improve clinical translation of tissue engineering technologies. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma.

PubMed

Matthews, G M; Lefebure, M; Doyle, M A; Shortt, J; Ellul, J; Chesi, M; Banks, K M; Vidacs, E; Faulkner, D; Atadja, P; Bergsagel, P L; Johnstone, R W

2013-09-12

Multiple myeloma (MM) is an incurable malignancy with an unmet need for innovative treatment options. Histone deacetylase inhibitors (HDACi) are a new class of anticancer agent that have demonstrated activity in hematological malignancies. Here, we investigated the efficacy and safety of HDACi (vorinostat, panobinostat, romidepsin) and novel combination therapies using in vitro human MM cell lines and in vivo preclinical screening utilizing syngeneic transplanted Vk*MYC MM. HDACi were combined with ABT-737, which targets the intrinsic apoptosis pathway, recombinant human tumour necrosis factor-related apoptosis-inducing ligand (rhTRAIL/MD5-1), that activates the extrinsic apoptosis pathway or the DNA methyl transferase inhibitor 5-azacytidine. We demonstrate that in vitro cell line-based studies provide some insight into drug activity and combination therapies that synergistically kill MM cells; however, they do not always predict in vivo preclinical efficacy or toxicity. Importantly, utilizing transplanted Vk*MYC MM, we report that panobinostat and 5-azacytidine synergize to prolong the survival of tumor-bearing mice. In contrast, combined HDACi/rhTRAIL-based strategies, while efficacious, demonstrated on-target dose-limiting toxicities that precluded prolonged treatment. Taken together, our studies provide evidence that the transplanted Vk*MYC model of MM is a useful screening tool for anti-MM drugs and should aid in the prioritization of novel drug testing in the clinic.

Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma

PubMed Central

Matthews, G M; Lefebure, M; Doyle, M A; Shortt, J; Ellul, J; Chesi, M; Banks, K-M; Vidacs, E; Faulkner, D; Atadja, P; Bergsagel, P L; Johnstone, R W

2013-01-01

Multiple myeloma (MM) is an incurable malignancy with an unmet need for innovative treatment options. Histone deacetylase inhibitors (HDACi) are a new class of anticancer agent that have demonstrated activity in hematological malignancies. Here, we investigated the efficacy and safety of HDACi (vorinostat, panobinostat, romidepsin) and novel combination therapies using in vitro human MM cell lines and in vivo preclinical screening utilizing syngeneic transplanted Vk*MYC MM. HDACi were combined with ABT-737, which targets the intrinsic apoptosis pathway, recombinant human tumour necrosis factor-related apoptosis-inducing ligand (rhTRAIL/MD5-1), that activates the extrinsic apoptosis pathway or the DNA methyl transferase inhibitor 5-azacytidine. We demonstrate that in vitro cell line-based studies provide some insight into drug activity and combination therapies that synergistically kill MM cells; however, they do not always predict in vivo preclinical efficacy or toxicity. Importantly, utilizing transplanted Vk*MYC MM, we report that panobinostat and 5-azacytidine synergize to prolong the survival of tumor-bearing mice. In contrast, combined HDACi/rhTRAIL-based strategies, while efficacious, demonstrated on-target dose-limiting toxicities that precluded prolonged treatment. Taken together, our studies provide evidence that the transplanted Vk*MYC model of MM is a useful screening tool for anti-MM drugs and should aid in the prioritization of novel drug testing in the clinic. PMID:24030150

Animal models of contraception: utility and limitations

PubMed Central

Liechty, Emma R; Bergin, Ingrid L; Bell, Jason D

2015-01-01

Appropriate animal modeling is vital for the successful development of novel contraceptive devices. Advances in reproductive biology have identified novel pathways for contraceptive intervention. Here we review species-specific anatomic and physiologic considerations impacting preclinical contraceptive testing, including efficacy testing, mechanistic studies, device design, and modeling off-target effects. Emphasis is placed on the use of nonhuman primate models in contraceptive device development. PMID:29386922

Animal models for microbicide studies.

PubMed

Veazey, Ronald S; Shattock, Robin J; Klasse, Per Johan; Moore, John P

2012-01-01

There have been encouraging recent successes in the development of safe and effective topical microbicides to prevent vaginal or rectal HIV-1 transmission, based on the use of anti-retroviral drugs. However, much work remains to be accomplished before a microbicide becomes a standard element of prevention science strategies. Animal models should continue to play an important role in pre-clinical testing, with emphasis on safety, pharmacokinetic and efficacy testing.

Cancer chemoprevention research with selenium in the post-SELECT era: Promises and challenges

PubMed Central

Lü, Junxuan; Zhang, Jinhui; Jiang, Cheng; Deng, Yibin; Özten, Nur; Bosland, Maarten C.

2016-01-01

The negative efficacy outcomes of double-blinded, randomized, placebo-controlled Phase III human clinical trials with selenomethionine (SeMet) and SeMet-rich selenized-yeast (Se-yeast) for prostate cancer prevention and Se-yeast for prevention of non-small cell lung cancer (NSCLC) in North America lead to rejection of SeMet/Se-yeast for cancer prevention in Se-adequate populations. We identify two major lessons from the outcomes of these trials: 1) The antioxidant hypothesis was tested in wrong subjects or patient populations. 2) The selection of Se agents was not supported by cell culture and preclinical animal efficacy data as is common in drug development. We propose that next-generation forms of Se (next-gen Se), such as methylselenol precursors, offer biologically appropriate approaches for cancer chemoprevention but these are faced with formidable challenges. Solid mechanism-based preclinical efficacy assessments and comprehensive safety studies with next-gen Se will be essential to re-vitalize the idea of cancer chemoprevention with Se in the post-SELECT era. We advocate smaller mechanism-driven Phase I/II trials with these next-gen Se to guide and justify future decisions for definitive Phase III chemoprevention efficacy trials. PMID:26595411

Cancer chemoprevention research with selenium in the post-SELECT era: Promises and challenges.

PubMed

Lü, Junxuan; Zhang, Jinhui; Jiang, Cheng; Deng, Yibin; Özten, Nur; Bosland, Maarten C

2016-01-01

The negative efficacy outcomes of double-blinded, randomized, placebo-controlled Phase III human clinical trials with selenomethionine (SeMet) and SeMet-rich selenized-yeast (Se-yeast) for prostate cancer prevention and Se-yeast for prevention of nonsmall cell lung cancer (NSCLC) in North America lead to rejection of SeMet/Se-yeast for cancer prevention in Se-adequate populations. We identify 2 major lessons from the outcomes of these trials: 1) the antioxidant hypothesis was tested in wrong subjects or patient populations, and 2) the selection of Se agents was not supported by cell culture and preclinical animal efficacy data as is common in drug development. We propose that next-generation forms of Se (next-gen Se), such as methylselenol precursors, offer biologically appropriate approaches for cancer chemoprevention but these are faced with formidable challenges. Solid mechanism-based preclinical efficacy assessments and comprehensive safety studies with next-gen Se will be essential to revitalize the idea of cancer chemoprevention with Se in the post-SELECT era. We advocate smaller mechanism-driven Phase I/II trials with these next-gen Se to guide and justify future decisions for definitive Phase III chemoprevention efficacy trials.

Preclinical to Clinical Translation of Studies of Transcranial Direct-Current Stimulation in the Treatment of Epilepsy: A Systematic Review

PubMed Central

Regner, Gabriela G.; Pereira, Patrícia; Leffa, Douglas T.; de Oliveira, Carla; Vercelino, Rafael; Fregni, Felipe; Torres, Iraci L. S.

2018-01-01

Epilepsy is a chronic brain syndrome characterized by recurrent seizures resulting from excessive neuronal discharges. Despite the development of various new antiepileptic drugs, many patients are refractory to treatment and report side effects. Non-invasive methods of brain stimulation, such as transcranial direct current stimulation (tDCS), have been tested as alternative approaches to directly modulate the excitability of epileptogenic neural circuits. Although some pilot and initial clinical studies have shown positive results, there is still uncertainty regarding the next steps of investigation in this field. Therefore, we reviewed preclinical and clinical studies using the following framework: (1) preclinical studies that have been successfully translated to clinical studies, (2) preclinical studies that have failed to be translated to clinical studies, and (3) clinical findings that were not previously tested in preclinical studies. We searched PubMed, Web of Science, Embase, and SciELO (2002–2017) using the keywords “tDCS,” “epilepsy,” “clinical trials,” and “animal models.” Our initial search resulted in 64 articles. After applying inclusion and exclusion criteria, we screened 17 full-text articles to extract findings about the efficacy of tDCS, with respect to the therapeutic framework used and the resulting reduction in seizures and epileptiform patterns. We found that few preclinical findings have been translated into clinical research (number of sessions and effects on seizure frequency) and that most findings have not been tested clinically (effects of tDCS on status epilepticus and absence epilepsy, neuroprotective effects in the hippocampus, and combined use with specific medications). Finally, considering that clinical studies on tDCS have been conducted for several epileptic syndromes, most were not previously tested in preclinical studies (Rasmussen's encephalitis, drug resistant epilepsy, and hippocampal sclerosis-induced epilepsy). Overall, most studies report positive findings. However, it is important to underscore that a successful preclinical study may not indicate success in a clinical study, considering the differences highlighted herein. Although most studies report significant findings, there are still important insights from preclinical work that must be tested clinically. Understanding these factors may improve the evidence for the potential use of this technique as a clinical tool in the treatment of epilepsy. PMID:29623027

The development of neural stimulators: a review of preclinical safety and efficacy studies.

PubMed

Shepherd, Robert K; Villalobos, Joel; Burns, Owen; Nayagam, David

2018-05-14

Given the rapid expansion of the field of neural stimulation and the rigorous regulatory approval requirements required before these devices can be applied clinically, it is important that there is clarity around conducting preclinical safety and efficacy studies required for the development of this technology. The present review examines basic design principles associated with the development of a safe neural stimulator and describes the suite of preclinical safety studies that need to be considered when taking a device to clinical trial. Neural stimulators are active implantable devices that provide therapeutic intervention, sensory feedback or improved motor control via electrical stimulation of neural or neuro-muscular tissue in response to trauma or disease. Because of their complexity, regulatory bodies classify these devices in the highest risk category (Class III), and they are therefore required to go through a rigorous regulatory approval process before progressing to market. The successful development of these devices is achieved through close collaboration across disciplines including engineers, scientists and a surgical/clinical team, and the adherence to clear design principles. Preclinical studies form one of several key components in the development pathway from concept to product release of neural stimulators. Importantly, these studies provide iterative feedback in order to optimise the final design of the device. Key components of any preclinical evaluation include: in vitro studies that are focussed on device reliability and include accelerated testing under highly controlled environments; in vivo studies using animal models of the disease or injury in order to assess safety and, given an appropriate animal model, the efficacy of the technology under both passive and electrically active conditions; and human cadaver and ex vivo studies designed to ensure the device's form factor conforms to human anatomy, to optimise the surgical approach and to develop any specialist surgical tooling required. The pipeline from concept to commercialisation of these devices is long and expensive; careful attention to both device design and its preclinical evaluation will have significant impact on the duration and cost associated with taking a device through to commercialisation. Carefully controlled in vitro and in vivo studies together with ex vivo and human cadaver trials are key components of a thorough preclinical evaluation of any new neural stimulator. © 2018 IOP Publishing Ltd.

A randomized controlled trial of high-fidelity simulation versus lecture-based education in preclinical medical students.

PubMed

Alluri, Ram Kiran; Tsing, Pamela; Lee, Edward; Napolitano, Jason

2016-01-01

The purpose of this study was to compare the efficacy of simulation versus lecture-based education among preclinical medical students. Twenty medical students participated in this randomized, controlled crossover study. Students were randomized to four groups. Each group received two simulations and two lectures covering four different topics. Students were administered a pre-test, post-test and delayed post-test. The mean percentage of questions answered correctly on each test was calculated. The mean of each student's change in score across the three tests was used to compare simulation- versus lecture-based education. Students in both the simulation and lecture groups demonstrated improvement between the pre-test and post-test (p < 0.05). Students in the simulation group demonstrated improvement between the immediate post-test and delayed post-test (p < 0.05), while students in the lecture group did not demonstrate improvement (p > 0.05). When comparing interventions, the change in score between the pre-test and post-test was similar among both the groups (p > 0.05). The change in score between the post-test and delayed post-test was greater in the simulation group (p < 0.05). High-fidelity simulation may serve as a viable didactic platform for preclinical medical education. Our study demonstrated equivalent immediate knowledge gain and superior long-term knowledge retention in comparison to lectures.

Enzastaurin: A lesson in drug development.

PubMed

Bourhill, T; Narendran, A; Johnston, R N

2017-04-01

Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. It was initially developed as an isozyme specific inhibitor of protein kinase Cβ (PKCβ), which is involved in both the AKT and MAPK signalling pathways that are active in many cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. In this review, we will discuss the development of enzastaurin from drug design to clinical testing, exploring target identification, validation and preclinical assessment. Finally, we will consider the clinical evaluation of enzastaurin as an example of the challenges associated with drug development. In particular, we discuss the poor translation of drug efficacy from preclinical animal models, inappropriate end point analysis, limited standards in phase I clinical trials, insufficient use of biomarker analysis and also patient stratification, all of which contributed to the failure to achieve approval of enzastaurin as an anticancer therapeutic. Copyright © 2017 Elsevier B.V. All rights reserved.

Preclinical evaluations of norcantharidin-loaded intravenous lipid microspheres with low toxicity.

PubMed

Lin, Xia; Zhang, Bo; Zhang, Keru; Zhang, Yu; Wang, Juan; Qi, Na; Yang, Shenshen; He, Haibing; Tang, Xing

2012-12-01

The aim of this study was to perform a systematic preclinical evaluation of norcantharidin (NCTD)-loaded intravenous lipid microspheres (NLM). Pharmacokinetics, biodistribution, antitumor efficacy and drug safety assessment (including acute toxicity, subchronic toxicity, hemolysis testing, intravenous stimulation and injection anaphylaxis) of NLM were carried out in comparison with the commercial product disodium norcantharidate injection (NI). The pharmacokinetics of NLM in rats was similar to that of NI, and a non-linear correlation was observed between AUC and dose. A comparable antitumor efficacy of NLM and NI was observed in mice inoculated with A549, BEL7402 and BCAP-37 cell lines. It was worth noting that the NLM produced a lower drug concentration in heart compared with NI, and significantly reduced the cardiac and renal toxicity. The LD(50) of NLM was twice higher than that of NI. In NLM, over 80% of NCTD was loaded in the lipid phase or bound with phospholipids. Thus, NCTD was sequestered by direct contacting with body fluids and largely avoided distribution into tissues, consequently leading to significantly reduced cardiac and renal toxicity. These preclinical results suggested that NLM could be a useful potential carrier for parenteral administration of NCTD, while providing a superior safety profile.

Animal models for microbicide studies

PubMed Central

Veazey, Ronald S.; Shattock, Robin J; Klasse, Per Johan; Moore, John P.

2013-01-01

There have been encouraging recent successes in the development of safe and effective topical microbicides to prevent vaginal or rectal HIV-1 transmission, based on the use of anti-retroviral drugs. However, much work remains to be accomplished before a microbicide becomes a standard element of prevention science strategies. Animal models should continue to play an important role in pre-clinical testing, with emphasis on safety, pharmacokinetic and efficacy testing. PMID:22264049

T-cell receptor gene therapy: critical parameters for clinical success.

PubMed

Linnemann, Carsten; Schumacher, Ton N M; Bendle, Gavin M

2011-09-01

T-cell receptor (TCR) gene therapy aims to induce immune reactivity against tumors by introducing genes encoding a tumor-reactive TCR into patient T cells. This approach has been extensively tested in preclinical mouse models, and initial clinical trials have demonstrated the feasibility and potential of TCR gene therapy as a cancer treatment. However, data obtained from preclinical and clinical studies suggest that both the therapeutic efficacy and the safety of TCR gene therapy can be and needs to be further enhanced. This review highlights those strategies that can be followed to develop TCR gene therapy into a clinically relevant treatment option for cancer patients.

Animal Testing

NASA Astrophysics Data System (ADS)

Moretto, Johnny; Chauffert, Bruno; Bouyer, Florence

The development of a new anticancer drug is a long, complex and multistep process which is supervised by regulatory authorities from the different countries all around the world [1]. Application of a new drug for admission to the market is supported by preclinical and clinical data, both including the determination of pharmacodynamics, toxicity, antitumour activity, therapeutic index, etc. As preclinical studies are associated with high cost, optimization of animal experiments is crucial for the overall development of a new anticancer agent. Moreover, in vivo efficacy studies remain a determinant panel for advancement of agents to human trials and thus, require cautious design and interpretation from experimental and ethical point of views.

Animal Models in Genomic Research: Techniques, Applications, and Roles for Nurses

PubMed Central

Osier, Nicole D.; Pham, Lan; Savarese, Amanda; Sayles, Kendra

2016-01-01

Animal research has been conducted by scientists for over two millennia resulting in a better understanding of human anatomy, physiology, and pathology, as well as testing of novel therapies. In the molecular genomic era, pre-clinical models represent a key tool for understanding the genomic underpinnings of health and disease and are relevant to precision medicine initiatives. Nurses contribute to improved health by collecting and translating evidence from clinically relevant pre-clinical models. Using animal models, nurses can ask questions that would not be feasible or ethical to address in humans, and establish the safety and efficacy of interventions before translating them to clinical trials. Two advantages of using pre-clinical models are reduced variability between test subjects and the opportunity for precisely controlled experimental exposures. Standardized care controls the effects of diet and environment, while the availability of inbred strains significantly reduces the confounding effects of genetic differences. Outside the laboratory, nurses can contribute to the approval and oversight of animal studies, as well as translation to clinical trials and, ultimately, patient care. This review is intended as a primer on the use of animal models to advance nursing science; specifically, the paper discusses the utility of preclinical models for studying the pathophysiologic and genomic contributors to health and disease, testing interventions, and evaluating effects of environmental exposures. Considerations specifically geared to nurse researchers are also introduced, including discussion of how to choose an appropriate model and controls, potential confounders, as well as legal and ethical concerns. Finally, roles for nurse clinicians in pre-clinical research are also highlighted. PMID:27969037

Animal models in genomic research: Techniques, applications, and roles for nurses.

PubMed

Osier, Nicole D; Pham, Lan; Savarese, Amanda; Sayles, Kendra; Alexander, Sheila A

2016-11-01

Animal research has been conducted by scientists for over two millennia resulting in a better understanding of human anatomy, physiology, and pathology, as well as testing of novel therapies. In the molecular genomic era, pre-clinical models represent a key tool for understanding the genomic underpinnings of health and disease and are relevant to precision medicine initiatives. Nurses contribute to improved health by collecting and translating evidence from clinically relevant pre-clinical models. Using animal models, nurses can ask questions that would not be feasible or ethical to address in humans, and establish the safety and efficacy of interventions before translating them to clinical trials. Two advantages of using pre-clinical models are reduced variability between test subjects and the opportunity for precisely controlled experimental exposures. Standardized care controls the effects of diet and environment, while the availability of inbred strains significantly reduces the confounding effects of genetic differences. Outside the laboratory, nurses can contribute to the approval and oversight of animal studies, as well as translation to clinical trials and, ultimately, patient care. This review is intended as a primer on the use of animal models to advance nursing science; specifically, the paper discusses the utility of preclinical models for studying the pathophysiologic and genomic contributors to health and disease, testing interventions, and evaluating effects of environmental exposures. Considerations specifically geared to nurse researchers are also introduced, including discussion of how to choose an appropriate model and controls, potential confounders, as well as legal and ethical concerns. Finally, roles for nurse clinicians in pre-clinical research are also highlighted. Copyright © 2016 Elsevier Inc. All rights reserved.

Targeting Signaling to YAP for the Therapy of NF2

DTIC Science & Technology

2016-12-01

at any step of our newly identified pathway, and to test the preclinical efficacy of lead compounds in xenograft models of NF2. During this grant...Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness. The Journal of Biological Chemistry. 2015. 290(32):19387-401.

In search of antiepileptogenic treatments for post-traumatic epilepsy.

PubMed

Saletti, Patricia G; Ali, Idrish; Casillas-Espinosa, Pablo M; Semple, Bridgette D; Lisgaras, Christos; Moshé, Solomon L; Galanopoulou, Aristea S

2018-06-21

Post-traumatic epilepsy (PTE) occurs in 20% of individuals with acquired epilepsy, and can impact significantly the quality of life due to the seizures and other functional or cognitive and behavioral outcomes of the traumatic brain injury (TBI) and PTE. There is no available antiepileptogenic or disease modifying treatment for PTE. Animal models of TBI and PTE have been developed, offering useful insights on the value of inflammatory, neurodegenerative pathways, hemorrhages and iron accumulation, calcium channels and other target pathways that could be used for treatment development. Most of the existing preclinical studies test efficacy towards pathologies of functional recovery after TBI, while a few studies are emerging testing the effects towards induced or spontaneous seizures. Here we review the existing preclinical trials testing new candidate treatments for TBI sequelae and PTE, and discuss future directions for efforts aiming at developing antiepileptogenic and disease-modifying treatments. Copyright © 2018. Published by Elsevier Inc.

Characterization of recent and minimally passaged Brazilian dengue viruses inducing robust infection in rhesus macaques.

PubMed

Borges, Maria Beatriz; Marchevsky, Renato Sergio; Mendes, Ygara S; Mendes, Luiz Gustavo; Duarte, Ana Claudia; Cruz, Michael; de Filippis, Ana Maria Bispo; Vasconcelos, Pedro Fernando C; Freire, Marcos; Homma, Akira; Mossman, Sally; Lepine, Edith; Vanloubbeeck, Yannick; Lorin, Clarisse; Malice, Marie-Pierre; Caride, Elena; Warter, Lucile

2018-01-01

The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model's predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-γ and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans.

Characterization of recent and minimally passaged Brazilian dengue viruses inducing robust infection in rhesus macaques

PubMed Central

Borges, Maria Beatriz; Marchevsky, Renato Sergio; Mendes, Ygara S.; Mendes, Luiz Gustavo; Duarte, Ana Claudia; Cruz, Michael; de Filippis, Ana Maria Bispo; Vasconcelos, Pedro Fernando C.; Freire, Marcos; Homma, Akira; Mossman, Sally; Lepine, Edith; Vanloubbeeck, Yannick; Lorin, Clarisse; Malice, Marie-Pierre; Caride, Elena

2018-01-01

The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model’s predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-γ and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans. PMID:29694440

Peer-Assisted Learning: Filling the Gaps in Basic Science Education for Preclinical Medical Students

ERIC Educational Resources Information Center

Sammaraiee, Yezen; Mistry, Ravi D.; Lim, Julian; Wittner, Liora; Deepak, Shantal; Lim, Gareth

2016-01-01

In contrast to peer-assisted learning (PAL) in clinical training, there is scant literature on the efficacy of PAL during basic medical sciences teaching for preclinical students. A group of senior medical students aimed to design and deliver clinically oriented small-group tutorials after every module in the preclinical curriculum at a United…

Pica in Rats as a Preclinical Model of Emesis.

PubMed

Davis, T Gregg

2016-10-03

The ability to assess the potential for gastrointestinal adverse events in a preclinical setting is a challenge in the development of new drugs, as the vast majority of in vivo research is conducted in rodent species lacking a vomiting reflex. The use of higher species capable of emesis is often limited by cost, technical experience, and relevant efficacy models to define a therapeutic index. Additionally, investigators should be mindful of ethical considerations when using more sentient species when an alternative in lower species is available. This unit describes the use of pica behavior in rodents as an alternative for evaluating emetic potential in vivo. After an acclimation period, the incidence of rats engaging in pica following the administration of a test article can be used to generate a dose-response curve of the pica behavior. When linked with an appropriate efficacy model, this allows compounds to be ranked based on therapeutic index. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

Targeting Signaling to YAP for the Therapy of NF2

DTIC Science & Technology

2016-12-01

any step of our newly identified pathway, and to test the preclinical efficacy of lead compounds in xenograft models of NF2. During this grant, we have...Phosphorylation of the Hippo Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness. The Journal of Biological Chemistry. 2015. 290(32):19387-401.

Minnelide reduces tumor burden in preclinical models of osteosarcoma.

PubMed

Banerjee, Sulagna; Thayanithy, Venugopal; Sangwan, Veena; Mackenzie, Tiffany N; Saluja, Ashok K; Subramanian, Subbaya

2013-07-28

Osteosarcoma is the most common bone cancer in children and adolescents with a 5-year survival rate of about 70%. In this study, we have evaluated the preclinical therapeutic efficacy of the novel synthetic drug, Minnelide, a prodrug of triptolide on osteosarcoma. Triptolide was effective in significantly inducing apoptosis in all osteosarcoma cell lines tested but had no significant effect on the human osteoblast cells. Notably, Minnelide treatment significantly reduced tumor burden and lung metastasis in the orthotopic and lung colonization models. Triptolide/Minnelide effectively downregulated the levels of pro-survival proteins such as heat shock proteins, cMYC, survivin and targets the NF-κB pathway. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Efficacy of curcumin for age-associated cognitive decline: a narrative review of preclinical and clinical studies.

PubMed

Sarker, Marjana Rahman; Franks, Susan F

2018-04-21

Processes such as aberrant redox signaling and chronic low-grade systemic inflammation have been reported to modulate age-associated pathologies such as cognitive impairment. Curcumin, the primary therapeutic component of the Indian spice, Turmeric (Curcuma longa), has long been known for its strong anti-inflammatory and antioxidant activity attributable to its unique molecular structure. Recently, an interest in this polyphenol as a cognitive therapeutic for the elderly has emerged. The purpose of this paper is to critically review preclinical and clinical studies that have evaluated the efficacy of curcumin in ameliorating and preventing age-associated cognitive decline and address the translational progress of preclinical to clinical efficacy. PubMed, semantic scholar, and Google scholar searches were used for preclinical studies; and clinicaltrials.gov , the Australian and New Zealand clinical trials registry, and PubMed search were used to select relevant completed clinical studies. Results from preclinical studies consistently demonstrate curcumin and its analogues to be efficacious for various aspects of cognitive impairment and processes that contribute to age-associated cognitive impairment. Results of published clinical studies, while mixed, continue to show promise for curcumin's use as a therapeutic for cognitive decline but overall remain inconclusive at this time. Both in vitro and in vivo studies have found that curcumin can significantly decrease oxidative stress, systemic inflammation, and obstruct pathways that activate transcription factors that augment these processes. Future clinical studies would benefit from including evaluation of peripheral and cerebrospinal fluid biomarkers of dementia and behavioral markers of cognitive decline, as well as targeting the appropriate population.

Ibandronate treatment for osteoporosis: rationale, preclinical, and clinical development of extended dosing regimens.

PubMed

Epstein, Solomon

2006-03-01

Ibandronate is a potent nitrogen-containing bisphosphonate available as a once-monthly oral formulation for the treatment and prevention of osteoporosis. Preclinical experiments with estrogen-depleted rats, dogs, and monkeys demonstrated the efficacy of daily and intermittent ibandronate dosing. Initial clinical trials explored the optimal dosing regimens for oral administration in humans. The Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE) and Monthly Oral Ibandronate in Ladies (MOBILE) trials demonstrated that long-term daily and intermittent administration of ibandronate was efficacious for increasing bone mineral density, reducing markers of bone turnover, and preventing fractures, while maintaining bone quality. These preclinical and clinical ibandronate trials provided progressive evidence that a simple, long interval dosing regimen could offer efficacy and safety comparable with currently available bisphosphonates. It is anticipated that once-monthly ibandronate may have a positive impact on patient adherence, and ultimately, on fracture protection in osteoporotic women.

A preclinical physiological assay to test modulation of knee joint pain in the spinal cord: effects of oxycodone and naproxen.

PubMed

Miranda, Jason A; Stanley, Phil; Gore, Katrina; Turner, Jamie; Dias, Rebecca; Rees, Huw

2014-01-01

Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain.

A Preclinical Physiological Assay to Test Modulation of Knee Joint Pain in the Spinal Cord: Effects of Oxycodone and Naproxen

PubMed Central

Miranda, Jason A.; Stanley, Phil; Gore, Katrina; Turner, Jamie; Dias, Rebecca; Rees, Huw

2014-01-01

Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain. PMID:25157947

Bioengineered Temporomandibular Joint Disk Implants: Study Protocol for a Two-Phase Exploratory Randomized Preclinical Pilot Trial in 18 Black Merino Sheep (TEMPOJIMS)

PubMed Central

Monje, Florencio Gil; González-García, Raúl; Little, Christopher B; Mónico, Lisete; Pinho, Mário; Santos, Fábio Abade; Carrapiço, Belmira; Gonçalves, Sandra Cavaco; Morouço, Pedro; Alves, Nuno; Moura, Carla; Wang, Yadong; Jeffries, Eric; Gao, Jin; Sousa, Rita; Neto, Lia Lucas; Caldeira, Daniel; Salvado, Francisco

2017-01-01

Background Preclinical trials are essential to test efficacious options to substitute the temporomandibular joint (TMJ) disk. The contemporary absence of an ideal treatment for patients with severe TMJ disorders can be related to difficulties concerning the appropriate study design to conduct preclinical trials in the TMJ field. These difficulties can be associated with the use of heterogeneous animal models, the use of the contralateral TMJ as control, the absence of rigorous randomized controlled preclinical trials with blinded outcomes assessors, and difficulties involving multidisciplinary teams. Objective This study aims to develop a new, reproducible, and effective study design for preclinical research in the TMJ domain, obtaining rigorous data related to (1) identify the impact of bilateral discectomy in black Merino sheep, (2) identify the impact of bilateral discopexy in black Merino sheep, and (3) identify the impact of three different bioengineering TMJ discs in black Merino sheep. Methods A two-phase exploratory randomized controlled preclinical trial with blinded outcomes is proposed. In the first phase, nine sheep are randomized into three different surgical bilateral procedures: bilateral discectomy, bilateral discopexy, and sham surgery. In the second phase, nine sheep are randomized to bilaterally test three different TMJ bioengineering disk implants. The primary outcome is the histological gradation of TMJ. Secondary outcomes are imaging changes, absolute masticatory time, ruminant time per cycle, ruminant kinetics, ruminant area, and sheep weight. Results Previous preclinical studies in this field have used the contralateral unoperated side as a control, different animal models ranging from mice to a canine model, with nonrandomized, nonblinded and uncontrolled study designs and limited outcomes measures. The main goal of this exploratory preclinical protocol is to set a new standard for future preclinical trials in oromaxillofacial surgery, particularly in the TMJ field, by proposing a rigorous design in black Merino sheep. The authors also intend to test the feasibility of pilot outcomes. The authors expect to increase the quality of further studies in this field and to progress in future treatment options for patients undergoing surgery for TMJ disk replacement. Conclusions The study has commenced, but it is too early to provide results or conclusions. PMID:28254733

Regulatory considerations on new adjuvants and delivery systems.

PubMed

Sesardic, D

2006-04-12

New and improved vaccines and delivery systems are increasingly being developed for prevention, treatment and diagnosis of human diseases. Prior to their use in humans, all new biological products must undergo pre-clinical evaluation. These pre-clinical studies are important not only to establish the biological properties of the material and to evaluate its possible risk to the public, but also to plan protocols for subsequent clinical trials from which safety and efficacy can be evaluated. For vaccines, evaluation in pre-clinical studies is particularly important as information gained may also contribute to identifying the optimum composition and formulation process and provide an opportunity to develop suitable indicator tests for quality control. Data from pre-clinical and laboratory evaluation studies, which continue during clinical studies, is used to support an application for marketing authorisation. Addition of a new adjuvant and exploration of new delivery systems for vaccines presents challenges to both manufacturers and regulatory authorities. Because no adjuvant is licensed as a medicinal product in its own right, but only as a component of a particular vaccine, pre-clinical and appropriate toxicology studies need to be designed on a case-by-case basis to evaluate the safety profile of the adjuvant and adjuvant/vaccine combination. Current regulatory requirements for the pharmaceutical and pre-clinical safety assessment of vaccines are insufficient and initiatives are in place to develop more specific guidelines for evaluation of adjuvants in vaccines.

A systematic review of the effect of cannabidiol on cognitive function: Relevance to schizophrenia.

PubMed

Osborne, Ashleigh L; Solowij, Nadia; Weston-Green, Katrina

2017-01-01

Cognitive impairment is a core symptom domain of schizophrenia, neurological disorders and substance abuse. It is characterised by deficits in learning, memory, attention and executive functioning and can severely impact daily living. Antipsychotic drugs prescribed to treat schizophrenia provide limited cognitive benefits and novel therapeutic targets are required. Cannabidiol (CBD), a component of the cannabis plant, has anti-inflammatory and antipsychotic-like properties; however, its ability to improve cognitive impairment has not been thoroughly explored. The aim of this systematic review was to evaluate preclinical and clinical literature on the effects of CBD in cognitive domains relevant to schizophrenia. A systematic literature search was performed across numerous electronic databases for English language articles (January 1990-March 2016), with 27 articles (18 preclinical and 9 clinical studies) included in the present review. CBD improves cognition in multiple preclinical models of cognitive impairment, including models of neuropsychiatric (schizophrenia), neurodegenerative (Alzheimer's disease), neuro-inflammatory (meningitis, sepsis and cerebral malaria) and neurological disorders (hepatic encephalopathy and brain ischemia). To date, there is one clinical investigation into the effects of CBD on cognition in schizophrenia patients, with negative results for the Stroop test. CBD attenuates Δ 9 -THC-induced cognitive deficits. The efficacy of CBD to improve cognition in schizophrenia cannot be elucidated due to lack of clinical evidence; however, given the ability of CBD to restore cognition in multiple studies of impairment, further investigation into its efficacy in schizophrenia is warranted. Potential mechanisms underlying the efficacy of CBD to improve cognition are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Preclinical neuroprotective actions of xenon and possible implications for human therapeutics: a narrative review.

PubMed

Maze, Mervyn

2016-02-01

The purpose of this report is to facilitate an understanding of the possible application of xenon for neuroprotection in critical care settings. This narrative review appraises the literature assessing the efficacy and safety of xenon in preclinical models of acute ongoing neurologic injury. Databases of the published literature (MEDLINE® and EMBASE™) were appraised for peer-reviewed manuscripts addressing the use of xenon in both preclinical models and disease states of acute ongoing neurologic injury. For randomized clinical trials not yet reported, the investigators' declarations in the National Institutes of Health clinical trials website were considered. While not a primary focus of this review, to date, xenon cannot be distinguished as superior for surgical anesthesia over existing alternatives in adults. Nevertheless, studies in a variety of preclinical disease models from multiple laboratories have consistently shown xenon's neuroprotective properties. These properties are enhanced in settings where xenon is combined with hypothermia. Small randomized clinical trials are underway to explore xenon's efficacy and safety in clinical settings of acute neurologic injury where hypothermia is the current standard of care. According to the evidence to date, the neuroprotective efficacy of xenon in preclinical models and its safety in clinical anesthesia set the stage for the launch of randomized clinical trials to determine whether these encouraging neuroprotective findings can be translated into clinical utility.

Preclinical pharmacokinetics of the novel PI3K inhibitor GDC-0941 and prediction of its pharmacokinetics and efficacy in human.

PubMed

Salphati, Laurent; Pang, Jodie; Plise, Emile G; Chou, Bilin; Halladay, Jason S; Olivero, Alan G; Rudewicz, Patrick J; Tian, Qingping; Wong, Susan; Zhang, Xiaolin

2011-12-01

The phosphatidylinositol 3-kinase (PI3K) pathway is a major determinant of cell cycling and proliferation. Its deregulation is associated with the development of many cancers. GDC-0941, a potent and selective inhibitor of PI3K, was characterised preclinically in in vitro and in vivo studies. Plasma protein binding was extensive, with free fraction less than 7%, and blood-to-plasma ratio ranged from 0.6 to 1.2 among the species tested. GDC-0941 human hepatic clearance was predicted to be moderate by liver microsomal incubations. GDC-0941 had high permeability in Madin-Darby canine kidney cells. The clearance of GDC-0941 was high in mouse (63.7 mL/min/kg), rat (49.3 mL/min/kg) and cynomolgus monkey (58.6 mL/min/kg), and moderate in dog (11.9 mL/min/kg). The volume of distribution ranged from 2.52 L/kg in rat to 2.94 L/kg in monkey. Oral bioavailability ranged from 18.6% in monkey to 77.9% in mouse. Predicted human clearance and volume of distribution using allometry were 6 mL/min/kg and 2.9 L/kg, respectively. The human efficacious doses were predicted based on results from preclinical pharmacokinetic studies and xenograft models. GDC-0941 preclinical characterisation and predictions of its properties in human supported its progression towards clinical development. GDC-0941 is currently in phase II clinical trials.

Design of clinical trials for therapeutic cancer vaccines development.

PubMed

Mackiewicz, Jacek; Mackiewicz, Andrzej

2009-12-25

Advances in molecular and cellular biology as well as biotechnology led to definition of a group of drugs referred to as medicinal products of advanced technologies. It includes gene therapy products, somatic cell therapeutics and tissue engineering. Therapeutic cancer vaccines including whole cell tumor cells vaccines or gene modified whole cells belong to somatic therapeutics and/or gene therapy products category. The drug development is a multistep complex process. It comprises of two phases: preclinical and clinical. Guidelines on preclinical testing of cell based immunotherapy medicinal products have been defined by regulatory agencies and are available. However, clinical testing of therapeutic cancer vaccines is still under debate. It presents a serious problem since recently clinical efficacy of the number of cancer vaccines has been demonstrated that focused a lot of public attention. In general clinical testing in the current form is very expensive, time consuming and poorly designed what may lead to overlooking of products clinically beneficial for patients. Accordingly regulatory authorities and researches including Cancer Vaccine Clinical Trial Working Group proposed three regulatory solutions to facilitate clinical development of cancer vaccines: cost-recovery program, conditional marketing authorization, and a new development paradigm. Paradigm includes a model in which cancer vaccines are investigated in two types of clinical trials: proof-of-principle and efficacy. The proof-of-principle trial objectives are: safety; dose selection and schedule of vaccination; and demonstration of proof-of-principle. Efficacy trials are randomized clinical trials with objectives of demonstrating clinical benefit either directly or through a surrogate. The clinical end points are still under debate.

A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke

PubMed Central

Maysami, Samaneh; Wong, Raymond; Pradillo, Jesus M; Denes, Adam; Dhungana, Hiramani; Malm, Tarja; Koistinaho, Jari; Orset, Cyrille; Rahman, Mahbubur; Rubio, Marina; Schwaninger, Markus; Vivien, Denis; Bath, Philip M; Rothwell, Nancy J

2015-01-01

Stroke represents a global challenge and is a leading cause of permanent disability worldwide. Despite much effort, translation of research findings to clinical benefit has not yet been successful. Failure of neuroprotection trials is considered, in part, due to the low quality of preclinical studies, low level of reproducibility across different laboratories and that stroke co-morbidities have not been fully considered in experimental models. More rigorous testing of new drug candidates in different experimental models of stroke and initiation of preclinical cross-laboratory studies have been suggested as ways to improve translation. However, to our knowledge, no drugs currently in clinical stroke trials have been investigated in preclinical cross-laboratory studies. The cytokine interleukin 1 is a key mediator of neuronal injury, and the naturally occurring interleukin 1 receptor antagonist has been reported as beneficial in experimental studies of stroke. In the present paper, we report on a preclinical cross-laboratory stroke trial designed to investigate the efficacy of interleukin 1 receptor antagonist in different research laboratories across Europe. Our results strongly support the therapeutic potential of interleukin 1 receptor antagonist in experimental stroke and provide further evidence that interleukin 1 receptor antagonist should be evaluated in more extensive clinical stroke trials. PMID:26661169

Update on Standard Operating Procedures in Preclinical Research for DMD and SMA Report of TREAT-NMD Alliance Workshop, Schiphol Airport, 26 April 2015, The Netherlands.

PubMed

van Putten, Maaike; Aartsma-Rus, Annemieke; Grounds, Miranda D; Kornegay, Joe N; Mayhew, Anna; Gillingwater, Thomas H; Takeda, Shin'ichi; Rüegg, Markus A; De Luca, Annamaria; Nagaraju, Kanneboyina; Willmann, Raffaella

A workshop took place in 2015 to follow up TREAT-NMD activities dedicated to improving quality in the preclinical phase of drug development for neuromuscular diseases. In particular, this workshop adressed necessary future steps regarding common standard experimental protocols and the issue of improving the translatability of preclinical efficacy studies.

Problem-based learning versus a traditional educational methodology: a comparison of preclinical and clinical periodontics performance.

PubMed

Rich, Sandra K; Keim, Robert G; Shuler, Charles F

2005-06-01

To evaluate efficacy of a problem-based learning (PBL) pedagogy in preclinical and clinical teaching, test scores of 234 undergraduate dental students from the conventionally taught classes of 2003 and 2004 were compared with scores of 274 dental students from the PBL classes of 2005 and 2006. Although the groups' means were close together, t-test analysis of scores revealed that PBL students performed significantly better than traditional (TRAD) students on midterm (p=.0001) and final (p=.015) examinations taken on student partner/mock patients. ANOVA comparing the classes with each other showed significant differences for the midterm and final, but not for the clinical examination. Further multiple comparison tests (Tukey HSD) for the midterm and final revealed that differences specifically reflected superior performance of PBL classes against one of the TRAD classes (2004). There was no difference in performance between PBL (n=134) and TRAD (n=233) students on examinations taken with actual clinical patients who were undergoing nonsurgical periodontal treatment. Over a two-year period, PBL students rated their program instructors at a mean of 4.41 on a Likert-type scale of 1 (not helpful) to 5 (outstanding). The program provides a PBL model for teaching preclinical and clinical skills supported by a four-year evaluation of manual skills outcomes.

From Bench to Bedside: Utility of the Rabbit Elastase Aneurysm Model in Pre-Clinical Studies of Intracranial Aneurysm Treatment

PubMed Central

Brinjikji, Waleed; Ding, Yong H; Kallmes, David F; Kadirvel, Ramanathan

2016-01-01

Summary Pre-clinical studies are important in helping practitioners and device developers improve techniques and tools for endovascular treatment of intracranial aneurysms. Thus, an understanding of the major animal models used in such studies is important. The New Zealand rabbit elastase induced arterial aneurysm of the common carotid artery is one of the most commonly used models in testing the safety and efficacy of new endovascular devices. In this review we discuss 1) various techniques used to create the aneurysm, 2) complications of aneurysm creation, 3) natural history of the arterial aneurysm, 4) histopathologic and hemodynamic features of the aneurysm 5) devices tested using this model and 6) weaknesses of the model. We demonstrate how pre-clinical studies using this model are applied in treatment of intracranial aneurysms in humans. The model has a similar hemodynamic, morphological and histologic characteristics to human aneurysms and demonstrates similar healing responses to coiling as human aneurysms. Despite these strengths however, the model does have many weaknesses including the fact that the model does not emulate the complex inflammatory processes affecting growing and ruptured aneurysms. Furthermore the model’s extracranial location affects its ability to be used in preclinical safety assessments of new devices. We conclude that the rabbit elastase model has characteristics that make it a simple and effective model for preclinical studies on the endovascular treatment of intracranial aneurysms however further work is needed to develop aneurysm models that simulate the histopathologic and morphologic characteristics of growing and ruptured aneurysms. PMID:25904642

The ongoing evolution of antibody-based treatments for Ebola virus infection.

PubMed

Mendoza, Emelissa J; Racine, Trina; Kobinger, Gary P

2017-03-01

The 2014-2016 Ebola virus outbreak in West Africa was the deadliest in history, prompting the evaluation of various drug candidates, including antibody-based therapeutics for the treatment of Ebola hemorrhagic fever (EHF). Prior to 2014, only convalescent blood products from EHF survivors had been administered to newly infected individuals as a form of treatment. However, during the recent outbreak, monoclonal antibody cocktails such as ZMapp, ZMAb and MB-003 were either tested in a human clinical safety and efficacy trial or provided to some based on compassionate grounds. This review aims to discuss the evolution of antibody-based treatments for EHF, their clinical trial efficacy and the development of new antibody-based therapies currently advancing in preclinical testing.

Psychedelic Drugs in Biomedicine.

PubMed

Kyzar, Evan J; Nichols, Charles D; Gainetdinov, Raul R; Nichols, David E; Kalueff, Allan V

2017-11-01

Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

A low-cost, high-quality new drug discovery process using patient-derived induced pluripotent stem cells.

PubMed

Giri, Shibashish; Bader, Augustinus

2015-01-01

Knockout, knock-in and conditional mutant gene-targeted mice are routinely used for disease modeling in the drug discovery process, but the human response is often difficult to predict from these models. It is believed that patient-derived induced pluripotent stem cells (iPSCs) could replace millions of animals currently sacrificed in preclinical testing and provide a route to new safer pharmaceutical products. In this review, we discuss the use of IPSCs in the drug discovery process. We highlight how they can be used to assess the toxicity and clinical efficacy of drug candidates before the latter are moved into costly and lengthy preclinical and clinical trials. Copyright © 2014 Elsevier Ltd. All rights reserved.

Single vs. combination immunotherapeutic strategies for glioma

PubMed Central

Chandran, Mayuri; Candolfi, Marianela; Shah, Diana; Mineharu, Yohei; Yadav, Vivek; Koschmann, Carl; Asad, Antonela S.; Lowenstein, Pedro R.; Castro, Maria G.

2017-01-01

Introduction Malignant gliomas are highly invasive tumors, associated with a dismal survival rate despite standard of care, which includes surgical resection, radiotherapy and chemotherapy with temozolomide (TMZ). Precision immunotherapies or combinations of immunotherapies that target unique tumor-specific featuresmay substantially improve upon existing treatments. Areas covered Clinical trials of single immunotherapies have shown therapeutic potential in high-grade glioma patients, and emerging preclinical studies indicate that combinations of immunotherapies may be more effective than monotherapies. In this review we discuss emerging combinations of immunotherapies and compare efficacy of single vs. combined therapies tested in preclinical brain tumor models. Expert opinion Malignant gliomas are characterized by a number of factors which may limit the success of single immunotherapies including inter-tumor and intra-tumor heterogeneity, intrinsic resistance to traditional therapies, immunosuppression, and immune selection for tumor cells with low antigenicity. Combination of therapies which target multiple aspects of tumor physiology are likely to be more effective than single therapies. While we describe a limited number of combination immunotherapies which are currently being tested in preclinical and clinical studies, the field is expanding at an astounding rate, and endless combinations remain open for exploration. PMID:28286975

Extracurricular activities associated with stress and burnout in preclinical medical students.

PubMed

Fares, Jawad; Saadeddin, Zein; Al Tabosh, Hayat; Aridi, Hussam; El Mouhayyar, Christopher; Koleilat, Mohamad Karim; Chaaya, Monique; El Asmar, Khalil

2016-09-01

This study aims to assess the prevalence of stress and burnout among preclinical medical students in a private university in Beirut, Lebanon, and evaluate the association between extracurricular involvement and stress and burnout relief in preclinical medical students. A cross-sectional survey was conducted on a random sample of 165 preclinical medical students. Distress level was measured using the 12-item General Health Questionnaire (GHQ-12) while that of burnout was measured through the Maslach Burnout Inventory-Student Survey (MBI-SS). The MBI-SS assesses three interrelated dimensions: emotional exhaustion, cynicism, and academic efficacy. Extracurricular activities were divided into four categories: physical exercise, music, reading, and social activities. All selected participants responded. A substantial proportion of preclinical medical students suffered from stress (62%) and burnout (75%). Bivariate and multivariate regression analyses revealed that being a female or a 1st year medical student correlated with higher stress and burnout. Music-related activities were correlated with lower burnout. Social activities or living with parents were associated with lower academic efficacy. The high stress and burnout levels call for action. Addressing the studying conditions and attending to the psychological wellbeing of preclinical medical students are recommendations made in the study. Copyright © 2015 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.

From bench to almost bedside: the long road to a licensed Ebola virus vaccine.

PubMed

Wong, Gary; Mendoza, Emelissa J; Plummer, Francis A; Gao, George F; Kobinger, Gary P; Qiu, Xiangguo

2018-02-01

The Ebola virus (EBOV) disease epidemic during 2014-16 in West Africa has accelerated the clinical development of several vaccine candidates that have demonstrated efficacy in the gold standard nonhuman primate (NHP) model, namely cynomolgus macaques. Areas covered: This review discusses the pre-clinical research and if available, clinical evaluation of the currently available EBOV vaccine candidates, while emphasizing the translatability of pre-clinical data generated in the NHP model to clinical data in humans. Expert opinion: Despite the existence of many successful EBOV vaccine candidates in the pre-clinical stages, only two platforms became the focus of Phase 2/3 efficacy trials in Liberia, Sierra Leone, and Guinea near the peak of the epidemic: the Vesicular stomatitis virus (VSV)-vectored vaccine and the chimpanzee adenovirus type 3 (ChAd3)-vectored vaccine. The results of three distinct clinical trials involving these candidates may soon pave the way for a licensed, safe and efficacious EBOV vaccine to help combat future epidemics.

From bench to almost bedside: The long road to a licensed Ebola virus vaccine

PubMed Central

Wong, Gary; Mendoza, Emelissa J.; Plummer, Francis A.; Gao, George F.; Kobinger, Gary P.; Qiu, Xiangguo

2018-01-01

Introduction The Ebola virus (EBOV) disease epidemic during 2014-16 in West Africa has accelerated the clinical development of several vaccine candidates that have demonstrated efficacy in the gold standard nonhuman primate (NHP) model, namely cynomolgus macaques. Areas covered This review discusses the pre-clinical research and if available, clinical evaluation of the currently available EBOV vaccine candidates, while emphasizing the translatability of pre-clinical data generated in the NHP model to clinical data in humans. Expert opinion Despite the existence of many successful EBOV vaccine candidates in the pre-clinical stages, only two platforms became the focus of Phase 2/3 efficacy trials in Liberia, Sierra Leone, and Guinea near the peak of the epidemic: the Vesicular stomatitis virus (VSV)-vectored vaccine and the chimpanzee adenovirus type 3 (ChAd3)-vectored vaccine. The results of three distinct clinical trials involving these candidates may soon pave the way for a licensed, safe and efficacious EBOV vaccine to help combat future epidemics. PMID:29148858

Efficacy and Safety of Human Retinal Progenitor Cells

PubMed Central

Semo, Ma'ayan; Haamedi, Nasrin; Stevanato, Lara; Carter, David; Brooke, Gary; Young, Michael; Coffey, Peter; Sinden, John; Patel, Sara; Vugler, Anthony

2016-01-01

Purpose We assessed the long-term efficacy and safety of human retinal progenitor cells (hRPC) using established rodent models. Methods Efficacy of hRPC was tested initially in Royal College of Surgeons (RCS) dystrophic rats immunosuppressed with cyclosporine/dexamethasone. Due to adverse effects of dexamethasone, this drug was omitted from a subsequent dose-ranging study, where different hRPC doses were tested for their ability to preserve visual function (measured by optokinetic head tracking) and retinal structure in RCS rats at 3 to 6 months after grafting. Safety of hRPC was assessed by subretinal transplantation into wild type (WT) rats and NIH-III nude mice, with analysis at 3 to 6 and 9 months after grafting, respectively. Results The optimal dose of hRPC for preserving visual function/retinal structure in dystrophic rats was 50,000 to 100,000 cells. Human retinal progenitor cells integrated/survived in dystrophic and WT rat retina up to 6 months after grafting and expressed nestin, vimentin, GFAP, and βIII tubulin. Vision and retinal structure remained normal in WT rats injected with hRPC and there was no evidence of tumors. A comparison between dexamethasone-treated and untreated dystrophic rats at 3 months after grafting revealed an unexpected reduction in the baseline visual acuity of dexamethasone-treated animals. Conclusions Human retinal progenitor cells appear safe and efficacious in the preclinical models used here. Translational Relevance Human retinal progenitor cells could be deployed during early stages of retinal degeneration or in regions of intact retina, without adverse effects on visual function. The ability of dexamethasone to reduce baseline visual acuity in RCS dystrophic rats has important implications for the interpretation of preclinical and clinical cell transplant studies. PMID:27486556

Metabotropic Glutamate Receptor 5 as a Target for the Treatment of Depression and Smoking: Robust Preclinical Data but Inconclusive Clinical Efficacy.

PubMed

Barnes, Samuel A; Sheffler, Douglas J; Semenova, Svetlana; Cosford, Nicholas D P; Bespalov, Anton

2018-06-01

The ability of novel pharmacological compounds to improve outcomes in preclinical models is often not translated into clinical efficacy. Psychiatric disorders do not have biological boundaries, and identifying mechanisms to improve the translational bottleneck between preclinical and clinical research domains is an important and challenging task. Glutamate transmission is disrupted in several neuropsychiatric disorders. Metabotropic glutamate (mGlu) receptors represent a diverse class of receptors that contribute to excitatory neurotransmission. Given the wide, yet region-specific manner of expression, developing pharmacological compounds to modulate mGlu receptor activity provides an opportunity to subtly and selectively modulate excitatory neurotransmission. This review focuses on the potential involvement of mGlu5 receptor disruption in major depressive disorder and substance and/or alcohol use disorders. We provide an overview of the justification of targeting mGlu5 receptors in the treatment of these disorders, summarize the preclinical evidence for negatively modulating mGlu5 receptors as a therapeutic target for major depressive disorders and nicotine dependence, and highlight the outcomes of recent clinical trials. While the evidence of mGlu5 receptor negative allosteric modulation has been promising in preclinical investigations, these beneficial effects have not translated into clinical efficacy. In this review, we identify key challenges that may contribute to poor clinical translation and provide suggested approaches moving forward to potentially improve the translation from preclinical to clinical domains. Such approaches may increase the success of clinical trials and may reduce the translational bottleneck that exists in drug discovery for psychiatric disorders. Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Preclinical drug evaluation for combination therapy in acute stroke using systematic review, meta-analysis, and subsequent experimental testing

PubMed Central

O'Collins, Victoria E; Macleod, Malcolm R; Cox, Susan F; Van Raay, Leena; Aleksoska, Elena; Donnan, Geoffrey A; Howells, David W

2011-01-01

There is some evidence that in animal models of acute ischaemic stroke, combinations of neuroprotective agents might be more efficacious than the same agents administered alone. Hence, we developed pragmatic, empirical criteria based on therapeutic target, cost, availability, efficacy, administration, and safety to select drugs for testing in combination in animal models of acute stroke. Magnesium sulphate, melatonin, and minocycline were chosen from a library of neuroprotective agents, and were tested in a more ‘realistic' model favoured by the STAIR (Stroke Therapy Academic Industry Roundtable). Outcome was assessed with infarct volume, neurologic score, and two newly developed scales measuring general health and physiologic homeostasis. Owing to the failure to achieve neuroprotection in aged, hypertensive animals with drug delivery at 3 hours, the bar was lowered in successive experiments to determine whether neuroprotection could be achieved under conditions more conducive to recovery. Testing in younger animals showed more favourable homeostasis and general health scores than did testing in older animals, but infarct volume and neurologic scores did not differ with age, and treatment efficacy was again not shown. Testing with shorter occlusions resulted in smaller infarct volumes; nevertheless, treatment efficacy was still not observed. It was concluded that this combination, in these stroke models, was not effective. PMID:20978519

Improving Translation from Preclinical Studies to Clinical Trials in Acute Kidney Injury.

PubMed

Fiorentino, Marco; Kellum, John A

2018-05-23

Several cellular and molecular targets and mechanisms have been investigated in preclinical studies of acute kidney injury (AKI), but translation in successful clinical studies has failed to date. This article reviews many issues that have limited this and the potential future perspectives in AKI prevention and treatment. Preclinical models of AKI should closely mimic the complexity of human AKI, considering the importance of several comorbidities in determining the clinical course and outcomes in the human disease. Moreover, studies should test novel interventions in models where AKI is already established, instead of focusing only at primary prevention. AKI definitions and endpoints in animal studies should be similar to those applied in clinical studies; in particular, AKI biomarkers should be implemented to guide patient selection for clinical trials and monitor intervention efficacy. In this scenario, cell-cycle arrest biomarkers have been widely investigated as AKI predictors in both preclinical and clinical studies and they serve as useful tools for future interventional studies. A better understanding of human AKI through a large collection of biological samples and kidney biopsies and omics applications, and an iterative relationship between preclinical and clinical studies are critical steps to improve future preclinical models and clinical trials. Finally, given the great variability in clinical manifestation of AKI, a strong collaboration between research centers and industry is recommended. Key messages: Several methodological issues have hampered the translation of basic research findings in clinical studies, and overcoming these obstacles is necessary to achieve success. © 2018 S. Karger AG, Basel.

Alzheimer's Therapeutics: Translation of Preclinical Science to Clinical Drug Development

PubMed Central

Savonenko, Alena V; Melnikova, Tatiana; Hiatt, Andrew; Li, Tong; Worley, Paul F; Troncoso, Juan C; Wong, Phil C; Price, Don L

2012-01-01

Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer's disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a revision of our theoretical views and questions every stage of translation—from how we model the disease to how we run clinical trials. In the following sections, we will use some specific examples of the therapeutics from acetylcholinesterase inhibitors to recent anti-Aβ immunization and γ-secretase inhibition to discuss whether preclinical studies could predict the limitations in efficacy and side effects that we were so disappointed to observe in recent clinical trials. We discuss ways to improve both the predictive validity of mouse models and the translation of knowledge between preclinical and clinical stages of drug development. PMID:21937983

Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments.

PubMed

Henderson, Valerie C; Kimmelman, Jonathan; Fergusson, Dean; Grimshaw, Jeremy M; Hackam, Dan G

2013-01-01

The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external) or programmatic research activity they primarily address. We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria--most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation. By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice. Please see later in the article for the Editors' Summary.

Biopsychosocial influence on shoulder pain: rationale and protocol for a pre-clinical trial

PubMed Central

George, Steven Z.; Staud, Roland; Borsa, Paul A.; Wu, Samuel S.; Wallace, Margaret R.; Greenfield, Warren. H.; Mackie, Lauren N.; Fillingim, Roger B.

2017-01-01

Background Chronic musculoskeletal pain conditions are a prevalent and disabling problem. Preventing chronic musculoskeletal pain requires multifactorial treatment approaches that address its complex etiology. Prior cohort studies identified a high risk subgroup comprised of variation in COMT genotype and pain catastrophizing. This subgroup had increased chance of heightened pain responses (in a pre-clinical model) and higher 12 month post-operatives pain intensity ratings (in a clinical model). This pre-clinical trial will test mechanisms and efficacy of personalized pain interventions matched to the genetic and psychological characteristics of the high-risk subgroup. Methods Potential participants will be screened for high risk subgroup membership, appropriateness for exercise-induced muscle injury protocol, and appropriateness for propranolol administration. Eligible participants that consent to the study will then be randomized into one of four treatment groups; 1) personalized pharmaceutical and psychological education; 2) personalized pharmaceutical and general education; 3) placebo pharmaceutical and psychological education; 4) placebo pharmaceutical and psychological education. Over the 5-day study period participants will complete an exercise-induced muscle injury protocol and receive study interventions. Pain and disability assessments will be completed daily, with primary outcomes being duration of shoulder pain (number of days until recovery), peak shoulder pain intensity, and peak shoulder disability. Secondary outcomes include inflammatory markers, psychological mediators, and measures of pain sensitivity regulation. Conclusion This pre-clinical trial builds on prior cohort studies and its completion will provide foundational data supporting efficacy and mechanisms of personalized interventions for individuals that may be at increased risk for developing chronic shoulder pain. Trial Registration ClinicalTrials.gov registry, NCT02620579 (Registered on November 13, 2015) PMID:28315479

Biopsychosocial influence on shoulder pain: Rationale and protocol for a pre-clinical trial.

PubMed

George, Steven Z; Staud, Roland; Borsa, Paul A; Wu, Samuel S; Wallace, Margaret R; Greenfield, Warren H; Mackie, Lauren N; Fillingim, Roger B

2017-05-01

Chronic musculoskeletal pain conditions are a prevalent and disabling problem. Preventing chronic musculoskeletal pain requires multifactorial treatment approaches that address its complex etiology. Prior cohort studies identified a high risk subgroup comprised of variation in COMT genotype and pain catastrophizing. This subgroup had increased chance of heightened pain responses (in a pre-clinical model) and higher 12month post-operatives pain intensity ratings (in a clinical model). This pre-clinical trial will test mechanisms and efficacy of personalized pain interventions matched to the genetic and psychological characteristics of the high-risk subgroup. Potential participants will be screened for high risk subgroup membership, appropriateness for exercise-induced muscle injury protocol, and appropriateness for propranolol administration. Eligible participants that consent to the study will then be randomized into one of four treatment groups; 1) personalized pharmaceutical and psychological education; 2) personalized pharmaceutical and general education; 3) placebo pharmaceutical and psychological education; 4) placebo pharmaceutical and psychological education. Over the 5-day study period participants will complete an exercise-induced muscle injury protocol and receive study interventions. Pain and disability assessments will be completed daily, with primary outcomes being duration of shoulder pain (number of days until recovery), peak shoulder pain intensity, and peak shoulder disability. Secondary outcomes include inflammatory markers, psychological mediators, and measures of pain sensitivity regulation. This pre-clinical trial builds on prior cohort studies and its completion will provide foundational data supporting efficacy and mechanisms of personalized interventions for individuals that may be at increased risk for developing chronic shoulder pain. ClinicalTrials.gov registry, NCT02620579 (Registered on November 13, 2015). Copyright © 2017 Elsevier Inc. All rights reserved.

Development of regional chemotherapies: feasibility, safety and efficacy in clinical use and preclinical studies

PubMed Central

Cai, Shuang; Bagby, Taryn R; Forrest, M Laird

2011-01-01

Conventional oral and intravenous chemotherapies permeate throughout the body, exposing healthy tissues to similar cytotoxic drug levels as tumors. This leads to significant dose-limiting toxicities that may prevent patients from receiving sufficient treatment to overcome cancers. Therefore, a number of locoregional drug-delivery strategies have been evaluated and implemented in preclinical studies, clinical trials and in practice, in the past decades to minimize systemic toxicities from chemotherapeutic agents and to improve treatment outcomes. Localized treatment is beneficial because many cancers, such as melanoma, peritoneal cancer and breast cancer, advance locally adjacent to the site of the primary tumors prior to their circulatory invasion. In this article, we will review the feasibility, safety and efficacy of multiple localized chemotherapies in clinical use and preclinical development. PMID:22229080

Mouse Regenerating Myofibers Detected as False-Positive Donor Myofibers with Anti-Human Spectrin

PubMed Central

Rozkalne, Anete; Adkin, Carl; Meng, Jinhong; Lapan, Ariya; Morgan, Jennifer E.

2014-01-01

Abstract Stem cell transplantation is being tested as a potential therapy for a number of diseases. Stem cells isolated directly from tissue specimens or generated via reprogramming of differentiated cells require rigorous testing for both safety and efficacy in preclinical models. The availability of mice with immune-deficient background that carry additional mutations in specific genes facilitates testing the efficacy of cell transplantation in disease models. The muscular dystrophies are a heterogeneous group of disorders, of which Duchenne muscular dystrophy is the most severe and common type. Cell-based therapy for muscular dystrophy has been under investigation for several decades, with a wide selection of cell types being studied, including tissue-specific stem cells and reprogrammed stem cells. Several immune-deficient mouse models of muscular dystrophy have been generated, in which human cells obtained from various sources are injected to assess their preclinical potential. After transplantation, the presence of engrafted human cells is detected via immunofluorescence staining, using antibodies that recognize human, but not mouse, proteins. Here we show that one antibody specific to human spectrin, which is commonly used to evaluate the efficacy of transplanted human cells in mouse muscle, detects myofibers in muscles of NOD/Rag1nullmdx5cv, NOD/LtSz-scid IL2Rγnull mice, or mdx nude mice, irrespective of whether they were injected with human cells. These “reactive” clusters are regenerating myofibers, which are normally present in dystrophic tissue and the spectrin antibody is likely recognizing utrophin, which contains spectrin-like repeats. Therefore, caution should be used in interpreting data based on detection of single human-specific proteins, and evaluation of human stem cell engraftment should be performed using multiple human-specific labeling strategies. PMID:24152287

Preclinical Mouse Cancer Models: A Maze of Opportunities and Challenges

PubMed Central

Day, Chi-Ping; Merlino, Glenn; Van Dyke, Terry

2015-01-01

Significant advances have been made in developing novel therapeutics for cancer treatment, and targeted therapies have revolutionized the treatment of some cancers. Despite the promise, only about five percent of new cancer drugs are approved, and most fail due to lack of efficacy. The indication is that current preclinical methods are limited in predicting successful outcomes. Such failure exacts enormous cost, both financial and in the quality of human life. This primer explores the current status, promise and challenges of preclinical evaluation in advanced mouse cancer models and briefly addresses emerging models for early-stage preclinical development. PMID:26406370

Chemoprevention of Prostate Cancer by Naturally Occurring and Synthetic Organoselenium Compounds

DTIC Science & Technology

2010-12-01

the potential efficacy of combination sorafenib plus rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models. BMC...rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models. BMC Pharmacol 2009;9:8-22 36. Wan X, Harkavy B, Shen N, Grohar P

Safety and Antioxidant Efficacy Profiles of Rutin-Loaded Ethosomes for Topical Application.

PubMed

Cândido, Thalita Marcílio; De Oliveira, Camila Areias; Ariede, Maíra Bueno; Velasco, Maria Valéria Robles; Rosado, Catarina; Baby, André Rolim

2018-05-01

Topical application of dermocosmetics containing antioxidant and/or the intake of antioxidants through diet or supplementation are remarkable tools in an attempt to slow down some of the harmful effects of free radicals. Rutin is a strong antioxidant compound used in food and pharmaceutical industries. It was established that rutin presents a low skin permeation rate, a property that could be considered an inconvenience to the satisfactory action for a dermocosmetic formulation to perform its antioxidant activity onto the skin. Therefore, it is indispensable to improve its delivery, aiming at increasing its antioxidant capacity in deeper layers of the epidermis, being a possibility to associate the rutin to liposomal vesicles, such as ethosomes. Thus, in this work, the pre-clinical safety of rutin-loaded ethosomes was investigated employing an in vitro method, and the clinical safety and efficacy were also assessed. Rutin-loaded ethosomes were efficaciously obtained in a nanoscale dimension with a relevant bioactive compound loading (80.2%) and provided antioxidant in vitro activity in comparison with the blank sample. Pre-clinical and clinical safety assays assured the innocuous profile of the rutin-loaded ethosomes. The ethosomes containing the bioactive compound accomplished a more functional delivery system profile, since in the tape stripping assay, the deeper layers presented higher rutin amounts than the active delivered in its free state. However, the ex vivo antioxidant efficacy test detected no positive antioxidant activity from the rutin-loaded ethosomes, even though the in vitro assay demonstrated an affirmative antioxidant action.

Oncolytic Poxviruses

PubMed Central

Chan, Winnie M.; McFadden, Grant

2015-01-01

Current standard treatments of cancer can prolong survival of many cancer patients but usually do not effectively cure the disease. Oncolytic virotherapy is an emerging therapeutic for the treatment of cancer that exploits replication-competent viruses to selectively infect and destroy cancerous cells while sparing normal cells and tissues. Clinical and/or preclinical studies on oncolytic viruses have revealed that the candidate viruses being tested in trials are remarkably safe and offer potential for treating many classes of currently incurable cancers. Among these candidates are vaccinia and myxoma viruses, which belong to the family Poxviridae and possess promising oncolytic features. This article describes poxviruses that are being developed for oncolytic virotherapy and summarizes the outcomes of both clinical and preclinical studies. Additionally, studies demonstrating superior efficacy when poxvirus oncolytic virotherapy is combined with conventional therapies are described. PMID:25839047

The JAK2/STAT3 inhibitor pacritinib effectively inhibits patient-derived GBM brain tumor initiating cells in vitro and when used in combination with temozolomide increases survival in an orthotopic xenograft model.

PubMed

Jensen, Katharine Victoria; Cseh, Orsolya; Aman, Ahmed; Weiss, Samuel; Luchman, Hema Artee

2017-01-01

The prognosis for patients diagnosed with glioblastoma multiforme (GBM) remains dismal, with current treatment prolonging survival only modestly. As such, there remains a strong need for novel therapeutic strategies. The janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 pathway regulates many cellular processes in GBM, including survival, proliferation, invasion, anti-apoptosis, and immune evasion. Here, we evaluated the preclinical efficacy of pacritinib, a novel compound targeting JAK2, using a collection of diverse patient-derived brain tumor initiating cells (BTICs). The effects of pacritinib on BTIC viability and sphere forming capacity were evaluated in vitro using the alamarBlue and neurosphere assays, respectively. On-target inhibition of JAK2/STAT3 signaling was investigated using western blotting. The efficacy of pacritinib was tested in vivo in pharmacokinetic analyses, liver microsome analyses, and Kaplan-Meier survival studies. In vitro, pacritinib decreased BTIC viability and sphere forming potential at low micromolar doses and demonstrated on-target inhibition of STAT3 signaling. Additionally, pacritinib was found to improve the response to temozolomide (TMZ) in TMZ-resistant BTICs. In vivo, systemic treatment with pacritinib demonstrated blood-brain barrier penetration and led to improved overall median survival in combination with TMZ, in mice orthotopically xenografted with an aggressive recurrent GBM BTIC culture. This preclinical study demonstrates the efficacy of pacritinib and supports the feasibility of testing pacritinib for the treatment of GBM, in combination with the standard of care TMZ.

Hypoxia-Targeting Drug Evofosfamide (TH-302) Enhances Sunitinib Activity in Neuroblastoma Xenograft Models.

PubMed

Kumar, Sushil; Sun, Jessica D; Zhang, Libo; Mokhtari, Reza Bayat; Wu, Bing; Meng, Fanying; Liu, Qian; Bhupathi, Deepthi; Wang, Yan; Yeger, Herman; Hart, Charles; Baruchel, Sylvain

2018-05-23

Antiangiogenic therapy has shown promising results in preclinical and clinical trials. However, tumor cells acquire resistance to this therapy by gaining ability to survive and proliferate under hypoxia induced by antiangiogenic therapy. Combining antiangiogenic therapy with hypoxia-activated prodrugs can overcome this limitation. Here, we have tested the combination of antiangiogenic drug sunitinib in combination with hypoxia-activated prodrug evofosfamide in neuroblastoma. In vitro, neuroblastoma cell line SK-N-BE(2) was 40-folds sensitive to evofosfamide under hypoxia compared to normoxia. In IV metastatic model, evofosfamide significantly increased mice survival compared to the vehicle (P=.02). In SK-N-BE(2) subcutaneous xenograft model, we tested two different treatment regimens using 30 mg/kg sunitinib and 50 mg/kg evofosfamide. Here, sunitinib therapy when started along with evofosfamide treatment showed higher efficacy compared to single agents in subcutaneous SK-N-BE(2) xenograft model, whereas sunitinib when started 7 days after evofosfamide treatment did not have any advantage compared to treatment with either single agent. Immunofluorescence of tumor sections revealed higher number of apoptotic cells and hypoxic areas compared to either single agent when both treatments were started together. Treatment with 80 mg/kg sunitinib with 50 mg/kg evofosfamide was significantly superior to single agents in both xenograft and metastatic models. This study confirms the preclinical efficacy of sunitinib and evofosfamide in murine models of aggressive neuroblastoma. Sunitinib enhances the efficacy of evofosfamide by increasing hypoxic areas, and evofosfamide targets hypoxic tumor cells. Consequently, each drug enhances the activity of the other. Copyright © 2018. Published by Elsevier Inc.

Treatment with Uric Acid Reduces Infarct and Improves Neurologic Function in Female Mice After Transient Cerebral Ischemia.

PubMed

Dhanesha, Nirav; Vázquez-Rosa, Edwin; Cintrón-Pérez, Coral J; Thedens, Daniel; Kort, Alexa J; Chuong, Vicky; Rivera-Dompenciel, Adriana M; Chauhan, Anil K; Leira, Enrique C; Pieper, Andrew A

2018-05-01

Exogenous administration of uric acid, a naturally occurring antioxidant that scavenges reactive oxygen species in vasculature, has shown protective efficacy in both rodent models of stroke and human stroke patients in Spain as an adjuvant treatment to mechanical thrombectomy. Before clinical trials can be initiated in the United States, however, confirmation of efficacy in alternative preclinical models is required in accordance with stroke therapy academic industry roundtable-RIGOR criteria. To date, preclinical efficacy has only been established in the acute setting in male rodents. To address this need, we subjected 7- to 9-week old ovariectomized female mice to filament-induced right middle cerebral artery ischemia and reperfusion, an established preclinical model of mechanical thrombectomy. Fidelity of the procedure was monitored by laser Doppler flowmetry. A separate lab randomly assigned animals to vehicle versus uric acid infusion, which was initiated immediately after 45 minutes of reperfusion. Poststroke analysis of infarction size and neurologic function were conducted by investigators blind to treatment group, with a 7-day primary endpoint and a 3-day intermediary analysis at 1and. Infarct size and neurologic function at 7 days poststroke were significantly improved in uric acid-treated animals, relative to vehicle. Efficacy of uric acid in preclinical models of stroke is now expanded to include female mice analyzed at a later time point than has been investigated previously. These results support stroke therapy academic industry roundtable-RIGOR driven determination of the suitability of acute administration of uric acid as an adjuvant to mechanical thrombectomy in clinical trials for patients with stroke. Published by Elsevier Inc.

Developing a Measurement Tool for Assessing Physiotherapy Students' Self-Efficacy: A Pilot Study

ERIC Educational Resources Information Center

Jones, Anne; Sheppard, Lorraine

2012-01-01

The aim of this research was to determine if self-efficacy can be correlated with prior academic achievement and whether self-efficacy can be an outcome measure of education. A self-efficacy instrument was developed and administered to physiotherapy students following completion of their pre-clinical theory experience. The questionnaire results…

The effects of granulocyte colony-stimulating factor in preclinical models of infection and acute inflammation.

PubMed

Marshall, John C

2005-12-01

The cytokine granulocyte colony-stimulating factor (G-CSF) is a potent endogenous trigger for the release of neutrophils from bone marrow stores and for their activation for enhanced antimicrobial activity. G-CSF has been widely evaluated in preclinical models of acute illness, with generally promising though divergent results. A recombinant G-CSF molecule has recently undergone clinical trials to assess its efficacy as an adjuvant therapy in community-acquired and nosocomial pneumonia, however, these studies failed to provide convincing evidence of benefit. We undertook a systematic review of the published literature reporting the effects of modulation of G-CSF in preclinical in vivo models to determine whether evidence of differential efficacy might explain the disappointing results of human studies and point to disease states that might be more likely to benefit from G-CSF therapy. G-CSF has been evaluated in 86 such studies involving a variety of different models. The strongest evidence of benefit was seen in studies involving intraperitoneal challenge with live organisms; benefit was evident whether the agent was given before or after challenge. G-CSF demonstrates anti-inflammatory activity in models of systemic challenge with viable organisms or endotoxin, but only when the agent is given before challenge; evidence of benefit after challenge was minimal. Preclinical models of intrapulmonary challenge only show efficacy when the cytokine is administered before the infectious challenge, and suggested harm in gram-negative pneumonia resulting from challenge with Escherichia coli or Klebsiella. There is little evidence for therapeutic efficacy in noninfectious models of acute illness. We conclude that the most promising populations for evaluation of G-CSF are neutropenic patients with invasive infection and patients with intra-abdominal infection, particularly those with the syndrome of tertiary, or recurrent, peritonitis. Significant variability in the design and reporting of studies of preclinical models of acute illness precludes more sophisticated data synthesis.

Lessons from HIV-1 vaccine efficacy trials.

PubMed

Excler, Jean-Louis; Michael, Nelson L

2016-11-01

Only four HIV-1 vaccine concepts have been tested in six efficacy trials with no product licensed to date. Several scientific and programmatic lessons can be learned from these studies generating new hypotheses and guiding future steps. RV144 [ALVAC-HIV (canarypox vector) and AIDSVAX B/E (bivalent gp120 HIV-1 subtype B and CRF01_AE)] remains the only efficacy trial that demonstrated a modest vaccine efficacy, which led to the identification of immune correlates of risk. Progress on subtype-specific, ALVAC (canarypox vector) and gp120 vaccine prime-boost approaches has been slow, but we are finally close to the launch of an efficacy study in Africa in 2016. The quest of a globally effective HIV-1 vaccine has led to the development of new approaches. Efficacy studies of combinations of Adenovirus type 26 (Ad26)/Modified Vaccinia Ankara (MVA)/gp140 vaccines with mosaic designs will enter efficacy studies mid-2017 and cytomegalovirus (CMV)-vectored vaccines begin Phase I studies at the same time. Future HIV-1 vaccine efficacy trials face practical challenges as effective nonvaccine prevention programs are projected to decrease HIV-1 incidence. An HIV-1 vaccine is urgently needed. Increased industry involvement, mobilization of resources, expansion of a robust pipeline of new concepts, and robust preclinical challenge studies will be essential to accelerate efficacy testing of next generation HIV-1 vaccine candidates.

Investigation into metastatic processes and the therapeutic effects of gemcitabine on human pancreatic cancer using an orthotopic SUIT-2 pancreatic cancer mouse model

PubMed Central

Higuchi, Tamami; Yokobori, Takehiko; Naito, Tomoharu; Kakinuma, Chihaya; Hagiwara, Shinji; Nishiyama, Masahiko; Asao, Takayuki

2018-01-01

Prognosis of pancreatic cancer is poor, thus the development of novel therapeutic drugs is necessary. During preclinical studies, appropriate models are essential for evaluating drug efficacy. The present study sought to determine the ideal pancreatic cancer mouse model for reliable preclinical testing. Such a model could accurately reflect human pancreatic cancer phenotypes and predict future clinical trial results. Systemic pathology analysis was performed in an orthotopic transplantation model to prepare model mice for use in preclinical studies, mimicking the progress of human pancreatic cancer. The location and the timing of inoculated cancer cell metastases, pathogenesis and cause of fatality were analyzed. Furthermore, the efficacy of gemcitabine, a key pancreatic cancer drug, was evaluated in this model where liver metastasis and peritoneal dissemination occur. Results indicated that the SUIT-2 orthotopic pancreatic cancer model was similar to the phenotypic sequential progression of human pancreatic cancer, with extra-pancreatic invasion, intra-peritoneal dissemination and other hematogenous organ metastases. Notably, survival was prolonged by administering gemcitabine to mice with metastasized pancreatic cancer. Furthermore, the detailed effects of gemcitabine on the primary tumor and metastatic tumor lesions were pathologically evaluated in mice. The present study indicated the model accurately depicted pancreatic cancer development and metastasis. Furthermore, the detailed effects of pancreatic cancer drugs on the primary tumor and on metastatic tumor lesions. We present this model as a potential new standard for new drug development in pancreatic cancer. PMID:29435042

Zebrafish models for functional and toxicological screening of nanoscale drug delivery systems: promoting preclinical applications

PubMed Central

Lee, Keon Yong; Jang, Gun Hyuk; Byun, Cho Hyun; Jeun, Minhong

2017-01-01

Preclinical screening with animal models is an important initial step in clinical translation of new drug delivery systems. However, establishing efficacy, biodistribution, and biotoxicity of complex, multicomponent systems in small animal models can be expensive and time-consuming. Zebrafish models represent an alternative for preclinical studies for nanoscale drug delivery systems. These models allow easy optical imaging, large sample size, and organ-specific studies, and hence an increasing number of preclinical studies are employing zebrafish models. In this review, we introduce various models and discuss recent studies of nanoscale drug delivery systems in zebrafish models. Also in the end, we proposed a guideline for the preclinical trials to accelerate the progress in this field. PMID:28515222

Zebrafish models for functional and toxicological screening of nanoscale drug delivery systems: promoting preclinical applications.

PubMed

Lee, Keon Yong; Jang, Gun Hyuk; Byun, Cho Hyun; Jeun, Minhong; Searson, Peter C; Lee, Kwan Hyi

2017-06-30

Preclinical screening with animal models is an important initial step in clinical translation of new drug delivery systems. However, establishing efficacy, biodistribution, and biotoxicity of complex, multicomponent systems in small animal models can be expensive and time-consuming. Zebrafish models represent an alternative for preclinical studies for nanoscale drug delivery systems. These models allow easy optical imaging, large sample size, and organ-specific studies, and hence an increasing number of preclinical studies are employing zebrafish models. In this review, we introduce various models and discuss recent studies of nanoscale drug delivery systems in zebrafish models. Also in the end, we proposed a guideline for the preclinical trials to accelerate the progress in this field. © 2017 The Author(s).

Perceived sources and levels of stress, general self-efficacy and coping strategies in preclinical dental students.

PubMed

Ersan, Nilüfer; Dölekoğlu, Semanur; Fişekçioğlu, Erdoğan; İlgüy, Mehmet; Oktay, İnci

2018-06-01

Dental education programs are known to be highly stressful and stress can affect general health. The aims were to identify sources of stress among preclinical students and to evaluate their perceived levels of stress, self-efficacy and effective coping strategies in a private dental school. One hundred preclinical students in a Turkish private dental school were surveyed using dental environment stress (DES), perceived stress (PSS), general self-efficacy (G-SES) and brief coping scales (Brief-COPE). Age, gender, history of psychiatric treatment, factors that affected the choice of dentistry, choice rank of dental school, scholarship and income was recorded. 'Exams and grades' followed by 'Fear of failing course or year' were found to be the most stressprovoking factors. The most and the least stressprovoking DES domains were 'Workload' and 'Social stressors', respectively. 'Social stressors' affected male more than female (p < .05). The most and the least common coping strategies were found to be 'Planning', and 'Drug', respectively. Female used 'Instrumental support' more than male (p < .05). Demographic factors had impact on the perceived stress factors and levels, as well as coping strategies. Unlike previous studies establishing high stress levels in dental students, preclinical students displayed moderate level of stress. Clinical dental education might be more responsible for creating stress.

In vitro assessment of skin irritation potential of surfactant-based formulations by using a 3-D skin reconstructed tissue model and cytokine response.

PubMed

Walters, Russel M; Gandolfi, Lisa; Mack, M Catherine; Fevola, Michael; Martin, Katharine; Hamilton, Mathew T; Hilberer, Allison; Barnes, Nicole; Wilt, Nathan; Nash, Jennifer R; Raabe, Hans A; Costin, Gertrude-Emilia

2016-12-01

The personal care industry is focused on developing safe, more efficacious, and increasingly milder products, that are routinely undergoing preclinical and clinical testing before becoming available for consumer use on skin. In vitro systems based on skin reconstructed equivalents are now established for the preclinical assessment of product irritation potential and as alternative testing methods to the classic Draize rabbit skin irritation test. We have used the 3-D EpiDerm™ model system to evaluate tissue viability and primary cytokine interleukin-1α release as a way to evaluate the potential dermal irritation of 224 non-ionic, amphoteric and/or anionic surfactant-containing formulations, or individual raw materials. As part of our testing programme, two representative benchmark materials with known clinical skin irritation potential were qualified through repeated testing, for use as references for the skin irritation evaluation of formulations containing new surfactant ingredients. We have established a correlation between the in vitro screening approach and clinical testing, and are continually expanding our database to enhance this correlation. This testing programme integrates the efforts of global manufacturers of personal care products that focus on the development of increasingly milder formulations to be applied to the skin, without the use of animal testing. 2016 FRAME.

Efficacy and safety of selective glucocorticoid receptor modulators in comparison to glucocorticoids in arthritis, a systematic review.

PubMed

Safy, M; de Hair, M J H; Jacobs, J W G; Buttgereit, F; Kraan, M C; van Laar, J M

2017-01-01

Long-term treatment with glucocorticoids (GCs) plays an important role in the management of arthritis patients, although the efficacy/safety balance is unfavorable. Alternatives with less (severe) adverse effects but with good efficacy are needed. Selective GC receptor modulators (SGRMs) are designed to engage the GC receptor with dissociative characteristics: transactivation of genes, which is mainly responsible for unwanted effects, is less strong while trans-repression of genes, reducing inflammation, is maintained. It is expected that SGRMs thus have a better efficacy/safety balance than GCs. A systematic review providing an overview of the evidence in arthritis is lacking. To systematically review the current literature on efficacy and safety of oral SGRMs in comparison to GCs in arthritis. A search was performed in Medline, Embase and the Cochrane Library, from inception dates of databases until May 2017. Experimental studies involving animal arthritis models or human material of arthritis patients, as well as clinical studies in arthritis patients were included, provided they reported original data. All types of arthritis were included. Data was extracted on the SGRM studied and on the GC used as reference standard; the design or setting of the study was extracted as well as the efficacy and safety results. A total of 207 articles was retrieved of which 17 articles were eligible for our analysis. Two studies concerned randomized controlled trials (RCT), five studies were pre-clinical studies using human material, and 10 studies involved pre-clinical animal models (acute and/or chronic arthritis induced in mice or rats). PF-04171327, the only compound investigated in a clinical trial setting, had a better efficacy/safety balance compared to GCs: better clinical anti-inflammatory efficacy and similar safety. Studies assessing both efficacy and safety of SGRMs are scarce. There is limited evidence for dissociation of anti-inflammatory and metabolic effects of the SGRMs studied. Development of many SGRMs is haltered in a preclinical phase. One SGRM showed a better clinical efficacy/safety balance.

World association for the advancement of veterinary parasitology (WAAVP) guideline for testing the efficacy of ectoparasiticides for fish.

PubMed

Sommerville, C; Endris, R; Bell, T A; Ogawa, K; Buchmann, K; Sweeney, D

2016-03-30

This guideline is intended to assist in the planning and execution of studies designed to assess the efficacy of ectoparasiticides for fish. It is the first ectoparasite-specific guideline to deal with studies set in the aquatic environment and therefore provides details for the maintenance of environmental standards for finfish. Information is included on a range of pre-clinical study designs as well as clinical studies in commercial/production sites, set within a regulatory framework. It provides information on the study animals, their welfare, husbandry and environmental requirements during the study. The most commonly pathogenic ectoparasites are presented with relevant points regarding life history, host challenge and numeric evaluation. Preparation and presentation of both topical and oral test treatments is provided, together with guidance on data collection and analysis. The guideline provides a quality standard or efficacy studies on finfish, which will assist researchers and regulatory authorities worldwide and contribute to the wider objective of harmonisation of procedures.

Targeting HER2 Aberrations in Non-Small Cell Lung Cancer with Osimertinib.

PubMed

Liu, Shengwu; Li, Shuai; Hai, Josephine; Wang, Xiaoen; Chen, Ting; Quinn, Max M; Gao, Peng; Zhang, Yanxi; Ji, Hongbin; Cross, Darren A E; Wong, Kwok-Kin

2018-01-03

Purpose: HER2 (or ERBB2 ) aberrations, including both amplification and mutations, have been classified as oncogenic drivers that contribute to 2% to 6% of lung adenocarcinomas. HER2 amplification is also an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKI). However, due to limited preclinical studies and clinical trials, currently there is still no available standard of care for lung cancer patients with HER2 aberrations. To fulfill the clinical need for targeting HER2 in patients with non-small cell lung cancer (NSCLC), we performed a comprehensive preclinical study to evaluate the efficacy of a third-generation TKI, osimertinib (AZD9291). Experimental Design: Three genetically modified mouse models (GEMM) mimicking individual HER2 alterations in NSCLC were generated, and osimertinib was tested for its efficacy against these HER2 aberrations in vivo Results: Osimertinib treatment showed robust efficacy in HER2 wt overexpression and EGFR del19/HER2 models, but not in HER2 exon 20 insertion tumors. Interestingly, we further identified that combined treatment with osimertinib and the BET inhibitor JQ1 significantly increased the response rate in HER2 -mutant NSCLC, whereas JQ1 single treatment did not show efficacy. Conclusions: Overall, our data indicated robust antitumor efficacy of osimertinib against multiple HER2 aberrations in lung cancer, either as a single agent or in combination with JQ1. Our study provides a strong rationale for future clinical trials using osimertinib either alone or in combination with epigenetic drugs to target aberrant HER2 in patients with NSCLC. Clin Cancer Res; 24(11); 1-11. ©2018 AACR. See related commentary by Cappuzzo and Landi, p. 2470 . ©2018 American Association for Cancer Research.

The efficacy of chimeric antigen receptor (CAR) immunotherapy in animal models for solid tumors: A systematic review and meta-analysis.

PubMed

Wu, Yingcheng; Xu, Ran; Jia, Keren; Shi, Hui

2017-01-01

Most recently, an emerging theme in the field of tumor immunology predominates: chimeric antigen receptor (CAR) therapy in treating solid tumors. The number of related preclinical trials was surging. However, an evaluation of the effects of preclinical studies remained absent. Hence, a meta-analysis was conducted on the efficacy of CAR in animal models for solid tumors. The authors searched PubMed/Medline, Embase, and Google scholar up to April 2017. HR for survival was extracted based on the survival curve. The authors used fixed effect models to combine the results of all the trials. Heterogeneity was assessed by I-square statistic. Quality assessment was conducted following the Stroke Therapy Academic Industry Roundtable standard. Publication bias was assessed using Egger's test. Eleven trials were included, including 54 experiments with a total of 362 animals involved. CAR immunotherapy significantly improved the survival of animals (HR: 0.25, 95% CI: 0.13-0.37, P < 0.001). The quality assessment revealed that no study reported whether allocation concealment and blinded outcome assessment were conducted, and only five studies implemented randomization. This meta-analysis indicated that CAR therapy may be a potential clinical strategy in treating solid tumors.

Large animal models for vaccine development and testing.

PubMed

Gerdts, Volker; Wilson, Heather L; Meurens, Francois; van Drunen Littel-van den Hurk, Sylvia; Wilson, Don; Walker, Stewart; Wheler, Colette; Townsend, Hugh; Potter, Andrew A

2015-01-01

The development of human vaccines continues to rely on the use of animals for research. Regulatory authorities require novel vaccine candidates to undergo preclinical assessment in animal models before being permitted to enter the clinical phase in human subjects. Substantial progress has been made in recent years in reducing and replacing the number of animals used for preclinical vaccine research through the use of bioinformatics and computational biology to design new vaccine candidates. However, the ultimate goal of a new vaccine is to instruct the immune system to elicit an effective immune response against the pathogen of interest, and no alternatives to live animal use currently exist for evaluation of this response. Studies identifying the mechanisms of immune protection; determining the optimal route and formulation of vaccines; establishing the duration and onset of immunity, as well as the safety and efficacy of new vaccines, must be performed in a living system. Importantly, no single animal model provides all the information required for advancing a new vaccine through the preclinical stage, and research over the last two decades has highlighted that large animals more accurately predict vaccine outcome in humans than do other models. Here we review the advantages and disadvantages of large animal models for human vaccine development and demonstrate that much of the success in bringing a new vaccine to market depends on choosing the most appropriate animal model for preclinical testing. © The Author 2015. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Drug Discovery Algorithm for Cutaneous Leishmaniasis

PubMed Central

Grogl, Max; Hickman, Mark; Ellis, William; Hudson, Thomas; Lazo, John S.; Sharlow, Elizabeth R.; Johnson, Jacob; Berman, Jonathan; Sciotti, Richard J.

2013-01-01

Cutaneous leishmaniasis is clinically widespread but lacks treatments that are effective and well tolerated. Because all present drugs have been grandfathered into clinical use, there are no examples of a pre-clinical product evaluation scheme that lead to new candidates for formal development. To provide oral agents for development targeting cutaneous leishmaniasis, we have implemented a discovery scheme that incorporates in vitro and in vivo testing of efficacy, toxicity, and pharmacokinetics/metabolism. Particular emphasis is placed on in vivo testing, progression from higher-throughput models to those with most clinical relevance, and efficient use of resources. PMID:23390221

An immunologic model for rapid vaccine assessment -- a clinical trial in a test tube.

PubMed

Higbee, Russell G; Byers, Anthony M; Dhir, Vipra; Drake, Donald; Fahlenkamp, Heather G; Gangur, Jyoti; Kachurin, Anatoly; Kachurina, Olga; Leistritz, Del; Ma, Yifan; Mehta, Riyaz; Mishkin, Eric; Moser, Janice; Mosquera, Luis; Nguyen, Mike; Parkhill, Robert; Pawar, Santosh; Poisson, Louis; Sanchez-Schmitz, Guzman; Schanen, Brian; Singh, Inderpal; Song, Haifeng; Tapia, Tenekua; Warren, William; Wittman, Vaughan

2009-09-01

While the duration and size of human clinical trials may be difficult to reduce, there are several parameters in pre-clinical vaccine development that may be possible to further optimise. By increasing the accuracy of the models used for pre-clinical vaccine testing, it should be possible to increase the probability that any particular vaccine candidate will be successful in human trials. In addition, an improved model will allow the collection of increasingly more-informative data in pre-clinical tests, thus aiding the rational design and formulation of candidates entered into clinical evaluation. An acceleration and increase in sophistication of pre-clinical vaccine development will thus require the advent of more physiologically-accurate models of the human immune system, coupled with substantial advances in the mechanistic understanding of vaccine efficacy, achieved by using this model. We believe the best viable option available is to use human cells and/or tissues in a functional in vitro model of human physiology. Not only will this more accurately model human diseases, it will also eliminate any ethical, moral and scientific issues involved with use of live humans and animals. An in vitro model, termed "MIMIC" (Modular IMmune In vitro Construct), was designed and developed to reflect the human immune system in a well-based format. The MIMIC System is a laboratory-based methodology that replicates the human immune system response. It is highly automated, and can be used to simulate a clinical trial for a diverse population, without putting human subjects at risk. The MIMIC System uses the circulating immune cells of individual donors to recapitulate each individual human immune response by maintaining the autonomy of the donor. Thus, an in vitro test system has been created that is functionally equivalent to the donor's own immune system and is designed to respond in a similar manner to the in vivo response. 2009 FRAME.

Translation of nondopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys to success and roads to failure.

PubMed

Fox, Susan H; Lang, Anthony E; Brotchie, Jonathan M

2006-10-01

Studies in MPTP-lesioned nonhuman primates have demonstrated the potential of nondopaminergic drugs in reducing the problems of levodopa-induced dyskinesia (LID). Here we review the process of translating findings from the monkey to man. Agents targeting glutamate, adensosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems have been assessed for antidyskinetic potential in human studies. Eleven nondopaminergic drugs with antidyskinetic efficacy in the MPTP primate have been advanced to proof-of-concept phase IIa trials in PD patients (amantadine, istradefylline, idazoxan, fipamezole, sarizotan, quetiapine, clozapine, nabilone, rimonabant, naloxone, and naltrexone). For all six nondopaminergic transmitter systems reviewed, the MPTP-lesioned primate correctly predicted phase II efficacy of at least one drug. Of the 11 specific molecules tested in both monkeys and humans, 8 showed clear antidyskinetic properties in both human and monkey. In the instances where the primate studies did not, or did not consistently, predict the outcome of the human studies, the discrepancy may reflect limitations in the validity of the model or limitations in the design of either the clinical or the preclinical studies. We find that the major determinant of success in predicting efficacy is to ensure that primate studies are conducted in a statistically rigorous way and incorporate designs and outcome measures with clinical applicability. On the other hand, phase IIa trials should strive to replicate the preclinical study, especially in terms of protocol, drug dose equivalence, and outcome measure, so as to test the same hypothesis. Failure to meet these criteria carries the risk of false negative conclusions in phase IIa trials.

Food and Drug Administration regulation and evaluation of vaccines.

PubMed

Marshall, Valerie; Baylor, Norman W

2011-05-01

The vaccine-approval process in the United States is regulated by the Center for Biologics Evaluation and Research of the US Food and Drug Administration. Throughout the life cycle of development, from preclinical studies to after licensure, vaccines are subject to rigorous testing and oversight. Manufacturers must adhere to good manufacturing practices and control procedures to ensure the quality of vaccines. As mandated by Title 21 of the Code of Regulations, licensed vaccines must meet stringent criteria for safety, efficacy, and potency.

Preclinical Efficacy of [V4Q5]dDAVP, a Second Generation Vasopressin Analog, on Metastatic Spread and Tumor-Associated Angiogenesis in Colorectal Cancer.

PubMed

Garona, Juan; Sobol, Natasha T; Pifano, Marina; Segatori, Valeria I; Gomez, Daniel E; Ripoll, Giselle V; Alonso, Daniel F

2018-06-01

Control of metastatic spread of colorectal cancer (CRC) remains as a major therapeutic challenge. [V4Q5]dDAVP is a vasopressin peptide analog with previously reported anticancer activity against carcinoma tumors. By acting as a selective agonist of AVPR2 present in endothelial and tumor cells, [V4Q5]dDAVP is able to impair tumor aggressiveness and distant spread. Our aim was to evaluate the potential therapeutic benefits of [V4Q5]dDAVP on highly aggressive CRC disease using experimental models with translational relevance. Murine CT-26 and human Colo-205 AVPR2-expressing CRC cell lines were used to test the preclinical efficacy of [V4Q5]dDAVP, both in vitro and in vivo. In syngeneic mice surgically implanted with CT-26 cells in the spleen, sustained i.v. treatment with [V4Q5]dDAVP (0.3 µg/kg) dramatically impaired metastatic progression to liver without overt signs of toxicity, and also reduced experimental lung colonization. The compound inhibited in vivo angiogenesis driven by Colo-205 cells in athymic mice, as well as in vitro endothelial cell migration and capillary tube formation. [V4Q5]dDAVP exerted AVPR2-dependent cytostatic activity in vitro (IC50 1.08 µM) and addition to 5-FU resulted in synergistic antiproliferative effects both in CT-26 and Colo-205 cells. The present preclinical study establishes for the first time the efficacy of [V4Q5]dDAVP on CRC. These encouraging results suggest that the novel second generation vasopressin analog could be used for the management of aggressive CRC as an adjuvant agent during surgery or to complement standard chemotherapy, limiting tumor angiogenesis and metastasis and thus protecting the patient from CRC recurrence.

Deriving Therapies for Children with Primary CNS Tumors Using Pharmacokinetic Modeling and Simulation of Cerebral Microdialysis Data

PubMed Central

Jacus, M.O.; Throm, S.L.; Turner, D.C.; Patel, Y.T.; Freeman, B.B.; Morfouace, M.; Boulos, N.; Stewart, C. F.

2014-01-01

The treatment of children with primary central nervous system (CNS) tumors continues to be a challenge despite recent advances in technology and diagnostics. In this overview, we describe our approach for identifying and evaluating active anticancer drugs through a process that enables rational translation from the lab to the clinic. The preclinical approach we discuss uses tumor subgroup-specific models of pediatric CNS tumors, cerebral microdialysis sampling of tumor extracellular fluid (tECF), and pharmacokinetic modeling and simulation to overcome challenges that currently hinder researchers in this field. This approach involves performing extensive systemic (plasma) and target site (CNS tumor) pharmacokinetic studies. Pharmacokinetic modeling and simulation of the data derived from these studies are then used to inform future decisions regarding drug administration, including dosage and schedule. Here, we also present how our approach was used to examine two FDA approved drugs, simvastatin and pemetrexed, as candidates for new therapies for pediatric CNS tumors. We determined that due to unfavorable pharmacokinetic characteristics and insufficient concentrations in tumor tissue in a mouse model of ependymoma, simvastatin would not be efficacious in further preclinical trials. In contrast to simvastatin, pemetrexed was advanced to preclinical efficacy studies after our studies determined that plasma exposures were similar to those in humans treated at similar tolerable dosages and adequate unbound concentrations were found in tumor tissue of medulloblastoma-bearing mice. Generally speaking, the high clinical failure rates for CNS drug candidates can be partially explained by the fact that therapies are often moved into clinical trials without extensive and rational preclinical studies to optimize the transition. Our approach addresses this limitation by using pharmacokinetic and pharmacodynamic modeling of data generated from appropriate in vivo models to support the rational testing and usage of innovative therapies in children with CNS tumors. PMID:24269626

Pharmacologic Management of Duchenne Muscular Dystrophy: Target Identification and Preclinical Trials

PubMed Central

Kornegay, Joe N.; Spurney, Christopher F.; Nghiem, Peter P.; Brinkmeyer-Langford, Candice L.; Hoffman, Eric P.; Nagaraju, Kanneboyina

2014-01-01

Duchenne muscular dystrophy (DMD) is an X-linked human disorder in which absence of the protein dystrophin causes degeneration of skeletal and cardiac muscle. For the sake of treatment development, over and above definitive genetic and cell-based therapies, there is considerable interest in drugs that target downstream disease mechanisms. Drug candidates have typically been chosen based on the nature of pathologic lesions and presumed underlying mechanisms and then tested in animal models. Mammalian dystrophinopathies have been characterized in mice (mdx mouse) and dogs (golden retriever muscular dystrophy [GRMD]). Despite promising results in the mdx mouse, some therapies have not shown efficacy in DMD. Although the GRMD model offers a higher hurdle for translation, dogs have primarily been used to test genetic and cellular therapies where there is greater risk. Failed translation of animal studies to DMD raises questions about the propriety of methods and models used to identify drug targets and test efficacy of pharmacologic intervention. The mdx mouse and GRMD dog are genetically homologous to DMD but not necessarily analogous. Subcellular species differences are undoubtedly magnified at the whole-body level in clinical trials. This problem is compounded by disparate cultures in clinical trials and preclinical studies, pointing to a need for greater rigor and transparency in animal experiments. Molecular assays such as mRNA arrays and genome-wide association studies allow identification of genetic drug targets more closely tied to disease pathogenesis. Genes in which polymorphisms have been directly linked to DMD disease progression, as with osteopontin, are particularly attractive targets. PMID:24936034

Training future doctors to be patient-centred: efficacy of a communication skills training (CST) programme in a Malaysian medical institution.

PubMed

Lukman, H; Beevi, Z; Yeap, R

2009-03-01

This study evaluates the efficacy of the preclinical communication skills training (CST) programme at the International Medical University in Malaysia. Efficacy indicators include students' (1) perceived competency (2) attitude (3) conceptual knowledge, and (4) performance with regard to patient-centred communication. A longitudinal study with a before-after design tracked a preclinical cohort's progress on the aforementioned indicators as they advance through the training. Results indicate that following the CST, students perceived themselves to be more competent in interpersonal communication, had more positive attitude towards patient-centred communication, and developed a better conceptual knowledge of doctor-patient communication. In addition, those with good conceptual knowledge tend to demonstrate better communication skills performance at the Objective Structure Clinical Examination 12 months following the initial CST.

Adjuvant bisphosphonate treatment for breast cancer: Where are we heading and can the pre-clinical literature help us get there?

PubMed

Russell, Kent; Clemons, Mark; Costa, Luis; Addison, Christina L

2012-06-01

Bisphosphonates have demonstrated anti-tumour activity in preclinical studies of bone metastatic disease, thus it was natural to transition these agents into the adjuvant cancer therapy setting. Surprisingly, the results of adjuvant breast cancer trials have shown either modest to no benefit or even harm. We sought to explore whether the preclinical results supporting bisphosphonate use provided clues to help explain the current clinical data. Interestingly, the majority of preclinical data suggested that bisphosphonate treatment was more efficacious when administered after the establishment of osseous metastases. This is similar to the findings of one clinical study whereby patients with biopsy evidence of osseous micrometastases derive greater survival benefit from bisphosphonate treatment. Another clinical study found bisphosphonates were associated with increased incidence of visceral metastases, similar to what has been previously published in preclinical models using "preventative" dosing strategies. While the current clinical data suggest bisphosphonates may be more efficacious in post-menopausal or oestrogen depleted patients, or those with hormone receptor positive tumours, to date no appropriately designed preclinical studies have evaluated these effects. Furthermore, putative mechanisms that regulate response to bisphosphonates in other tumour types remain to be evaluated in breast cancer. Despite the initial optimism regarding adjuvant bisphosphonate therapy, the conflicting clinical results from large trials suggest that we should return to the bench to further investigate factors that may influence response to bisphosphonate treatment or identify appropriate characteristics that would indicate the sub-groups of patients most likely to benefit from bisphosphonate treatment.

Abuse liability assessment in preclinical drug development: predictivity of a translational approach for abuse liability testing using methylphenidate in four standardized preclinical study models.

PubMed

Teuns, Greet B A; Geys, Helena M; Geuens, Sonja M A; Stinissen, Piet; Meert, Theo F

2014-01-01

Preclinical abuse liability assessment of novel clinical CNS-active candidates involves several tests, addressing different aspects characteristic for abuse potential, which are considered predictive for substance abuse of these candidates, thus ensuring an appropriate translational approach. To demonstrate how such a strategy could work, a known drug of abuse, methylphenidate was evaluated in a full rodent test battery, comprising four test models, and in accordance with the requirements of the FDA, ICH and EMA guidelines. Methylphenidate was tested orally at 2.5, 5 or 10mg/kg for its physical dependence potential in a repeated dose non-precipitated withdrawal test, for its drug profiling in a drug discrimination learning procedure (single escalating doses), and for its reinforcing properties in a conditioned place preference test (alternate dosing days) and an intravenous self-administration procedure (0.05 to 1mg/kg/IV infusion during 5 daily 1-h test sessions). The stimulant d-amphetamine served as positive control and was administered subcutaneously at 0.8mg/kg in the first three test models. In the intravenous self-administration procedure rats were habituated to intravenously self-administer d-amphetamine at 0.06mg/kg/IV infusion prior to methylphenidate substitution. Cessation of subchronic dosing up to 10mg/kg methylphenidate led to sustained or even exacerbated effects on locomotion and behavior, body temperature, body weight, food consumption, and alteration of the diurnal rhythm during withdrawal. Clear generalization to d-amphetamine was obtained in the drug discrimination test at 5 and 10mg/kg. Distinct reinforcing properties were present in the conditioned place preference test at 10mg/kg and in the intravenous self-administration study from 0.05mg/kg/IV infusion onwards. The maximum plasma exposure after oral administration of methylphenidate over the dose ranges tested in the present rat studies covered at least 1.9-fold to 18.9-fold the recommended human therapeutic exposure of 10ng/ml, a plasma level that is considered representative of the human efficacious methylphenidate dose. The ratio Cmax Hu/rat calculated from the intravenous self-administration data ranged from 14.9 to 576.5. Consequently the regulatory requirements, stating that preclinical drug abuse liability studies should include high doses that produce plasma levels that are multiples of the therapeutic dose were fulfilled (FDA, EMA, ICH). The presented preclinical models, implemented within a drug development environment, were considered highly predictive to assess the abuse potential of methylphenidate, and in accordance with the regulatory requirements of drug licensing authorities in terms of appropriate methods, dose selection and subsequent plasma exposure. Copyright © 2014 Elsevier Inc. All rights reserved.

ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer.

PubMed

Lev, Avital; Lulla, Amriti R; Ross, Brian C; Ralff, Marie D; Makhov, Petr B; Dicker, David T; El-Deiry, Wafik S

2018-05-01

Androgen receptor (AR) signaling plays a key role in prostate cancer progression, and androgen deprivation therapy (ADT) is a mainstay clinical treatment regimen for patients with advanced disease. Unfortunately, most prostate cancers eventually become androgen-independent and resistant to ADT with patients progressing to metastatic castration-resistant prostate cancer (mCRPC). Constitutively activated AR variants (AR-V) have emerged as mediators of resistance to AR-targeted therapy and the progression of mCRPC, and they represent an important therapeutic target. Out of at least 15 AR-Vs described thus far, AR-V7 is the most abundant, and its expression correlates with ADT resistance. ONC201/TIC10 is the founding member of the imipridone class of small molecules and has shown anticancer activity in a broad range of tumor types. ONC201 is currently being tested in phase I/II clinical trials for advanced solid tumors, including mCRPC, and hematologic malignancies. There has been promising activity observed in patients in early clinical testing. This study demonstrates preclinical single-agent efficacy of ONC201 using in vitro and in vivo models of prostate cancer. ONC201 has potent antiproliferative and proapoptotic effects in both castration-resistant and -sensitive prostate cancer cells. Furthermore, the data demonstrate that ONC201 downregulates the expression of key drivers of prostate cancer such as AR-V7 and downstream target genes including the clinically used biomarker PSA (KLK3). Finally, the data also provide a preclinical rationale for combination of ONC201 with approved therapeutics for prostate cancer such as enzalutamide, everolimus (mTOR inhibitor), or docetaxel. Implications: The preclinical efficacy of ONC201 as a single agent or in combination, in hormone-sensitive or castration-resistant prostate cancer, suggests the potential for immediate clinical translation. Mol Cancer Res; 16(5); 754-66. ©2018 AACR . ©2018 American Association for Cancer Research.

Preclinical evaluation of hydrogel sealed fluropassivated indigenous vascular prosthesis.

PubMed

Unnikrishnan, Madathipat; Umashankar, P R; Viswanathan, Sidharth; Savlania, Ajay; Joseph, Roy; Muraleedharan, C V; Agrawal, Vivek; Shenoy, Sachin J; Krishnan, Lissy K; Mohanan, P V; Sabareeswaran, A

2017-11-01

Polyethylene terephthalate (PET) graft, designed and developed at our institute for vascular reconstruction, is porous to promote optimal incorporation and neointima formation, requiring pre-clotting or biomodification by sealing the pores before implantation. The objective of this study was to characterize, test and perform preclinical evaluation of hydrogel (alginate dialdehyde cross-linked gelatin) sealed fluoropassivated PET vascular prosthesis in pig model, so as to avoid pre-clotting, for its safety and efficacy before employing the indigenous and less expensive graft for clinical use. Hydrogel sealed, fluoropassivated PET vascular prosthesis were tested for haemocompatibility and toxicity followed by small animal toxicology tests and in vivo experiments in pigs receiving implantation at thoracic aorta. All 33 animals received test as well as control grafts with a plan for phased explantation at 2, 12 and 26 weeks. All animals underwent completion angiogram at the end of procedure as well as before graft explantation. Haemocompatibility tests for haemolysis and toxicity tests showed no adverse events in tested mice and rabbits. Completion angiogram showed intact anastamosis and patent graft in each animal in post-operative period and at explantation. Gross and histopathological examination showed well-encapsulated grafts, clean glistening neointima and no evidence of thrombus in both test and control grafts. Hydrogel sealed, fluoropassivated PET vascular prosthesis was found non-toxic, haemocompatible and remained patent in in vivo studies at planned intervals.

Preclinical evaluation of hydrogel sealed fluropassivated indigenous vascular prosthesis

PubMed Central

Unnikrishnan, Madathipat; Umashankar, P.R.; Viswanathan, Sidharth; Savlania, Ajay; Joseph, Roy; Muraleedharan, C.V.; Agrawal, Vivek; Shenoy, Sachin J.; Krishnan, Lissy K.; Mohanan, P.V.; Sabareeswaran, A.

2017-01-01

Background & objectives: Polyethylene terephthalate (PET) graft, designed and developed at our institute for vascular reconstruction, is porous to promote optimal incorporation and neointima formation, requiring pre-clotting or biomodification by sealing the pores before implantation. The objective of this study was to characterize, test and perform preclinical evaluation of hydrogel (alginate dialdehyde cross-linked gelatin) sealed fluoropassivated PET vascular prosthesis in pig model, so as to avoid pre-clotting, for its safety and efficacy before employing the indigenous and less expensive graft for clinical use. Methods: Hydrogel sealed, fluoropassivated PET vascular prosthesis were tested for haemocompatibility and toxicity followed by small animal toxicology tests and in vivo experiments in pigs receiving implantation at thoracic aorta. All 33 animals received test as well as control grafts with a plan for phased explantation at 2, 12 and 26 weeks. All animals underwent completion angiogram at the end of procedure as well as before graft explantation. Results: Haemocompatibility tests for haemolysis and toxicity tests showed no adverse events in tested mice and rabbits. Completion angiogram showed intact anastamosis and patent graft in each animal in post-operative period and at explantation. Gross and histopathological examination showed well-encapsulated grafts, clean glistening neointima and no evidence of thrombus in both test and control grafts. Interpretation & conclusions: Hydrogel sealed, fluoropassivated PET vascular prosthesis was found non-toxic, haemocompatible and remained patent in in vivo studies at planned intervals. PMID:29512608

Perspectives for Developing New Tuberculosis Vaccines Derived from the Pathogenesis of Tuberculosis: I. Basic Principles, II. Preclinical Testing, and III. Clinical Testing

PubMed Central

Dannenberg, Arthur M.; Dey, Bappaditya

2013-01-01

Part I. Basic Principles. TB vaccines cannot prevent establishment of the infection. They can only prevent an early pulmonary tubercle from developing into clinical disease. A more effective new vaccine should optimize both cell-mediated immunity (CMI) and delayed-type hypersensitivity (DTH) better than any existing vaccine. The rabbit is the only laboratory animal in which all aspects of the human disease can be reproduced: namely, the prevention of most primary tubercles, the arrestment of most primary tubercles, the formation of the tubercle’s solid caseous center, the liquefaction of this center, the formation of cavities and the bronchial spread of the disease. In liquefied caseum, virulent tubercle bacilli can multiply extracellularly, especially in the liquefied caseum next to the inner wall of a cavity where oxygen is plentiful. The bacilli in liquefied caseum cannot be reached by the increased number of activated macrophages produced by TB vaccines. Therefore, new TB vaccines will have little or no effect on the extracellular bacillary growth within liquefied caseum. TB vaccines can only increase the host’s ability to stop the development of new TB lesions that arise from the bronchial spread of tubercle bacilli from the cavity to other parts of the lung. Therefore, effective TB vaccines do not prevent the reactivation of latent TB. Such vaccines only control (or reduce) the number of metastatic lesions that result after the primary TB lesion was reactivated by the liquefaction process. (Note: the large number of tubercle bacilli growing extracellularly in liquefied caseum gives rise to mutations that enable antimicrobial resistance—which is a major reason why TB still exists today). Part II. Preclinical Testing. The counting of grossly visible tubercles in the lungs of rabbits after the inhalation of virulent human-type tubercle bacilli is the most pertinent preclinical method to assess the efficacy of new TB vaccines (because an effective vaccine will stop the growth of developing tubercles before while they are still microscopic in size). Unfortunately, rabbits are rarely used in preclinical vaccine trials, despite their relative ease of handling and human-like response to this infection. Mice do not generate an effective DTH response, and guinea pigs do not generate an effective CMI response. Only the rabbits and most humans can establish the proper amount of DTH and CMI that is necessary to contain this infection. Therefore, rabbits should be included in all pre-clinical testing of new TB vaccines. New drugs (and/or immunological procedures) to reduce liquefaction and cavity formation are urgently needed. A simple intradermal way to select such drugs or procedures is described herein. Part III. Clinical Testing. Vaccine trials would be much more precise if the variations in human populations (listed herein) were taken into consideration. BCG and successful new TB vaccines should always increase host resistance to TB in naive subjects. This is a basic immunological principle. The efficacies of new and old TB vaccines are often not recognized, because these variations were not identified in the populations evaluated. PMID:26343850

Neurobehavioral testing in subarachnoid hemorrhage: A review of methods and current findings in rodents.

PubMed

Turan, Nefize; Miller, Brandon A; Heider, Robert A; Nadeem, Maheen; Sayeed, Iqbal; Stein, Donald G; Pradilla, Gustavo

2017-11-01

The most important aspect of a preclinical study seeking to develop a novel therapy for neurological diseases is whether the therapy produces any clinically relevant functional recovery. For this purpose, neurobehavioral tests are commonly used to evaluate the neuroprotective efficacy of treatments in a wide array of cerebrovascular diseases and neurotrauma. Their use, however, has been limited in experimental subarachnoid hemorrhage studies. After several randomized, double-blinded, controlled clinical trials repeatedly failed to produce a benefit in functional outcome despite some improvement in angiographic vasospasm, more rigorous methods of neurobehavioral testing became critical to provide a more comprehensive evaluation of the functional efficacy of proposed treatments. While several subarachnoid hemorrhage studies have incorporated an array of neurobehavioral assays, a standardized methodology has not been agreed upon. Here, we review neurobehavioral tests for rodents and their potential application to subarachnoid hemorrhage studies. Developing a standardized neurobehavioral testing regimen in rodent studies of subarachnoid hemorrhage would allow for better comparison of results between laboratories and a better prediction of what interventions would produce functional benefits in humans.

CD28z CARs and Armored CARs

PubMed Central

Pegram, Hollie J.; Park, Jae H.; Brentjens, Renier J.

2015-01-01

CD19-targeted chimeric antigen receptor (CAR) T cells are currently being tested in the clinic with very promising outcomes. However, limitations to CAR T cell therapy exist. These include lack of efficacy against some tumors, specific targeting of tumor cells without affecting normal tissue and retaining activity within the suppressive tumor microenvironment. Whilst promising clinical trials are in progress, preclinical development is focused on optimizing CAR design, to generate “armored CAR T cells” which are protected from the inhibitory tumor microenvironment. Studies investigating the expression of cytokine transgenes, combination therapy with small molecule inhibitors or monoclonal antibodies are aimed at improving the anti-tumor efficacy of CAR T cell therapy. Other strategies aimed at improving CAR T cell therapy include utilizing dual CARs and chemokine receptors to more specifically target tumor cells. This review will describe the current clinical data and some novel “armored CAR T cell” approaches for improving anti-tumor efficacy therapy. PMID:24667958

CD28z CARs and armored CARs.

PubMed

Pegram, Hollie J; Park, Jae H; Brentjens, Renier J

2014-01-01

CD19-targeted chimeric antigen receptor (CAR) T cells are currently being tested in the clinic with very promising outcomes. However, limitations to CAR T cell therapy exist. These include lack of efficacy against some tumors, specific targeting of tumor cells without affecting normal tissue and retaining activity within the suppressive tumor microenvironment. Whereas promising clinical trials are in progress, preclinical development is focused on optimizing CAR design, to generate "armored CAR T cells," which are protected from the inhibitory tumor microenvironment. Studies investigating the expression of cytokine transgenes, combination therapy with small molecule inhibitors, or monoclonal antibodies, are aimed at improving the antitumor efficacy of CAR T cell therapy. Other strategies aimed at improving CAR T cell therapy include using dual CARs and chemokine receptors to more specifically target tumor cells. This review will describe the current clinical data and some novel armored CAR T cell approaches for improving antitumor efficacy therapy.

Designing malaria vaccines to circumvent antigen variability✩

PubMed Central

Ouattara, Amed; Barry, Alyssa E.; Dutta, Sheetij; Remarque, Edmond J.; Beeson, James G.; Plowe, Christopher V.

2016-01-01

Prospects for malaria eradication will be greatly enhanced by an effective vaccine, but parasite genetic diversity poses a major impediment to malaria vaccine efficacy. In recent pre-clinical and field trials, vaccines based on polymorphic Plasmodium falciparum antigens have shown efficacy only against homologous strains, raising the specter of allele-specific immunity such as that which plagues vaccines against influenza and HIV. The most advanced malaria vaccine, RTS,S, targets relatively conserved epitopes on the P. falciparum circumsporozoite protein. After more than 40 years of development and testing, RTS,S, has shown significant but modest efficacy against clinical malaria in phase 2 and 3 trials. Ongoing phase 2 studies of an irradiated sporozoite vaccine will ascertain whether the full protection against homologous experimental malaria challenge conferred by high doses of a whole organism vaccine can provide protection against diverse strains in the field. Here we review and evaluate approaches being taken to design broadly cross-protective malaria vaccines. PMID:26475447

NITRIC OXIDE FOR THE ADJUNCTIVE TREATMENT OF SEVERE MALARIA: HYPOTHESIS AND RATIONALE

PubMed Central

Hawkes, Michael; Opoka, Robert Opika; Namasopo, Sophie; Miller, Christopher; Conroy, Andrea L.; Serghides, Lena; Kim, Hani; Thampi, Nisha; Liles, W. Conrad; John, Chandy C.; Kain, Kevin C.

2011-01-01

We hypothesize that supplemental inhaled nitric oxide (iNO) will improve outcomes in children with severe malaria receiving standard antimalarial therapy. The rationale for the hypothesized efficacy of iNO rests on: (1) biological plausibility, based on known actions of NO in modulating endothelial activation; (2) pre-clinical efficacy data from animal models of experimental cerebral malaria; and (3) a human trial of the NO precursor L-arginine, which improved endothelial function in adults with severe malaria. iNO is an attractive new candidate for the adjunctive treatment of severe malaria, given its proven therapeutic efficacy in animal studies, track record of safety in clinical practice and numerous clinical trials, inexpensive manufacturing costs, and ease of administration in settings with limited healthcare infrastructure. We plan to test this hypothesis in a randomized controlled trial (ClinicalTrials.gov Identifier: NCT01255215). PMID:21745716

Preclinical efficacy and safety of herbal formulation for management of wounds.

PubMed

Ogwang, P E; Nyafuono, J; Agwaya, Moses; Omujal, F; Tumusiime, H R; Kyakulaga, A H

2011-09-01

Medicinal plants in Uganda and other developing countries have been scientifically demonstrated to have medicinal benefits but few or none have been translated to products for clinical use. Most herbal products developed by local herbalists and sold to the public are not standardized and lack efficacy and safety data to support use. To formulate from two Ugandan medicinal plants a herbal product for wound management and test its preclinical safety and efficacy using rat models. Thirty (30) Wistar albino rats were randomly divided into three groups and wounds were surgically created on the mid-dorsal region. The wounds were treated topically with distilled water (group I), Jena(®) (group II)and Neomycin sulfate cream (group III). The effects of the treatments on rate of wound closure, epithelialisation time and histological organization of tissue were assessed. The herbal formulation (Jena) had a significantly higher rate of wound closure than neomycin (p<0.05) which itself was better than distilled water. Epithelialisation time was also significantly shorter for the herbal product (p<0.01). Histological picture revealed more collagen fibers, less inflammation and better tissue remodeling for rats treated with herbal product. The herbal formulation Jena(®) systematically designed and formulated based on two Ugandan medicinal plants is according to this study better than neomycin and probably other imported products for wound management in Uganda. We recommend its trial in a clinical setting as an alternative in wound management.

Evaluation of helper-dependent canine adenovirus vectors in a 3D human CNS model

PubMed Central

Simão, Daniel; Pinto, Catarina; Fernandes, Paulo; Peddie, Christopher J.; Piersanti, Stefania; Collinson, Lucy M.; Salinas, Sara; Saggio, Isabella; Schiavo, Giampietro; Kremer, Eric J.; Brito, Catarina; Alves, Paula M.

2017-01-01

Gene therapy is a promising approach with enormous potential for treatment of neurodegenerative disorders. Viral vectors derived from canine adenovirus type 2 (CAV-2) present attractive features for gene delivery strategies in the human brain, by preferentially transducing neurons, are capable of efficient axonal transport to afferent brain structures, have a 30-kb cloning capacity and have low innate and induced immunogenicity in pre-clinical tests. For clinical translation, in-depth pre-clinical evaluation of efficacy and safety in a human setting is primordial. Stem cell-derived human neural cells have a great potential as complementary tools by bridging the gap between animal models, which often diverge considerably from human phenotype, and clinical trials. Herein, we explore helper-dependent CAV-2 (hd-CAV-2) efficacy and safety for gene delivery in a human stem cell-derived 3D neural in vitro model. Assessment of hd-CAV-2 vector efficacy was performed at different multiplicities of infection, by evaluating transgene expression and impact on cell viability, ultrastructural cellular organization and neuronal gene expression. Under optimized conditions, hd-CAV-2 transduction led to stable long-term transgene expression with minimal toxicity. hd-CAV-2 preferentially transduced neurons, while human adenovirus type 5 (HAdV5) showed increased tropism towards glial cells. This work demonstrates, in a physiologically relevant 3D model, that hd-CAV-2 vectors are efficient tools for gene delivery to human neurons, with stable long-term transgene expression and minimal cytotoxicity. PMID:26181626

Evaluation of helper-dependent canine adenovirus vectors in a 3D human CNS model.

PubMed

Simão, D; Pinto, C; Fernandes, P; Peddie, C J; Piersanti, S; Collinson, L M; Salinas, S; Saggio, I; Schiavo, G; Kremer, E J; Brito, C; Alves, P M

2016-01-01

Gene therapy is a promising approach with enormous potential for treatment of neurodegenerative disorders. Viral vectors derived from canine adenovirus type 2 (CAV-2) present attractive features for gene delivery strategies in the human brain, by preferentially transducing neurons, are capable of efficient axonal transport to afferent brain structures, have a 30-kb cloning capacity and have low innate and induced immunogenicity in preclinical tests. For clinical translation, in-depth preclinical evaluation of efficacy and safety in a human setting is primordial. Stem cell-derived human neural cells have a great potential as complementary tools by bridging the gap between animal models, which often diverge considerably from human phenotype, and clinical trials. Herein, we explore helper-dependent CAV-2 (hd-CAV-2) efficacy and safety for gene delivery in a human stem cell-derived 3D neural in vitro model. Assessment of hd-CAV-2 vector efficacy was performed at different multiplicities of infection, by evaluating transgene expression and impact on cell viability, ultrastructural cellular organization and neuronal gene expression. Under optimized conditions, hd-CAV-2 transduction led to stable long-term transgene expression with minimal toxicity. hd-CAV-2 preferentially transduced neurons, whereas human adenovirus type 5 (HAdV5) showed increased tropism toward glial cells. This work demonstrates, in a physiologically relevant 3D model, that hd-CAV-2 vectors are efficient tools for gene delivery to human neurons, with stable long-term transgene expression and minimal cytotoxicity.

The 2007 Feinberg lecture: a new road map for neuroprotection.

PubMed

Donnan, Geoffrey A

2008-01-01

There have now been numerous phase III trials of neuroprotection that have failed to live up to the expectations created by preclinical testing in animal models, the most recent of which was the second pivotal trial of the spin trap agent NXY-059. We have reached a stage at which research in this area should stop altogether or radical new approaches adopted. The purpose of this article is to review how we reached this stage and make recommendations for a new approach to neuroprotection research. The background to neuroprotection research is reviewed and its problems are highlighted based on the research of others and of our own research group. From this, a series of questions are posed that require answers if the field is to progress. A road map for future research is then proposed. The road map involves the following steps for putative neuroprotectants: (1) better proof of efficacy in animal models; (2) in vivo evidence of efficacy in human tissue using cell cultures or brain slices; (3) in vivo studies of their distribution in the normal and ischemic human brain, particularly focusing on the ischemic penumbra; (4) demonstration of efficacy in novel human models of cerebral ischemia; and (5) phase II and III clinical trails with penumbral selection using imaging techniques. The accumulated evidence suggests that neuroprotection failure in clinical trial is due to identifiable preclinical and clinical factors. Neuroprotection research should be pursued but with a very different and more rigorous approach.

Challenges for Preclinical Investigations of Human Biofield Modalities

PubMed Central

Gronowicz, Gloria; Bengston, William

2015-01-01

Preclinical models for studying the effects of the human biofield have great potential to advance our understanding of human biofield modalities, which include external qigong, Johrei, Reiki, therapeutic touch, healing touch, polarity therapy, pranic healing, and other practices. A short history of Western biofield studies using preclinical models is presented and demonstrates numerous and consistent examples of human biofields significantly affecting biological systems both in vitro and in vivo. Methodological issues arising from these studies and practical solutions in experimental design are presented. Important questions still left unanswered with preclinical models include variable reproducibility, dosing, intentionality of the practitioner, best preclinical systems, and mechanisms. Input from the biofield practitioners in the experimental design is critical to improving experimental outcomes; however, the development of standard criteria for uniformity of practice and for inclusion of multiple practitioners is needed. Research in human biofield studies involving preclinical models promises a better understanding of the mechanisms underlying the efficacy of biofield therapies and will be important in guiding clinical protocols and integrating treatments with conventional medical therapies. PMID:26665042

Translational Data from Adeno-Associated Virus-Mediated Gene Therapy of Hemophilia B in Dogs

PubMed Central

Whitford, Margaret H.; Arruda, Valder R.; Stedman, Hansell H.; Kay, Mark A.; High, Katherine A.

2015-01-01

Abstract Preclinical testing of new therapeutic strategies in relevant animal models is an essential part of drug development. The choice of animal models of disease that are used in these studies is driven by the strength of the translational data for informing about safety, efficacy, and success or failure of human clinical trials. Hemophilia B is a monogenic, X-linked, inherited bleeding disorder that results from absent or dysfunctional coagulation factor IX (FIX). Regarding preclinical studies of adeno-associated virus (AAV)-mediated gene therapy for hemophilia B, dogs with severe hemophilia B (<1% FIX) provide well-characterized phenotypes and genotypes in which a species-specific transgene can be expressed in a mixed genetic background. Correction of the hemophilic coagulopathy by sustained expression of FIX, reduction of bleeding events, and a comprehensive assessment of the humoral and cell-mediated immune responses to the expressed transgene and recombinant AAV vector are all feasible end points in these dogs. This review compares the preclinical studies of AAV vectors used to treat dogs with hemophilia B with the results obtained in subsequent human clinical trials using muscle- and liver-based approaches. PMID:25675273

Translational data from adeno-associated virus-mediated gene therapy of hemophilia B in dogs.

PubMed

Nichols, Timothy C; Whitford, Margaret H; Arruda, Valder R; Stedman, Hansell H; Kay, Mark A; High, Katherine A

2015-03-01

Preclinical testing of new therapeutic strategies in relevant animal models is an essential part of drug development. The choice of animal models of disease that are used in these studies is driven by the strength of the translational data for informing about safety, efficacy, and success or failure of human clinical trials. Hemophilia B is a monogenic, X-linked, inherited bleeding disorder that results from absent or dysfunctional coagulation factor IX (FIX). Regarding preclinical studies of adeno-associated virus (AAV)-mediated gene therapy for hemophilia B, dogs with severe hemophilia B (<1% FIX) provide well-characterized phenotypes and genotypes in which a species-specific transgene can be expressed in a mixed genetic background. Correction of the hemophilic coagulopathy by sustained expression of FIX, reduction of bleeding events, and a comprehensive assessment of the humoral and cell-mediated immune responses to the expressed transgene and recombinant AAV vector are all feasible end points in these dogs. This review compares the preclinical studies of AAV vectors used to treat dogs with hemophilia B with the results obtained in subsequent human clinical trials using muscle- and liver-based approaches.

Recent developments in the behavioural and pharmacological enhancement of extinction of drug seeking.

PubMed

Chesworth, Rose; Corbit, Laura H

2017-01-01

One of the principal barriers to overcoming addiction is the propensity to relapse, even after months or years of abstinence. Relapse can be precipitated by cues and contexts associated with drug use; thus, decreasing the conditioned properties of these cues and contexts may assist in preventing relapse. The predictive power of drug cues and contexts can be reduced by repeatedly presenting them in the absence of the drug reinforcer, a process known as extinction. The potential of extinction to limit relapse has generated considerable interest and research over the past few decades. While pre-clinical animal models suggest extinction learning assists relapse prevention, treatment efficacy is often lacking when extinction learning principles are translated into clinical trials. Conklin and Tiffany (Addiction, 2002) suggest the lack of efficacy in clinical practice may be due to limited translation of procedures demonstrated through animal research and propose several methodological improvements to enhance extinction learning for drug addiction. This review will examine recent advances in the behavioural and pharmacological manipulation of extinction learning, based on research from pre-clinical models. In addition, the translation of pre-clinical findings-both those suggested by Conklin and Tiffany () and novel demonstrations from the past 13 years-into clinical trials and the efficacy of these methods in reducing craving and relapse, where available, will be discussed. Finally, we highlight areas where promising pre-clinical models have not yet been integrated into current clinical practice but, if applied, could improve upon existing behavioural and pharmacological methods. © 2015 Society for the Study of Addiction.

Determinants of the Efficacy of Cardiac Ischemic Preconditioning: A Systematic Review and Meta-Analysis of Animal Studies

PubMed Central

Wever, Kimberley E.; Hooijmans, Carlijn R.; Riksen, Niels P.; Sterenborg, Thomas B.; Sena, Emily S.; Ritskes-Hoitinga, Merel; Warlé, Michiel C.

2015-01-01

Background Ischemic preconditioning (IPC) of the heart is a protective strategy in which a brief ischemic stimulus immediately before a lethal ischemic episode potently limits infarct size. Although very promising in animal models of myocardial infarction, IPC has not yet been successfully translated to benefit for patients. Objective To appraise all preclinical evidence on IPC for myocardial infarction and identify factors hampering translation. Methods and results Using systematic review and meta-analysis, we identified 503 animal studies reporting infarct size data from 785 comparisons between IPC-treated and control animals. Overall, IPC reduced myocardial infarction by 24.6% [95%CI 23.5, 25.6]. Subgroup analysis showed that IPC efficacy was reduced in comorbid animals and non-rodents. Efficacy was highest in studies using 2–3 IPC cycles applied <45 minutes before myocardial infarction. Local and remote IPC were equally effective. Reporting of study quality indicators was low: randomization, blinding and a sample size calculation were reported in 49%, 11% and 2% of publications, respectively. Conclusions Translation of IPC to the clinical setting may be hampered by the observed differences between the animals used in preclinical IPC studies and the patient population, regarding comorbidity, sex and age. Furthermore, the IPC protocols currently used in clinical trials could be optimized in terms of timing and the number of ischemic cycles applied. In order to inform future clinical trials successfully, future preclinical studies on IPC should aim to maximize both internal and external validity, since poor methodological quality may limit the value of the preclinical evidence. PMID:26580958

RAPA: a novel in vitro method to evaluate anti-bacterial skin cleansing products.

PubMed

Ansari, S A; Gafur, R B; Jones, K; Espada, L A; Polefka, T G

2010-04-01

Development of efficacious anti-bacterial skin cleansing products has been limited by the availability of a pre-clinical (in vitro) method to predict clinical efficacy adequately. We report a simple and rapid method, designated as rapid agar plate assay (RAPA), that uses the bacteriological agar surface as a surrogate substrate for skin and combines elements of two widely used in vivo (clinical) methods (Agar Patch and Cup Scrub). To simulate the washing of the human hand or forearm skin with the test product, trypticase soy agar plates were directly washed with the test product and rinsed under running tap water. After air-drying the washed plates, test bacteria (Staphylococcus aureus or Escherichia coli) were applied and the plates were incubated at 37 degrees C for 18-24 h. Using S. aureus as the test organism, anti-bacterial bar soap containing triclocarbanilide showed a strong linear relationship (R(2) = 0.97) between bacterial dose and their per cent reduction. A similar dose-response relationship (R(2) = 0.96) was observed for anti-bacterial liquid hand soap against E. coli. RAPA was able to distinguish between anti-bacterial products based on the nature and level of actives in them. In limited comparative tests, results obtained by RAPA were comparable with the results obtained by clinical agar patch and clinical cup scrub methods. In conclusion, RAPA provides a simple, rugged and reproducible in vitro method for testing the relative efficacy of anti-bacterial skin cleansing products with a likelihood of comparable clinical efficacy. Further testing is warranted to improve the clinical predictability of this method.

Preclinical evaluation of convection-enhanced delivery of liposomal doxorubicin to treat pediatric diffuse intrinsic pontine glioma and thalamic high-grade glioma.

PubMed

Sewing, A Charlotte P; Lagerweij, Tonny; van Vuurden, Dannis G; Meel, Michaël H; Veringa, Susanna J E; Carcaboso, Angel M; Gaillard, Pieter J; Peter Vandertop, W; Wesseling, Pieter; Noske, David; Kaspers, Gertjan J L; Hulleman, Esther

2017-05-01

OBJECTIVE Pediatric high-grade gliomas (pHGGs) including diffuse intrinsic pontine gliomas (DIPGs) are primary brain tumors with high mortality and morbidity. Because of their poor brain penetrance, systemic chemotherapy regimens have failed to deliver satisfactory results; however, convection-enhanced delivery (CED) may be an alternative mode of drug delivery. Anthracyclines are potent chemotherapeutics that have been successfully delivered via CED in preclinical supratentorial glioma models. This study aims to assess the potency of anthracyclines against DIPG and pHGG cell lines in vitro and to evaluate the efficacy of CED with anthracyclines in orthotopic pontine and thalamic tumor models. METHODS The sensitivity of primary pHGG cell lines to a range of anthracyclines was tested in vitro. Preclinical CED of free doxorubicin and pegylated liposomal doxorubicin (PLD) to the brainstem and thalamus of naïve nude mice was performed. The maximum tolerated dose (MTD) was determined based on the observation of clinical symptoms, and brains were analyzed after H & E staining. Efficacy of the MTD was tested in adult glioma E98-FM-DIPG and E98-FM-thalamus models and in the HSJD-DIPG-007-Fluc primary DIPG model. RESULTS Both pHGG and DIPG cells were sensitive to anthracyclines in vitro. Doxorubicin was selected for further preclinical evaluation. Convection-enhanced delivery of the MTD of free doxorubicin and PLD in the pons was 0.02 mg/ml, and the dose tolerated in the thalamus was 10 times higher (0.2 mg/ml). Free doxorubicin or PLD via CED was ineffective against E98-FM-DIPG or HSJD-DIPG-007-Fluc in the brainstem; however, when applied in the thalamus, 0.2 mg/ml of PLD slowed down tumor growth and increased survival in a subset of animals with small tumors. CONCLUSIONS Local delivery of doxorubicin to the brainstem causes severe toxicity, even at doxorubicin concentrations that are safe in the thalamus. As a consequence, the authors could not establish a therapeutic window for treating orthotopic brainstem tumors in mice. For tumors in the thalamus, therapeutic concentrations to slow down tumor growth could be reached. These data suggest that anatomical location determines the severity of toxicity after local delivery of therapeutic agents and that caution should be used when translating data from supratentorial CED studies to treat infratentorial tumors.

Recombinant Newcastle disease virus expressing human TRAIL as a potential candidate for hepatoma therapy

USDA-ARS?s Scientific Manuscript database

Newcastle disease virus (NDV) have shown oncolytic therapeutic efficacy in preclinical studies and are currently proved for clinical trials. We have previously reported, for the first time, NDV Anhinga strain has an efficient cancer therapeutic efficacy in hepatoma. Tumor necrosis factor-related apo...

A novel isoflavone, ME-344, targets the cytoskeleton in acute myeloid leukemia

PubMed Central

Jeyaraju, Danny V.; Hurren, Rose; Wang, Xiaoming; MacLean, Neil; Gronda, Marcela; Shamas-Din, Aisha; Minden, Mark D.; Giaever, Guri; Schimmer, Aaron D.

2016-01-01

The isoflavone ME-344 is a potent anti-cancer agent with preclinical and clinical efficacy in solid tumors. Yet, the mechanism of action of ME-344 has not been fully defined and the preclinical efficacy in leukemia has not been established. Therefore, we investigated the anti-leukemic properties and mechanism of action of ME-344. In a panel of 7 leukemia cell lines, ME-344 was cytotoxic with an IC50 in the range of 70–260 nM. In addition, ME-344 was cytotoxic to primary AML patient samples over normal hematopoietic cells. In an OCI-AML2 xenograft model, ME-344 reduced tumor growth by up to 95% of control without evidence of toxicity. Mechanistically, ME-344 increased mitochondrial ROS generation in leukemic cells. However, antioxidant treatment did not rescue cell death, suggesting that ME-344 had additional targets beyond the mitochondria. We demonstrated that ME-344 inhibited tubulin polymerization by interacting with tubulin near the colchicine-binding site. Furthermore, inhibition of tubulin polymerization was functionally important for ME-344 induced death. Finally, we showed that ME-344 synergizes with vinblastine in leukemia cells. Thus, our study demonstrates that ME-344 displays preclinical efficacy in leukemia through a mechanism at least partly related to targeting tubulin polymerization. PMID:27391350

A novel isoflavone, ME-344, targets the cytoskeleton in acute myeloid leukemia.

PubMed

Jeyaraju, Danny V; Hurren, Rose; Wang, Xiaoming; MacLean, Neil; Gronda, Marcela; Shamas-Din, Aisha; Minden, Mark D; Giaever, Guri; Schimmer, Aaron D

2016-08-02

The isoflavone ME-344 is a potent anti-cancer agent with preclinical and clinical efficacy in solid tumors. Yet, the mechanism of action of ME-344 has not been fully defined and the preclinical efficacy in leukemia has not been established. Therefore, we investigated the anti-leukemic properties and mechanism of action of ME-344. In a panel of 7 leukemia cell lines, ME-344 was cytotoxic with an IC50 in the range of 70-260 nM. In addition, ME-344 was cytotoxic to primary AML patient samples over normal hematopoietic cells. In an OCI-AML2 xenograft model, ME-344 reduced tumor growth by up to 95% of control without evidence of toxicity. Mechanistically, ME-344 increased mitochondrial ROS generation in leukemic cells. However, antioxidant treatment did not rescue cell death, suggesting that ME-344 had additional targets beyond the mitochondria. We demonstrated that ME-344 inhibited tubulin polymerization by interacting with tubulin near the colchicine-binding site. Furthermore, inhibition of tubulin polymerization was functionally important for ME-344 induced death. Finally, we showed that ME-344 synergizes with vinblastine in leukemia cells. Thus, our study demonstrates that ME-344 displays preclinical efficacy in leukemia through a mechanism at least partly related to targeting tubulin polymerization.

Noninvasive imaging of experimental lung fibrosis.

PubMed

Zhou, Yong; Chen, Huaping; Ambalavanan, Namasivayam; Liu, Gang; Antony, Veena B; Ding, Qiang; Nath, Hrudaya; Eary, Janet F; Thannickal, Victor J

2015-07-01

Small animal models of lung fibrosis are essential for unraveling the molecular mechanisms underlying human fibrotic lung diseases; additionally, they are useful for preclinical testing of candidate antifibrotic agents. The current end-point measures of experimental lung fibrosis involve labor-intensive histological and biochemical analyses. These measures fail to account for dynamic changes in the disease process in individual animals and are limited by the need for large numbers of animals for longitudinal studies. The emergence of noninvasive imaging technologies provides exciting opportunities to image lung fibrosis in live animals as often as needed and to longitudinally track the efficacy of novel antifibrotic compounds. Data obtained by noninvasive imaging provide complementary information to histological and biochemical measurements. In addition, the use of noninvasive imaging in animal studies reduces animal usage, thus satisfying animal welfare concerns. In this article, we review these new imaging modalities with the potential for evaluation of lung fibrosis in small animal models. Such techniques include micro-computed tomography (micro-CT), magnetic resonance imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), and multimodal imaging systems including PET/CT and SPECT/CT. It is anticipated that noninvasive imaging will be increasingly used in animal models of fibrosis to gain insights into disease pathogenesis and as preclinical tools to assess drug efficacy.

CRISPR-Cas9 Targeting of PCSK9 in Human Hepatocytes In Vivo-Brief Report.

PubMed

Wang, Xiao; Raghavan, Avanthi; Chen, Tao; Qiao, Lyon; Zhang, Yongxian; Ding, Qiurong; Musunuru, Kiran

2016-05-01

Although early proof-of-concept studies of somatic in vivo genome editing of the mouse ortholog of proprotein convertase subtilisin/kexin type 9 (Pcsk9) in mice have established its therapeutic potential for the prevention of cardiovascular disease, the unique nature of genome-editing technology-permanent alteration of genomic DNA sequences-mandates that it be tested in vivo against human genes in normal human cells with human genomes to give reliable preclinical insights into the efficacy (on-target mutagenesis) and safety (lack of off-target mutagenesis) of genome-editing therapy before it can be used in patients. We used a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) 9 genome-editing system to target the human PCSK9 gene in chimeric liver-humanized mice bearing human hepatocytes. We demonstrated high on-target mutagenesis (approaching 50%), greatly reduced blood levels of human PCSK9 protein, and minimal off-target mutagenesis. This work yields important information on the efficacy and safety of CRISPR-Cas9 therapy targeting the human PCSK9 gene in human hepatocytes in vivo, and it establishes humanized mice as a useful platform for the preclinical assessment of applications of somatic in vivo genome editing. © 2016 American Heart Association, Inc.

Targeting superficial or nodular Basal cell carcinoma with topically formulated small molecule inhibitor of smoothened.

PubMed

Tang, Tracy; Tang, Jean Y; Li, Dongwei; Reich, Mike; Callahan, Christopher A; Fu, Ling; Yauch, Robert L; Wang, Frank; Kotkow, Karen; Chang, Kris S; Shpall, Elana; Wu, Angela; Rubin, Lee L; Marsters, James C; Epstein, Ervin H; Caro, Ivor; de Sauvage, Frederic J

2011-05-15

Inappropriate activation of the Hedgehog (Hh) signaling pathway in skin is critical for the development of basal cell carcinomas (BCC). We have investigated the anti-BCC efficacy of topically-applied CUR61414, an inhibitor of the Hh signal transduction molecule Smoothened. In preclinical studies, we used a depilatory model to evaluate the ability of topical formulations of CUR61414 to repress Hh responsive cells found at the base of hair follicles in normal skin. We also tested the in vivo effects of topical CUR61414 on murine BCCs developed in Ptch1 (+/-) K14-CreER2 p53 fl/fl mice. In a phase I clinical study, we evaluated the safety, tolerability, and efficacy of a multidose regimen of CUR61414 (0.09%, 0.35%, 1.1%, and 3.1%) applied topically to human superficial or nodular BCCs for up to 28 days. In mice, topical CUR61414 significantly inhibited skin Hh signaling, blocked the induction of hair follicle anagen, and shrank existing BCCs. However, we observed no clinical activity of this formulation in human superficial or nodular BCCs in a phase I clinical study. Our data highlight some of the challenges of translating preclinical experience into successful human results for a topical anticancer agent. ©2011 AACR.

Assessment of Safety and Functional Efficacy of Stem Cell-Based Therapeutic Approaches Using Retinal Degenerative Animal Models

PubMed Central

Lin, Tai-Chi; Zhu, Danhong; Hinton, David R.; Clegg, Dennis O.; Humayun, Mark S.

2017-01-01

Dysfunction and death of retinal pigment epithelium (RPE) and or photoreceptors can lead to irreversible vision loss. The eye represents an ideal microenvironment for stem cell-based therapy. It is considered an “immune privileged” site, and the number of cells needed for therapy is relatively low for the area of focused vision (macula). Further, surgical placement of stem cell-derived grafts (RPE, retinal progenitors, and photoreceptor precursors) into the vitreous cavity or subretinal space has been well established. For preclinical tests, assessments of stem cell-derived graft survival and functionality are conducted in animal models by various noninvasive approaches and imaging modalities. In vivo experiments conducted in animal models based on replacing photoreceptors and/or RPE cells have shown survival and functionality of the transplanted cells, rescue of the host retina, and improvement of visual function. Based on the positive results obtained from these animal experiments, human clinical trials are being initiated. Despite such progress in stem cell research, ethical, regulatory, safety, and technical difficulties still remain a challenge for the transformation of this technique into a standard clinical approach. In this review, the current status of preclinical safety and efficacy studies for retinal cell replacement therapies conducted in animal models will be discussed. PMID:28928775

Development of dapivirine vaginal ring for HIV prevention.

PubMed

Devlin, Bríd; Nuttall, Jeremy; Wilder, Susan; Woodsong, Cynthia; Rosenberg, Zeda

2013-12-01

In the continuing effort to develop effective HIV prevention methods for women, a vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine is currently being tested in two safety and efficacy trials. This paper reviews dapivirine ring's pipeline development process, including efforts to determine safe and effective dosing levels as well as identify delivery platforms with the greatest likelihood of success for correct and consistent use. Dapivirine gel and other formulations were developed and tested in preclinical and clinical studies. Multiple vaginal ring prototypes were also tested, resulting in the current ring design as well as additional designs under consideration for future testing. Efficacy results from clinical trials are expected in 2015. Through ongoing consultations with national regulatory authorities, licensure requirements for dapivirine vaginal ring approval have been defined. This article is based on a presentation at the "Product Development Workshop 2013: HIV and Multipurpose Prevention Technologies," held in Arlington, Virginia on February 21-22, 2013. It forms part of a special supplement to Antiviral Research. Copyright © 2013 Elsevier B.V. All rights reserved.

Translational medicine in the field of ablative fractional laser (AFXL)-assisted drug delivery: A critical review from basics to current clinical status.

PubMed

Haedersdal, Merete; Erlendsson, Andrés M; Paasch, Uwe; Anderson, R Rox

2016-05-01

Ablative fractional lasers enhance uptake of topical therapeutics and the concept of fractional laser-assisted drug delivery has now been taken into clinical practice. We systematically reviewed preclinical data and clinical evidence for fractional lasers to enhance drug uptake and improve clinical efficacy. We searched PubMed and Embase databases; 34 articles met the inclusion criteria. Studies were categorized into experimental preclinical studies and clinical trials, the latter graded according to level of evidence. All preclinical trials (n = 16) documented enhanced topical drug uptake into skin after ablative fractional laser treatment. Clinical evidence encompassed 18 studies, of which 9 were randomized controlled trials and 2 were controlled trials, examining neoplastic lesions, photodamaged skin, scars, onychomycosis, and topical anesthetics. The highest level of evidence was reached for actinic keratoses treated with methylaminolevulinate for photodynamic therapy (level IB, 5 randomized controlled trials), substantiating superior and long-lasting efficacy versus conventional photodynamic therapy. No adverse events were reported, but ablative fractional laser-assisted drug delivery implies risks of systemic drug absorption, especially when performed over large skin areas. Fractional laser-assisted drug delivery is beneficial in enhancing preclinical and clinical outcomes for certain skin conditions. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Insights from Preclinical Choice Models on Treating Drug Addiction

PubMed Central

Banks, Matthew L.; Negus, S. Stevens

2016-01-01

Substance-use disorders are a global public health problem that arises from behavioral misallocation between drug use and more adaptive behaviors maintained by nondrug alternatives (e.g., food or money). Preclinical drug self-administration procedures that incorporate a concurrently available nondrug reinforcer (e.g., food) provide translationally relevant and distinct dependent measures of behavioral allocation (i.e., to assess the relative reinforcing efficacy of the drug) and behavioral rate (i.e., to assess motor competence). In particular, preclinical drug versus food ‘choice’ procedures have produced increasingly concordant results with both human laboratory drug self-administration studies and double-blind placebo-controlled clinical trials. Accordingly, here we provide a heuristic framework of substance-use disorders based on a behavioral-centric perspective and recent insights from these preclinical choice procedures. PMID:27916279

Non-invasive molecular imaging for preclinical cancer therapeutic development

PubMed Central

O'Farrell, AC; Shnyder, SD; Marston, G; Coletta, PL; Gill, JH

2013-01-01

Molecular and non-invasive imaging are rapidly emerging fields in preclinical cancer drug discovery. This is driven by the need to develop more efficacious and safer treatments, the advent of molecular-targeted therapeutics, and the requirements to reduce and refine current preclinical in vivo models. Such bioimaging strategies include MRI, PET, single positron emission computed tomography, ultrasound, and optical approaches such as bioluminescence and fluorescence imaging. These molecular imaging modalities have several advantages over traditional screening methods, not least the ability to quantitatively monitor pharmacodynamic changes at the cellular and molecular level in living animals non-invasively in real time. This review aims to provide an overview of non-invasive molecular imaging techniques, highlighting the strengths, limitations and versatility of these approaches in preclinical cancer drug discovery and development. PMID:23488622

Benefits of Case-Based versus Traditional Lecture-Based Instruction in a Preclinical Removable Prosthodontics Course.

PubMed

Samuelson, David B; Divaris, Kimon; De Kok, Ingeborg J

2017-04-01

This study compared the acceptability and relative effectiveness of case-based learning (CBL) versus traditional lecture-based (LB) instruction in a preclinical removable prosthodontics course in the University of North Carolina at Chapel Hill School of Dentistry DDS curriculum. The entire second-year class (N=82) comprised this crossover study's sample. Assessments of baseline comprehension and confidence in removable partial denture (RPD) treatment planning were conducted at the beginning of the course. Near the end of the course, half of the class received CBL and LB instruction in an RPD module in alternating sequence, with students serving as their own control group. Assessments of perceived RPD treatment planning efficacy, comprehension, and instruction method preference were administered directly after students completed the RPD module and six months later. Analyses of variance accounting for period, carryover, and sequence effects were used to determine the relative effects of each approach using a p<0.05 statistical significance threshold. The results showed that the students preferred CBL (81%) over LB instruction (9%), a pattern that remained unchanged after a six-month period. Despite notable period and carryover effects, CBL was also associated with higher gains in RPD treatment planning comprehension (p=0.04) and perceived efficacy (p=0.01) compared to LB instruction. These gains diminished six months after the course-a finding based on a 49% follow-up response rate. Overall, the students overwhelmingly preferred CBL to LB instruction, and the findings suggest small albeit measurable educational benefits associated with CBL. This study's findings support the introduction and further testing of CBL in the preclinical dental curriculum, in anticipation of possible future benefits evident during clinical training.

Regulatory considerations for pluripotent stem cell therapies.

PubMed

Carpenter, Melissa K

2017-01-01

The development of pluripotent stem cell (PSC) therapies is rapidly advancing, and a number of PSC-derived cell products are currently being tested in clinical trials. The biological complexity of these therapies results in specific challenges in complying with regulatory guidelines. This includes the choice of starting material, reproducible and consistent manufacturing, and preclinical safety and efficacy assessment of the PSC-derived product. This review discusses current US cell therapy regulations and strategies for compliance with these regulations when developing PSC-derived products. © 2017 Elsevier B.V. All rights reserved.

Thunder and lightning: immunotherapy and oncolytic viruses collide.

PubMed

Melcher, Alan; Parato, Kelley; Rooney, Cliona M; Bell, John C

2011-06-01

For the last several decades, the development of antitumor immune-based strategies and the engineering and testing of oncolytic viruses (OVs) has occurred largely in parallel tracks. Indeed, the immune system is often thought of as an impediment to successful oncolytic virus delivery and efficacy. More recently, however, both preclinical and clinical results have revealed potential synergy between these two promising therapeutic strategies. Here, we summarize some of the evidence that supports combining OVs with immuno-therapeutics and suggest new ways to mount a multipronged biological attack against cancers.

Thunder and Lightning: Immunotherapy and Oncolytic Viruses Collide

PubMed Central

Melcher, Alan; Parato, Kelley; Rooney, Cliona M; Bell, John C

2011-01-01

For the last several decades, the development of antitumor immune-based strategies and the engineering and testing of oncolytic viruses (OVs) has occurred largely in parallel tracks. Indeed, the immune system is often thought of as an impediment to successful oncolytic virus delivery and efficacy. More recently, however, both preclinical and clinical results have revealed potential synergy between these two promising therapeutic strategies. Here, we summarize some of the evidence that supports combining OVs with immuno-therapeutics and suggest new ways to mount a multipronged biological attack against cancers. PMID:21505424

Toxicity Testing in the 21st Century Beyond Environmental Chemicals

PubMed Central

Rovida, Costanza; Asakura, Shoji; Daneshian, Mardas; Hofman-Huether, Hana; Leist, Marcel; Meunier, Leo; Reif, David; Rossi, Anna; Schmutz, Markus; Valentin, Jean-Pierre; Zurlo, Joanne; Hartung, Thomas

2018-01-01

Summary After the publication of the report titled Toxicity Testing in the 21st Century – A Vision and a Strategy, many initiatives started to foster a major paradigm shift for toxicity testing – from apical endpoints in animal-based tests to mechanistic endpoints through delineation of pathways of toxicity (PoT) in human cell based systems. The US EPA has funded an important project to develop new high throughput technologies based on human cell based in vitro technologies. These methods are currently being incorporated into the chemical risk assessment process. In the pharmaceutical industry, the efficacy and toxicity of new drugs are evaluated during preclinical investigations that include drug metabolism, pharmacokinetics, pharmacodynamics and safety toxicology studies. The results of these studies are analyzed and extrapolated to predict efficacy and potential adverse effects in humans. However, due to the high failure rate of drugs during the clinical phases, a new approach for a more predictive assessment of drugs both in terms of efficacy and adverse effects is getting urgent. The food industry faces the challenge of assessing novel foods and food ingredients for the general population, while using animal safety testing for extrapolation purposes is often of limited relevance. The question is whether the latest paradigm shift proposed by the Tox21c report for chemicals may provide a useful tool to improve the risk assessment approach also for drugs and food ingredients. PMID:26168280

Investigating the Efficacy of Practical Skill Teaching: A Pilot-Study Comparing Three Educational Methods

ERIC Educational Resources Information Center

Maloney, Stephen; Storr, Michael; Paynter, Sophie; Morgan, Prue; Ilic, Dragan

2013-01-01

Effective education of practical skills can alter clinician behaviour, positively influence patient outcomes, and reduce the risk of patient harm. This study compares the efficacy of two innovative practical skill teaching methods, against a traditional teaching method. Year three pre-clinical physiotherapy students consented to participate in a…

Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma

PubMed Central

Vandenberk, Lien; Van Woensel, Matthias; Schaaf, Marco; De Vleeschouwer, Steven; Agostinis, Patrizia

2017-01-01

ABSTRACT Glioblastoma (GBM) is resistant to most multimodal therapies. Clinical success of immune-checkpoint inhibitors (ICIs) has spurred interest in applying ICIs targeting CTLA4, PD1 or IDO1 against GBM. This amplifies the need to ascertain GBM's intrinsic susceptibility (or resistance) toward these ICIs, through clinical biomarkers that may also “guide and prioritize” preclinical testing. Here, we interrogated the TCGA and/or REMBRANDT human patient-cohorts to predict GBM's predisposition toward ICIs. We exploited various broad clinical biomarkers, including mutational or predicted-neoantigen burden, pre-existing or basal levels of tumor-infiltrating T lymphocytes (TILs), differential expression of immune-checkpoints within the tumor and their correlation with particular TILs/Treg-associated functional signature and prognostic impact of differential immune-checkpoint expression. Based on these analyses, we found that predictive biomarkers of ICI responsiveness exhibited inconsistent patterns in GBM patients, i.e., they either predicted ICI resistance (as compared with typical ICI-responsive cancer-types like melanoma, lung cancer or bladder cancer) or susceptibility to therapeutic targeting of CTLA4 or IDO1. On the other hand, our comprehensive literature meta-analysis and preclinical testing of ICIs using an orthotopic GL261-glioma mice model, indicated significant antitumor properties of anti-PD1 antibody, whereas blockade of IDO1 or CTLA4 either failed or provided very marginal advantage. These trends raise the need to better assess the applicability of ICIs and associated biomarkers for GBM. PMID:28507806

3D breast cancer microtissue reveals the role of tumor microenvironment on the transport and efficacy of free-doxorubicin in vitro.

PubMed

Brancato, Virginia; Gioiella, Filomena; Imparato, Giorgia; Guarnieri, Daniela; Urciuolo, Francesco; Netti, Paolo A

2018-06-01

The use of 3D cancer models will have both ethical and economic impact in drug screening and development, to promote the reduction of the animals employed in preclinical studies. Nevertheless, to be effective, such cancer surrogates must preserve the physiological relevance of the in vivo models in order to provide realistic information on drugs' efficacy. To figure out the role of the architecture and composition of 3D cancer models on their tumor-mimicking capability, here we studied the efficacy of doxorubicin (DOX), a well-known anticancer molecule in two different 3D cancer models: our 3D breast cancer microtissue (3D-μTP) versus the golden standard represented by spheroid model (sph). Both models were obtained by using cancer associated fibroblast (CAF) and breast cancer cells (MCF-7) as cellular component. Unlike spheroid model, 3D-μTP was engineered in order to induce the production of endogenous extracellular matrix by CAF. 3D-μTP have been compared to spheroid in mono- (MCF-7 alone) and co-culture (MCF-7/CAF), after the treatment with DOX in order to study cytotoxicity effect, diffusional transport and expression of proteins related to cancer progression. Compared to the spheroid model, 3D-μTP showed higher diffusion coefficient of DOX and lower cell viability. Also, the expression of some tumoral biomarkers related to cell junctions were different in the two models. Cancer biology has made progress in unraveling the mechanism of cancer progression, anyway the most of the results are still obtained by 2D cell cultures or animal models, that do not faithfully copycat the tumor microenvironment. The lack of correlation between preclinical models and in vivo organisms negatively influences the clinical efficacy of chemotherapeutic drugs. Consequently, even if a huge amount of new drugs has been developed in the last decades, still people are dying because of cancer. Pharmaceutical companies are interested in 3D tumor model as valid alternative in drug screening in preclinical studies. However, a 3D tumor model that completely mimics tumor heterogeneity is still far to achieve. In our work we compare 3D human breast cancer microtissues and spheroids in terms of response to doxorubicin and drug diffusion. We believe that our results are interesting because they highlight the potential role of the proposed tumor model in the attempts to improve efficacy tests. Copyright © 2018. Published by Elsevier Ltd.

Fostering efficacy and toxicity evaluation of traditional Chinese medicine and natural products: Chick embryo as a high throughput model bridging in vitro and in vivo studies.

PubMed

Wu, Tong; Yu, Gui-Yuan; Xiao, Jia; Yan, Chang; Kurihara, Hiroshi; Li, Yi-Fang; So, Kwok-Fai; He, Rong-Rong

2018-04-19

Efficacy and safety assessments are essential thresholds for drug candidates from preclinical to clinical research. Conventional mammalian in vivo models cannot offer rapid pharmacological and toxicological screening, whereas cell-based or cell-free in vitro systems often lead to inaccurate results because of the lack of physiological environment. Within the avian species, gallus gallus is the first bird to have its genome sequencing. Meantime, chick embryo is an easily operating, relatively transparent and extensively accessible model, whose physiological and pathological alterations can be visualized by egg candler, staining and image technologies. These features facilitate chick embryo as a high-throughput screening platform bridging in vivo and in vitro gaps in the pharmaceutical research. Due to the complicated ingredients and multiple-targets natures of traditional Chinese medicine (TCM), testing the efficacy and safety of TCM by in vitro methods are laborious and inaccurate, while testing in mammalian models consume massive cost and time. As such, the productive living organism chick embryo serves as an ideal biological system for pharmacodynamics studies of TCM. Herein, we comprehensively update recent progresses on the specialty of chick embryo in evaluation of efficacy and toxicity of drugs, with special concerns of TCM. Copyright © 2018 Elsevier Ltd. All rights reserved.

Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials.

PubMed

Carlezon, William A; Krystal, Andrew D

2016-10-01

Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to characterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry. This research established that exposure to drugs of abuse or stress increases the activity of the transcription factor CREB (cAMP response element binding protein) in the NAc, which leads to elevated expression of the opioid peptide dynorphin that in turn causes core signs of depressive- and anxiety-related disorders. Disruption of KORs-the endogenous receptors for dynorphin-produces antidepressant- and anxiolytic-like actions in screening procedures that identify standard drugs of these classes, and reduces stress effects in tests used to study addiction and stress-related disorders. Although interest in this target is high, prototypical KOR antagonists have extraordinarily persistent pharmacodynamic effects that complicate clinical trials. The development of shorter acting KOR antagonists together with more rapid designs for clinical trials may soon provide insight on whether these drugs are efficacious as would be predicted by preclinical work. If successful, KOR antagonists would represent a unique example in psychiatry where the therapeutic mechanism of a drug class is understood before it is shown to be efficacious in humans. © 2016 Wiley Periodicals, Inc.

Insights from Preclinical Choice Models on Treating Drug Addiction.

PubMed

Banks, Matthew L; Negus, S Stevens

2017-02-01

Substance-use disorders are a global public health problem that arises from behavioral misallocation between drug use and more adaptive behaviors maintained by nondrug alternatives (e.g., food or money). Preclinical drug self-administration procedures that incorporate a concurrently available nondrug reinforcer (e.g., food) provide translationally relevant and distinct dependent measures of behavioral allocation (i.e., to assess the relative reinforcing efficacy of the drug) and behavioral rate (i.e., to assess motor competence). In particular, preclinical drug versus food 'choice' procedures have produced increasingly concordant results with both human laboratory drug self-administration studies and double-blind placebo-controlled clinical trials. Accordingly, here we provide a heuristic framework of substance-use disorders based on a behavioral-centric perspective and recent insights from these preclinical choice procedures. Copyright © 2016 Elsevier Ltd. All rights reserved.

USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE

PubMed Central

Langbaum, Jessica B.S.; Fleisher, Adam S.; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T.; Caselli, Richard J.; Tariot, Pierre N.; Reiman, Eric M.

2014-01-01

Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of or completely prevent clinical decline. Here, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how these advances have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research. PMID:23752908

Ushering in the study and treatment of preclinical Alzheimer disease.

PubMed

Langbaum, Jessica B; Fleisher, Adam S; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T; Caselli, Richard J; Tariot, Pierre N; Reiman, Eric M

2013-07-01

Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of, or completely prevent clinical decline. In this Review, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how advances in the field have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research.

A Comprehensive Review of mTOR-Inhibiting Pharmacotherapy for the Treatment of Non-Infectious Uveitis.

PubMed

Blair, Joshua; Barry, Robert; Moore, David J; Denniston, Alastair K

2017-01-01

Non-infectious uveitis is a sight-threatening inflammatory disease that often necessitates prolonged use of high-dose corticosteroids, resulting in significant systemic side effects. There is a need for efficacious steroid-sparing immunomodulatory therapy for these patients, and the mTOR inhibitors (sirolimus and everolimus) may be contenders for this role. A comprehensive review of preclinical and clinical research on mTOR inhibitors for non-infectious uveitis was performed. Articles were identified by a search of MEDLINE (PubMed/OVID) and EMBASE (OVID) the terms (uveitis OR non-infectious uveitis) AND (mTOR inhibitor OR sirolimus OR everolimus). Assessment of study aims, methods, efficacy outcomes and adverse events was performed. Seven pre-clinical and nine clinical studies were identified. One study in each group was on everolimus, the rest sirolimus. Preclinical studies have been performed in rabbit, rat, mouse and in-vitro models. Clinical studies range from comparative open-label trials to case reports, with reported clinical efficacy ranging from 40% to 100% depending on endpoint assessed. The overall rate of drug-related adverse events (such as ocular irritation, visual floaters, nausea and vomiting) was 0.640 events per patient-year with sirolimus, and 0.111 events per patient-year with everolimus. Published evidence suggests that sirolimus and everolimus may be useful in the management of noninfectious uveitis. Both appear to be well tolerated, especially when locally administered. Further high-quality RCTs adopting standardised end-points are required to definitively determine the efficacy of each agent. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases.

PubMed

Tatem, Kathleen S; Quinn, James L; Phadke, Aditi; Yu, Qing; Gordish-Dressman, Heather; Nagaraju, Kanneboyina

2014-09-29

The open field activity monitoring system comprehensively assesses locomotor and behavioral activity levels of mice. It is a useful tool for assessing locomotive impairment in animal models of neuromuscular disease and efficacy of therapeutic drugs that may improve locomotion and/or muscle function. The open field activity measurement provides a different measure than muscle strength, which is commonly assessed by grip strength measurements. It can also show how drugs may affect other body systems as well when used with additional outcome measures. In addition, measures such as total distance traveled mirror the 6 min walk test, a clinical trial outcome measure. However, open field activity monitoring is also associated with significant challenges: Open field activity measurements vary according to animal strain, age, sex, and circadian rhythm. In addition, room temperature, humidity, lighting, noise, and even odor can affect assessment outcomes. Overall, this manuscript provides a well-tested and standardized open field activity SOP for preclinical trials in animal models of neuromuscular diseases. We provide a discussion of important considerations, typical results, data analysis, and detail the strengths and weaknesses of open field testing. In addition, we provide recommendations for optimal study design when using open field activity in a preclinical trial.

Preclinical efficacy of the MDM2 inhibitor RG7112 in MDM2 amplified and TP53 wild-type glioblastomas

PubMed Central

Verreault, Maite; Schmitt, Charlotte; Goldwirt, Lauriane; Pelton, Kristine; Haidar, Samer; Levasseur, Camille; Guehennec, Jeremy; Knoff, David; Labussiere, Marianne; Marie, Yannick; Ligon, Azra H.; Mokhtari, Karima; Hoang-Xuan, Khe; Sanson, Marc; Alexander, Brian M; Wen, Patrick Y.; Delattre, Jean-Yves; Ligon, Keith L.; Idbaih, Ahmed

2016-01-01

Rationale p53 pathway alterations are key molecular events in glioblastoma (GBM). MDM2 inhibitors increase expression and stability of p53 and are presumed to be most efficacious in patients with TP53 wild-type and MDM2-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient-derived models for GBM. Methods We performed a preclinical evaluation of RG7112 MDM2 inhibitor, across a panel of 36 patient-derived GBM cell lines (PDCLs), each genetically characterized according to their P53 pathway status. We then performed a pharmacokinetic (PK) profiling of RG7112 distribution in mice and evaluated the therapeutic activity of RG7112 in orthotopic and subcutaneous GBM models. Results MDM2-amplified PDCLs were 44 times more sensitive than TP53 mutated lines that showed complete resistance at therapeutically attainable concentrations (avg. IC50 of 0.52 μM vs 21.9 μM). MDM4 amplified PDCLs were highly sensitive but showed intermediate response (avg. IC50 of 1.2 μM), whereas response was heterogeneous in TP53 wild-type PDCLs with normal MDM2/4 levels (avg. IC50 of 7.7 μM). In MDM2-amplified lines, RG7112 restored p53 activity inducing robust p21 expression and apoptosis. PK profiling of RG7112-treated PDCL intracranial xenografts demonstrated that the compound significantly crosses the blood-brain and the blood-tumor barriers. Most importantly, treatment of MDM2-amplified/TP53 wild-type PDCL-derived model (subcutaneous and orthotopic) reduced tumor growth, was cytotoxic, and significantly increased survival. Conclusion These data strongly support development of MDM2 inhibitors for clinical testing in MDM2-amplified GBM patients. Moreover, significant efficacy in a subset of non-MDM2 amplified models suggests that additional markers of response to MDM2 inhibitors must be identified. PMID:26482041

New endocrine therapies for breast cancer.

PubMed

Howell, A; Downey, S; Anderson, E

1996-04-01

How do the new endocrine therapies stand up to the aims of modern endocrine therapy outlined in Table 1? We wish to see increased efficacy, decreased toxicity and improved general health in women taking a new agent. None of the new non-steroidal anti-oestrogens have shown unequivocal evidence of improved efficacy in the clinic to mirror their improved profiles over tamoxifen in preclinical studies. We know that toremifene is equivalent to tamoxifen, but we do not have any phase III data from the other four compounds in development. The specific steroidal antioestrogen, ICI 182,780, looks very promising, but is early in its developmental programme. The new aromatase inhibitors are likely to prove equal to tamoxifen or progestagens, but it is disappointing that improved oestrogen suppression has not led, to date, to improved efficacy. No comment can be made about adjuvant or preventative therapy for any of the new agents, although trials are planned for the new aromatase inhibitors in this clinical situation. Currently, the antiprogestins are disappointing and we will need to wait a considerable time for new agents in preclinical testing to reach the clinic. Many of the new agents are associated with decreased toxicity. It is likely that the NSAEs will be equitoxic with tamoxifen. The steroidal antioestrogen looks particularly non-toxic as do the new aromatase inhibitors, and thus we have an advance in terms of reduced toxicity. The effects of the new agents on the uterus, lipids and bone are in the early stages of testing. Raloxifene, ICI 182,780 and the new aromatase inhibitors are expected to have no proliferative effects on the endometrium, but only the new NSAEs are expected to have beneficial cardiovascular and skeletal effects. If the steroidal anti-oestrogens and new aromatase inhibitors become adjuvant therapies of choice, other agents to prevent osteoporosis and cardiovascular events may also have to be administered.

Biomimetic three-dimensional tissue models for advanced high-throughput drug screening

PubMed Central

Nam, Ki-Hwan; Smith, Alec S.T.; Lone, Saifullah; Kwon, Sunghoon; Kim, Deok-Ho

2015-01-01

Most current drug screening assays used to identify new drug candidates are 2D cell-based systems, even though such in vitro assays do not adequately recreate the in vivo complexity of 3D tissues. Inadequate representation of the human tissue environment during a preclinical test can result in inaccurate predictions of compound effects on overall tissue functionality. Screening for compound efficacy by focusing on a single pathway or protein target, coupled with difficulties in maintaining long-term 2D monolayers, can serve to exacerbate these issues when utilizing such simplistic model systems for physiological drug screening applications. Numerous studies have shown that cell responses to drugs in 3D culture are improved from those in 2D, with respect to modeling in vivo tissue functionality, which highlights the advantages of using 3D-based models for preclinical drug screens. In this review, we discuss the development of microengineered 3D tissue models which accurately mimic the physiological properties of native tissue samples, and highlight the advantages of using such 3D micro-tissue models over conventional cell-based assays for future drug screening applications. We also discuss biomimetic 3D environments, based-on engineered tissues as potential preclinical models for the development of more predictive drug screening assays for specific disease models. PMID:25385716

A humanized mouse model for HIV-2 infection and efficacy testing of a single-pill triple-drug combination anti-retroviral therapy.

PubMed

Hu, Shuang; Neff, Charles Preston; Kumar, Dipu Mohan; Habu, Yuichiro; Akkina, Sarah R; Seki, Takahiro; Akkina, Ramesh

2017-01-15

While HIV-2 is a causative agent for AIDS in addition to the better studied HIV-1, there is currently no suitable animal model for experimental studies for HIV-2 infection and evaluating promising drugs in vivo. Here we evaluated humanized mice for their susceptibility to HIV-2 infection and tested a single-pill three drug formulation of anti-retrovirals (NRTIs abacavir and lamivudine, integrase inhibitor dolutegravir) (trade name, Triumeq R ). Our results showed that hu-mice are susceptible to HIV-2 infection showing persistent viremia and CD4 T cell loss, key hallmarks of AIDS pathogenesis. Oral drug treatment led to full viral suppression and protection from CD4 T cell depletion. Cessation of therapy resulted in viral rebound and CD4 T cell loss. These proof-of-concept studies establish the utility of hu-mice for evaluating HIV-2 pathogenesis in more detail in the future, testing novel therapies and providing pre-clinical efficacy data of a three drug combination to treat HIV-2 infections. Copyright © 2016. Published by Elsevier Inc.

Benefits of Personality Characteristics and Self-Efficacy in the Perceived Academic Achievement of Medical Students

ERIC Educational Resources Information Center

Guntern, Sabine; Korpershoek, Hanke; van der Werf, Greetje

2017-01-01

This study investigates the joint impact of personality characteristics and self-efficacy on the perceived academic achievement of medical students on top of their prior high school performance. The sample consisted of medical students in their pre-clinical years. The students' grade point average scores at high school were included as control…

Recombinant Newcastle disease virus (NDV/Anh-IL-2) expressing human IL-2 as a potential candidate for suppresses growth of hepatoma therapy

USDA-ARS?s Scientific Manuscript database

Newcastle disease virus (NDV) have shown oncolytic therapeutic efficacy in preclinical study and are currently approved for clinical trials. NDV Anhinga strain which is a mesogenic strain should be classified as lytic strain and has a therapeutic efficacy in hepatocellular cancer. In this study, we ...

Pre-clinical and clinical development of the first placental malaria vaccine.

PubMed

Pehrson, Caroline; Salanti, Ali; Theander, Thor G; Nielsen, Morten A

2017-06-01

Malaria during pregnancy is a massive health problem in endemic areas. Placental malaria infections caused by Plasmodium falciparum are responsible for up to one million babies being born with a low birth weight every year. Significant efforts have been invested into preventing the condition. Areas covered: Pub Med was searched using the broad terms 'malaria parasite placenta' to identify studies of interactions between parasite and host, 'prevention of placental malaria' to identify current strategies to prevent placental malaria, and 'placental malaria vaccine' to identify pre-clinical vaccine development. However, all papers from these searches were not systematically included. Expert commentary: The first phase I clinical trials of vaccines are well underway. Trials testing efficacy are more complicated to carry out as only women that are exposed to parasites during pregnancy will contribute to endpoint measurements, further it may require extensive follow-up to establish protection. Future second generation vaccines may overcome the inherent challenges in making an effective placental malaria vaccine.

Preclinical studies for induced pluripotent stem cell-based therapeutics.

PubMed

Harding, John; Mirochnitchenko, Oleg

2014-02-21

Induced pluripotent stem cells (iPSCs) and their differentiated derivatives can potentially be applied to cell-based therapy for human diseases. The properties of iPSCs are being studied intensively both to understand the basic biology of pluripotency and cellular differentiation and to solve problems associated with therapeutic applications. Examples of specific preclinical applications summarized briefly in this minireview include the use of iPSCs to treat diseases of the liver, nervous system, eye, and heart and metabolic conditions such as diabetes. Early stage studies illustrate the potential of iPSC-derived cells and have identified several challenges that must be addressed before moving to clinical trials. These include rigorous quality control and efficient production of required cell populations, improvement of cell survival and engraftment, and development of technologies to monitor transplanted cell behavior for extended periods of time. Problems related to immune rejection, genetic instability, and tumorigenicity must be solved. Testing the efficacy of iPSC-based therapies requires further improvement of animal models precisely recapitulating human disease conditions.

Targeting Hsp90 in urothelial carcinoma

PubMed Central

Skotnicki, Kamil; Landas, Steve; Bratslavsky, Gennady; Bourboulia, Dimitra

2015-01-01

Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs. Despite use of current chemotherapies and immunotherapies, long-term remission in patients with muscle-invasive or metastatic disease remains low, and disease recurrence is common. The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation. Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation. Despite promising preclinical data, clinical trials utilizing Hsp90 inhibitors for other malignancies had modest efficacy. Therefore, we propose that Hsp90 inhibition would best serve as an adjuvant treatment in advanced muscle-invasive or metastatic bladder cancers to potentiate other therapies. An overview of bladder cancer biology, current treatments, molecular targeted therapies, and the role for Hsp90 inhibitors in the treatment of urothelial carcinoma is the focus of this review. PMID:25909217

The Challenges of First-in-Human Stem Cell Clinical Trials: What Does This Mean for Ethics and Institutional Review Boards?

PubMed

Barker, Roger A; Carpenter, Melissa K; Forbes, Stuart; Goldman, Steven A; Jamieson, Catriona; Murry, Charles E; Takahashi, Jun; Weir, Gordon

2018-05-08

Stem cell-based clinical interventions are increasingly advancing through preclinical testing and approaching clinical trials. The complexity and diversity of these approaches, and the confusion created by unproven and untested stem cell-based "therapies," create a growing need for a more comprehensive review of these early-stage human trials to ensure they place the patients at minimal risk of adverse events but are also based on solid evidence of preclinical efficacy with a clear scientific rationale for that effect. To address this issue and supplement the independent review process, especially that of the ethics and institutional review boards who may not be experts in stem cell biology, the International Society for Stem Cell Research (ISSCR) has developed a set of practical questions to cover the major issues for which clear evidence-based answers need to be obtained before approving a stem cell-based trial. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Preclinical imaging methods for assessing the safety and efficacy of regenerative medicine therapies

NASA Astrophysics Data System (ADS)

Scarfe, Lauren; Brillant, Nathalie; Kumar, J. Dinesh; Ali, Noura; Alrumayh, Ahmed; Amali, Mohammed; Barbellion, Stephane; Jones, Vendula; Niemeijer, Marije; Potdevin, Sophie; Roussignol, Gautier; Vaganov, Anatoly; Barbaric, Ivana; Barrow, Michael; Burton, Neal C.; Connell, John; Dazzi, Francesco; Edsbagge, Josefina; French, Neil S.; Holder, Julie; Hutchinson, Claire; Jones, David R.; Kalber, Tammy; Lovatt, Cerys; Lythgoe, Mark F.; Patel, Sara; Patrick, P. Stephen; Piner, Jacqueline; Reinhardt, Jens; Ricci, Emanuelle; Sidaway, James; Stacey, Glyn N.; Starkey Lewis, Philip J.; Sullivan, Gareth; Taylor, Arthur; Wilm, Bettina; Poptani, Harish; Murray, Patricia; Goldring, Chris E. P.; Park, B. Kevin

2017-10-01

Regenerative medicine therapies hold enormous potential for a variety of currently incurable conditions with high unmet clinical need. Most progress in this field to date has been achieved with cell-based regenerative medicine therapies, with over a thousand clinical trials performed up to 2015. However, lack of adequate safety and efficacy data is currently limiting wider uptake of these therapies. To facilitate clinical translation, non-invasive in vivo imaging technologies that enable careful evaluation and characterisation of the administered cells and their effects on host tissues are critically required to evaluate their safety and efficacy in relevant preclinical models. This article reviews the most common imaging technologies available and how they can be applied to regenerative medicine research. We cover details of how each technology works, which cell labels are most appropriate for different applications, and the value of multi-modal imaging approaches to gain a comprehensive understanding of the responses to cell therapy in vivo.

Histone deacetylase inhibition enhances the lymphomacidal activity of the anti-CD22 monoclonal antibody HB22.7.

PubMed

Kong, YanGuo; Barisone, Gustavo A; Abuhay, Mastewal; O'Donnell, Robert T; Buksh, Zaneb; Yousefian, Faraz; Tuscano, Joseph M

2014-11-01

HB22.7, an anti-CD22 monoclonal antibody has shown consistent preclinical activity against non-Hodgkin lymphoma (NHL). Histone deacetylase inhibitors (HDACi) have demonstrated efficacy in lymphoma and can modulate cell surface receptor expression. To augment the lymphomacidal activity of HB22.7 we examined the combination of AR42 (an HDACi) and HB22.7 in vitro and in vivo. The combination resulted in 10-fold increased potency in 6 NHL cell lines when compared to either drug alone. Both drugs reduced tumor progression in xenografts, but the combination was significantly more efficacious and resulted in regression of established tumors, without toxicity. AR42 inhibited HB22.7-mediated CD22 internalization, suggesting that increased efficacy could be due to higher availability of CD22. Overall, the synergistic effects of HB22.7 and AR42 on in vitro cytotoxicity and in vivo anti-tumor activity make this combination an attractive option for further pre-clinical and clinical evaluation. Published by Elsevier Ltd.

Designing malaria vaccines to circumvent antigen variability.

PubMed

Ouattara, Amed; Barry, Alyssa E; Dutta, Sheetij; Remarque, Edmond J; Beeson, James G; Plowe, Christopher V

2015-12-22

Prospects for malaria eradication will be greatly enhanced by an effective vaccine, but parasite genetic diversity poses a major impediment to malaria vaccine efficacy. In recent pre-clinical and field trials, vaccines based on polymorphic Plasmodium falciparum antigens have shown efficacy only against homologous strains, raising the specter of allele-specific immunity such as that which plagues vaccines against influenza and HIV. The most advanced malaria vaccine, RTS,S, targets relatively conserved epitopes on the P. falciparum circumsporozoite protein. After more than 40 years of development and testing, RTS,S, has shown significant but modest efficacy against clinical malaria in phase 2 and 3 trials. Ongoing phase 2 studies of an irradiated sporozoite vaccine will ascertain whether the full protection against homologous experimental malaria challenge conferred by high doses of a whole organism vaccine can provide protection against diverse strains in the field. Here we review and evaluate approaches being taken to design broadly cross-protective malaria vaccines. Copyright © 2015. Published by Elsevier Ltd.

Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor.

PubMed

Mulvihill, Mark J; Cooke, Andrew; Rosenfeld-Franklin, Maryland; Buck, Elizabeth; Foreman, Ken; Landfair, Darla; O'Connor, Matthew; Pirritt, Caroline; Sun, Yingchaun; Yao, Yan; Arnold, Lee D; Gibson, Neil W; Ji, Qun-Sheng

2009-09-01

The IGF-1 receptor (IGF-1R) has been implicated in the promotion of tumorigenesis, metastasis and resistance to cancer therapies. Therefore, this receptor has become a major focus for the development of anticancer agents. Our lead optimization efforts that blended structure-based design and empirical medicinal chemistry led to the discovery of OSI-906, a novel small-molecule dual IGF-1R/insulin receptor (IR) kinase inhibitor. OSI-906 potently and selectively inhibits autophosphorylation of both human IGF-1R and IR, displays in vitro antiproliferative effects in a variety of tumor cell lines and shows robust in vivo anti-tumor efficacy in an IGF-1R-driven xenograft model when administered orally once daily. OSI-906 is a novel, potent, selective and orally bioavailable dual IGF-1R/IR kinase inhibitor with favorable preclinical drug-like properties, which has demonstrated in vivo efficacy in tumor models and is currently in clinical testing.

Riluzole does not improve lifespan or motor function in three ALS mouse models.

PubMed

Hogg, Marion C; Halang, Luise; Woods, Ina; Coughlan, Karen S; Prehn, Jochen H M

2018-08-01

Riluzole is the most widespread therapeutic for treatment of the progressive degenerative disease amyotrophic lateral sclerosis (ALS). Riluzole gained FDA approval in 1995 before the development of ALS mouse models. We assessed riluzole in three transgenic ALS mouse models: the SOD1 G93A model, the TDP-43 A315T model, and the recently developed FUS (1-359) model. Age, sex and litter-matched mice were treated with riluzole (22 mg/kg) in drinking water or vehicle (DMSO) from symptom onset. Lifespan was assessed and motor function tests were carried out twice weekly to determine whether riluzole slowed disease progression. Riluzole treatment had no significant benefit on lifespan in any of the ALS mouse models tested. Riluzole had no significant impact on decline in motor performance in the FUS (1-359) and SOD1 G93A transgenic mice as assessed by Rotarod and stride length analysis. Riluzole is widely prescribed for ALS patients despite questions surrounding its efficacy. Our data suggest that if riluzole was identified as a therapeutic candidate today it would not progress past pre-clinical assessment. This raises questions about the standards used in pre-clinical assessment of therapeutic candidates for the treatment of ALS.

Preclinical pharmacokinetic/pharmacodynamic modeling and simulation in the pharmaceutical industry: an IQ consortium survey examining the current landscape.

PubMed

Schuck, Edgar; Bohnert, Tonika; Chakravarty, Arijit; Damian-Iordache, Valeriu; Gibson, Christopher; Hsu, Cheng-Pang; Heimbach, Tycho; Krishnatry, Anu Shilpa; Liederer, Bianca M; Lin, Jing; Maurer, Tristan; Mettetal, Jerome T; Mudra, Daniel R; Nijsen, Marjoleen Jma; Raybon, Joseph; Schroeder, Patricia; Schuck, Virna; Suryawanshi, Satyendra; Su, Yaming; Trapa, Patrick; Tsai, Alice; Vakilynejad, Majid; Wang, Shining; Wong, Harvey

2015-03-01

The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses, ~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its broad application. An important goal of preclinical PK/PD analysis in all pharmaceutical companies is for the selection/optimization of doses and/or dose regimens, including prediction of human efficacious doses. Oncology was the therapeutic area with the most PK/PD analysis support and where it showed the most impact. Consistent use of more complex systems pharmacology models and hybrid physiologically based pharmacokinetic models with PK/PD components was less common compared to traditional PK/PD models. Preclinical PK/PD analysis is increasingly being included in regulatory submissions with ~73% of companies including these data to some degree. Most companies (~86%) have seen impact of preclinical PK/PD analyses in drug development. Finally, ~59% of pharmaceutical companies have plans to expand their PK/PD modeling groups over the next 2 years indicating continued growth. The growth of preclinical PK/PD modeling groups in pharmaceutical industry is necessary to establish required resources and skills to further expand use of preclinical PK/PD modeling in a meaningful and impactful manner.

Nutraceuticals: do they represent a new era in the management of osteoarthritis? - a narrative review from the lessons taken with five products.

PubMed

Henrotin, Y; Lambert, C; Couchourel, D; Ripoll, C; Chiotelli, E

2011-01-01

The aim of this first global systematic review on selected nutraceuticals was to synthesize and evaluate scientific relevant data available in the literature. Evidences that can support health, physiological or functional benefit on osteoarthritis (OA) were gathered and the level of evidence relative to each of these ingredients was highlighted. Relevant scientific data (positive or not) regarding OA were searched for five groups of compounds (avocado/soybean unsaponifiables (ASU), n-3 polyunsaturated fatty acids, collagen hydrosylates (CHs), vitamin D, polyphenols) within preclinical (in vitro and in vivo), epidemiological, and clinical studies. The following criteria were evaluated to assess the methodology quality of each study: (1) study question; (2) study population; (3) primary endpoint; (4) study design (randomization, control, blinding, duration of follow up); (5) data analysis and interpretation. A scientific consensus was determined for all studied nutraceuticals to evaluate their efficacy in OA. The studied compounds demonstrated different potencies in preclinical studies. Most of them have demonstrated anti-catabolic and anti-inflammatory effects by various inhibitory activities on different mediators. Vitamin D showed a pro-catabolic effect in vitro and the polyphenol, Genistein, had only anti-inflammatory potency. The evaluation of the clinical data showed that ASU was the only one of the studied ingredients to present a good evidence of efficacy, but the efficient formulation was considered as a drug in some countries. Pycnogenol showed moderate evidence of efficacy, and vitamin D and collagen hydrolysate demonstrated a suggestive evidence of efficacy, whereas curcumin, epigallocatechin-3-gallate (EGCG) and resveratrol had only preclinical evidence of efficacy due to the lack of clinical data. The literature gathered for n-3 PUFA, nobiletin and genistein was insufficient to conclude for their efficacy in OA. Additional data are needed for most of the studied nutraceuticals. Studies of good quality are needed to draw solid conclusions regarding their efficacy but nutraceuticals could represent good alternates for OA management. Their use should be driven by any recommendations. Copyright © 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Balancing paediatric anaesthesia: preclinical insights into analgesia, hypnosis, neuroprotection, and neurotoxicity.

PubMed

Sanders, R D; Ma, D; Brooks, P; Maze, M

2008-11-01

Logistical and ethical reasons make conducting clinical research in paediatric practice difficult, and therefore safe and efficacious advances are dependent on good preclinical research. For example, notable advances have been made in preclinical studies of pain processing that correlate well with patient data. Other areas of paediatric anaesthetic research remain in their infancy including mechanisms of anaesthesia and anaesthetic neuroprotection and neurotoxicity. Animal data have identified the potential 'double-edged' sword of administering anaesthetic agents in the young; although these agents can be neuroprotective in certain circumstances, they can be neurotoxic in others. The potential for this toxicity must be balanced against the importance of providing adequate anaesthesia for which there can be no compromise. We review the current state of preclinical research in paediatric anaesthesia and identify areas which require further exploration in order to provide the foundations for well-conducted clinical trials.

Models for preclinical studies in aging-related disorders: One is not for all

PubMed Central

Santulli, Gaetano; Borras, Consuelo; Bousquet, Jean; Calzà, Laura; Cano, Antonio; Illario, Maddalena; Franceschi, Claudio; Liotta, Giuseppe; Maggio, Marcello; Molloy, William D.; Montuori, Nunzia; O’Caoimh, Rónán; Orfila, Francesc; Rauter, Amelia P.; Santoro, Aurelia; Iaccarino, Guido

2015-01-01

Preclinical studies are essentially based on animal models of a particular disease. The primary purpose of preclinical efficacy studies is to support generalization of treatment–effect relationships to human subjects. Researchers aim to demonstrate a causal relationship between an investigational agent and a disease-related phenotype in such models. Numerous factors can muddle reliable inferences about such cause-effect relationships, including biased outcome assessment due to experimenter expectations. For instance, responses in a particular inbred mouse might be specific to the strain, limiting generalizability. Selecting well-justified and widely acknowledged model systems represents the best start in designing preclinical studies, especially to overcome any potential bias related to the model itself. This is particularly true in the research that focuses on aging, which carries unique challenges, mainly attributable to the fact that our already long lifespan makes designing experiments that use people as subjects extremely difficult and largely impractical. PMID:27042427

Current state and future prospects of immunotherapy for glioma.

PubMed

Kamran, Neha; Alghamri, Mahmoud S; Nunez, Felipe J; Shah, Diana; Asad, Antonela S; Candolfi, Marianela; Altshuler, David; Lowenstein, Pedro R; Castro, Maria G

2018-02-01

There is a large unmet need for effective therapeutic approaches for glioma, the most malignant brain tumor. Clinical and preclinical studies have enormously expanded our knowledge about the molecular aspects of this deadly disease and its interaction with the host immune system. In this review we highlight the wide array of immunotherapeutic interventions that are currently being tested in glioma patients. Given the molecular heterogeneity, tumor immunoediting and the profound immunosuppression that characterize glioma, it has become clear that combinatorial approaches targeting multiple pathways tailored to the genetic signature of the tumor will be required in order to achieve optimal therapeutic efficacy.

Methodological issues associated with preclinical drug development and increased placebo effects in schizophrenia clinical trials.

PubMed

Brown, Matt A; Bishnoi, Ram J; Dholakia, Sara; Velligan, Dawn I

2016-01-20

Recent failures to detect efficacy in clinical trials investigating pharmacological treatments for schizophrenia raise concerns regarding the potential contribution of methodological shortcomings to this research. This review provides an examination of two key methodological issues currently suspected of playing a role in hampering schizophrenia drug development; 1) limitations on the translational utility of preclinical development models, and 2) methodological challenges posed by increased placebo effects. Recommendations for strategies to address these methodological issues are addressed.

[Kagocel in the therapy of influenza and acute respiratory viral infections: Data analysis and systematization from the results of preclinical and clinical trials].

PubMed

Sologub, T V; Tsvetkov, V V

The article provides the summarized data of clinical trials evaluating the efficacy and safety of kagocel used to prevent and treat influenza and acute respiratory viral infections of different etiologies. The results of numerous preclinical and clinical trials suggest that the kagocel substance is highly safe and that it is appropriate to use the drug for the treatment and prevention of influenza and acute respiratory viral infections of another etiology.

Preclinical Development of New Therapy for Glycogen Storage Diseases

PubMed Central

Sun, Baodong; Brooks, Elizabeth D.; Koeberl, Dwight D.

2015-01-01

Glycogen storage disease (GSD) consists of more than 10 discrete conditions for which the biochemical and genetic bases have been determined, and new therapies have been under development for several of these conditions. Gene therapy research has generated proof-of-concept for GSD types I (von Gierke disease) and II (Pompe disease). Key features of these gene therapy strategies include the choice of vector and regulatory cassette, and recently adeno-associated virus (AAV) vectors containing tissue-specific promoters have achieved a high degree of efficacy. Efficacy of gene therapy for Pompe disease depend upon the induction of immune tolerance to the therapeutic enzyme. Efficacy of von Gierke disease is transient, waning gradually over the months following vector administration. Small molecule therapies have been evaluated with the goal of improving standard of care therapy or ameliorating the cellular abnormalities associated with specific GSDs. The receptor-mediated uptake of the therapeutic enzyme in Pompe disease was enhanced by administration of β2 agonists. Rapamycin reduced the liver fibrosis observed in GSD III. Further development of gene therapy could provide curative therapy for patients with GSD, if efficacy from preclinical research is observed in future clinical trials and these treatments become clinically available. PMID:26122079

Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma.

PubMed

Dolman, M Emmy M; Poon, Evon; Ebus, Marli E; den Hartog, Ilona J M; van Noesel, Carel J M; Jamin, Yann; Hallsworth, Albert; Robinson, Simon P; Petrie, Kevin; Sparidans, Rolf W; Kok, Robbert J; Versteeg, Rogier; Caron, Huib N; Chesler, Louis; Molenaar, Jan J

2015-11-15

MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment regimens and novel therapeutic drugs are therefore urgently needed. In previous preclinical studies, we have shown that targeted inhibition of cyclin-dependent kinase 2 (CDK2) resulted in specific killing of MYCN-amplified neuroblastoma cells. This study describes the in vivo preclinical evaluation of the CDK inhibitor AT7519. Preclinical drug testing was performed using a panel of MYCN-amplified and MYCN single copy neuroblastoma cell lines and different MYCN-dependent mouse models of neuroblastoma. AT7519 killed MYCN-amplified neuroblastoma cell lines more potently than MYCN single copy cell lines with a median LC50 value of 1.7 compared to 8.1 μmol/L (P = 0.0053) and a significantly stronger induction of apoptosis. Preclinical studies in female NMRI homozygous (nu/nu) mice with neuroblastoma patient-derived MYCN-amplified AMC711T xenografts revealed dose-dependent growth inhibition, which correlated with intratumoral AT7519 levels. CDK2 target inhibition by AT7519 was confirmed by significant reductions in levels of phosphorylated retinoblastoma (p-Rb) and nucleophosmin (p-NPM). AT7519 treatment of Th-MYCN transgenic mice resulted in improved survival and clinically significant tumor regression (average tumor size reduction of 86% at day 7 after treatment initiation). The improved efficacy of AT7519 observed in Th-MYCN mice correlated with higher tumor exposure to the drug. This study strongly suggests that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification. ©2015 American Association for Cancer Research.

Affective Biases in Humans and Animals.

PubMed

Robinson, E S J; Roiser, J P

Depression is one of the most common but poorly understood psychiatric conditions. Although drug treatments and psychological therapies are effective in some patients, many do not achieve full remission and some patients receive no apparent benefit. Developing new improved treatments requires a better understanding of the aetiology of symptoms and evaluation of novel therapeutic targets in pre-clinical studies. Recent developments in our understanding of the basic cognitive processes that may contribute to the development of depression and its treatment offer new opportunities for both clinical and pre-clinical research. This chapter discusses the clinical evidence supporting a cognitive neuropsychological model of depression and antidepressant efficacy, and how this information may be usefully translated to pre-clinical investigation. Studies using neuropsychological tests in depressed patients and at risk populations have revealed basic negative emotional biases and disrupted reward and punishment processing, which may also impact on non-affective cognition. These affective biases are sensitive to antidepressant treatments with early onset effects observed, suggesting an important role in recovery. This clinical work into affective biases has also facilitated back-translation to animals and the development of assays to study affective biases in rodents. These animal studies suggest that, similar to humans, rodents in putative negative affective states exhibit negative affective biases on decision-making and memory tasks. Antidepressant treatments also induce positive biases in these rodent tasks, supporting the translational validity of this approach. Although still in the early stages of development and validation, affective biases in depression have the potential to offer new insights into the clinical condition, as well as facilitating the development of more translational approaches for pre-clinical studies.

Dissociable Effects of the Cannabinoid Receptor Agonists Δ9-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats

PubMed Central

Kwilasz, Andrew J.

2012-01-01

Cannabinoid receptor agonists produce reliable antinociception in most preclinical pain assays but have inconsistent analgesic efficacy in humans. This disparity suggests that conventional preclinical assays of nociception are not sufficient for the prediction of cannabinoid effects related to clinical analgesia. To extend the range of preclinical cannabinoid assessment, this study compared the effects of the marijuana constituent and low-efficacy cannabinoid agonist Δ9-tetrahydrocannabinol (THC) and the high-efficacy synthetic cannabinoid agonist 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol (CP55940) in assays of pain-stimulated and pain-depressed behavior. Intraperitoneal injection of dilute lactic acid (1.8% in 1 ml/kg) stimulated a stretching response or depressed intracranial self-stimulation (ICSS) in separate groups of male Sprague-Dawley rats. THC (0.1–10 mg/kg) and CP55940 (0.0032–0.32 mg/kg) dose-dependently blocked acid- stimulated stretching but only exacerbated acid-induced depression of ICSS at doses that also decreased control ICSS in the absence of a noxious stimulus. Repeated THC produced tolerance to sedative rate-decreasing effects of THC on control ICSS in the absence of the noxious stimulus but failed to unmask antinociception in the presence of the noxious stimulus. THC and CP55940 also failed to block pain-related depression of feeding in rats, although THC did attenuate satiation-related depression of feeding. In contrast to the effects of the cannabinoid agonists, the clinically effective analgesic and nonsteroidal anti-inflammatory drug ketoprofen (1 mg/kg) blocked acid-stimulated stretching and acid-induced depression of both ICSS and feeding. The poor efficacy of THC and CP55940 to block acute pain-related depression of behavior in rats agrees with the poor efficacy of cannabinoids to treat acute pain in humans. PMID:22892341

Antinociceptive Activity of an Ethanol Extract of Justicia spicigera.

PubMed

Zapata-Morales, Juan Ramón; Alonso-Castro, Angel Josabad; Domínguez, Fabiola; Carranza-Álvarez, Candy; Castellanos, Luis Manuel Orozco; Martínez-Medina, Rosa María; Pérez-Urizar, José

2016-06-01

Preclinical Research The aim of the present study was to evaluate the antinociceptive and sedative activity of an ethanol extract of Justicia spicigera an evergreen used in Mexican traditional medicine for the relief of pain, wounds, fever and inflammation. At 200 mg/kg po, the maximum dose examined, the ethanol extract of J. spicigera (JSE) had analgesic activity in mice in the acetic acid writhing test, the second phase of the formalin test and the tail flick test that was similar in efficacy to the NSAID, naproxen (150 mg/kg po). JSE was inactive in the hot plate test and and the ketamine-induced sleeping time test; it had no sedative effects. These results show that the ethanol extract from the leaves of J. spicigera has antinociceptive effects in mice without inducing sedation. Drug Dev Res 77 : 180-186, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

In Vivo Imaging of Influenza Virus Infection in Immunized Mice

PubMed Central

Czakó, Rita; Vogel, Leatrice; Lamirande, Elaine W.; Bock, Kevin W.; Moore, Ian N.; Ellebedy, Ali H.; Ahmed, Rafi

2017-01-01

ABSTRACT Immunization is the cornerstone of seasonal influenza control and represents an important component of pandemic preparedness strategies. Using a bioluminescent reporter virus, we demonstrate the application of noninvasive in vivo imaging system (IVIS) technology to evaluate the preclinical efficacy of candidate vaccines and immunotherapy in a mouse model of influenza. Sequential imaging revealed distinct spatiotemporal kinetics of bioluminescence in groups of mice passively or actively immunized by various strategies that accelerated the clearance of the challenge virus at different rates and by distinct mechanisms. Imaging findings were consistent with conclusions derived from virus titers in the lungs and, notably, were more informative than conventional efficacy endpoints in some cases. Our findings demonstrate the reliability of IVIS as a qualitative approach to support preclinical evaluation of candidate medical countermeasures for influenza in mice. PMID:28559489

Preclinical evaluation of anti-HIV microbicide products: New models and biomarkers.

PubMed

Doncel, Gustavo F; Clark, Meredith R

2010-12-01

A safe and effective microbicide product designed to prevent sexual transmission of HIV-1 rests on a solid foundation provided by the proper selection and preclinical characterization of both its active pharmaceutical ingredient (API) and formulation. The evaluation of API and formulation physicochemical properties, drug release, specific antiviral activity, cell and tissue toxicity, organ toxicity, pharmacokinetics, and pharmacodynamics and efficacy provides information to understand the product, make go/no go decisions in the critical path of product development and complete a regulatory dossier to file an investigational new drug (IND) with the US Food and Drug Administration. Incorporation of new models, assays and biomarkers has expanded our ability to understand the mechanisms of action underlying microbicide toxicity and efficacy, enabling a more rational selection of drug and formulation candidates. This review presents an overview of the models and endpoints used to comprehensively evaluate an anti-HIV microbicide in preclinical development. This article forms part of a special supplement on presentations covering HIV transmission and microbicides, based on the symposium "Trends in Microbicide Formulations", held on 25 and 26 January 2010, Arlington, VA. Copyright © 2010 Elsevier B.V. All rights reserved.

Fc-Mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models.

PubMed

Sharma, Sai Kiran; Chow, Andrew; Monette, Sebastien; Vivier, Delphine; Pourat, Jacob; Edwards, Kimberly J; Dilling, Thomas R; Abdel-Atti, Dalya; Zeglis, Brian M; Poirier, John T; Lewis, Jason S

2018-04-01

A critical benchmark in the development of antibody-based therapeutics is demonstration of efficacy in preclinical mouse models of human disease, many of which rely on immunodeficient mice. However, relatively little is known about how the biology of various immunodeficient strains impacts the in vivo fate of these drugs. Here we used immunoPET radiotracers prepared from humanized, chimeric, and murine mAbs against four therapeutic oncologic targets to interrogate their biodistribution in four different strains of immunodeficient mice bearing lung, prostate, and ovarian cancer xenografts. The immunodeficiency status of the mouse host as well as both the biological origin and glycosylation of the antibody contributed significantly to the anomalous biodistribution of therapeutic monoclonal antibodies in an Fc receptor-dependent manner. These findings may have important implications for the preclinical evaluation of Fc-containing therapeutics and highlight a clear need for biodistribution studies in the early stages of antibody drug development. Significance: Fc/FcγR-mediated immunobiology of the experimental host is a key determinant to preclinical in vivo tumor targeting and efficacy of therapeutic antibodies. Cancer Res; 78(7); 1820-32. ©2018 AACR . ©2018 American Association for Cancer Research.

Anesthetic neuroprotection: antecedents and an appraisal of preclinical and clinical data quality.

PubMed

Ishida, Kazuyoshi; Berger, Miles; Nadler, Jacob; Warner, David S

2014-01-01

Anesthetics have been studied for nearly fifty years as potential neuroprotective compounds in both perioperative and resuscitation medicine. Although anesthetics present pharmacologic properties consistent with preservation of brain viability in the context of an ischemic insult, no anesthetic has been proven efficacious for neuroprotection in humans. After such effort, it could be concluded that anesthetics are simply not neuroprotective in humans. Moreover, pharmacologic neuroprotection with non-anesthetic drugs has also repeatedly failed to be demonstrated in human acute brain injury. Recent focus has been on rectification of promising preclinical neuroprotection data and subsequent failed clinical trials. This has led to consensus guidelines for the process of transferring purported therapeutics from bench to bedside. In this review we first examined the history of anesthetic neuroprotection research. Then, a systematic review was performed to identify major clinical trials of anesthetic neuroprotection. Both the preclinical neuroprotection portfolio cited to justify a clinical trial and the design and conduct of that clinical trial were evaluated using modern standards that include the Stroke Therapy Academic Industry Roundtable (STAIR) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. In publications intended to define anesthetic neuroprotection, we found overall poor quality of both preclinical efficacy analysis portfolios and clinical trial designs and conduct. Hence, using current translational research standards, it was not possible to conclude from existing data whether anesthetics ameliorate perioperative ischemic brain injury. Incorporation of advances in translational neuroprotection research conduct may provide a basis for more definitive and potentially successful clinical trials of anesthetics as neuroprotectants.

Preclinical Magnetic Resonance Fingerprinting (MRF) at 7 T: Effective Quantitative Imaging for Rodent Disease Models

PubMed Central

Gao, Ying; Chen, Yong; Ma, Dan; Jiang, Yun; Herrmann, Kelsey A.; Vincent, Jason A.; Dell, Katherine M.; Drumm, Mitchell L.; Brady-Kalnay, Susann M.; Griswold, Mark A.; Flask, Chris A.; Lu, Lan

2015-01-01

High field, preclinical magnetic resonance imaging (MRI) scanners are now commonly used to quantitatively assess disease status and efficacy of novel therapies in a wide variety of rodent models. Unfortunately, conventional MRI methods are highly susceptible to respiratory and cardiac motion artifacts resulting in potentially inaccurate and misleading data. We have developed an initial preclinical, 7.0 T MRI implementation of the highly novel Magnetic Resonance Fingerprinting (MRF) methodology that has been previously described for clinical imaging applications. The MRF technology combines a priori variation in the MRI acquisition parameters with dictionary-based matching of acquired signal evolution profiles to simultaneously generate quantitative maps of T1 and T2 relaxation times and proton density. This preclinical MRF acquisition was constructed from a Fast Imaging with Steady-state Free Precession (FISP) MRI pulse sequence to acquire 600 MRF images with both evolving T1 and T2 weighting in approximately 30 minutes. This initial high field preclinical MRF investigation demonstrated reproducible and differentiated estimates of in vitro phantoms with different relaxation times. In vivo preclinical MRF results in mouse kidneys and brain tumor models demonstrated an inherent resistance to respiratory motion artifacts as well as sensitivity to known pathology. These results suggest that MRF methodology may offer the opportunity for quantification of numerous MRI parameters for a wide variety of preclinical imaging applications. PMID:25639694

Preclinical MR fingerprinting (MRF) at 7 T: effective quantitative imaging for rodent disease models.

PubMed

Gao, Ying; Chen, Yong; Ma, Dan; Jiang, Yun; Herrmann, Kelsey A; Vincent, Jason A; Dell, Katherine M; Drumm, Mitchell L; Brady-Kalnay, Susann M; Griswold, Mark A; Flask, Chris A; Lu, Lan

2015-03-01

High-field preclinical MRI scanners are now commonly used to quantitatively assess disease status and the efficacy of novel therapies in a wide variety of rodent models. Unfortunately, conventional MRI methods are highly susceptible to respiratory and cardiac motion artifacts resulting in potentially inaccurate and misleading data. We have developed an initial preclinical 7.0-T MRI implementation of the highly novel MR fingerprinting (MRF) methodology which has been described previously for clinical imaging applications. The MRF technology combines a priori variation in the MRI acquisition parameters with dictionary-based matching of acquired signal evolution profiles to simultaneously generate quantitative maps of T1 and T2 relaxation times and proton density. This preclinical MRF acquisition was constructed from a fast imaging with steady-state free precession (FISP) MRI pulse sequence to acquire 600 MRF images with both evolving T1 and T2 weighting in approximately 30 min. This initial high-field preclinical MRF investigation demonstrated reproducible and differentiated estimates of in vitro phantoms with different relaxation times. In vivo preclinical MRF results in mouse kidneys and brain tumor models demonstrated an inherent resistance to respiratory motion artifacts as well as sensitivity to known pathology. These results suggest that MRF methodology may offer the opportunity for the quantification of numerous MRI parameters for a wide variety of preclinical imaging applications. Copyright © 2015 John Wiley & Sons, Ltd.

Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism Phenotypes

DTIC Science & Technology

2014-09-01

AD_________________ Award Number: TITLE: Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism ...AUG 2013-7 Aug 2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism ...a genetic mouse model of autism -like phenotypes, the Grin1 knockdown mouse. The Grin1 gene encodes the NR1 subunit of the NMDA receptor . In the

Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models.

PubMed

Hennika, Tammy; Hu, Guo; Olaciregui, Nagore G; Barton, Kelly L; Ehteda, Anahid; Chitranjan, Arjanna; Chang, Cecilia; Gifford, Andrew J; Tsoli, Maria; Ziegler, David S; Carcaboso, Angel M; Becher, Oren J

2017-01-01

Diffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG. A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo. In vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice. Our collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation.

The Potential of Cellular- and Viral-Based Immunotherapies for Malignant Glioma-Dendritic Cell Vaccines, Adoptive Cell Transfer, and Oncolytic Viruses.

PubMed

Maxwell, Russell; Luksik, Andrew S; Garzon-Muvdi, Tomas; Lim, Michael

2017-06-01

Malignant gliomas, including glioblastoma and anaplastic astrocytoma, are the most frequent primary brain tumors and present with many treatment challenges. In this review, we discuss the potential of cellular- and viral-based immunotherapies in the treatment of malignant glioma, specifically focusing on dendritic cell vaccines, adoptive cell therapy, and oncolytic viruses. Diverse cellular- and viral-based strategies have been engineered and optimized to generate either a specific or broad antitumor immune response in malignant glioma. Due to their successes in the preclinical arena, many of these therapies have undergone phase I and II clinical testing. These early clinical trials have demonstrated the feasibility, safety, and efficacy of these immunotherapies. Dendritic cell vaccines, adoptive cell transfer, and oncolytic viruses may have a potential role in the treatment of malignant glioma. However, these modalities must be investigated in well-designed phase III trials to prove their efficacy.

Role of preliminary registry data in development of a clinical trial for an innovative device: a small but integral piece of a health policy initiative

PubMed Central

Ricci, Donald R.; de Vries, Joost; Blanc, Raphael

2017-01-01

ABSTRACT Establishing a national health policy at a macro level involves the integration of a series of health initiatives across a spectrum of activities, including clinical care. Evaluation of the safety and efficacy of a new medical device ultimately evolves to testing in humans. The pathway to a formal prospective clinical trial includes a stepwise appreciation of pre-clinical data and detailed analysis of data obtained from preliminary registries, where information about appropriate patient selection and use of the device is obtained. Evaluation of procedural and follow-up efficacy and safety data in a preliminary series of cases, chosen to simulate published data, allows the design and conduct of clinical trials that are required to verify preliminary observations, closing the loop on one aspect of modifying health policy decisions. PMID:28321285

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koizumi, Yoshiki; Nakajim, Syo; Ohash, Hirofumi

Cell culture study combing a mathematical model and computer simulation quantifies the anti-hepatitis C virus drug efficacy at any concentrations and any combinations in preclinical settings, and can obtain rich basic evidences for selecting optimal treatments prior to costly clinical trials.

Experimental models for aging and their potential for novel drug discovery.

PubMed

Folch, Jaume; Busquets, Oriol; Sánchez-López, Miren EttchetoElena; Pallàs, Mercè; Beas-Zarate, Carlos; Marin, Miguel; Casadesus, Gemma; Olloquequi, Jordi; Auladell, Carme; Camins, Antoni

2017-07-07

The development of antiaging drugs is an interesting area of scientific research. In order to evaluate the beneficial effects of new potential drugs, it is necessary to gather the specific knowledge on the adequate preclinical models that are available. This review focuses on invertebrate and vertebrate preclinical models used to evaluate the efficacy of antiaging compounds, with the objective to extend lifespan and health span. Dietary restriction (DR), a common experimental process to extend lifespan in all organisms, is also discussed. Besides, classical antiaging drugs such as resveratrol, rapamycin and metformin, denominated DR mimetics, are reviewed. The main therapeutic targets of these drugs include sirtuins, IGF-1, and mTOR, all of them being modulated by DR. The National Institute on Aging (NIA) developed the Interventions Testing Program (ITP). At the preclinical level, the ITP uses genetically heterogeneous mice model (HET), which is probably the most suitable rodent model to study potential drugs preventing aging-related diseases. The accelerated-senescence mouse P8 is also an interesting rodent model for the research in the field of aging. Notwithstanding, non-human primates are still necessary prior to clinical trials, since they allow an easier extrapolation to humans due to their anatomical and physiological similarities. In this review, the different models and approaches for antiaging studies were evaluated. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pre-clinical and Clinical Safety Studies of CMX-2043: A Cytoprotective Lipoic Acid Analogue for Ischaemia–Reperfusion Injury

PubMed Central

Kates, Steven A; Lader, Alan S; Casale, Ralph; Beeuwkes, Reinier

2014-01-01

CMX-2043 is an α-lipoic acid analogue targeted to reduction of cellular injury and organ damage due to ischaemia–reperfusion injury (IRI). It has been shown to be effective in a rat model of cardiac IRI. The studies here reported evaluate its safety and pharmacokinetic profile in preparation for human clinical studies in procedures associated with IRI. Safety and tolerability were tested in standard pre-clinical in vitro and animal models and in a Phase 1 human clinical trial. CMX-2043 did not bind to a wide range of receptors and specific targets at approximately 4 μg/mL (10 μM). It was not mutagenic by Ames assay, did not produce chromosome aberrations in Chinese hamster ovary (CHO) cells, and was negative for clastogenic potential. Toxicological studies in rats including both single and 14-day repeat intravenous doses and in dogs (single intravenous dose) with a 2-week recovery period were conducted. The NOAEL in rats and dogs was 30 and >10 mg/kg, respectively. No serious adverse events were reported in a placebo-controlled, sequential dose escalation Phase 1 clinical trial. The low toxicity in the pre-clinical studies and the absence of adverse events in the Phase 1 trial have supported investigation of CMX-2043 in a human efficacy trial. PMID:24751172

HIV enhancing activity of semen impairs the antiviral efficacy of microbicides

PubMed Central

Zirafi, Onofrio; Kim, Kyeong-Ae; Roan, Nadia R.; Kluge, Silvia F.; Müller, Janis A.; Jiang, Shibo; Mayer, Benjamin; Greene, Warner C.; Kirchhoff, Frank; Münch, Jan

2015-01-01

Topically applied microbicides potently inhibit HIV in vitro but have largely failed to exert protective effects in clinical trials. One possible reason for this discrepancy is that the preclinical testing of microbicides does not faithfully reflect the conditions of HIV sexual transmission. Here, we report that candidate microbicides that target HIV components show greatly reduced antiviral efficacy in the presence of semen, the main vector for HIV transmission. This diminished antiviral activity was dependent on the ability of amyloid fibrils in semen to enhance the infectivity of HIV. Thus, the anti-HIV efficacy of microbicides determined in the absence of semen greatly underestimated the drug concentrations needed to block semen-exposed virus. One notable exception was Maraviroc. This HIV entry inhibitor targets the host cell CCR5 coreceptor and was highly active against both untreated and semen-exposed HIV. These data help explain why microbicides have failed to protect against HIV in clinical trials and suggest that antiviral compounds targeting host factors hold promise for further development. These findings also suggest that the in vitro efficacy of candidate microbicides should be determined in the presence of semen to identify the best candidates for the prevention of HIV sexual transmission. PMID:25391483

ABBV-105, a selective and irreversible inhibitor of Bruton's Tyrosine Kinase (BTK), is efficacious in multiple preclinical models of inflammation.

PubMed

Goess, Christian; Harris, Christopher M; Murdock, Sara; McCarthy, Richard W; Sampson, Erik; Twomey, Rachel; Mathieu, Suzanne; Mario, Regina; Perham, Matthew; Goedken, Eric R; Long, Andrew J

2018-06-02

Bruton's Tyrosine Kinase (BTK) is a non-receptor tyrosine kinase required for intracellular signaling downstream of multiple immunoreceptors. We evaluated ABBV-105, a covalent BTK inhibitor, using in vitro and in vivo assays to determine potency, selectivity, and efficacy to validate the therapeutic potential of ABBV-105 in inflammatory disease. ABBV-105 potency and selectivity were evaluated in enzymatic and cellular assays. The impact of ABBV-105 on B cell function in vivo was assessed using mechanistic models of antibody production. Efficacy of ABBV-105 in chronic inflammatory disease was evaluated in animal models of arthritis and lupus. Measurement of BTK occupancy was employed as a target engagement biomarker. ABBV-105 irreversibly inhibits BTK, demonstrating superior kinome selectivity and is potent in B cell receptor, Fc receptor, and TLR-9-dependent cellular assays. Oral administration resulted in rapid clearance in plasma, but maintenance of BTK splenic occupancy. ABBV-105 inhibited antibody responses to thymus-independent and thymus-dependent antigens, paw swelling and bone destruction in rat collagen induced arthritis (CIA), and reduced disease in an IFNα-accelerated lupus nephritis model. BTK occupancy in disease models correlated with in vivo efficacy. ABBV-105, a selective BTK inhibitor, demonstrates compelling efficacy in pre-clinical mechanistic models of antibody production and in models of rheumatoid arthritis and lupus.

Improved therapy for neuroblastoma using a combination approach: superior efficacy with vismodegib and topotecan

PubMed Central

Chaturvedi, Nagendra K.; McGuire, Timothy R.; Coulter, Don W.; Shukla, Ashima; McIntyre, Erin M.; Sharp, John Graham; Joshi, Shantaram S.

2016-01-01

Aberrant activation/expression of pathways/molecules including NF-kB, mTOR, hedgehog and polo-like-kinase-1 (PLK1) are correlated with poor-prognosis neuroblastoma. Therefore, to identify a most efficacious treatment for neuroblastoma, we investigated the efficacy of NF-kB/mTOR dual-inhibitor 13-197, hedgehog inhibitor vismodegib and PLK1 inhibitor BI2536 alone or combined with topotecan against high-risk neuroblastoma. The in vitro efficacy of the inhibitors alone or combined with topotecan on cell growth/apoptosis and molecular mechanism(s) were investigated. Results showed that as single agents 13-197, BI2536 and vismodegib significantly decreased neuroblastoma cell growth and induced apoptosis by targeting associated pathways/molecules. In combination with topotecan, 13-197 did not show significant additive/synergistic effects against neuroblastoma. However, BI2536 or vismodegib further significantly decreased neuroblastoma cell growth/survival. These results clearly showed that vismodegib combination with topotecan was synergistic and more efficacious compared with BI2536 in combination. Together, in vitro data demonstrated that vismodegib was most efficacious in potentiating topotecan-induced antineuroblastoma effects. Therefore, we tested the combined efficacy of vismodegib and topotecan against neuroblastoma in vivo using NSG mice. This resulted in significantly (p<0.001) reduced tumor growth and increased survival of mice. Together, the combination of vismodegib and topotecan showed a significant enhanced antineuroblastoma efficacy by targeting associated pathways/molecules which warrants further preclinical evaluation for translation to the clinic. PMID:26934655

DNA vaccination protects mice against Zika virus-induced damage to the testes

PubMed Central

Griffin, Bryan D.; Muthumani, Kar; Warner, Bryce M.; Majer, Anna; Hagan, Mable; Audet, Jonathan; Stein, Derek R.; Ranadheera, Charlene; Racine, Trina; De La Vega, Marc-Antoine; Piret, Jocelyne; Kucas, Stephanie; Tran, Kaylie N.; Frost, Kathy L.; De Graff, Christine; Soule, Geoff; Scharikow, Leanne; Scott, Jennifer; McTavish, Gordon; Smid, Valerie; Park, Young K.; Maslow, Joel N.; Sardesai, Niranjan Y.; Kim, J. Joseph; Yao, Xiao-jian; Bello, Alexander; Lindsay, Robbin; Boivin, Guy; Booth, Stephanie A.; Kobasa, Darwyn; Embury-Hyatt, Carissa; Safronetz, David; Weiner, David B.; Kobinger, Gary P.

2017-01-01

Zika virus (ZIKV) is an emerging pathogen causally associated with serious sequelae in fetuses, inducing fetal microcephaly and other neurodevelopment defects. ZIKV is primarily transmitted by mosquitoes, but can persist in human semen and sperm, and sexual transmission has been documented. Moreover, exposure of type-I interferon knockout mice to ZIKV results in severe damage to the testes, epididymis and sperm. Candidate ZIKV vaccines have shown protective efficacy in preclinical studies carried out in animal models, and several vaccines have entered clinical trials. Here, we report that administration of a synthetic DNA vaccine encoding ZIKV pre-membrane and envelope (prME) completely protects mice against ZIKV-associated damage to the testes and sperm and prevents viral persistence in the testes following challenge with a contemporary strain of ZIKV. These data suggest that DNA vaccination merits further investigation as a potential means to reduce ZIKV persistence in the male reproductive tract. PMID:28589934

Linear Combinations of Multiple Outcome Measures to Improve the Power of Efficacy Analysis ---Application to Clinical Trials on Early Stage Alzheimer Disease

PubMed Central

Xiong, Chengjie; Luo, Jingqin; Morris, John C; Bateman, Randall

2018-01-01

Modern clinical trials on Alzheimer disease (AD) focus on the early symptomatic stage or even the preclinical stage. Subtle disease progression at the early stages, however, poses a major challenge in designing such clinical trials. We propose a multivariate mixed model on repeated measures to model the disease progression over time on multiple efficacy outcomes, and derive the optimum weights to combine multiple outcome measures by minimizing the sample sizes to adequately power the clinical trials. A cross-validation simulation study is conducted to assess the accuracy for the estimated weights as well as the improvement in reducing the sample sizes for such trials. The proposed methodology is applied to the multiple cognitive tests from the ongoing observational study of the Dominantly Inherited Alzheimer Network (DIAN) to power future clinical trials in the DIAN with a cognitive endpoint. Our results show that the optimum weights to combine multiple outcome measures can be accurately estimated, and that compared to the individual outcomes, the combined efficacy outcome with these weights significantly reduces the sample size required to adequately power clinical trials. When applied to the clinical trial in the DIAN, the estimated linear combination of six cognitive tests can adequately power the clinical trial. PMID:29546251

Mesenchymal stromal cells: a novel therapy for the treatment of chronic obstructive pulmonary disease?

PubMed Central

Broekman, Winifred; Khedoe, Padmini P S J; Schepers, Koen; Roelofs, Helene; Stolk, Jan; Hiemstra, Pieter S

2018-01-01

COPD is characterised by tissue destruction and inflammation. Given the lack of curative treatments and the progressive nature of the disease, new treatments for COPD are highly relevant. In vitro cell culture and animal studies have demonstrated that mesenchymal stromal cells (MSCs) have the capacity to modify immune responses and to enhance tissue repair. These properties of MSCs provided a rationale to investigate their potential for treatment of a variety of diseases, including COPD. Preclinical models support the hypothesis that MSCs may have clinical efficacy in COPD. However, although clinical trials have demonstrated the safety of MSC treatment, thus far they have not provided evidence for MSC efficacy in the treatment of COPD. In this review, we discuss the rationale for MSC-based cell therapy in COPD, the main findings from in vitro and in vivo preclinical COPD model studies, clinical trials in patients with COPD and directions for further research. PMID:29653970

Clinical development of Ebola vaccines

PubMed Central

Sridhar, Saranya

2015-01-01

The ongoing outbreak of Ebola virus disease in West Africa highlighted the lack of a licensed drug or vaccine to combat the disease and has renewed the urgency to develop a pipeline of Ebola vaccines. A number of different vaccine platforms are being developed by assessing preclinical efficacy in animal models and expediting clinical development. Over 15 different vaccines are in preclinical development and 8 vaccines are now in different stages of clinical evaluation. These vaccines include DNA vaccines, virus-like particles and viral vectors such as live replicating vesicular stomatitis virus (rVSV), human and chimpanzee adenovirus, and vaccinia virus. Recently, in preliminary results reported from the first phase III trial of an Ebola vaccine, the rVSV-vectored vaccine showed promising efficacy. This review charts this rapidly advancing area of research focusing on vaccines in clinical development and discusses the future opportunities and challenges faced in the licensure and deployment of Ebola vaccines. PMID:26668751

Mind the gap: a survey of how cancer drug carriers are susceptible to the gap between research and practice

PubMed Central

Stirland, Darren Lars; Nichols, Joseph W.; Miura, Seiji; Bae, You Han

2013-01-01

With countless research papers using preclinical models and showing the superiority of nanoparticle design over current drug therapies used to treat cancers, it is surprising how deficient the translation of these nano-sized drug carriers into the clinical setting is. This review article seeks to compare the preclinical and clinical results for Doxil®, PK1, Abraxane®, Genexol-PM®, Xyotax™, NC-6004, Mylotarg®, PK2, and CALAA-01. While not comprehensive, it covers nano-sized drug carriers designed to improve the efficacy of common drugs used in chemotherapy. While not always available or comparable, effort was made to compare the pharmacokinetics, toxicity, and efficacy between the animal and human studies. Discussion is provided to suggest what might be causing the gap. Finally, suggestions and encouragement are dispensed for the potential that nano-sized drug carriers hold. PMID:24096014

Exploiting Epigenetic Alterations in Prostate Cancer.

PubMed

Baumgart, Simon J; Haendler, Bernard

2017-05-09

Prostate cancer affects an increasing number of men worldwide and is a leading cause of cancer-associated deaths. Beside genetic mutations, many epigenetic alterations including DNA and histone modifications have been identified in clinical prostate tumor samples. They have been linked to aberrant activity of enzymes and reader proteins involved in these epigenetic processes, leading to the search for dedicated inhibitory compounds. In the wake of encouraging anti-tumor efficacy results in preclinical models, epigenetic modulators addressing different targets are now being tested in prostate cancer patients. In addition, the assessment of microRNAs as stratification biomarkers, and early clinical trials evaluating suppressor microRNAs as potential prostate cancer treatment are being discussed.

Immunotherapy in new pre-clinical models of HPV-associated oral cancers.

PubMed

Paolini, Francesca; Massa, Silvia; Manni, Isabella; Franconi, Rosella; Venuti, Aldo

2013-03-01

Cervical, anal, penile and a sub-set of head and neck (HN) tumors are critical health problems caused by high risk Human Papilloma Viruses (HPVs), like HPV type 16. No specific/effective pharmacological treatments exist. A valid preventive vaccination as well as the immunotherapy of persistent infections, pre-cancerous lesions or early-stage cancers could drive the HPV disease burden down. These treatments might be featured through low-cost platforms like those based on DNA and plant biotechnologies to produce tailored and enhanced formulations taking profit from the use of plants as bio-factories and as a source of immune-stimulators. Finally, and regardless of the formulation type, pre-clinical tests and models are crucial to foresee efficacy of immunotherapy before clinical trials.   In this study, we created an orthotopic mouse model for HPV-related oral tumors, a subset of HN tumors for which no models have been generated before. The model was obtained by inducing the stable expression of the HPV16 E7 protein into the mouse oral squamous cell carcinoma (OSCC) AT-84 (AT-84 E7). The AT-84 E7 cells were injected into the mouth pavement of C3H mice via an extra-oral route to obtain orthotopic tumors. The model turned out to mimic the natural history of the human HPV oral cancer. From AT-84 E7, through engineering to express luciferase, the bioluminescent AT-84 E7-Luc cells were obtained for a fast and easy monitoring by imaging. The AT-84 E7 and the AT-84 E7-Luc tumors were used to test the efficacy of E7-based therapeutic vaccines that we had previously generated and that had been already proven to be active in mice against non-orthotopic E7-expressing tumors (TC-1 cells). In particular, we used genetic and plant-derived formulations based on attenuated HPV16 E7 variants either fused to plant virus genes with immunological activity or produced by tobacco plants. Mice were monitored by imaging allowing to test the size reduction of the mouth implanted experimental tumors in function of the different regimens used. The proposed tumor model is easy to handle and to reproduce and it is efficacious in monitoring immunotherapy. Furthermore, it is expected to be more predictive of clinical outcome of therapeutic vaccines than non-orthotopic models that are currently used. Finally, imaging offers unique opportunities to predict formulation efficacy through measuring tumor growth in vivo.

Clinical Trials in a Dish: A Perspective on the Coming Revolution in Drug Development.

PubMed

Fermini, Bernard; Coyne, Shawn T; Coyne, Kevin P

2018-05-01

The pharmaceutical industry is facing unprecedented challenges as the cost of developing new drugs has reached unsustainable levels, fueled in large parts by a high attrition rate in clinical development. Strategies to bridge studies between preclinical testing and clinical trials are needed to reduce the knowledge gap and allow earlier decisions to be made on the continuation or discontinuation of further development of drugs. The discovery and development of human induced pluripotent stem cells (hiPSCs) have opened up new avenues that support the concept of screening for cell-based safety and toxicity at the level of a population. This approach, termed "Clinical Trials in a Dish" (CTiD), allows testing medical therapies for safety or efficacy on cells collected from a representative sample of human patients, before moving into actual clinical trials. It can be applied to the development of drugs for specific populations, and it allows predicting not only the magnitude of effects but also the incidence of patients in a population who will benefit or be harmed by these drugs. This, in turn, can lead to the selection of safer drugs to move into clinical development, resulting in a reduction in attrition. The current article offers a perspective of this new model for "humanized" preclinical drug development.

Preclinical optimization of a broad-spectrum anti-bladder cancer tri-drug regimen via the Feedback System Control (FSC) platform

NASA Astrophysics Data System (ADS)

Liu, Qi; Zhang, Cheng; Ding, Xianting; Deng, Hui; Zhang, Daming; Cui, Wei; Xu, Hongwei; Wang, Yingwei; Xu, Wanhai; Lv, Lei; Zhang, Hongyu; He, Yinghua; Wu, Qiong; Szyf, Moshe; Ho, Chih-Ming; Zhu, Jingde

2015-06-01

Therapeutic outcomes of combination chemotherapy have not significantly advanced during the past decades. This has been attributed to the formidable challenges of optimizing drug combinations. Testing a matrix of all possible combinations of doses and agents in a single cell line is unfeasible due to the virtually infinite number of possibilities. We utilized the Feedback System Control (FSC) platform, a phenotype oriented approach to test 100 options among 15,625 possible combinations in four rounds of assaying to identify an optimal tri-drug combination in eight distinct chemoresistant bladder cancer cell lines. This combination killed between 82.86% and 99.52% of BCa cells, but only 47.47% of the immortalized benign bladder epithelial cells. Preclinical in vivo verification revealed its markedly enhanced anti-tumor efficacy as compared to its bi- or mono-drug components in cell line-derived tumor xenografts. The collective response of these pathways to component drugs was both cell type- and drug type specific. However, the entire spectrum of pathways triggered by the tri-drug regimen was similar in all four cancer cell lines, explaining its broad spectrum killing of BCa lines, which did not occur with its component drugs. Our findings here suggest that the FSC platform holdspromise for optimization of anti-cancer combination chemotherapy.

Multi-Center Trial of Baclofen for Abstinence Initiation in Severe Cocaine Dependent Individuals

PubMed Central

Kahn, Roberta; Biswas, Kousick; Childress, Anna-Rose; Shoptaw, Steve; Fudala, Paul J.; Gorgon, Liza; Montoya, Ivan; Collins, Joseph; McSherry, Frances; Li, Shou-Hua; Chiang, Nora; Alathari, Husam; Watson, Donnie; Liberto, Joseph; Beresford, Thomas; Stock, Christopher; Wallace, Christopher; Gruber, Valerie; Elkashef, Ahmed

2009-01-01

Background Cocaine dependence is a major public health problem for which there is no FDA-approved pharmacological treatment. Baclofen is a GABAB receptor agonist that in preclinical and early pilot clinical trials has shown promise for the treatment of cocaine dependence. The purpose of this multi-site, double-blind study, was to compare the safety and efficacy of baclofen (60 mg/day) versus placebo in an 8-week treatment of individuals with severe cocaine dependence. The primary outcome measure was subjects' self-reported cocaine use substantiated by urine benzoylecgonine (BE). Analysis of the data did not show a significant difference between the groups treated with baclofen and placebo. The current results do not support a role for 60mg baclofen in treating cocaine dependence in the population studied. The contrast of this result to earlier, preclinical and human pilot data with baclofen may reflect the trial's focus on severe cocaine-dependent users, and/or the need for a higher baclofen dose. Baclofen's potential as a relapse prevention agent was not tested by the current design, but may be a useful target for future studies. PMID:19414226

Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy.

PubMed

Bouyssou, Thierry; Hoenke, Christoph; Rudolf, Klaus; Lustenberger, Philipp; Pestel, Sabine; Sieger, Peter; Lotz, Ralf; Heine, Claudia; Büttner, Frank H; Schnapp, Andreas; Konetzki, Ingo

2010-02-15

Compound 4p was identified from a series of 6-hydroxy-4H-benzo[1,4]oxazin-3-ones as potent agonist of the human beta2-adrenoceptor with a high beta1/beta2-selectivity. A complete reversal of acetylcholine-induced bronchoconstriction which lasted over the whole study period of 5h was demonstrated for 4p in a guinea pig in vivo model without any signs of cardiovascular effects up to 10-fold above the first dose reaching 100% bronchoprotection. The enantiomerically pure (R)-form of 4p exerted a bronchodilatory efficacy over 24 h in dogs and guinea pigs in the absence of systemic pharmacodynamic effects. Formoterol which was tested as comparator in the same in vivo models of acetylcholine-induced bronchoconstriction did not retain efficacy after 24 h. In summary, the preclinical profile of compound (R)-4p (olodaterol, also known as BI 1744 CL) suggests a potential for once-daily dosing in man accompanied with an improved safety profile. Copyright 2010 Elsevier Ltd. All rights reserved.

Chemophototherapy: An Emerging Treatment Option for Solid Tumors

PubMed Central

Luo, Dandan; Carter, Kevin A.; Miranda, Dyego

2016-01-01

Near infrared (NIR) light penetrates human tissues with limited depth, thereby providing a method to safely deliver non‐ionizing radiation to well‐defined target tissue volumes. Light‐based therapies including photodynamic therapy (PDT) and laser‐induced thermal therapy have been validated clinically for curative and palliative treatment of solid tumors. However, these monotherapies can suffer from incomplete tumor killing and have not displaced existing ablative modalities. The combination of phototherapy and chemotherapy (chemophototherapy, CPT), when carefully planned, has been shown to be an effective tumor treatment option preclinically and clinically. Chemotherapy can enhance the efficacy of PDT by targeting surviving cancer cells or by inhibiting regrowth of damaged tumor blood vessels. Alternatively, PDT‐mediated vascular permeabilization has been shown to enhance the deposition of nanoparticulate drugs into tumors for enhanced accumulation and efficacy. Integrated nanoparticles have been reported that combine photosensitizers and drugs into a single agent. More recently, light‐activated nanoparticles have been developed that release their payload in response to light irradiation to achieve improved drug bioavailability with superior efficacy. CPT can potently eradicate tumors with precise spatial control, and further clinical testing is warranted. PMID:28105389

Pre-Clinical Testing of Real-Time PCR Assays for Diarrheal Disease Agents of Genera Escherichia and Shigella

DTIC Science & Technology

2014-05-16

FOR DIARRHEAL DISEASE AGENTS OF GENERA ESCHERICHIA AND SHIGELLA May 16, 2014 Reporting Period: October 1, 2010 to September 30, 2013...10-2010 - 30-09-2013 PRE-CLINICAL TESTING OF REAL-TIME PCR ASSAYS FOR DIARRHEAL DISEASE AGENTS OF GENERA ESCHERICHIA AND SHIGELLA ...Texas (MOA 2007 - 2013. Agreement No.: DODI 4000.19; AFI 25-201). Pre-clinical test results qualify ETEC and Shigella real-time PCR assays as lead

Potential Role of N-Acetylcysteine in the Management of Substance Use Disorders

PubMed Central

Gipson, Cassandra D.; Malcolm, Robert J.; Kalivas, Peter W.; Gray, Kevin M.

2014-01-01

There is a clear and pressing need to expand pharmacotherapy options for substance use disorders (SUDs) in order to improve sustained abstinence outcomes. Preclinical literature has demonstrated the role of glutamate in addiction, suggesting that new targets for pharmacotherapy should focus on the restoration of glutamatergic function. Glutamatergic agents for SUDs may span multiple addictive behaviors and help demonstrate potentially overlapping mechanisms in addiction. The current review will focus specifically on N-acetylcysteine (NAC), a safe and well-tolerated glutamatergic agent, as a promising potential pharmacotherapy for the treatment of SUDs across several substances of abuse. Building on recently published reviews of the clinical efficacy of NAC across a broad range of conditions, this review will more specifically discuss NAC as a pharmacotherapy for SUDs, devoting particular attention to the safety and tolerability profile of NAC, the wealth of preclinical evidence that has demonstrated the role of glutamate dysregulation in addiction, and the limited but growing clinical literature that has assessed the efficacy of NAC across multiple substances of abuse. Preliminary clinical studies show the promise of NAC in terms of safety, tolerability, and potential efficacy for promoting abstinence from cocaine, nicotine, and cannabis. Results from randomized clinical trials have been mixed, but several mechanistic and methodological factors are discussed to refine the use of NAC in promoting abstinence and relapse prevention across several substances of abuse. Further preclinical and clinical investigation into the use of NAC for SUDs will be vital in addressing current deficits in the treatment of SUDs. PMID:24442756

NCI Pediatric Preclinical Testing Consortium

Cancer.gov

NCI has awarded grants to five research teams to participate in its Pediatric Preclinical Testing Consortium, which is intended to help to prioritize which agents to pursue in pediatric clinical trials.

High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the γ-secretase inhibitor, RO4929097.

PubMed

He, Wei; Luistro, Leopoldo; Carvajal, Daisy; Smith, Melissa; Nevins, Tom; Yin, Xuefeng; Cai, James; Higgins, Brian; Kolinsky, Kenneth; Rizzo, Christine; Packman, Kathryn; Heimbrook, David; Boylan, John F

2011-06-01

Interest continues to build around the early application of patient selection markers to prospectively identify patients likely to show clinical benefit from cancer therapies. Hypothesis generation and clinical strategies often begin at the preclinical stage where responder and nonresponder tumor cell lines are first identified and characterized. In the present study, we investigate the drivers of in vivo resistance to the γ-secretase inhibitor RO4929097. Beginning at the tissue culture level, we identified apparent IL6 and IL8 expression differences that characterized tumor cell line response to RO4929097. We validated this molecular signature at the preclinical efficacy level identifying additional xenograft models resistant to the in vivo effects of RO4929097. Our data suggest that for IL6 and IL8 overexpressing tumors, RO4929097 no longer impacts angiogenesis or the infiltration of tumor associated fibroblasts. These preclinical data provide a rationale for preselecting patients possessing low levels of IL6 and IL8 prior to RO4929097 dosing. Extending this hypothesis into the clinic, we monitored patient IL6 and IL8 serum levels prior to dosing with RO4929097 during Phase I. Interestingly, the small group of patients deriving some type of clinical benefit from RO4929097 presented with low baseline levels of IL6 and IL8. Our data support the continued investigation of this patient selection marker for RO4929097 and other types of Notch inhibitors undergoing early clinical evaluation. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Validation of a Preclinical Spinal Safety Model: Effects of Intrathecal Morphine in the Neonatal Rat

PubMed Central

Westin, B. David; Walker, Suellen M.; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L.

2010-01-01

Background Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long term function following intrathecal morphine in the neonatal rat. Methods Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P)3, 10 and 21. The relationship between injectate volume and segmental spread was assessed post mortem and by in-vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 minutes following intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis and glial response were evaluated 1 and 7 days following P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Results Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally-mediated analgesia at all ages with lower dose requirements in younger pups. High dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. Conclusions The therapeutic ratio for intrathecal morphine (toxic dose / antinociceptive dose) was at least 300 at P3, and at least 20 at P21 (latter doses limited by side effects). This data provides relative efficacy and safety data for comparison with other analgesic preparations and contributes supporting evidence for the validity of this preclinical neonatal safety model. PMID:20526189

Validation of a preclinical spinal safety model: effects of intrathecal morphine in the neonatal rat.

PubMed

Westin, B David; Walker, Suellen M; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L

2010-07-01

Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long-term function after intrathecal morphine in the neonatal rat. Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P) 3, 10, and 21. The relationship between injectate volume and segmental spread was assessed postmortem and by in vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 min after intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis, and glial response were evaluated 1 and 7 days after P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally mediated analgesia at all ages with lower dose requirements in younger pups. High-dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. The therapeutic ratio for intrathecal morphine (toxic dose/antinociceptive dose) was at least 300 at P3 and at least 20 at P21 (latter doses limited by side effects). These data provide relative efficacy and safety for comparison with other analgesic preparations and contribute supporting evidence for the validity of this preclinical neonatal safety model.

Development of CAR T cells designed to improve antitumor efficacy and safety

PubMed Central

Jaspers, Janneke E.; Brentjens, Renier J.

2017-01-01

Chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy against hematologic malignancies. Antitumor activity of CAR T cells, however, needs to be improved to increase therapeutic efficacy in both hematologic and solid cancers. Limitations to overcome are ‘on-target, off-tumor’ toxicity, antigen escape, short CAR T cell persistence, little expansion, trafficking to the tumor and inhibition of T cell activity by an inhibitory tumor microenvironment. Here we will discuss how optimizing the design of CAR T cells through genetic engineering addresses these limitations and improves the antitumor efficacy of CAR T cell therapy in pre-clinical models. PMID:28342824

Development of CAR T cells designed to improve antitumor efficacy and safety.

PubMed

Jaspers, Janneke E; Brentjens, Renier J

2017-10-01

Chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy against hematologic malignancies. Antitumor activity of CAR T cells, however, needs to be improved to increase therapeutic efficacy in both hematologic and solid cancers. Limitations to overcome are 'on-target, off-tumor' toxicity, antigen escape, short CAR T cell persistence, little expansion, trafficking to the tumor and inhibition of T cell activity by an inhibitory tumor microenvironment. Here we will discuss how optimizing the design of CAR T cells through genetic engineering addresses these limitations and improves the antitumor efficacy of CAR T cell therapy in pre-clinical models. Published by Elsevier Inc.

Turning the gene tap off; implications of regulating gene expression for cancer therapeutics

PubMed Central

Curtin, James F.; Candolfi, Marianela; Xiong, Weidong; Lowenstein, Pedro R.; Castro, Maria G.

2008-01-01

Cancer poses a tremendous therapeutic challenge worldwide, highlighting the critical need for developing novel therapeutics. A promising cancer treatment modality is gene therapy, which is a form of molecular medicine designed to introduce into target cells genetic material with therapeutic intent. Anticancer gene therapy strategies currently used in preclinical models, and in some cases in the clinic, include proapoptotic genes, oncolytic/replicative vectors, conditional cytotoxic approaches, inhibition of angiogenesis, inhibition of growth factor signaling, inactivation of oncogenes, inhibition of tumor invasion and stimulation of the immune system. The translation of these novel therapeutic modalities from the preclinical setting to the clinic has been driven by encouraging preclinical efficacy data and advances in gene delivery technologies. One area of intense research involves the ability to accurately regulate the levels of therapeutic gene expression to achieve enhanced efficacy and provide the capability to switch gene expression off completely if adverse side effects should arise. This feature could also be implemented to switch gene expression off when a successful therapeutic outcome ensues. Here, we will review recent developments related to the engineering of transcriptional switches within gene delivery systems, which could be implemented in clinical gene therapy applications directed at the treatment of cancer. PMID:18347132

Implantable Sensors for Regenerative Medicine

PubMed Central

Klosterhoff, Brett S.; Tsang, Melissa; She, Didi; Ong, Keat Ghee; Allen, Mark G.; Willett, Nick J.; Guldberg, Robert E.

2017-01-01

The translation of many tissue engineering/regenerative medicine (TE/RM) therapies that demonstrate promise in vitro are delayed or abandoned due to reduced and inconsistent efficacy when implemented in more complex and clinically relevant preclinical in vivo models. Determining mechanistic reasons for impaired treatment efficacy is challenging after a regenerative therapy is implanted due to technical limitations in longitudinally measuring the progression of key environmental cues in vivo. The ability to acquire real-time measurements of environmental parameters of interest including strain, pressure, pH, temperature, oxygen tension, and specific biomarkers within the regenerative niche in situ would significantly enhance the information available to tissue engineers to monitor and evaluate mechanisms of functional healing or lack thereof. Continued advancements in material and fabrication technologies utilized by microelectromechanical systems (MEMSs) and the unique physical characteristics of passive magnetoelastic sensor platforms have created an opportunity to implant small, flexible, low-power sensors into preclinical in vivo models, and quantitatively measure environmental cues throughout healing. In this perspective article, we discuss the need for longitudinal measurements in TE/RM research, technical progress in MEMS and magnetoelastic approaches to implantable sensors, the potential application of implantable sensors to benefit preclinical TE/RM research, and the future directions of collaborative efforts at the intersection of these two important fields. PMID:27987300

Assessment of vaccine testing at three laboratories using the guinea pig model of tuberculosis.

PubMed

Grover, Ajay; Troudt, Jolynn; Arnett, Kimberly; Izzo, Linda; Lucas, Megan; Strain, Katie; McFarland, Christine; Hall, Yper; McMurray, David; Williams, Ann; Dobos, Karen; Izzo, Angelo

2012-01-01

The guinea pig model of tuberculosis is used extensively in different locations to assess the efficacy of novel tuberculosis vaccines during pre-clinical development. Two key assays are used to measure protection against virulent challenge: a 30 day post-infection assessment of mycobacterial burden and long-term post-infection survival and pathology analysis. To determine the consistency and robustness of the guinea pig model for testing vaccines, a comparative assessment between three sites that are currently involved in testing tuberculosis vaccines from external providers was performed. Each site was asked to test two "subunit" type vaccines in their routine animal model as if testing vaccines from a provider. All sites performed a 30 day study, and one site also performed a long-term survival/pathology study. Despite some differences in experimental approach between the sites, such as the origin of the Mycobacterium tuberculosis strain and the type of aerosol exposure device used to infect the animals and the source of the guinea pigs, the data obtained between sites were consistent in regard to the ability of each "vaccine" tested to reduce the mycobacterial burden. The observations also showed that there was good concurrence between the results of short-term and long-term studies. This validation exercise means that efficacy data can be compared between sites. Copyright © 2011 Elsevier Ltd. All rights reserved.

In Vivo Assessment of Drug Efficacy against Mycobacterium abscessus Using the Embryonic Zebrafish Test System

PubMed Central

Bernut, Audrey; Le Moigne, Vincent; Lesne, Tiffany; Lutfalla, Georges; Herrmann, Jean-Louis

2014-01-01

Mycobacterium abscessus is responsible for a wide spectrum of clinical syndromes and is one of the most intrinsically drug-resistant mycobacterial species. Recent evaluation of the in vivo therapeutic efficacy of the few potentially active antibiotics against M. abscessus was essentially performed using immunocompromised mice. Herein, we assessed the feasibility and sensitivity of fluorescence imaging for monitoring the in vivo activity of drugs against acute M. abscessus infection using zebrafish embryos. A protocol was developed where clarithromycin and imipenem were directly added to water containing fluorescent M. abscessus-infected embryos in a 96-well plate format. The status of the infection with increasing drug concentrations was visualized on a spatiotemporal level. Drug efficacy was assessed quantitatively by measuring the index of protection, the bacterial burden (CFU), and the number of abscesses through fluorescence measurements. Both drugs were active in infected embryos and were capable of significantly increasing embryo survival in a dose-dependent manner. Protection from bacterial killing correlated with restricted mycobacterial growth in the drug-treated larvae and with reduced pathophysiological symptoms, such as the number of abscesses within the brain. In conclusion, we present here a new and efficient method for testing and compare the in vivo activity of two clinically relevant drugs based on a fluorescent reporter strain in zebrafish embryos. This approach could be used for rapid determination of the in vivo drug susceptibility profile of clinical isolates and to assess the preclinical efficacy of new compounds against M. abscessus. PMID:24798271

Wire-bending test as a predictor of preclinical performance by dental students.

PubMed

Kao, E C; Ngan, P W; Wilson, S; Kunovich, R

1990-10-01

Traditional Dental Aptitude Test and academic grade point average have been shown to be poor predictors of clinical performance by dental students. To refine predictors of psychomotor skills, a wire-bending test was given to 105 freshmen at the beginning of their dental education. Grades from seven restorative preclinical courses in their freshman and sophomore years were compared to scores on wire bending and the three traditional predictors: GPA, academic aptitude, and perceptual aptitude scores. Wire-bending scores correlated significantly with six out of seven preclinical restorative courses. The predictive power for preclinical performance was doubled when wire bending was added to traditional predictors in stepwise multiple regression analysis. Wire-bending scores identified students of low performance. These preliminary results suggest that the wire-bending test shows some potential as a screening test for identifying students who may hae psychomotor difficulties, early in their dental education.

Skeletal Muscle Differentiation on a Chip Shows Human Donor Mesoangioblasts' Efficiency in Restoring Dystrophin in a Duchenne Muscular Dystrophy Model.

PubMed

Serena, Elena; Zatti, Susi; Zoso, Alice; Lo Verso, Francesca; Tedesco, F Saverio; Cossu, Giulio; Elvassore, Nicola

2016-12-01

: Restoration of the protein dystrophin on muscle membrane is the goal of many research lines aimed at curing Duchenne muscular dystrophy (DMD). Results of ongoing preclinical and clinical trials suggest that partial restoration of dystrophin might be sufficient to significantly reduce muscle damage. Different myogenic progenitors are candidates for cell therapy of muscular dystrophies, but only satellite cells and pericytes have already entered clinical experimentation. This study aimed to provide in vitro quantitative evidence of the ability of mesoangioblasts to restore dystrophin, in terms of protein accumulation and distribution, within myotubes derived from DMD patients, using a microengineered model. We designed an ad hoc experimental strategy to miniaturize on a chip the standard process of muscle regeneration independent of variables such as inflammation and fibrosis. It is based on the coculture, at different ratios, of human dystrophin-positive myogenic progenitors and dystrophin-negative myoblasts in a substrate with muscle-like physiological stiffness and cell micropatterns. Results showed that both healthy myoblasts and mesoangioblasts restored dystrophin expression in DMD myotubes. However, mesoangioblasts showed unexpected efficiency with respect to myoblasts in dystrophin production in terms of the amount of protein produced (40% vs. 15%) and length of the dystrophin membrane domain (210-240 µm vs. 40-70 µm). These results show that our microscaled in vitro model of human DMD skeletal muscle validated previous in vivo preclinical work and may be used to predict efficacy of new methods aimed at enhancing dystrophin accumulation and distribution before they are tested in vivo, reducing time, costs, and variability of clinical experimentation. This study aimed to provide in vitro quantitative evidence of the ability of human mesoangioblasts to restore dystrophin, in terms of protein accumulation and distribution, within myotubes derived from patients with Duchenne muscular dystrophy (DMD), using a microengineered model. An ad hoc experimental strategy was designed to miniaturize on a chip the standard process of muscle regeneration independent of variables such as inflammation and fibrosis. This microscaled in vitro model, which validated previous in vivo preclinical work, revealed that mesoangioblasts showed unexpected efficiency as compared with myoblasts in dystrophin production. Consequently, this model may be used to predict efficacy of new drugs or therapies aimed at enhancing dystrophin accumulation and distribution before they are tested in vivo. ©AlphaMed Press.

Preclinical testing for aortic endovascular grafts: results of a Food and Drug Administration workshop.

PubMed

Abel, Dorothy B; Beebe, Hugh G; Dedashtian, Mark M; Morton, Michael C; Moynahan, Megan; Smith, Loius J; Weinberg, Steven L

2002-05-01

Since their introduction into clinical trials in the United States, endovascular aortic grafts have shown various types of problems. Although details of design and construction vary between different endovascular grafts and failure modes have had a variety of causes and clinical effects, the inability of preclinical testing to predict these failures remains common to all endovascular grafts. The need to improve preclinical testing in an attempt to reduce clinical device failures resulted in a Food and Drug Administration-sponsored workshop on endovascular graft preclinical testing held in Rockville, Md, from July 31 to August 1, 2001. FORMAT: The workshop was not designed as a consensus conference. Instead, it provided a forum for bringing stakeholders together to define problems and identify areas of agreement and disagreement. The workshop had 34 invited participants who represented device manufacturers, the medical community, the Food and Drug Administration, and testing facilities, and international attendance was more than 120 people. Discussion centered on: 1, defining the physiologic, anatomic, and morphologic characteristics of abdominal aortic aneurysms before and after endovascular graft treatment; 2, identifying the types of failures that have been observed clinically; and 3, determining which characteristics should be considered during preclinical modeling to better predict clinical performance. Attendees agreed to the need to better define and address anatomic characteristics and changes in the aneurysm after endograft treatment to optimize preclinical testing. Much discussion and little agreement occurred on the importance of flow-related forces on graft performance or the need or ability to define and model physiologic compliance during durability testing. The discussion and conclusions are summarized in this paper and are provided in detail at: http://www.fda.gov/cdrh/meetings/073101workshop.html. The workshop raised awareness of significant performance issues and the challenges of modeling the extremely variable and relatively undefined environment of abdominal aortic aneurysms. Through the interactive format of the workshop, participants identified areas of preclinical testing, device design, and aspects of the simulated environment that need further consideration.

Systematic review and meta-analysis of Saccharomyces boulardii in adult patients.

PubMed

McFarland, Lynne V

2010-05-14

This article reviews the evidence for efficacy and safety of Saccharomyces boulardii (S. boulardii) for various disease indications in adults based on the peer-reviewed, randomized clinical trials and pre-clinical studies from the published medical literature (Medline, Clinical Trial websites and meeting abstracts) between 1976 and 2009. For meta-analysis, only randomized, blinded controlled trials unrestricted by language were included. Pre-clinical studies, volunteer studies and uncontrolled studies were excluded from the review of efficacy and meta-analysis, but included in the systematic review. Of 31 randomized, placebo-controlled treatment arms in 27 trials (encompassing 5029 study patients), S. boulardii was found to be significantly efficacious and safe in 84% of those treatment arms. A meta-analysis found a significant therapeutic efficacy for S. boulardii in the prevention of antibiotic-associated diarrhea (AAD) (RR = 0.47, 95% CI: 0.35-0.63, P < 0.001). In adults, S. boulardii can be strongly recommended for the prevention of AAD and the traveler's diarrhea. Randomized trials also support the use of this yeast probiotic for prevention of enteral nutrition-related diarrhea and reduction of Helicobacter pylori treatment-related symptoms. S. boulardii shows promise for the prevention of C. difficile disease recurrences; treatment of irritable bowel syndrome, acute adult diarrhea, Crohn's disease, giardiasis, human immunodeficiency virus-related diarrhea; but more supporting evidence is recommended for these indications. The use of S. boulardii as a therapeutic probiotic is evidence-based for both efficacy and safety for several types of diarrhea.

Systematic review and meta-analysis of Saccharomyces boulardii in adult patients

PubMed Central

McFarland, Lynne V

2010-01-01

This article reviews the evidence for efficacy and safety of Saccharomyces boulardii (S. boulardii) for various disease indications in adults based on the peer-reviewed, randomized clinical trials and pre-clinical studies from the published medical literature (Medline, Clinical Trial websites and meeting abstracts) between 1976 and 2009. For meta-analysis, only randomized, blinded controlled trials unrestricted by language were included. Pre-clinical studies, volunteer studies and uncontrolled studies were excluded from the review of efficacy and meta-analysis, but included in the systematic review. Of 31 randomized, placebo-controlled treatment arms in 27 trials (encompassing 5029 study patients), S. boulardii was found to be significantly efficacious and safe in 84% of those treatment arms. A meta-analysis found a significant therapeutic efficacy for S. boulardii in the prevention of antibiotic-associated diarrhea (AAD) (RR = 0.47, 95% CI: 0.35-0.63, P < 0.001). In adults, S. boulardii can be strongly recommended for the prevention of AAD and the traveler’s diarrhea. Randomized trials also support the use of this yeast probiotic for prevention of enteral nutrition-related diarrhea and reduction of Heliobacter pylori treatment-related symptoms. S. boulardii shows promise for the prevention of C. difficile disease recurrences; treatment of irritable bowel syndrome, acute adult diarrhea, Crohn’s disease, giardiasis, human immunodeficiency virus-related diarrhea; but more supporting evidence is recommended for these indications. The use of S. boulardii as a therapeutic probiotic is evidence-based for both efficacy and safety for several types of diarrhea. PMID:20458757

Combination Therapy with NHS-muIL12 and Avelumab (anti-PD-L1) Enhances Antitumor Efficacy in Preclinical Cancer Models.

PubMed

Xu, Chunxiao; Zhang, Yanping; Rolfe, P Alexander; Hernández, Vivian M; Guzman, Wilson; Kradjian, Giorgio; Marelli, Bo; Qin, Guozhong; Qi, Jin; Wang, Hong; Yu, Huakui; Tighe, Robert; Lo, Kin-Ming; English, Jessie M; Radvanyi, Laszlo; Lan, Yan

2017-10-01

Purpose: To determine whether combination therapy with NHS-muIL12 and the anti-programmed death ligand 1 (PD-L1) antibody avelumab can enhance antitumor efficacy in preclinical models relative to monotherapies. Experimental Design: BALB/c mice bearing orthotopic EMT-6 mammary tumors and μMt - mice bearing subcutaneous MC38 tumors were treated with NHS-muIL12, avelumab, or combination therapy; tumor growth and survival were assessed. Tumor recurrence following remission and rechallenge was evaluated in EMT-6 tumor-bearing mice. Immune cell populations within spleen and tumors were evaluated by FACS and IHC. Immune gene expression in tumor tissue was profiled by NanoString® assay and plasma cytokine levels were determined by multiplex cytokine assay. The frequency of tumor antigen-reactive IFNγ-producing CD8 + T cells was evaluated by ELISpot assay. Results: NHS-muIL12 and avelumab combination therapy enhanced antitumor efficacy relative to either monotherapy in both tumor models. Most EMT-6 tumor-bearing mice treated with combination therapy had complete tumor regression. Combination therapy also induced the generation of tumor-specific immune memory, as demonstrated by protection against tumor rechallenge and induction of effector and memory T cells. Combination therapy enhanced cytotoxic NK and CD8 + T-cell proliferation and T-bet expression, whereas NHS-muIL12 monotherapy induced CD8 + T-cell infiltration into the tumor. Combination therapy also enhanced plasma cytokine levels and stimulated expression of a greater number of innate and adaptive immune genes compared with either monotherapy. Conclusions: These data indicate that combination therapy with NHS-muIL12 and avelumab increased antitumor efficacy in preclinical models, and suggest that combining NHS-IL12 and avelumab may be a promising approach to treating patients with solid tumors. Clin Cancer Res; 23(19); 5869-80. ©2017 AACR . ©2017 American Association for Cancer Research.

Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours

PubMed Central

2012-01-01

Background Ewing sarcoma/PNET is managed with treatment paradigms involving combinations of chemotherapy, surgery, and sometimes radiation. Although the 5-year survival rate of non-metastatic disease approaches 70%, those cases that are metastatic and those that recur have 5-year survival rates of less than 20%. Molecularly targeted treatments offer the potential to further improve treatment outcomes. Methods A PUBMED search was performed from 1997 to 2011. Published literature that included the topic of the Ewing sarcoma/PNET was also referenced. Results Insulin-like growth factor-1 receptor (IGF-1R) antagonists have demonstrated modest single agent efficacy in phase I/II clinical trials in Ewing sarcoma/PNET, but have a strong preclinical rationale. Based on in vitro and animal data, treatment using antisense RNA and cDNA oligonucleotides directed at silencing the EWS-FLI chimera that occurs in most Ewing sarcoma/PNET may have potential therapeutic importance. However drug delivery and degradation problems may limit this therapeutic approach. Protein-protein interactions can be targeted by inhibition of RNA helicase A, which binds to EWS/FLI as part of the transcriptional complex. Tumour necrosis factor related apoptosis inducing ligand induction using interferon has been used in preclinical models. Interferons may be incorporated into future chemotherapeutic treatment paradigms. Histone deacetylase inhibitors can restore TGF-β receptor II allowing TFF-β signalling, which appears to inhibit growth of Ewing sarcoma/PNET cell lines in vitro. Immunotherapy using allogeneic natural killer cells has activity in Ewing sarcoma/PNET cell lines and xenograft models. Finally, cyclin dependent kinase inhibitors such as flavopiridol may be clinically efficacious in relapsed Ewing sarcoma/PNET. Conclusion Preclinical evidence exists that targeted therapeutics may be efficacious in the ESFT. IGF-1R antagonists have demonstrated efficacy in phase I/II clinical trials, although predicting responses remains a challenge. The future treatment of Ewing sarcoma/PNET is likely to be improved by these scientific advances. PMID:22587874

Preclinical acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of [(18)F]fluorocholine in mice.

PubMed

Silveira, Marina B; Ferreira, Soraya M Z M D; Nascimento, Leonardo T C; Costa, Flávia M; Mendes, Bruno M; Ferreira, Andrea V; Malamut, Carlos; Silva, Juliana B; Mamede, Marcelo

2016-10-01

[(18)F]Fluorocholine ([(18)F]FCH) has been proven to be effective in prostate cancer. Since [(18)F]FCH is classified as a new radiopharmaceutical in Brazil, preclinical safety and efficacy data are required to support clinical trials and to obtain its approval. The aim of this work was to perform acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of [(18)F]FCH. The results could support its use in nuclear medicine as an important piece of work for regulatory in Brazil. Copyright © 2016 Elsevier Ltd. All rights reserved.

Drugs in development for toxoplasmosis: advances, challenges, and current status.

PubMed

Alday, P Holland; Doggett, Joseph Stone

2017-01-01

Toxoplasma gondii causes fatal and debilitating brain and eye diseases. Medicines that are currently used to treat toxoplasmosis commonly have toxic side effects and require prolonged courses that range from weeks to more than a year. The need for long treatment durations and the risk of relapsing disease are in part due to the lack of efficacy against T. gondii tissue cysts. The challenges for developing a more effective treatment for toxoplasmosis include decreasing toxicity, achieving therapeutic concentrations in the brain and eye, shortening duration, eliminating tissue cysts from the host, safety in pregnancy, and creating a formulation that is inexpensive and practical for use in resource-poor areas of the world. Over the last decade, significant progress has been made in identifying and developing new compounds for the treatment of toxoplasmosis. Unlike clinically used medicines that were repurposed for toxoplasmosis, these compounds have been optimized for efficacy against toxoplasmosis during preclinical development. Medicines with enhanced efficacy as well as features that address the unique aspects of toxoplasmosis have the potential to greatly improve toxoplasmosis therapy. This review discusses the facets of toxoplasmosis that are pertinent to drug design and the advances, challenges, and current status of preclinical drug research for toxoplasmosis.

Using translational medicine to understand clinical differences between botulinum toxin formulations.

PubMed

Aoki, K R; Ranoux, D; Wissel, J

2006-12-01

When using botulinum toxin-based products, the physician must decide the optimal location and dose required to alleviate symptoms and improve the patient's quality of life. To deliver effective treatment, the physician needs to understand the importance of accurate target muscle selection and localization and the implications of each product's migration properties when diluted in different volumes. Pre-clinical mouse models of efficacy and safety have been utilized to compare local and distal muscle relaxation effects following defined intramuscular administration. Data from the model allow the products to be ranked based on their propensity for local efficacy versus their distal migration properties. Using standardized dilutions, the non-parallel dose-response curves for the various formulations demonstrate that they have different efficacy profiles. Distal effects were also noted at different treatment doses, which are reflected in the different safety and/or therapeutic margins. Based on these pre-clinical data, the safety and therapeutic margin rankings are ordered, largest to smallest, as BOTOX, Dysport and Myobloc. The results of subsequent clinical trials are variable and dose comparisons are inconclusive, thus supporting the regulatory position that the dose units of the individual preparations are unique and cannot be simply converted between products.

Drugs in development for toxoplasmosis: advances, challenges, and current status

PubMed Central

Alday, P Holland; Doggett, Joseph Stone

2017-01-01

Toxoplasma gondii causes fatal and debilitating brain and eye diseases. Medicines that are currently used to treat toxoplasmosis commonly have toxic side effects and require prolonged courses that range from weeks to more than a year. The need for long treatment durations and the risk of relapsing disease are in part due to the lack of efficacy against T. gondii tissue cysts. The challenges for developing a more effective treatment for toxoplasmosis include decreasing toxicity, achieving therapeutic concentrations in the brain and eye, shortening duration, eliminating tissue cysts from the host, safety in pregnancy, and creating a formulation that is inexpensive and practical for use in resource-poor areas of the world. Over the last decade, significant progress has been made in identifying and developing new compounds for the treatment of toxoplasmosis. Unlike clinically used medicines that were repurposed for toxoplasmosis, these compounds have been optimized for efficacy against toxoplasmosis during preclinical development. Medicines with enhanced efficacy as well as features that address the unique aspects of toxoplasmosis have the potential to greatly improve toxoplasmosis therapy. This review discusses the facets of toxoplasmosis that are pertinent to drug design and the advances, challenges, and current status of preclinical drug research for toxoplasmosis. PMID:28182168

Differential Rearing Alters Forced Swim Test Behavior, Fluoxetine Efficacy, and Post-Test Weight Gain in Male Rats.

PubMed

Arndt, David L; Peterson, Christy J; Cain, Mary E

2015-01-01

Environmental factors play a key role in the etiology of depression. The rodent forced swim test (FST) is commonly used as a preclinical model of depression, with increases in escape-directed behavior reflecting antidepressant effects, and increases in immobility reflecting behavioral despair. Environmental enrichment leads to serotonergic alterations in rats, but it is unknown whether these alterations may influence the efficacy of common antidepressants. Male Sprague-Dawley rats were reared in enriched (EC), standard (SC), or isolated (IC) conditions. Following the rearing period, fluoxetine (10 or 20 mg/kg, i.p.) was administered 23.5 hrs, 5 hrs, and 1 hr before locomotor and FST measures. Following locomotor testing and FST exposure, rats were weighed to assess fluoxetine-, FST-, and environmental condition-induced moderations in weight gain. Results revealed an antidepressant effect of environmental enrichment and a depressant effect of isolation. Regardless of significant fluoxetine effects on locomotor activity, fluoxetine generally decreased swimming and increased immobility in all three environmental conditions, with IC-fluoxetine (10 mg/kg) rats and EC-fluoxetine (20 mg/kg) rats swimming less than vehicle counterparts. Subchronic 20 mg/kg fluoxetine also induced significant weight loss, and differential rearing appeared to moderate weight gain following FST stress. These results suggest that differential rearing has the ability to alter FST behaviors, fluoxetine efficacy, and post-stressor well-being. Moreover, 20 mg/kg fluoxetine, administered subchronically, may lead to atypical effects of those commonly observed in the FST, highlighting the importance and impact of both environmental condition and dosing regimen in common animal models of depression.

Differential Rearing Alters Forced Swim Test Behavior, Fluoxetine Efficacy, and Post-Test Weight Gain in Male Rats

PubMed Central

Arndt, David L.; Peterson, Christy J.; Cain, Mary E.

2015-01-01

Environmental factors play a key role in the etiology of depression. The rodent forced swim test (FST) is commonly used as a preclinical model of depression, with increases in escape-directed behavior reflecting antidepressant effects, and increases in immobility reflecting behavioral despair. Environmental enrichment leads to serotonergic alterations in rats, but it is unknown whether these alterations may influence the efficacy of common antidepressants. Male Sprague-Dawley rats were reared in enriched (EC), standard (SC), or isolated (IC) conditions. Following the rearing period, fluoxetine (10 or 20 mg/kg, i.p.) was administered 23.5 hrs, 5 hrs, and 1 hr before locomotor and FST measures. Following locomotor testing and FST exposure, rats were weighed to assess fluoxetine-, FST-, and environmental condition-induced moderations in weight gain. Results revealed an antidepressant effect of environmental enrichment and a depressant effect of isolation. Regardless of significant fluoxetine effects on locomotor activity, fluoxetine generally decreased swimming and increased immobility in all three environmental conditions, with IC-fluoxetine (10 mg/kg) rats and EC-fluoxetine (20 mg/kg) rats swimming less than vehicle counterparts. Subchronic 20 mg/kg fluoxetine also induced significant weight loss, and differential rearing appeared to moderate weight gain following FST stress. These results suggest that differential rearing has the ability to alter FST behaviors, fluoxetine efficacy, and post-stressor well-being. Moreover, 20 mg/kg fluoxetine, administered subchronically, may lead to atypical effects of those commonly observed in the FST, highlighting the importance and impact of both environmental condition and dosing regimen in common animal models of depression. PMID:26154768

Safety assessment and toxicological profiling of a novel combinational sunprotective dermal formulation containing melatonin and pumpkin seed oil.

PubMed

Bora, Nilutpal Sharma; Pathak, Manash Pratim; Mandal, Santa; Mazumder, Bhaskar; Policegoudra, Rudragoud; Raju, Pakalapati Srinivas; Chattopadhyay, Pronobesh

2017-10-01

Ultraviolet (UV) radiation exposure has been known to cause irreparable damages to human skin. The daunting risk of UV radiation exposure faced by military personnel led to the development of a sunscreen formulation which has superior sun protection factor combined with the ability to counteract reactive oxygen species. The present work deals with the preclinical safety evaluation of the sunscreen formulation comprising of four US FDA approved UV filters; namely avobenzone, octinoxate, oxybenzone, titanium dioxide along with melatonin and pumpkin seed oil, via OECD protocols of assessing acute oral and dermal toxicity; skin sensitizing; skin irritating; ocular irritating and genotoxic potential. Both oral and dermal LD 50 values were found to be ˃2000 mg/kg body weight in adult Wistar albino rats using acute dermal and oral toxicity tests. The sunscreen formulation was found to be non-sensitizing to the skin of guinea pigs and non-irritating to both skin and eyes of rabbits. The sunscreen formulation was also found to be non-mutagenic which was affirmed by a battery of genotoxicity and muagenicity assays. The results obtained from this preclinical study indicated that the sunscreen formulation is non toxic and safe in animal models. This study along with additional preclinical evaluations may serve as a basis for considering the formulation as a potential candidate for further trials to establish its efficacy, tolerability and applicability. Copyright © 2017 Elsevier Inc. All rights reserved.

Molecular Pharmacology of Malignant Pleural Mesothelioma: Challenges and Perspectives From Preclinical and Clinical Studies.

PubMed

Thellung, Stefano; Favoni, Roberto E; Würth, Roberto; Nizzari, Mario; Pattarozzi, Alessandra; Daga, Antonio; Florio, Tullio; Barbieri, Federica

2016-01-01

Malignant pleural mesothelioma (MPM) is one of the deadliest and most heterogeneous tumors, highly refractory to multimodal therapeutic approach, including surgery, chemo- and radiotherapy. Preclinical and clinical studies exploring the efficacy of drugs targeting tyrosine kinases, angiogenesis and histone deacetylases, did not fulfil the expected clinical benefits. Thus, novel molecular targets should be identified from a definite knowledge of the unique biology and most relevant transduction pathways of MPM cells. Cancer stem cells (CSCs) are a subset of malignant precursors responsible for initiation, progression, resistance to cytotoxic drugs, recurrence and metastatic diffusion of tumor cells. CSCs are putative driving factors for MPM development and contribute to its clinical and biological heterogeneity; hence, targeted eradication of CSCs represents an ineludible goal to counteract MPM aggressiveness. In this context, innovative preclinical models could be exploited to identify novel intracellular pathway inhibitors able to target CSC viability. Novel drug targets have been identified among key factors responsible for the oncogenic transformation of mesothelial cells, often directly induced by asbestos. These include mitogenic and anti-apoptotic signaling that may also be activated by autocrine and paracrine cytokine pathways controlling cell plasticity. Both signaling pathways affecting proto-oncogene and transcription factor expression, or genetic and epigenetic alterations, such as mutations in cell cycle genes and silencing of tumor suppressor genes, represent promising disease-specific targets. In this review we describe current knowledge of MPM cell biology, focusing on potential targets to be tested in pharmacological studies, and highlighting results and challenges of clinical translation.

Targeting the UPR to Circumvent Endocrine Resistance in Breast Cancer

DTIC Science & Technology

2014-10-01

activity relationship analyses ( QSAR ) to develop rationally designed NPPTA analogs with increased potency and optimized pharmacologic properties...vitro, with the strongest candidates being studied in vivo to provide preclinical safety, efficacy, and toxicology data to support later first-in-human

The neuropsychology of normal aging and preclinical Alzheimer’s disease

PubMed Central

Caselli, Richard J.; Locke, Dona E.C.; Dueck, Amylou C.; Knopman, David S.; Woodruff, Bryan K.; Hoffman-Snyder, Charlene; Rademakers, Rosa; Fleisher, Adam S.; Reiman, Eric M.

2013-01-01

Background An NIA-sponsored workgroup on preclinical Alzheimer’s disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD. Methods 71 apolipoprotein E (APOE) e4 homozygotes (HMZ), 194 e3/4 heterozygotes (HTZ), and 356 e4 noncarriers (NC) aged 21–87 years who were cognitively healthy underwent neuropsychological testing every two years. Longitudinal trajectories of test scores were compared between APOE subgroups. Results There was a significant effect of age on all cognitive domains in both APOE e4 carriers and NC. A significant effect of APOE e4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross sectional comparisons did not discriminate the groups. Conclusions While cognitive aging patterns are similar in APOE e4 carriers and NC, preclinical AD is characterized by a significant e4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory sensitive measures and longitudinal design. PMID:23541188

The neuropsychology of normal aging and preclinical Alzheimer's disease.

PubMed

Caselli, Richard J; Locke, Dona E C; Dueck, Amylou C; Knopman, David S; Woodruff, Bryan K; Hoffman-Snyder, Charlene; Rademakers, Rosa; Fleisher, Adam S; Reiman, Eric M

2014-01-01

A National Institute on Aging-sponsored work group on preclinical Alzheimer's disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD. Seventy-one apolipoprotein E (APOE) ε4 homozygotes, 194 ε3/ε4 heterozygotes, and 356 ε4 noncarriers age 21 to 87 years who were cognitively healthy underwent neuropsychological testing every 2 years. Longitudinal trajectories of test scores were compared between APOE subgroups. There was a significant effect of age on all cognitive domains in both APOE ε4 carriers and noncarriers. A significant effect of APOE ε4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross-sectional comparisons did not discriminate the groups. Although cognitive aging patterns are similar in APOE ε4 carriers and noncarriers, preclinical AD is characterized by a significant ε4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory-sensitive measures and longitudinal design. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Vitamins in Pancreatic Cancer: A Review of Underlying Mechanisms and Future Applications12

PubMed Central

Davis-Yadley, Ashley H; Malafa, Mokenge P

2015-01-01

Although there is increasing evidence that vitamins influence pancreatic adenocarcinoma biology and carcinogenesis, a comprehensive review is lacking. In this study, we performed a PubMed literature search to review the anticancer mechanisms and the preclinical and clinical studies that support the development of the bioactive vitamins A, C, D, E, and K in pancreatic cancer intervention. Preclinical studies have shown promising results for vitamin A in pancreatic cancer prevention, with clinical trials showing intriguing responses in combination with immunotherapy. For vitamin C, preclinical studies have shown slower tumor growth rates and/or increased survival when used alone or in combination with gemcitabine, with clinical trials with this combination revealing decreased primary tumor sizes and improved performance status. Preclinical studies with vitamin D analogues have shown potent antiproliferative effects and repression of migration and invasion of pancreatic cancer cells, with a clinical trial showing increased time to progression when calciferol was added to docetaxel. For vitamin E, preclinical studies have shown that δ-tocotrienol and γ-tocotrienol inhibited tumor cell growth and survival and augmented gemcitabine activity. Early-phase clinical trials with δ-tocotrienol are ongoing. Vitamin K demonstrates activation of apoptosis and inhibition of cellular growth in pancreatic tumor cells; however, there are no clinical studies available for further evaluation. Although preclinical and clinical studies are encouraging, randomized controlled trials with endpoints based on insights gained from mechanistic and preclinical studies and early-phase clinical trials are required to determine the efficacy of bioactive vitamin interventions in pancreatic cancer. PMID:26567201

Vitamins in pancreatic cancer: a review of underlying mechanisms and future applications.

PubMed

Davis-Yadley, Ashley H; Malafa, Mokenge P

2015-11-01

Although there is increasing evidence that vitamins influence pancreatic adenocarcinoma biology and carcinogenesis, a comprehensive review is lacking. In this study, we performed a PubMed literature search to review the anticancer mechanisms and the preclinical and clinical studies that support the development of the bioactive vitamins A, C, D, E, and K in pancreatic cancer intervention. Preclinical studies have shown promising results for vitamin A in pancreatic cancer prevention, with clinical trials showing intriguing responses in combination with immunotherapy. For vitamin C, preclinical studies have shown slower tumor growth rates and/or increased survival when used alone or in combination with gemcitabine, with clinical trials with this combination revealing decreased primary tumor sizes and improved performance status. Preclinical studies with vitamin D analogues have shown potent antiproliferative effects and repression of migration and invasion of pancreatic cancer cells, with a clinical trial showing increased time to progression when calciferol was added to docetaxel. For vitamin E, preclinical studies have shown that δ-tocotrienol and γ-tocotrienol inhibited tumor cell growth and survival and augmented gemcitabine activity. Early-phase clinical trials with δ-tocotrienol are ongoing. Vitamin K demonstrates activation of apoptosis and inhibition of cellular growth in pancreatic tumor cells; however, there are no clinical studies available for further evaluation. Although preclinical and clinical studies are encouraging, randomized controlled trials with endpoints based on insights gained from mechanistic and preclinical studies and early-phase clinical trials are required to determine the efficacy of bioactive vitamin interventions in pancreatic cancer. © 2015 American Society for Nutrition.

Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models

PubMed Central

Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L

2013-01-01

Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin. PMID:24151975

New Kids on the Block: RNA-Based Influenza Virus Vaccines.

PubMed

Scorza, Francesco Berlanda; Pardi, Norbert

2018-04-01

RNA-based immunization strategies have emerged as promising alternatives to conventional vaccine approaches. A substantial body of published work demonstrates that RNA vaccines can elicit potent, protective immune responses against various pathogens. Consonant with its huge impact on public health, influenza virus is one of the best studied targets of RNA vaccine research. Currently licensed influenza vaccines show variable levels of protection against seasonal influenza virus strains but are inadequate against drifted and pandemic viruses. In recent years, several types of RNA vaccines demonstrated efficacy against influenza virus infections in preclinical models. Additionally, comparative studies demonstrated the superiority of some RNA vaccines over the currently used inactivated influenza virus vaccines in animal models. Based on these promising preclinical results, clinical trials have been initiated and should provide valuable information about the translatability of the impressive preclinical data to humans. This review briefly describes RNA-based vaccination strategies, summarizes published preclinical and clinical data, highlights the roadblocks that need to be overcome for clinical applications, discusses the landscape of industrial development, and shares the authors' personal perspectives about the future of RNA-based influenza virus vaccines.

Stem cell stratagems in alternative medicine.

PubMed

Sipp, Douglas

2011-05-01

Stem cell research has attracted an extraordinary amount of attention and expectation due to its potential for applications in the treatment of numerous medical conditions. These exciting clinical prospects have generated widespread support from both the public and private sectors, and numerous preclinical studies and rigorous clinical trials have already been initiated. Recent years, however, have also seen alarming growth in the number and variety of claims of clinical uses of notional 'stem cells' that have not been adequately tested for safety and/or efficacy. In this article, I will survey the contours of the stem cell industry as practiced by alternative medicine providers, and highlight points of commonality in their strategies for marketing.

Targeting DNA Methyltranferases in Urological Tumors

PubMed Central

Marques-Magalhães, Ângela; Graça, Inês; Henrique, Rui; Jerónimo, Carmen

2018-01-01

Urological cancers are a heterogeneous group of malignancies accounting for a considerable proportion of cancer-related morbidity and mortality worldwide. Aberrant epigenetic traits, especially altered DNA methylation patterns constitute a hallmark of these tumors. Nonetheless, these alterations are reversible, and several efforts have been carried out to design and test several epigenetic compounds that might reprogram tumor cell phenotype back to a normal state. Indeed, several DNMT inhibitors are currently under evaluation for therapeutic efficacy in clinical trials. This review highlights the critical role of DNA methylation in urological cancers and summarizes the available data on pre-clinical assays and clinical trials with DNMT inhibitors in bladder, kidney, prostate, and testicular germ cell cancers. PMID:29706891

Stakeholders' Perspectives on Preclinical Testing for Alzheimer's Disease.

PubMed

Arias, Jalayne J; Cummings, Jeffrey; Grant, Alexander Rae; Ford, Paul J

2015-01-01

Progress towards validating amyloid beta as an early indicator of Alzheimer's disease (AD) heightens the need for evaluation of stakeholders' perspectives of the benefits and harms of preclinical testing in asymptomatic individuals. Investigators conducted and analyzed 14 semi-structured interviews with family members of patients diagnosed with AD. Participants reported benefits, including the potential to seek treatment, make lifestyle changes, and prepare for cognitive impairment. Participants identified harms, including social harms, adverse life decisions, and psychological harms. Nine participants reported either a "positive global perspective" or a "positive global perspective (qualified)." Results from this study characterized stakeholders' perspectives on the potential benefits and harms of clinical use of preclinical testing for AD. Investigators used data from this study to develop a framework that contributes to ongoing discussions that will evaluate widespread adoption of preclinical testing and will inform future research. Copyright 2015 The Journal of Clinical Ethics. All rights reserved.

Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapeutics for addictions and related disorders

PubMed Central

Heidbreder, Christian A.; Newman, Amy H.

2011-01-01

Repeated exposure to drugs of abuse produces long-term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D3 receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D3 receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self-administer drugs and disrupt drug-associated cue-induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D3 receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D2/D3 receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D3 versus D2 receptor, and their efficacy profile is related primarily to functional antagonism at D2 receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D3 receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed. PMID:20201845

Efficacy of multiple exposure with low level He-Ne laser dose on acute wound healing: a pre-clinical study

NASA Astrophysics Data System (ADS)

Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore

2014-02-01

Investigations on the use of Low Level Laser Therapy (LLLT) for wound healing especially with the red laser light have demonstrated its pro-healing potential on a variety of pre-clinical and surgical wounds. However, until now, in LLLT the effect of multiple exposure of low dose laser irradiation on acute wound healing on well-designed pre-clinical model is not much explored. The present study aimed to investigate the effect of multiple exposure of low dose Helium Neon laser on healing progression of full thickness excision wounds in Swiss albino mice. Further, the efficacy of the multiple exposure of low dose laser irradiation was compared with the single exposure of optimum dose. Full thickness excision wounds (circular) of 15 mm diameter were created, and subsequently illuminated with the multiple exposures (1, 2, 3, 4 and 5 exposure/ week until healing) of He-Ne (632.8 nm, 4.02 mWcm-2) laser at 0.5 Jcm-2 along with single exposure of optimum laser dose (2 J/cm-2) and un-illuminated controls. Classical biophysical parameters such as contraction kinetics, area under the curve and the mean healing time were documented as the assessment parameters to examine the efficacy of multiple exposures with low level laser dose. Experimental findings substantiated that either single or multiple exposures of 0.5 J/cm2 failed to produce any detectable alterations on wound contraction, area under the curve and mean healing time compared to single exposure of optimum dose (2 Jcm-2) and un-illuminated controls. Single exposure of optimum, laser dose was found to be ideal for acute wound healing.

Current perspectives on selective dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders.

PubMed

Heidbreder, Christian A; Newman, Amy H

2010-02-01

Repeated exposure to drugs of abuse produces long-term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D(3) receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D(3) receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self-administer drugs and disrupt drug-associated cue-induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D(3) receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D(2)/D(3) receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D(3) versus D(2) receptor, and their efficacy profile is related primarily to functional antagonism at D(2) receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D(3) receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed.

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics.

PubMed

Knezevic, Nebojsa Nick; Yekkirala, Ajay; Yaksh, Tony L

2017-11-01

Opioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management has limitations, and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of reinforcing activity in the absence of a pain state. The present work provides a nonexclusive overview of current drug targets and potential future directions of research and development. We discuss channel activators and blockers, including sodium channel blockers, potassium channel activators, and calcium channel blockers; glutamate receptor-targeted agents, including N-methyl-D-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and metabotropic receptors. Furthermore, we discuss therapeutics targeted at γ-aminobutyric acid, α2-adrenergic, and opioid receptors. We also considered antagonists of angiotensin 2 and Toll receptors and agonists/antagonists of adenosine, purine receptors, and cannabinoids. Novel targets considered are those focusing on lipid mediators and anti-inflammatory cytokines. Of interest is development of novel targeting strategies, which produce long-term alterations in pain signaling, including viral transfection and toxins. We consider issues in the development of druggable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising preclinical candidates may unexpectedly fail during clinical trials because the preclinical models may not recapitulate the particular human pain condition being addressed. Molecular target characterization can diminish the disconnect between preclinical and humans' targets, which should assist in developing nonaddictive analgesics.

Concise Review: Mesenchymal Stem (Stromal) Cells: Biology and Preclinical Evidence for Therapeutic Potential for Organ Dysfunction Following Trauma or Sepsis.

PubMed

Matthay, Michael A; Pati, Shibani; Lee, Jae-Woo

2017-02-01

Several experimental studies have provided evidence that bone-marrow derived mesenchymal stem (stromal) cells (MSC) may be effective in treating critically ill surgical patients who develop traumatic brain injury, acute renal failure, or the acute respiratory distress syndrome. There is also preclinical evidence that MSC may be effective in treating sepsis-induced organ failure, including evidence that MSC have antimicrobial properties. This review considers preclinical studies with direct relevance to organ failure following trauma, sepsis or major infections that apply to critically ill patients. Progress has been made in understanding the mechanisms of benefit, including MSC release of paracrine factors, transfer of mitochondria, and elaboration of exosomes and microvesicles. Regardless of how well they are designed, preclinical studies have limitations in modeling the complexity of clinical syndromes, especially in patients who are critically ill. In order to facilitate translation of the preclinical studies of MSC to critically ill patients, there will need to be more standardization regarding MSC production with a focus on culture methods and cell characterization. Finally, well designed clinical trials will be needed in critically ill patient to assess safety and efficacy. Stem Cells 2017;35:316-324. © 2016 AlphaMed Press.

Animal Models of Depression and Drug Delivery with Food as an Effective Dosing Method: Evidences from Studies with Celecoxib and Dicholine Succinate.

PubMed

Costa-Nunes, João P; Cline, Brandon H; Araújo-Correia, Margarida; Valença, Andreia; Markova, Natalyia; Dolgov, Oleg; Kubatiev, Aslan; Yeritsyan, Naira; Steinbusch, Harry W M; Strekalova, Tatyana

2015-01-01

Multiple models of human neuropsychiatric pathologies have been generated during the last decades which frequently use chronic dosing. Unfortunately, some drug administration methods may result in undesirable effects creating analysis confounds hampering model validity and preclinical assay outcomes. Here, automated analysis of floating behaviour, a sign of a depressive-like state, revealed that mice, subjected to a three-week intraperitoneal injection regimen, had increased floating. In order to probe an alternative dosing design that would preclude this effect, we studied the efficacy of a low dose of the antidepressant imipramine (7 mg/kg/day) delivered via food pellets. Antidepressant action for this treatment was found while no other behavioural effects were observed. We further investigated the potential efficacy of chronic dosing via food pellets by testing the antidepressant activity of new drug candidates, celecoxib (30 mg/kg/day) and dicholine succinate (50 mg/kg/day), against standard antidepressants, imipramine (7 mg/kg/day) and citalopram (15 mg/kg/day), utilizing the forced swim and tail suspension tests. Antidepressant effects of these compounds were found in both assays. Thus, chronic dosing via food pellets is efficacious in small rodents, even with a low drug dose design, and can prevail against potential confounds in translational research within depression models applicable to adverse chronic invasive pharmacotherapies.

Animal Models of Depression and Drug Delivery with Food as an Effective Dosing Method: Evidences from Studies with Celecoxib and Dicholine Succinate

PubMed Central

Costa-Nunes, João P.; Cline, Brandon H.; Araújo-Correia, Margarida; Valença, Andreia; Markova, Natalyia; Dolgov, Oleg; Kubatiev, Aslan; Yeritsyan, Naira; Steinbusch, Harry W. M.

2015-01-01

Multiple models of human neuropsychiatric pathologies have been generated during the last decades which frequently use chronic dosing. Unfortunately, some drug administration methods may result in undesirable effects creating analysis confounds hampering model validity and preclinical assay outcomes. Here, automated analysis of floating behaviour, a sign of a depressive-like state, revealed that mice, subjected to a three-week intraperitoneal injection regimen, had increased floating. In order to probe an alternative dosing design that would preclude this effect, we studied the efficacy of a low dose of the antidepressant imipramine (7 mg/kg/day) delivered via food pellets. Antidepressant action for this treatment was found while no other behavioural effects were observed. We further investigated the potential efficacy of chronic dosing via food pellets by testing the antidepressant activity of new drug candidates, celecoxib (30 mg/kg/day) and dicholine succinate (50 mg/kg/day), against standard antidepressants, imipramine (7 mg/kg/day) and citalopram (15 mg/kg/day), utilizing the forced swim and tail suspension tests. Antidepressant effects of these compounds were found in both assays. Thus, chronic dosing via food pellets is efficacious in small rodents, even with a low drug dose design, and can prevail against potential confounds in translational research within depression models applicable to adverse chronic invasive pharmacotherapies. PMID:26064929

EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss.

PubMed

Sampson, John H; Choi, Bryan D; Sanchez-Perez, Luis; Suryadevara, Carter M; Snyder, David J; Flores, Catherine T; Schmittling, Robert J; Nair, Smita K; Reap, Elizabeth A; Norberg, Pamela K; Herndon, James E; Kuan, Chien-Tsun; Morgan, Richard A; Rosenberg, Steven A; Johnson, Laura A

2014-02-15

Chimeric antigen receptor (CAR) transduced T cells represent a promising immune therapy that has been shown to successfully treat cancers in mice and humans. However, CARs targeting antigens expressed in both tumors and normal tissues have led to significant toxicity. Preclinical studies have been limited by the use of xenograft models that do not adequately recapitulate the immune system of a clinically relevant host. A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues. We developed a third-generation, EGFRvIII-specific murine CAR (mCAR), and performed tests to determine its efficacy in a fully immunocompetent mouse model of malignant glioma. At elevated doses, infusion with EGFRvIII mCAR T cells led to cures in all mice with brain tumors. In addition, antitumor efficacy was found to be dependent on lymphodepletive host conditioning. Selective blockade with EGFRvIII soluble peptide significantly abrogated the activity of EGFRvIII mCAR T cells in vitro and in vivo, and may offer a novel strategy to enhance the safety profile for CAR-based therapy. Finally, mCAR-treated, cured mice were resistant to rechallenge with EGFRvIII(NEG) tumors, suggesting generation of host immunity against additional tumor antigens. All together, these data support that third-generation, EGFRvIII-specific mCARs are effective against gliomas in the brain and highlight the importance of syngeneic, immunocompetent models in the preclinical evaluation of tumor immunotherapies. ©2013 AACR

Design and Evolution of the Asporto Heart Preservation Device.

PubMed

Rivard, Andrew L

2015-06-01

The Asporto Heart Preservation Device is a system providing perfusion of cardioplegia to the donor heart using a computer-controlled peristaltic pump in a thermoelectrically cooled and insulated container. In 1998, a user interface was developed at the University of Minnesota consisting of a touch screen and battery-backed microcontroller. Power was supplied by a 120 VAC to 12 VDC converter. An upgrade to the insulated cooler and microcontroller occurred in 2002, which was followed by proof of concept experimental pre-clinical transplants and tests demonstrating the efficacy of the device with isolated donor hearts. During the period between 2002 and 2006, a variety of donor organ containers were developed, modified, and tested to provide an optimal sterile environment and fluid path. Parallel development paths encompass formalized design specifications for final prototypes of the touch screen/microcontroller, organ container, and thermoelectric cooler.

Advances in Degradable Embolic Microspheres: A State of the Art Review

PubMed Central

Doucet, Jensen; Kiri, Lauren; O’Connell, Kathleen; Kehoe, Sharon; Lewandowski, Robert J.; Liu, David M.; Abraham, Robert J.; Boyd, Daniel

2018-01-01

Considerable efforts have been placed on the development of degradable microspheres for use in transarterial embolization indications. Using the guidance of the U.S. Food and Drug Administration (FDA) special controls document for the preclinical evaluation of vascular embolization devices, this review consolidates all relevant data pertaining to novel degradable microsphere technologies for bland embolization into a single reference. This review emphasizes intended use, chemical composition, degradative mechanisms, and pre-clinical safety, efficacy, and performance, while summarizing the key advantages and disadvantages for each degradable technology that is currently under development for transarterial embolization. This review is intended to provide an inclusive reference for clinicians that may facilitate an understanding of clinical and technical concepts related to this field of interventional radiology. For materials scientists, this review highlights innovative devices and current evaluation methodologies (i.e., preclinical models), and is designed to be instructive in the development of innovative/new technologies and evaluation methodologies. PMID:29373510

Cannabinoids and Dementia: A Review of Clinical and Preclinical Data

PubMed Central

Walther, Sebastian; Halpern, Michael

2010-01-01

The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia. We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD) and vascular dementia (VD). Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have demonstrated efficacy in vitro. However, some of the substances produced inconclusive results in vivo. Therefore, only few trials have aimed to replicate the effects seen in animal studies in patients. Indeed, the literature on cannabinoid administration in patients is scarce. While preclinical findings suggest causal treatment strategies involving cannabinoids, clinical trials have only assessed the suitability of cannabinoid receptor agonists, antagonists and cannabidiol for the symptomatic treatment of dementia. Further research is needed, including in vivo models of dementia and human studies. PMID:27713372

Gut microbiota-bone axis.

PubMed

Villa, Christopher R; Ward, Wendy E; Comelli, Elena M

2017-05-24

The gut microbiota (GM) is an important regulator of body homeostasis, including intestinal and extra-intestinal effects. This review focuses on the GM-bone axis, which we define as the effect of the gut-associated microbial community or the molecules they synthesize, on bone health. While research in this field is limited, findings from preclinical studies support that gut microbes positively impact bone mineral density and strength parameters. Moreover, administration of beneficial bacteria (probiotics) in preclinical models has demonstrated higher bone mineralization and greater bone strength. The preferential bacterial genus that has shown these beneficial effects in bone is Lactobacillus and thus lactobacilli are among the best candidates for future clinical intervention trials. However, their effectiveness is dependent on stage of development, as early life constitutes an important time for impacting bone health, perhaps via modulation of the GM. In addition, sex-specific difference also impacts the efficacy of the probiotics. Although auspicious, many questions regarding the GM-bone axis require consideration of potential mechanisms; sex-specific efficacy; effective dose of probiotics; and timing and duration of treatment.

Human adipose-derived mesenchymal stem cells for osteoarthritis: a pilot study with long-term follow-up and repeated injections.

PubMed

Song, Yang; Du, Hui; Dai, Chengxiang; Zhang, Li; Li, Suke; Hunter, David J; Lu, Liangjing; Bao, Chunde

2018-04-01

This study aimed to evaluate the safety and therapeutic potential of autologous human adipose-derived mesenchymal stem cells (haMSCs) in patients with osteoarthritis. Safety and efficacy of haMSCs were preclinically assessed in vitro and in BALB/c-nu nude mice. 18 patients were enrolled and divided into three dose groups: the low-dose, mid-dose and high-dose group (1 × 10 7 , 2 × 10 7 and 5 × 10 7 cells, respectively), provided three injections and followed up for 96 weeks. The preclinical study established the safety and efficacy of haMSCs. Intra-articular injections of haMSCs were safe and improved pain, function and cartilage volume of the knee joint, rendering them a promising novel treatment for knee osteoarthritis. The dosage of 5 × 10 7 haMSCs exhibited the highest improvement (ClinicalTrials.gov Identifier: NCT01809769).

Mexican medicinal plants with anxiolytic or antidepressant activity: Focus on preclinical research.

PubMed

López-Rubalcava, Carolina; Estrada-Camarena, Erika

2016-06-20

Anxiety and depression are considered the most prevalent psychiatric disorders worldwide. In Mexico, the use of medicinal plants to alleviate the symptoms associated with these psychiatric disorders is increasing. However, there is little scientific evidence that validates the efficacy of these plants. This evidence needs to be critically revised, and further studied to provided scientific support for their use. To identify the plants that are used in Mexico for the treatment of disorders related to anxiety and depression, and to review the current preclinical and when available, clinical information of these plants. We searched in scientific databases (Pubmed, Web of Science, Scopus and other web sources such as "Biblioteca digital de la medicina tradicional Mexicana" ) for Mexican plants used for the treatment of anxiety and depression that have been analyzed in preclinical studies. Additional information was obtained from published books. For this review, we also consider those plants used in Mexican traditional medicine for the treatment of "nervios," "susto" or "espanto;" common terms that describe symptoms related to anxiety and depression disorders. The bibliographic search identified 49 plants used in Mexican traditional medicine for the treatment of disorders related to anxiety and depression. From all these plants, 59% were analyzed in preclinical research, and only 8% were tested in clinical studies; only a few of these studies tried to elucidate their mechanism of action. In general, it is proposed that the plant extracts interact with the GABAergic system. However, only part of these studies attempted to analyze other neurotransmitter systems. Finally, in some cases, drug-herbal interactions were reported. There is a large number of Mexican medicinal plants used as a treatment for anxiety and depression disorders. Although some of these plants have been studied in preclinical research, in most cases these studies are preliminary, and the understanding of the mechanism of action is inconclusive. The need for systematic studies in preclinical and clinical research is evident, and efforts should be done to fulfill these research. Finally, it is important also to study possible drug-herbal interactions to establish specific recommendations for people that use these plants as anxiolytic or antidepressant treatments either alone or in combination with another type of medicine. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Oxytocin under opioid antagonism leads to supralinear enhancement of social attention.

PubMed

Dal Monte, Olga; Piva, Matthew; Anderson, Kevin M; Tringides, Marios; Holmes, Avram J; Chang, Steve W C

2017-05-16

To provide new preclinical evidence toward improving the efficacy of oxytocin (OT) in treating social dysfunction, we tested the benefit of administering OT under simultaneously induced opioid antagonism during dyadic gaze interactions in monkeys. OT coadministered with a μ-opioid receptor antagonist, naloxone, invoked a supralinear enhancement of prolonged and selective social attention, producing a stronger effect than the summed effects of each administered separately. These effects were consistently observed when averaging over entire sessions, as well as specifically following events of particular social importance, including mutual eye contact and mutual reward receipt. Furthermore, attention to various facial regions was differentially modulated depending on social context. Using the Allen Institute's transcriptional atlas, we further established the colocalization of μ-opioid and κ-opioid receptor genes and OT genes at the OT-releasing sites in the human brain. These data across monkeys and humans support a regulatory relationship between the OT and opioid systems and suggest that administering OT under opioid antagonism may boost the therapeutic efficacy of OT for enhancing social cognition.

Translational strategies for therapeutic development in nicotine addiction: rethinking the conventional bench to bedside approach.

PubMed

Le Foll, Bernard; Pushparaj, Abhiram; Pryslawsky, Yaroslaw; Forget, Benoit; Vemuri, Kiran; Makriyannis, Alexandros; Trigo, Jose M

2014-07-03

Tobacco produces an impressive burden of disease resulting in premature death in half of users. Despite effective smoking cessation medications (nicotine replacement therapies, bupropion and varenicline), there is a very high rate of relapse following quit attempts. The use of efficient strategies for the development of novel treatments is a necessity. A 'bench to bedside strategy' was initially used to develop cannabinoid CB1 receptor antagonists for the treatment of nicotine addiction. Unfortunately, after being tested on experimental animals, what seemed to be an interesting approach for the treatment of nicotine addiction resulted in serious unwanted side effects when tested in humans. Current research is focusing again on pre-clinical models in an effort to eliminate unwanted side effects while preserving the initially observed efficacy. A 'bed side to bench strategy' was used to study the role of the insula (part of the frontal cortex) in nicotine addiction. This line of research started based on clinical observations that patients suffering stroke-induced lesions to the insula showed a greater likelihood to report immediate smoking cessation without craving or relapse. Subsequently, animal models of addiction are used to explore the role of insula in addiction. Due to the inherent limitations existing in clinical versus preclinical studies, the possibility of close interaction between both models seems to be critical for the successful development of novel therapeutic strategies for nicotine dependence. © 2013.

Spotlight on ceritinib in the treatment of ALK+ NSCLC: design, development and place in therapy

PubMed Central

Santarpia, Mariacarmela; Daffinà, Maria Grazia; D’Aveni, Alessandro; Marabello, Grazia; Liguori, Alessia; Giovannetti, Elisa; Karachaliou, Niki; Gonzalez Cao, Maria; Rosell, Rafael; Altavilla, Giuseppe

2017-01-01

The identification of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) fusion gene in non-small cell lung cancer (NSCLC) has radically changed the treatment of a subset of patients harboring this oncogenic driver. Crizotinib was the first ALK tyrosine kinase inhibitor to receive fast approval and is currently indicated as the first-line therapy for advanced, ALK-positive NSCLC patients. However, despite crizotinib’s efficacy, patients almost invariably progress, with the central nervous system being one of the most common sites of relapse. Different mechanisms of acquired resistance have been identified, including secondary ALK mutations, ALK copy number alterations and activation of bypass tracks. Different highly potent and brain-penetrant next-generation ALK inhibitors have been developed and tested in NSCLC patients with ALK rearrangements. Ceritinib, a structurally distinct and selective ALK inhibitor, showed 20 times higher potency than crizotinib in inhibiting ALK and had activity against the most common crizotinib-resistant mutations, including L1196M and G1269A, in preclinical models. In Phase I and II studies, ceritinib demonstrated pronounced activity in both crizotinib-naïve and crizotinib-refractory patients, with responses observed regardless of the presence of ALK resistance mutations. Ceritinib was the first ALK inhibitor to be approved for the treatment of crizotinib-refractory, ALK-rearranged NSCLC, and recent results from a Phase III study have demonstrated superior efficacy compared to standard chemotherapy in the first- and second-line setting. We provide an extensive overview of ceritinib from the design of the compound through preclinical data until efficacy and toxicity results from Phase I–III clinical studies. We review the molecular alterations associated with resistance to ceritinib and highlight the importance of obtaining tumor biopsy at progression to tailor therapy based upon the underlying resistance mechanism. We finally provide an outlook on novel rational therapeutic combinations. PMID:28740365

Alternatives to currently used antimalarial drugs: in search of a magic bullet.

PubMed

Bhagavathula, Akshaya Srikanth; Elnour, Asim Ahmed; Shehab, Abdulla

2016-11-04

Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America. Novel approaches to combating the disease have emerged in recent years and several drug candidates are now being tested clinically. However, it is long before these novel drugs can hit the market, especially due to a scarcity of safety and efficacy data.To reduce the malaria burden, the Medicines for Malaria Venture (MMV) was established in 1999 to develop novel medicines through industry and academic partners' collaboration. However, no reviews were focused following various preclinical and clinical studies published since the MMV initiation (2000) to till date.We identify promising approaches in the global portfolio of antimalarial medicines, and highlight challenges and patient specific concerns of these novel molecules. We discuss different clinical studies focusing on the evaluation of novel drugs against malaria in different human trials over the past five years.The drugs KAE609 and DDD107498 are still being evaluated in Phase I trials and preclinical developmental studies. Both the safety and efficacy of novel compounds such as KAF156 and DSM265 need to be assessed further, especially for use in pregnant women. Synthetic non-artemisinin ozonides such as OZ277 raised concerns in terms of its insufficient efficacy against high parasitic loads. Aminoquinoline-based scaffolds such as ferroquine are promising but should be combined with good partner drugs for enhanced efficacy. AQ-13 induced electrocardiac events, which led to prolonged QTc intervals. Tafenoquine, the only new anti-relapse scaffold for patients with a glucose-6-phosphate dehydrogenase deficiency, has raised significant concerns due to its hemolytic activity. Other compounds, including methylene blue (potential transmission blocker) and fosmidomycin (DXP reductoisomerase inhibitor), are available but cannot be used in children.At this stage, we are unable to identify a single magic bullet against malaria. Future studies should focus on effective single-dose molecules that can act against all stages of malaria in order to prevent transmission. Newer medicines have also raised concerns in terms of efficacy and safety. Overall, more evidence is needed to effectively reduce the current malaria burden. Treatment strategies that target the blood stage with transmission-blocking properties are needed to prevent future drug resistance.

A Preclinical Consortium Approach for Assessing the Efficacy of Combined Anti-CD3 Plus IL-1 Blockade in Reversing New-Onset Autoimmune Diabetes in NOD Mice

PubMed Central

Gill, Ronald G.; Pagni, Philippe P.; Kupfer, Tinalyn; Wasserfall, Clive H.; Deng, Songyan; Posgai, Amanda; Manenkova, Yulia; Bel Hani, Amira; Straub, Laura; Bernstein, Philip; Atkinson, Mark A.; Herold, Kevan C.; von Herrath, Matthias; Staeva, Teodora; Ehlers, Mario R.; Nepom, Gerald T.

2016-01-01

There is an ongoing need to develop strategic combinations of therapeutic agents to prevent type 1 diabetes (T1D) or to preserve islet β-cell mass in new-onset disease. Although clinical trials using candidate therapeutics are commonly based on preclinical studies, concern is growing regarding the reproducibility as well as the potential clinical translation of reported results using animal models of human disorders. In response, the National Institutes of Health Immune Tolerance Network and JDRF established a multicenter consortium of academic institutions designed to assess the efficacy and intergroup reproducibility of clinically applicable immunotherapies for reversing new-onset disease in the NOD mouse model of T1D. Predicated on prior studies, this consortium conducted coordinated, prospective studies, using joint standard operating procedures, fixed criteria for study entry, and common reagents, to optimize combined anti-CD3 treatment plus interleukin-1 (IL-1) blockade to reverse new-onset disease in NOD mice. We did not find that IL-1 blockade with anti–IL-1β monoclonal antibody or IL-1trap provided additional benefit for reversing new-onset disease compared with anti-CD3 treatment alone. These results demonstrate the value of larger, multicenter preclinical studies for vetting and prioritizing therapeutics for future clinical use. PMID:26718498

Introduction: the goals of antimicrobial therapy.

PubMed

Song, Jae-Hoon

2003-03-01

Antimicrobial agents are generally evaluated in preclinical studies assessing in vitro activity, animal models demonstrating in vivo bacteriologic efficacy, and clinical trials primarily investigating safety and clinical efficacy. However, large sample sizes are required to detect any differences in outcomes between antimicrobials in clinical trials, and, generally, studies are powered to show only clinical equivalence. In addition, diagnosis is often based on clinical symptoms, rather than microbiological evidence of bacterial infection, and the patients most likely to have resistant pathogens are often excluded. Clinical efficacy can be achieved in some bacterial infections in which antimicrobials are suboptimal or even not prescribed. However, bacterial eradication maximizes clinical efficacy and may also reduce the development and spread of resistant organisms. The goal of antimicrobial therapy is, therefore, to eradicate bacteria at the site of infection. Bacterial eradication is not usually assessed as a primary endpoint within the limits of currently recommended clinical trial design. However, pharmacokinetic (PK) (serum concentration profiles, penetration to site of infection) and pharmacodynamic (PD) (susceptibility, concentration- versus time-dependent killing, post-antimicrobial effects) criteria can be used to predict bacteriologic efficacy. PK/PD predictions should be confirmed during all phases of antimicrobial development and throughout clinical use in response to changing patterns of resistance. A clear rationale for dose recommendations can be determined preclinically based on PK/PD parameters, and correlated with efficacy, safety and resistance endpoints in clinical trials. The duration of treatment and dose should be the shortest that will reliably eradicate the pathogen(s), and that is safe and well tolerated. Currently available agents vary significantly in their ability to achieve PK/PD parameters necessary for bacteriologic eradication. Recommendations for appropriate antimicrobial therapy should be based on PK/PD parameters, with the aim of achieving the maximum potential for eradication of both existing and emerging resistant pathogens.

An Economic Evaluation of Preclinical Testing Strategies Compared to the Compulsory Scrapie Flock Scheme in the Control of Classical Scrapie

PubMed Central

Hawkins, Neil; Houston, Fiona; Fryer, Helen; Kao, Rowland

2012-01-01

Cost-benefit is rarely combined with nonlinear dynamic models when evaluating control options for infectious diseases. The current strategy for scrapie in Great Britain requires that all genetically susceptible livestock in affected flocks be culled (Compulsory Scrapie Flock Scheme or CSFS). However, this results in the removal of many healthy sheep, and a recently developed pre-clinical test for scrapie now offers a strategy based on disease detection. We explore the flock level cost-effectiveness of scrapie control using a deterministic transmission model and industry estimates of costs associated with genotype testing, pre-clinical tests and the value of a sheep culled. Benefit was measured in terms of the reduction in the number of infected sheep sold on, compared to a baseline strategy of doing nothing, using Incremental Cost Effectiveness analysis to compare across strategies. As market data was not available for pre-clinical testing, a threshold analysis was used to set a unit-cost giving equal costs for CSFS and multiple pre-clinical testing (MT, one test each year for three consecutive years). Assuming a 40% within-flock proportion of susceptible genotypes and a test sensitivity of 90%, a single test (ST) was cheaper but less effective than either the CSFS or MT strategies (30 infected-sales-averted over the lifetime of the average epidemic). The MT strategy was slightly less effective than the CSFS and would be a dominated strategy unless preclinical testing was cheaper than the threshold price of £6.28, but may be appropriate for flocks with particularly valuable livestock. Though the ST is not currently recommended, the proportion of susceptible genotypes in the national flock is likely to continue to decrease; this may eventually make it a cost-effective alternative to the MT or CSFS. PMID:22412943

Spinal Cord Stimulation for Treating Chronic Pain: Reviewing Preclinical and Clinical Data on Paresthesia-Free High-Frequency Therapy.

PubMed

Chakravarthy, Krishnan; Richter, Hira; Christo, Paul J; Williams, Kayode; Guan, Yun

2018-01-01

Traditional spinal cord stimulation (SCS) requires that paresthesia overlaps chronic painful areas. However, the new paradigm high-frequency SCS (HF-SCS) does not rely on paresthesia. A review of preclinical and clinical studies regarding the use of paresthesia-free HF-SCS for various chronic pain states. We reviewed available literatures on HF-SCS, including Nevro's paresthesia-free ultra high-frequency 10 kHz therapy (HF10-SCS). Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, and SCOPUS, and manual searches of the bibliographies of known primary and review articles. The primary goal is to describe the present developing conceptions of preclinical mechanisms of HF-SCS and to review clinical efficacy on paresthesia-free HF10-SCS for various chronic pain states. HF10-SCS offers a novel pain reduction tool without paresthesia for failed back surgery syndrome and chronic axial back pain. Preclinical findings indicate that potential mechanisms of action for paresthesia-free HF-SCS differ from those of traditional SCS. To fully understand and utilize paresthesia-free HF-SCS, mechanistic study and translational research will be very important, with increasing collaboration between basic science and clinical communities to design better trials and optimize the therapy based on mechanistic findings from effective preclinical models and approaches. Future research in these vital areas may include preclinical and clinical components conducted in parallel to optimize the potential of this technology. © 2017 International Neuromodulation Society.

Persistent post-stroke depression in mice following unilateral medial prefrontal cortical stroke

PubMed Central

Vahid-Ansari, F; Lagace, D C; Albert, P R

2016-01-01

Post-stroke depression (PSD) is a common outcome following stroke that is associated with poor recovery. To develop a preclinical model of PSD, we targeted a key node of the depression–anxiety circuitry by inducing a unilateral ischemic lesion to the medial prefrontal cortex (mPFC) stroke. Microinjection of male C57/BL6 mice with endothelin-1 (ET-1, 1600 pmol) induced a small (1 mm3) stroke consistently localized within the left mPFC. Compared with sham control mice, the stroke mice displayed a robust behavioral phenotype in four validated tests of anxiety including the elevated plus maze, light–dark, open-field and novelty-suppressed feeding tests. In addition, the stroke mice displayed depression-like behaviors in both the forced swim and tail suspension test. In contrast, there was no effect on locomotor activity or sensorimotor function in the horizontal ladder, or cylinder and home cage activity tests, indicating a silent stroke due to the absence of motor abnormalities. When re-tested at 6 weeks post stroke, the stroke mice retained both anxiety and depression phenotypes. Surprisingly, at 6 weeks post stroke the lesion site was infiltrated by neurons, suggesting that the ET-1-induced neuronal loss in the mPFC was reversible over time, but was insufficient to promote behavioral recovery. In summary, unilateral ischemic lesion of the mPFC results in a pronounced and persistent anxiety and depression phenotype with no evident sensorimotor deficits. This precise lesion of the depression circuitry provides a reproducible model to study adaptive cellular changes and preclinical efficacy of novel interventions to alleviate PSD symptoms. PMID:27483381

Prediction of practical performance in preclinical laboratory courses - the return of wire bending for admission of dental students in Hamburg.

PubMed

Kothe, Christian; Hissbach, Johanna; Hampe, Wolfgang

2014-01-01

Although some recent studies concluded that dexterity is not a reliable predictor of performance in preclinical laboratory courses in dentistry, they could not disprove earlier findings which confirmed the worth of manual dexterity tests in dental admission. We developed a wire bending test (HAM-Man) which was administered during dental freshmen's first week in 2008, 2009, and 2010. The purpose of our study was to evaluate if the HAM-Man is a useful selection criterion additional to the high school grade point average (GPA) in dental admission. Regression analysis revealed that GPA only accounted for a maximum of 9% of students' performance in preclinical laboratory courses, in six out of eight models the explained variance was below 2%. The HAM-Man incrementally explained up to 20.5% of preclinical practical performance over GPA. In line with findings from earlier studies the HAM-Man test of manual dexterity showed satisfactory incremental validity. While GPA has a focus on cognitive abilities, the HAM-Man reflects learning of unfamiliar psychomotor skills, spatial relationships, and dental techniques needed in preclinical laboratory courses. The wire bending test HAM-Man is a valuable additional selection instrument for applicants of dental schools.

Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP

PubMed Central

Lev, Avital; Lulla, Amriti R.; Wagner, Jessica; Ralff, Marie D.; Kiehl, Joshua B.; Zhou, Yan; Benes, Cyril H.; Prabhu, Varun V.; Oster, Wolfgang; Astsaturov, Igor; Dicker, David T.; El-Deiry, Wafik S.

2017-01-01

Pancreatic cancer is chemo-resistant and metastasizes early with an overall five-year survival of ∼8.2%. First-in-class imipridone ONC201 is a small molecule in clinical trials with anti-cancer activity. ONC212, a fluorinated-ONC201 analogue, shows preclinical efficacy in melanoma and hepatocellular-cancer models. We investigated efficacy of ONC201 and ONC212 against pancreatic cancer cell lines (N=16 including 9 PDX-cell lines). We demonstrate ONC212 efficacy in 4 in-vivo models including ONC201-resistant tumors. ONC212 is active in pancreatic cancer as single agent or in combination with 5-fluorouracil, irinotecan, oxaliplatin or RTK inhibitor crizotinib. Based on upregulation of pro-survival IGF1-R in some tumors, we found an active combination of ONC212 with inhibitor AG1024, including in vivo. We show a rationale for targeting pancreatic cancer using ONC212 combined with targeting the unfolded-protein response and ER chaperones such as GRP78/BIP. Our results lay the foundation to test imipridones, anti-cancer agents, in pancreatic cancer, that is refractory to most drugs. PMID:29137221

Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP.

PubMed

Lev, Avital; Lulla, Amriti R; Wagner, Jessica; Ralff, Marie D; Kiehl, Joshua B; Zhou, Yan; Benes, Cyril H; Prabhu, Varun V; Oster, Wolfgang; Astsaturov, Igor; Dicker, David T; El-Deiry, Wafik S

2017-10-10

Pancreatic cancer is chemo-resistant and metastasizes early with an overall five-year survival of ∼8.2%. First-in-class imipridone ONC201 is a small molecule in clinical trials with anti-cancer activity. ONC212, a fluorinated-ONC201 analogue, shows preclinical efficacy in melanoma and hepatocellular-cancer models. We investigated efficacy of ONC201 and ONC212 against pancreatic cancer cell lines ( N =16 including 9 PDX-cell lines). We demonstrate ONC212 efficacy in 4 in-vivo models including ONC201-resistant tumors. ONC212 is active in pancreatic cancer as single agent or in combination with 5-fluorouracil, irinotecan, oxaliplatin or RTK inhibitor crizotinib. Based on upregulation of pro-survival IGF1-R in some tumors, we found an active combination of ONC212 with inhibitor AG1024, including in vivo . We show a rationale for targeting pancreatic cancer using ONC212 combined with targeting the unfolded-protein response and ER chaperones such as GRP78/BIP. Our results lay the foundation to test imipridones, anti-cancer agents, in pancreatic cancer, that is refractory to most drugs.

Mesenchymal stromal cell-based therapy: Regulatory and translational aspects in gastroenterology.

PubMed

Dothel, Giovanni; Raschi, Emanuel; Rimondini, Roberto; De Ponti, Fabrizio

2016-11-07

The past decade has witnessed an outstanding scientific production focused towards the possible clinical applications of mesenchymal stromal cells (MSCs) in autoimmune and chronic inflammatory diseases. This raised the need of novel standards to adequately address quality, efficacy and safety issues of this advanced therapy. The development of a streamlined regulation is currently hampered by the complexity of analyzing dynamic biological entities rather than chemicals. Although numerous pieces of evidence show efficacy in reducing intestinal inflammation, some inconsistencies between the mechanisms of action of rodent vs human MSCs suggest caution before assigning translational value to preclinical studies. Preliminary evidence from clinical trials showed efficacy of MSCs in the treatment of fistulizing Crohn's disease (CD), and preparations of heterologous MSCs for CD treatment are currently tested in ongoing clinical trials. However, safety issues, especially in long-term treatment, still require solid clinical data. In this regard, standardized guidelines for appropriate dosing and methods of infusion could enhance the likelihood to predict more accurately the number of responders and the duration of remission periods. In addition, elucidating MSC mechanisms of action could lead to novel and more reliable formulations such as those derived from the MSCs themselves ( e.g ., supernatants).

Synthesis, Structure-Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5-HT4 Receptor Partial Agonists.

PubMed

Nirogi, Ramakrishna; Mohammed, Abdul Rasheed; Shinde, Anil K; Gagginapally, Shankar Reddy; Kancharla, Durga Malleshwari; Middekadi, Vanaja Reddy; Bogaraju, Narsimha; Ravella, Srinivasa Rao; Singh, Pooja; Birangal, Sumit Raosaheb; Subramanian, Ramkumar; Palacharla, Raghava Choudary; Benade, Vijay; Muddana, Nageswararao; Jayarajan, Pradeep

2018-05-31

Alzheimer's disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT 4 receptor (5-HT 4 R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT 4 R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure-activity relationships, compound 4o was identified as a potent 5-HT 4 R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT 4 R antagonist, attenuated the activity of compound 4o in the novel-object-recognition-test cognition model.

Pediatric cancer gone viral. Part I: strategies for utilizing oncolytic herpes simplex virus-1 in children

PubMed Central

Cripe, Timothy P; Chen, Chun-Yu; Denton, Nicholas L; Haworth, Kellie B; Hutzen, Brian; Leddon, Jennifer L; Streby, Keri A; Wang, Pin-Yi; Markert, James M; Waters, Alicia M; Gillespie, George Yancey; Beierle, Elizabeth A; Friedman, Gregory K

2015-01-01

Progress for improving outcomes in pediatric patients with solid tumors remains slow. In addition, currently available therapies are fraught with numerous side effects, often causing significant life-long morbidity for long-term survivors. The use of viruses to kill tumor cells based on their increased vulnerability to infection is gaining traction, with several viruses moving through early and advanced phase clinical testing. The prospect of increased efficacy and decreased toxicity with these agents is thus attractive for pediatric cancer. In part I of this two-part review, we focus on strategies for utilizing oncolytic engineered herpes simplex virus (HSV) to target pediatric malignancies. We discuss mechanisms of action, routes of delivery, and the role of preexisting immunity on antitumor efficacy. Challenges to maximizing oncolytic HSV in children are examined, and we highlight how these may be overcome through various arming strategies. We review the preclinical and clinical evidence demonstrating safety of a variety of oncolytic HSVs. In Part II, we focus on the antitumor efficacy of oncolytic HSV in pediatric tumor types, pediatric clinical advances made to date, and future prospects for utilizing HSV in pediatric patients with solid tumors. PMID:26436135

Antimalarial Pyrido[1,2-a]benzimidazoles: Lead Optimization, Parasite Life Cycle Stage Profile, Mechanistic Evaluation, Killing Kinetics, and in Vivo Oral Efficacy in a Mouse Model.

PubMed

Singh, Kawaljit; Okombo, John; Brunschwig, Christel; Ndubi, Ferdinand; Barnard, Linley; Wilkinson, Chad; Njogu, Peter M; Njoroge, Mathew; Laing, Lizahn; Machado, Marta; Prudêncio, Miguel; Reader, Janette; Botha, Mariette; Nondaba, Sindisiwe; Birkholtz, Lyn-Marie; Lauterbach, Sonja; Churchyard, Alisje; Coetzer, Theresa L; Burrows, Jeremy N; Yeates, Clive; Denti, Paolo; Wiesner, Lubbe; Egan, Timothy J; Wittlin, Sergio; Chibale, Kelly

2017-02-23

Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of hemozoin formation possibly contributes to the mechanism of action.

Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burks, Heather E.; Abrams, Tinya; Kirby, Christina A.

Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.

Reverse and Forward Translational Neuropharmacology in Psychiatric Drug Discovery.

PubMed

Shaffer, Christopher L

2018-02-01

The probability of achieving marketing approval of a novel therapeutic for psychiatric indications is extremely low due largely to the inability to demonstrate durable and reproducible efficacy in phase II trials and beyond. These failures are often attributed to the lack of translation of the underlying neuropharmacology from animal model(s) to the disease population. However, how assured is such a conclusion considering the clinical efficacy path rarely meticulously parallels the preclinical experiment(s) that underwrote it? © 2017 American Society for Clinical Pharmacology and Therapeutics.

Nasal-to-CNS drug delivery: where are we now and where are we heading? An industrial perspective.

PubMed

Landis, Margaret S; Boyden, Tracey; Pegg, Simon

2012-02-01

Delivery of drug therapeutics across the blood-brain barrier is a challenging task for pharmaceutical scientists. Nasal-to-CNS drug delivery has shown promising results in preclinical efficacy models and investigatory human clinical trials. The further development of this technology with respect to the establishment of valid, predictable preclinical species models, translatable pharmacokinetic-pharmacodynamic relationships and definition of toxicology impact will help attract additional pharmaceutical investment in this drug-delivery approach. Further discoveries in nasal nanotechnology, targeted delivery devices and diagnostic olfactory imaging will serve to fuel the advancements in this area of drug delivery.

Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

PubMed Central

Sperling, Reisa A.; Aisen, Paul S.; Beckett, Laurel A.; Bennett, David A.; Craft, Suzanne; Fagan, Anne M.; Iwatsubo, Takeshi; Jack, Clifford R.; Kaye, Jeffrey; Montine, Thomas J.; Park, Denise C.; Reiman, Eric M.; Rowe, Christopher C.; Siemers, Eric; Stern, Yaakov; Yaffe, Kristine; Carrillo, Maria C.; Thies, Bill; Morrison-Bogorad, Marcelle; Wagster, Molly V.; Phelps, Creighton H.

2011-01-01

The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long “preclinical” phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from “normal” cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious. PMID:21514248

[Clinical-pharmacological aspects to accelerate the development process from the preclinical to the clinical phase/1st communication: The contribution of clinical pharmacology].

PubMed

Kuhlmann, Jochen

2004-01-01

To improve the transition from research to development a critical evaluation of the individual project by research and disease area teams is required to include input from pharmacology, toxicology, pharmacokinetics, galenics, clinical pharmacology, clinical as well as regulatory experts and marketing. Decisions on the individual development strategy should be made prior to the start of development and all projects should be reviewed at predefined stages throughout the product development life cycle. This ensures consistency of decision-making not only during the development of individual products but throughout the entire development pipeline. Studies in the exploratory stage of drug development should be designed for decision making in contrast to later clinical trials in the confirmatory stage that require power for proof-of-safety and proof-of-efficacy. The more thorough and profound studies have been carried out during this exploratory stage of drug development, the earlier a decision can be made on the continuation or discontinuation of further development, thus saving development time and money and assessing and considerably reducing the risk for the patients and increasing the success rate of the project in the later confirmatory effectiveness trial with an adequate number of subjects receiving the new therapy under typical conditions of use. Strategies which may be helpful to improve the quality of decisions in drug discovery and drug development are: discovery experiments should be done to critically evaluate the compound, the "killer" experiments should be done as early as possible, continuous effort on preclinical disease models is necessary to improve predictability of efficacy in patients ("humanized" research): genomic technology should be used to identify novel, disease-related targets and to characterise preclinical test systems, improvement of knowledge and experience concerning the relevance of new technologies for the clinical picture; genotyping of clinical trial patients to select patient groups which are likely to respond to treatment (pharmacogenomics), modelling and simulation of preclinical and clinical trials, integration of pharmacokinetic and pharmacodynamic principles into drug development, assessment of the interaction potential (CYP-450, trasporter proteins and others), increasing use of biomarker/surrogate marker for rapid clinical feedback, involvement of the target population as soon as possible, applying statistical data analysis techniques for proving effectiveness, co-operation with high quality centers. To reach this goal clinical pharmacology must be fully integrated in the whole process from the candidate selection to its positioning within the market.

[Clinical-pharmacological aspects to accelerate the development process from the preclinical to the clinical phase/2nd communication: promising strategies].

PubMed

Kuhlmann, Jochen

2004-01-01

To improve the transition from research to development a critical evaluation of the individual project by research and disease area teams is required to include input from pharmacology, toxicology, pharmacokinetics, galenics, clinical pharmacology, clinical as well as regulatory experts and marketing. Decisions on the individual development strategy should be made prior to the start of development and all projects should be reviewed at predefined stages throughout the product development life cycle. This ensures consistency of decision-making not only during the development of individual products but throughout the entire development pipeline. Studies in the exploratory stage of drug development should be designed for decision making in contrast to later clinical trials in the confirmatory stage that require power for proof-of-safety and proof-of-efficacy. The more thorough and profound studies have been carried out during this exploratory stage of drug development, the earlier a decision can be made on the continuation or discontinuation of further development, thus saving development time and money and assessing and considerably reducing the risk for the patients and increasing the success rate of the project in the later confirmatory effectiveness trial with an adequate number of subjects receiving the new therapy under typical conditions of use. Strategies which may be helpful to improve the quality of decisions in drug discovery and drug development are: discovery experiments should be done to critically evaluate the compound, the "killer" experiments should be done as early as possible, continuous effort on preclinical disease models is necessary to improve predictability of efficacy in patients ("humanized" research): genomic technology should be used to identify novel, disease-related targets and to characterise preclinical test systems, improvement of knowledge and experience concerning the relevance of new technologies for the clinical picture, genotyping of clinical trial patients to select patient groups which are likely to respond to treatment (pharmacogenomics), modelling and simulation of preclinical and clinical trials, integration of pharmacokinetic and pharmacodynamic principles into drug development, assessment of the interaction potential (CYP-450, trasporter proteins and others), increasing use of biomarker/surrogate marker for rapid clinical feedback, involvement of the target population as soon as possible, applying statistical data analysis techniques for proving effectiveness, co-operation with high quality centers. To reach this goal clinical pharmacology must be fully integrated in the whole process from the candidate selection to its positioning within the market.

Solution formulation development and efficacy of MJC13 in a preclinical model of castration-resistant prostate cancer.

PubMed

Liang, Su; Bian, Xiaomei; Liang, Dong; Sivils, Jeffrey C; Neckers, Leonard M; Cox, Marc B; Xie, Huan

2016-01-01

MJC13, a novel FKBP52 targeting agent, has potential use for the treatment of castration-resistant prostate cancer. The purpose of this work was to develop a solution formulation of MJC13, and obtain its efficacy profile in a human prostate cancer xenograft mouse model. Preformulation studies were conducted to evaluate the physicochemical properties. Co-solvent systems were evaluated for aqueous solubility and tolerance. A human prostate cancer xenograft mouse model was established by growing 22Rv1 prostate cancer cells in C.B-17 SCID mice. The optimal formulation was used to study the efficacy of MJC13 in this preclinical model of castrate-resistant prostate cancer. We found that MJC13 was stable (at least for 1 month), highly lipophilic (logP = 6.49), poorly soluble in water (0.28 µg/mL), and highly plasma protein bound (>98%). The optimal formulation consisting of PEG 400 and Tween 80 (1:1, v/v) allowed us to achieve a MJC13 concentration of 7.5 mg/mL, and tolerated an aqueous environment. After twice weekly intratumoral injection with 10 mg/kg MJC13 in this formulation for four consecutive weeks, tumor volumes were significantly reduced compared to vehicle-treated controls.

Impact of protein D-containing pneumococcal conjugate vaccines on non-typeable Haemophilus influenzae acute otitis media and carriage.

PubMed

Clarke, Christopher; Bakaletz, Lauren O; Ruiz-Guiñazú, Javier; Borys, Dorota; Mrkvan, Tomas

2017-07-01

Protein D-containing vaccines may decrease acute otitis media (AOM) burden and nasopharyngeal carriage of non-typeable Haemophilus influenzae (NTHi). Protein D-containing pneumococcal conjugate vaccine PHiD-CV (Synflorix, GSK Vaccines) elicits robust immune responses against protein D. However, the phase III Clinical Otitis Media and PneumoniA Study (COMPAS), assessing PHiD-CV efficacy against various pneumococcal diseases, was not powered to demonstrate efficacy against NTHi; only trends of protective efficacy against NTHi AOM in children were shown. Areas covered: This review aims to consider all evidence available to date from pre-clinical and clinical phase III studies together with further evidence emerging from post-marketing studies since PHiD-CV has been introduced into routine clinical practice worldwide, to better describe the clinical utility of protein D in preventing AOM due to NTHi and its impact on NTHi nasopharyngeal carriage. Expert commentary: Protein D is an effective carrier protein in conjugate vaccines and evidence gathered from pre-clinical, clinical and observational studies suggest that it also elicits immune response that can help to reduce the burden of AOM due to NTHi. There remains a need to develop improved vaccines for prevention of NTHi disease, which could be achieved by combining protein D with other antigens.

Development of replication-deficient adenovirus malaria vaccines.

PubMed

Hollingdale, Michael R; Sedegah, Martha; Limbach, Keith

2017-03-01

Malaria remains a major threat to endemic populations and travelers, including military personnel to these areas. A malaria vaccine is feasible, as radiation attenuated sporozoites induce nearly 100% efficacy. Areas covered: This review covers current malaria clinical trials using adenoviruses and pre-clinical research. Heterologous prime-boost regimens, including replication-deficient human adenovirus 5 (HuAd5) carrying malaria antigens, are efficacious. However, efficacy appears to be adversely affected by pre-existing anti-HuAd5 antibodies. Current strategies focus on replacing HuAd5 with rarer human adenoviruses or adenoviruses isolated from non-human primates (NHPs). The chimpanzee adenovirus ChAd63 is undergoing evaluation in clinical trials including infants in malaria-endemic areas. Key antigens have been identified and are being used alone, in combination, or with protein subunit vaccines. Gorilla adenoviruses carrying malaria antigens are also currently being evaluated in preclinical models. These replacement adenovirus vectors will be successfully used to develop vaccines against malaria, as well as other infectious diseases. Expert commentary: Simplified prime-boost single shot regimens, dry-coated live vector vaccines or silicon microneedle arrays could be developed for malaria or other vaccines. Replacement vectors with similar or superior immunogenicity have rapidly advanced, and several are now in extensive Phase 2 and beyond in malaria as well as other diseases, notably Ebola.

Solution Formulation Development and Efficacy of MJC13 in a Preclinical Model of Castrate-Resistant Prostate Cancer

PubMed Central

Liang, Su; Bian, Xiaomei; Liang, Dong; Sivils, Jeffrey C.; Neckers, Leonard M.; Cox, Marc B.; Xie, Huan

2015-01-01

MJC13, a novel FKBP52 targeting agent, has potential use for the treatment of castrate-resistant prostate cancer. The purpose of this work was to develop a solution formulation of MJC13, and obtain its efficacy profile in a human prostate cancer xenograft mouse model. Preformulation studies were conducted to evaluate the physicochemical properties. Co-solvent systems were evaluated for aqueous solubility and tolerance. A human prostate cancer xenograft mouse model was established by growing 22Rv1 prostate cancer cells in C.B-17 SCID mice. The optimal formulation was used to study the efficacy of MJC13 in this preclinical model of castrate-resistant prostate cancer. We found that MJC13 was stable (at least for 1 month), very lipophilic (logP = 6.49), poorly soluble in water (0.28 μg/mL), and highly plasma protein bound (> 98%). The optimal formulation consisting of PEG 400 and Tween 80 (1:1, v/v) allowed us to achieve a MJC13 concentration of 7.5 mg/mL, and tolerated an aqueous environment. After twice weekly intratumoral injection with 10 mg/kg MJC13 in this formulation for 4 consecutive weeks, tumor volumes were significantly reduced compared to vehicle-treated controls. PMID:25380396

Available Resources | Division of Cancer Prevention

Cancer.gov

Preclinical pharmacology and efficacy studies Identification and evaluation of intermediate biomarkers Formulation optimization for enhanced bioavailability and clinical usefulness Analytical method development for investigational agents in bulk form and in biological fluids and tissues PK and PK-PD modeling to optimize dosing regimen Scale-up non-cGMP and cGMP production of

Bupropion-SR plus naltrexone-SR for the treatment of mild-to-moderate obesity.

PubMed

Ali, Khawla F; Shukla, Alpana P; Aronne, Louis J

2016-01-01

Naltrexone-bupropion is a recently approved drug combination for chronic weight management. In this article, we discuss the rationale for its use as a combination followed by a comprehensive review of safety and efficacy data from major preclinical, phase II and III clinical trials.

Canine Models of Duchenne Muscular Dystrophy and Their Use in Therapeutic Strategies

PubMed Central

Kornegay, Joe N.; Bogan, Janet R.; Bogan, Daniel J.; Childers, Martin K.; Li, Juan; Nghiem, Peter; Detwiler, David A.; Larsen, C. Aaron; Grange, Robert W.; Bhavaraju-Sanka, Ratna K.; Tou, Sandra; Keene, Bruce P.; Howard, James F.; Wang, Jiahui; Fan, Zheng; Schatzberg, Scott J.; Styner, Martin A.; Flanigan, Kevin M.; Xiao, Xiao; Hoffman, Eric P.

2013-01-01

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which the loss of dystrophin causes progressive degeneration of skeletal and cardiac muscle. Potential therapies that carry substantial risk, such as gene and cell-based approaches, must first be tested in animal models, notably the mdx mouse and several dystrophin-deficient breeds of dogs, including golden retriever muscular dystrophy (GRMD). Affected dogs have a more severe phenotype, in keeping with that of DMD, so may better predict disease pathogenesis and treatment efficacy. We and others have developed various phenotypic tests to characterize disease progression in the GRMD model. These biomarkers range from measures of strength and joint contractures to magnetic resonance imaging. Some of these tests are routinely used in clinical veterinary practice, while others require specialized equipment and expertise. By comparing serial measurements from treated and untreated groups, one can document improvement or delayed progression of disease. Potential treatments for DMD may be broadly categorized as molecular, cellular, or pharmacologic. The GRMD model has increasingly been used to assess efficacy of a range of these therapies. While some of these studies have largely provided general proof-of-concept for the treatment under study, others have demonstrated efficacy using the biomarkers discussed. Importantly, just as symptoms in DMD vary among patients, GRMD dogs display remarkable phenotypic variation. While confounding statistical analysis in preclinical trials, this variation offers insight regarding the role that modifier genes play in disease pathogenesis. By correlating functional and mRNA profiling results, gene targets for therapy development can be identified. PMID:22218699

Preclinical development of a humanized neutralizing antibody targeting HGF.

PubMed

Kim, Hyori; Hong, Sung Hee; Kim, Jung Yong; Kim, In-Chull; Park, Young-Whan; Lee, Song-Jae; Song, Seong-Won; Kim, Jung Ju; Park, Gunwoo; Kim, Tae Min; Kim, Yun-Hee; Park, Jong Bae; Chung, Junho; Kim, In-Hoo

2017-03-24

Hepatocyte growth factor (HGF) and its receptor, cMET, play critical roles in cell proliferation, angiogenesis and invasion in a wide variety of cancers. We therefore examined the anti-tumor activity of the humanized monoclonal anti-HGF antibody, YYB-101, in nude mice bearing human glioblastoma xenografts as a single agent or in combination with temozolomide. HGF neutralization, The extracellular signal-related kinases 1 and 2 (ERK1/2) phosphorylation, and HGF-induced scattering were assessed in HGF-expressing cell lines treated with YYB-101. To support clinical development, we also evaluated the preclinical pharmacokinetics and toxicokinetics in cynomolgus monkeys, and human and cynomolgus monkey tissue was stained with YYB-101 to test tissue cross-reactivity. We found that YYB-101 inhibited cMET activation in vitro and suppressed tumor growth in the orthotopic mouse model of human glioblastoma. Combination treatment with YYB-101 and temozolomide decreased tumor growth and increased overall survival compared with the effects of either agent alone. Five cancer-related genes (TMEM119, FST, RSPO3, ROS1 and NBL1) were overexpressed in YYB-101-treated mice that showed tumor regrowth. In the tissue cross-reactivity assay, critical cross-reactivity was not observed. The terminal elimination half-life was 21.7 days. Taken together, the in vitro and in vivo data demonstrated the anti-tumor efficacy of YYB-101, which appeared to be mediated by blocking the HGF/cMET interaction. The preclinical pharmacokinetics, toxicokinetics and tissue cross-reactivity data support the clinical development of YYB-101 for advanced cancer.

Importance of preclinical evaluation of wear in hip implant designs using simulator machines.

PubMed

Trommer, Rafael Mello; Maru, Márcia Marie

2017-01-01

Total hip arthroplasty (THA) is a surgical procedure that involves the replacement of the damaged joint of the hip by an artificial device. Despite the recognized clinical success of hip implants, wear of the articulating surfaces remains as one of the critical issues influencing performance. Common material combinations used in hip designs comprise metal-on-polymer (MoP), ceramic-on-polymer (CoP), metal-on-metal (MoM), and ceramic-on-ceramic (CoC). However, when the design of the hip implant is concerned besides the materials used, several parameters can influence its wear performance. In this scenario, where the safety and efficacy for the patient are the main issues, it is fundamental to evaluate and predict the wear rate of the hip implant design before its use in THA. This is one of the issues that should be taken into account in the preclinical evaluation step of the product, in which simulated laboratory tests are necessary. However, it is fundamental that the applied motions and loads can reproduce the wear mechanisms physiologically observed in the patient. To replicate the in vivo angular displacements and loadings, special machines known as joint simulators are employed. This article focuses on the main characteristics related to the wear simulation of hip implants using mechanical simulators, giving information to surgeons, researchers, regulatory bodies, etc., about the importance of preclinical wear evaluation. A critical analysis is performed on the differences in the principles of operation of simulators and their effects on the final results, and about future trends in wear simulation.

Don't stress about CRF: assessing the translational failures of CRF1antagonists.

PubMed

Spierling, Samantha R; Zorrilla, Eric P

2017-05-01

Dr. Athina Markou sought treatments for a common neural substrate shared by depression and drug dependence. Antagonists of corticotropin-releasing factor (CRF) receptors, a target of interest to her, have not reached the clinic despite strong preclinical rationale and sustained translational efforts. We explore potential causes for the failure of CRF 1 antagonists and review recent findings concerning CRF-CRF 1 systems in psychopathology. Potential causes for negative outcomes include (1) poor safety and efficacy of initial drug candidates due to bad pharmacokinetic and physicochemical properties, (2) specificity problems with preclinical screens, (3) the acute nature of screens vs. late-presenting patients, (4) positive preclinical results limited to certain models and conditions with dynamic CRF-CRF 1 activation not homologous to tested patients, (5) repeated CRF 1 activation-induced plasticity that reduces the importance of ongoing CRF 1 agonist stimulation, and (6) therapeutic silencing which may need to address CRF 2 receptor or CRF-binding protein molecules, constitutive CRF 1 activity, or molecules that influence agonist-independent activity or to target structural regions other than the allosteric site bound by all drug candidates. We describe potential markers of activation towards individualized treatment, human genetic, and functional data that still implicate CRF 1 systems in emotional disturbance, sex differences, and suggestive clinical findings for CRF 1 antagonists in food craving and CRF-driven HPA-axis overactivation. The therapeutic scope of selective CRF 1 antagonists now appears narrower than had been hoped. Yet, much remains to be learned about CRF's role in the neurobiology of dysphoria and addiction and the potential for novel anti-CRF therapies therein.

PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples.

PubMed

Winterhoff, Boris; Freyer, Luisa; Hammond, Edward; Giri, Shailendra; Mondal, Susmita; Roy, Debarshi; Teoman, Attila; Mullany, Sally A; Hoffmann, Robert; von Bismarck, Antonia; Chien, Jeremy; Block, Matthew S; Millward, Michael; Bampton, Darryn; Dredge, Keith; Shridhar, Viji

2015-05-01

Despite the utility of antiangiogenic drugs in ovarian cancer, efficacy remains limited due to resistance linked to alternate angiogenic pathways and metastasis. Therefore, we investigated PG545, an anti-angiogenic and anti-metastatic agent which is currently in Phase I clinical trials, using preclinical models of ovarian cancer. PG545's anti-cancer activity was investigated in vitro and in vivo as a single agent, and in combination with paclitaxel, cisplatin or carboplatin using various ovarian cancer cell lines and tumour models. PG545, alone, or in combination with chemotherapeutics, inhibited proliferation of ovarian cancer cells, demonstrating synergy with paclitaxel in A2780 cells. PG545 inhibited growth factor-mediated cell migration and reduced HB-EGF-induced phosphorylation of ERK, AKT and EGFR in vitro and significantly reduced tumour burden which was enhanced when combined with paclitaxel in an A2780 model or carboplatin in a SKOV-3 model. Moreover, in the immunocompetent ID8 model, PG545 also significantly reduced ascites in vivo. In the A2780 maintenance model, PG545 initiated with, and following paclitaxel and cisplatin treatment, significantly improved overall survival. PG545 increased plasma VEGF levels (and other targets) in preclinical models and in a small cohort of advanced cancer patients which might represent a potential biomarker of response. Our results support clinical testing of PG545, particularly in combination with paclitaxel, as a novel therapeutic strategy for ovarian cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Evaluating the Impact of Naltrexone on the Rat Gambling Task to Test Its Predictive Validity for Gambling Disorder.

PubMed

Di Ciano, Patricia; Le Foll, Bernard

2016-01-01

Gambling Disorder has serious consequences and no medications are currently approved for the treatment of this disorder. One factor that may make medication development difficult is the lack of animal models of gambling that would allow for the pre-clinical screening of efficacy. Despite this, there is evidence from clinical trials that opiate antagonists, in particular naltrexone, may be useful in treating gambling disorder. To-date, the effects of naltrexone on pre-clinical models of gambling have not been evaluated. The purpose of the present study was to evaluate the effects of naltrexone in an animal model of gambling, the rat gambling task (rGT), to determine whether this model has some predictive validity. The rGT is a model in which rats are given a choice of making either a response that produces a large reward or a small reward. The larger the reward, the greater the punishment, and thus this task requires that the animal inhibit the 'tempting' choice, as the smaller reward option produces overall the most number of rewards per session. People with gambling disorder chose the tempting option more, thus the rGT may provide a model of problem gambling. It was found that naltrexone improved performance on this task in a subset of animals that chose the 'tempting', disadvantageous choice, more at baseline. Thus, the results of this study suggest that the rGT should be further investigated as a pre-clinical model of gambling disorder and that further investigation into whether opioid antagonists are effective in treating Gambling Disorder may be warranted.

Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements

PubMed Central

Sprouse, Alyssa A.

2016-01-01

The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug–botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John’s wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug–botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug–botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism. PMID:26438626

Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements.

PubMed

Sprouse, Alyssa A; van Breemen, Richard B

2016-02-01

The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug-botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John's wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug-botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug-botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Gene Therapy and Targeted Toxins for Glioma

PubMed Central

Castro, Maria G.; Candolfi, Marianela; Kroeger, Kurt; King, Gwendalyn D.; Curtin, James F.; Yagiz, Kader; Mineharu, Yohei; Assi, Hikmat; Wibowo, Mia; Muhammad, AKM Ghulam; Foulad, David; Puntel, Mariana; Lowenstein, Pedro R.

2011-01-01

The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of nine to twelve months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted; this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors. PMID:21453286

A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug‐induced liver injury and postinjury inflammation in mice

PubMed Central

Lea, Jonathan D.; Sowinska, Agnieszka; Ottosson, Lars; Fürst, Camilla Melin; Steen, Johanna; Aulin, Cecilia; Clarke, Joanna I.; Kipar, Anja; Klevenvall, Lena; Yang, Huan; Palmblad, Karin; Park, B. Kevin; Tracey, Kevin J.; Blom, Anna M.; Andersson, Ulf

2016-01-01

Acetaminophen (APAP) overdoses are of major clinical concern. Growing evidence underlines a pathogenic contribution of sterile postinjury inflammation in APAP‐induced acute liver injury (APAP‐ALI) and justifies development of anti‐inflammatory therapies with therapeutic efficacy beyond the therapeutic window of the only current treatment option, N‐acetylcysteine (NAC). The inflammatory mediator, high mobility group box 1 (HMGB1), is a key regulator of a range of liver injury conditions and is elevated in clinical and preclinical APAP‐ALI. The anti‐HMGB1 antibody (m2G7) is therapeutically beneficial in multiple inflammatory conditions, and anti‐HMGB1 polyclonal antibody treatment improves survival in a model of APAP‐ALI. Herein, we developed and investigated the therapeutic efficacy of a partly humanized anti‐HMGB1 monoclonal antibody (mAb; h2G7) and identified its mechanism of action in preclinical APAP‐ALI. The mouse anti‐HMGB1 mAb (m2G7) was partly humanized (h2G7) by merging variable domains of m2G7 with human antibody‐Fc backbones. Effector function‐deficient variants of h2G7 were assessed in comparison with h2G7 in vitro and in preclinical APAP‐ALI. h2G7 retained identical antigen specificity and comparable affinity as m2G7. 2G7 treatments significantly attenuated APAP‐induced serum elevations of alanine aminotransferase and microRNA‐122 and completely abrogated markers of APAP‐induced inflammation (tumor necrosis factor, monocyte chemoattractant protein 1, and chemokine [C‐X‐C motif] ligand 1) with prolonged therapeutic efficacy as compared to NAC. Removal of complement and/or Fc receptor binding did not affect h2G7 efficacy. Conclusion: This is the first report describing the generation of a partly humanized HMGB1‐neutralizing antibody with validated therapeutic efficacy and with a prolonged therapeutic window, as compared to NAC, in APAP‐ALI. The therapeutic effect was mediated by HMGB1 neutralization and attenuation of postinjury inflammation. These results represent important progress toward clinical implementation of HMGB1‐specific therapy as a means to treat APAP‐ALI and other inflammatory conditions. (Hepatology 2016;64:1699‐1710). PMID:27474782

Quantifying lead-time bias in risk factor studies of cancer through simulation.

PubMed

Jansen, Rick J; Alexander, Bruce H; Anderson, Kristin E; Church, Timothy R

2013-11-01

Lead-time is inherent in early detection and creates bias in observational studies of screening efficacy, but its potential to bias effect estimates in risk factor studies is not always recognized. We describe a form of this bias that conventional analyses cannot address and develop a model to quantify it. Surveillance Epidemiology and End Results (SEER) data form the basis for estimates of age-specific preclinical incidence, and log-normal distributions describe the preclinical duration distribution. Simulations assume a joint null hypothesis of no effect of either the risk factor or screening on the preclinical incidence of cancer, and then quantify the bias as the risk-factor odds ratio (OR) from this null study. This bias can be used as a factor to adjust observed OR in the actual study. For this particular study design, as average preclinical duration increased, the bias in the total-physical activity OR monotonically increased from 1% to 22% above the null, but the smoking OR monotonically decreased from 1% above the null to 5% below the null. The finding of nontrivial bias in fixed risk-factor effect estimates demonstrates the importance of quantitatively evaluating it in susceptible studies. Copyright © 2013 Elsevier Inc. All rights reserved.

A psychological approach to providing self-management education for people with type 2 diabetes: the Diabetes Manual

PubMed Central

Sturt, Jackie; Taylor, Hafrun; Docherty, Andrea; Dale, Jeremy; Louise, Taylor

2006-01-01

Background The objectives of this study were twofold (i) to develop the Diabetes Manual, a self-management educational intervention aimed at improving biomedical and psychosocial outcomes (ii) to produce early phase evidence relating to validity and clinical feasibility to inform future research and systematic reviews. Methods Using the UK Medical Research Council's complex intervention framework, the Diabetes Manual and associated self management interventions were developed through pre-clinical, and phase I evaluation phases guided by adult-learning and self-efficacy theories, clinical feasibility and health policy protocols. A qualitative needs assessment and an RCT contributed data to the pre-clinical phase. Phase I incorporated intervention development informed by the pre-clinical phase and a feasibility survey. Results The pre-clinical and phase I studies resulted in the production in the Diabetes Manual programme for trial evaluation as delivered within routine primary care consultations. Conclusion This complex intervention shows early feasibility and face validity for both diabetes health professionals and people with diabetes. Randomised trial will determine effectiveness against clinical and psychological outcomes. Further study of some component parts, delivered in alternative combinations, is recommended. PMID:17129376

Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models.

PubMed

Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L

2013-09-01

Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin. © 2013 The Authors. Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy.

PubMed

Leverson, Joel D; Phillips, Darren C; Mitten, Michael J; Boghaert, Erwin R; Diaz, Dolores; Tahir, Stephen K; Belmont, Lisa D; Nimmer, Paul; Xiao, Yu; Ma, Xiaoju Max; Lowes, Kym N; Kovar, Peter; Chen, Jun; Jin, Sha; Smith, Morey; Xue, John; Zhang, Haichao; Oleksijew, Anatol; Magoc, Terrance J; Vaidya, Kedar S; Albert, Daniel H; Tarrant, Jacqueline M; La, Nghi; Wang, Le; Tao, Zhi-Fu; Wendt, Michael D; Sampath, Deepak; Rosenberg, Saul H; Tse, Chris; Huang, David C S; Fairbrother, Wayne J; Elmore, Steven W; Souers, Andrew J

2015-03-18

The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by thrombocytopenia caused by BCL-XL inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL-XL-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-XL to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-XL did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. These studies demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors and highlight their potential as improved cancer therapeutics. Copyright © 2015, American Association for the Advancement of Science.

2017 Military Supplement: Dodecafluoropentane Emulsion (Ddfpe) as a Resuscitation Fluid for Treatment of Hemorrhagic Shock and Traumatic Brain Injury: A Review.

PubMed

Graham, Kaitlin; Moon-Massat, Paula F; Unger, Evan C

2017-11-15

Dodecafluoropentane emulsion (DDFPe) is a novel nanotechnology for oxygen delivery with therapeutic potential for hemorrhagic shock and/or traumatic brain injury (TBI). DDFPe demonstrates efficacy at smaller doses than previously tested perfluorocarbon oxygen therapeutics. This smaller dose potentially eliminates toxicities exhibited by previous oxygen therapeutics, while anti-inflammatory properties of DDFPe may alleviate damage from ischemia reperfusion injury. This mini-review summarizes our progress in developing a battle-field ready product to prevent combat death due to hemorrhagic shock and/or TBI. Preclinical studies, for both indications, show promising effects of DDFPe as a resuscitation fluid. DDFPe may become a part of the toolkit for tactical healthcare professionals in battlefield and domestic emergency medicine.

Genetic Variation among Plasmodium vivax Isolates Adapted to Non-Human Primates and the Implication for Vaccine Development

PubMed Central

Ntumngia, Francis B.; McHenry, Amy M.; Barnwel, John W.; Cole-Tobian, Jennifer; King, Christopher L.; Adams, John H.

2009-01-01

Plasmodium vivax Duffy binding protein (DBP) is vital for parasite development, thereby making this molecule a good vaccine candidate. Preclinical development of a P. vivax vaccine often involves use of primate models prior to testing efficacy in humans, but primate isolates are poorly characterized. We analyzed the complete gene coding for the DBP in several P. vivax isolates that are used for experimental primate infections and compared these sequences with the Salvador I DBP isolate, which is being used for vaccine development. Our results affirm that primate-adapted isolates are genetically similar to P. vivax circulating in humans, but variability is greatest in the putative target of protective antibodies. In addition, some P. vivax isolates contain multiple genetically different clones. Testing a DBP vaccine may therefore be complicated by heterogeneity and diversity of the P. vivax isolates available for in vivo challenge. PMID:19190217

Prediction of practical performance in preclinical laboratory courses – the return of wire bending for admission of dental students in Hamburg

PubMed Central

Kothe, Christian; Hissbach, Johanna; Hampe, Wolfgang

2014-01-01

Although some recent studies concluded that dexterity is not a reliable predictor of performance in preclinical laboratory courses in dentistry, they could not disprove earlier findings which confirmed the worth of manual dexterity tests in dental admission. We developed a wire bending test (HAM-Man) which was administered during dental freshmen’s first week in 2008, 2009, and 2010. The purpose of our study was to evaluate if the HAM-Man is a useful selection criterion additional to the high school grade point average (GPA) in dental admission. Regression analysis revealed that GPA only accounted for a maximum of 9% of students’ performance in preclinical laboratory courses, in six out of eight models the explained variance was below 2%. The HAM-Man incrementally explained up to 20.5% of preclinical practical performance over GPA. In line with findings from earlier studies the HAM-Man test of manual dexterity showed satisfactory incremental validity. While GPA has a focus on cognitive abilities, the HAM-Man reflects learning of unfamiliar psychomotor skills, spatial relationships, and dental techniques needed in preclinical laboratory courses. The wire bending test HAM-Man is a valuable additional selection instrument for applicants of dental schools. PMID:24872857

EU-approved rapid tests might underestimate bovine spongiform encephalopathy infection in goats.

PubMed

Meloni, Daniela; Bozzetta, Elena; Langeveld, Jan P M; Groschup, Martin H; Goldmann, Wilfred; Andrèoletti, Olivier; Lantier, Isabelle; Van Keulen, Lucien; Bossers, Alex; Pitardi, Danilo; Nonno, Romolo; Sklaviadis, Theodoros; Ingravalle, Francesco; Peletto, Simone; Colussi, Silvia; Acutis, Pier Luigi

2017-03-01

We report the diagnostic sensitivity of 3 EU-approved rapid tests (ELISAs; 1 from IDEXX and 2 from Bio-Rad) for the detection of transmissible spongiform encephalopathy diseases in goats. Ninety-eight goat brainstem samples were tested. All the rapid tests had 100% specificity and ≥80% sensitivity, with the IDEXX test significantly more sensitive than the 2 Bio-Rad tests. All tests detected 100% of samples from goats with clinical scrapie, but missed 8% (IDEXX) to 33% (Bio-Rad SG) of samples from preclinical goats. Importantly, only IDEXX picked up all samples from clinical bovine spongiform encephalopathy (BSE)-infected goats, whereas the other 2 rapid tests missed 15% (Bio-Rad SG) to 25% (Bio-Rad SAP). These results show that a fraction of preclinical scrapie infections are likely missed by EU surveillance, with sensitivity of detection strongly dependent on the choice of the rapid test. Moreover, a significant proportion of clinical BSE infections are underestimated by using either Bio-Rad test. Assuming that the same sensitivity on preclinical goats would also occur in BSE-infected goats, our data suggest that IDEXX is likely the most sensitive test for detecting preclinical field cases of BSE infection in goats, although with an 8% failure rate. These results raise some concerns about the reliability of current EU surveillance figures on BSE infection in goats.

An empirically derived composite cognitive test score with improved power to track and evaluate treatments for preclinical Alzheimer's disease.

PubMed

Langbaum, Jessica B; Hendrix, Suzanne B; Ayutyanont, Napatkamon; Chen, Kewei; Fleisher, Adam S; Shah, Raj C; Barnes, Lisa L; Bennett, David A; Tariot, Pierre N; Reiman, Eric M

2014-11-01

There is growing interest in the evaluation of preclinical Alzheimer's disease (AD) treatments. As a result, there is a need to identify a cognitive composite that is sensitive to track preclinical AD decline to be used as a primary endpoint in treatment trials. Longitudinal data from initially cognitively normal, 70- to 85-year-old participants in three cohort studies of aging and dementia from the Rush Alzheimer's Disease Center were examined to empirically define a composite cognitive endpoint that is sensitive to detect and track cognitive decline before the onset of cognitive impairment. The mean-to-standard deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of cognitive tests/subtests drawn from the neuropsychological battery in cognitively normal participants who subsequently progressed to clinical stages of AD during 2- and 5-year periods, using data from those who remained unimpaired during the same period to correct for aging and practice effects. Combinations that performed well were then evaluated for representation of relevant cognitive domains, robustness across individual years before diagnosis, and occurrence of selected items within top performing combinations. The optimal composite cognitive test score comprised seven cognitive tests/subtests with an MSDR = 0.964. By comparison, the most sensitive individual test score was Logical Memory Delayed Recall with an MSDR = 0.64. We have identified a composite cognitive test score representing multiple cognitive domains that has improved power compared with the most sensitive single test item to track preclinical AD decline and evaluate preclinical AD treatments. We are confirming the power of the composite in independent cohorts and with other analytical approaches, which may result in refinements, have designated it as the primary endpoint in the Alzheimer's Prevention Initiative's preclinical treatment trials for individuals at high imminent risk for developing symptoms due to late-onset AD. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Memantine for the Treatment of Dementia: A Review on its Current and Future Applications

PubMed Central

Folch, Jaume; Busquets, Oriol; Ettcheto, Miren; Sánchez-López, Elena; Castro-Torres, Ruben Dario; Verdaguer, Ester; Garcia, Maria Luisa; Olloquequi, Jordi; Casadesús, Gemma; Beas-Zarate, Carlos; Pelegri, Carme; Vilaplana, Jordi; Auladell, Carme; Camins, Antoni

2017-01-01

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered. PMID:29254093

Positioning, labelling, and medical information control of co-artemether tablets (CPG 56697): a fixed novel combination of artemether and benflumetol. Novartis Co-Artemether International Development Team.

PubMed

Skelton-Stroud, P; Mull, R

1998-01-01

Coartemether is a fixed 1:6 ratio of artemether and lumefantrine (benflumetol), a joint development between Novartis Pharma and the Academy of Military Medical Sciences (Beijing, China). It is well tolerated and has a high efficacy against uncomplicated and drug resistant falciparum malaria by oral administration. The preclinical profile of coartemether revealed no prohibitive toxicological, teratogenic or mutagenic findings. No evidence of neurotoxicity was seen in oral preclinical studies. It shows a negative response to the induction of resistance and prevents recrudescence. Clinically, coartemether shows a rapid onset of antiparasitic action, resolution of symptoms, no clinical neurotoxicity and excellent parasite clearance.

Anxiolytic- and Antidepressant-like Effects of the Methadone Metabolite 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP)

PubMed Central

Lee, Bridgin G.; Olson, Thao T.; Xie, Teresa; Xiao, Yingxian; Blendy, Julie A.; Kellar, Kenneth J.

2015-01-01

The enhancement of GABAergic and monoaminergic neurotransmission has been the mainstay of pharmacotherapy and the focus of drug-discovery for anxiety and depressive disorders for several decades. However, the significant limitations of drugs used for these disorders underscores the need for novel therapeutic targets. Neuronal nicotinic acetylcholine receptors (nAChRs) may represent one such target. For example, mecamylamine, a non-competitive antagonist of nAChRs, displays positive effects in preclinical tests for anxiolytic and antidepressant activity in rodents. In addition, nicotine elicits similar effects in rodent models, possibly by receptor desensitization. Previous studies (Xiao et al., 2001) have identified two metabolites of methadone, EMDP (2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline) and EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), which are considered to be inactive at opiate receptors, as relatively potent noncompetitive channel blockers of rat α3β4 nAChRs. Here, we show that these compounds are likewise highly effective blockers of human α3β4 and α4β2 nAChRs. Moreover, we show that they display relatively low affinity for opiate binding sites labeled by [3H]-naloxone. We then evaluated these compounds in rats and mice in preclinical behavioral models predictive of potential anxiolytic and antidepressant efficacy. We found that EMDP, but not EDDP, displayed robust effects predictive of anxiolytic and antidepressant efficacy without significant effects on locomotor activity. Moreover, EMDP at behaviorally active doses, unlike mecamylamine, did not produce eyelid ptosis, suggesting it may produce fewer autonomic side effects than mecamylamine. Thus, the methadone metabolite EMDP may represent a novel therapeutic avenue for the treatment of some affective disorders. PMID:26365569

Quetiapine and its metabolite norquetiapine: translation from in vitro pharmacology to in vivo efficacy in rodent models

PubMed Central

Widzowski, D; Maciag, C; Zacco, A; Hudzik, T; Liu, J; Nyberg, S; Wood, M W

2015-01-01

Background and Purpose Quetiapine has a range of clinical activity distinct from other atypical antipsychotic drugs, demonstrating efficacy as monotherapy in bipolar depression, major depressive disorder and generalized anxiety disorder. The neuropharmacological mechanisms underlying this clinical profile are not completely understood; however, the major active metabolite, norquetiapine, has been shown to have a distinct in vitro pharmacological profile consistent with a broad therapeutic range and may contribute to the clinical profile of quetiapine. Experimental Approach We evaluated quetiapine and norquetiapine, using in vitro binding and functional assays of targets known to be associated with antidepressant and anxiolytic drug actions and compared these activities with a representative range of established antipsychotics and antidepressants. To determine how the in vitro pharmacological properties translate into in vivo activity, we used preclinical animal models with translational relevance to established antidepressant‐like and anxiolytic‐like drug action. Key Results Norquetiapine had equivalent activity to established antidepressants at the noradrenaline transporter (NET), while quetiapine was inactive. Norquetiapine was active in the mouse forced swimming and rat learned helplessness tests. In in vivo receptor occupancy studies, norquetiapine had significant occupancy at NET at behaviourally relevant doses. Both quetiapine and norquetiapine were agonists at 5‐HT1A receptors, and the anxiolytic‐like activity of norquetiapine in rat punished responding was blocked by the 5‐HT1A antagonist, WAY100635. Conclusions and Implications Quetiapine and norquetiapine have multiple in vitro pharmacological actions, and results from preclinical studies suggest that activity at NET and 5‐HT1A receptors contributes to the antidepressant and anxiolytic effects in patients treated with quetiapine. PMID:26436896

Naturally Occurring Disk Herniation in Dogs: An Opportunity for Pre-Clinical Spinal Cord Injury Research

PubMed Central

Levine, Gwendolyn J.; Porter, Brian F.; Topp, Kimberly; Noble-Haeusslein, Linda J.

2011-01-01

Abstract Traumatic spinal cord injuries represent a significant source of morbidity in humans. Despite decades of research using experimental models of spinal cord injury to identify candidate therapeutics, there has been only limited progress toward translating beneficial findings to human spinal cord injury. Thoracolumbar intervertebral disk herniation is a naturally occurring disease that affects dogs and results in compressive/contusive spinal cord injury. Here we discuss aspects of this disease that are analogous to human spinal cord injury, including injury mechanisms, pathology, and metrics for determining outcomes. We address both the strengths and weaknesses of conducting pre-clinical research in these dogs, and include a review of studies that have utilized these animals to assess efficacy of candidate therapeutics. Finally, we consider a two-species approach to pre-clinical data acquisition, beginning with a reproducible model of spinal cord injury in the rodent as a tool for discovery with validation in pet dogs with intervertebral disk herniation. PMID:21438715

Nanoparticles in targeted cancer therapy: mesoporous silica nanoparticles entering preclinical development stage.

PubMed

Rosenholm, Jessica M; Mamaeva, Veronika; Sahlgren, Cecilia; Lindén, Mika

2012-01-01

Nanotechnology may help overcome persisting limitations of current cancer treatment and thus contribute to the creation of more effective, safer and more affordable therapies. While some nanotechnology-based drug delivery systems are already being marketed and others are in clinical trial, most still remain in the preclinical development stage. Mesoporous silica nanoparticles have been highlighted as an interesting drug delivery platform, due to their flexibility and high drug load potential. Although numerous reports demonstrate sophisticated drug delivery mechanisms in vitro, the therapeutic benefit of these systems for in vivo applications have been under continuous debate. This has been due to nontranslatable conditions used in the in vitro studies, as well as contradictory conclusions drawn from preclinical (in vivo) studies. However, recent studies have indicated that the encouraging cellular studies could in fact be repeated also in vivo. Here, we report on these recent advances regarding therapeutic efficacy, targeting and safety issues related to the application of mesoporous silica nanoparticles in cancer therapy.

Developing EZH2-Targeted Therapy for Lung Cancer | Office of Cancer Genomics

Cancer.gov

Epigenetic targets are exciting new avenues for cancer drug discovery. Zhang and colleagues have designed the open-source EZH2 inhibitor JQEZ5 and shown antitumor efficacy in vitro and in vivo in preclinical studies in murine and human lung adenocarcinoma models expressing high levels of EZH2.

Discovery and preclinical development of dasabuvir for the treatment of hepatitis C infection.

PubMed

El Kassas, Mohamed; Elbaz, Tamer; Hafez, Enas; Wifi, Mohamed Naguib; Esmat, Gamal

2017-06-01

Hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality. Positively, the introduction of new directly-acting antivirals (DAAs) have led to dramatic improvements in response rates to antiviral therapy. Furthermore, newer generations of DAAs have demonstrated better safety profiles as well as efficacy than older generations. Current treatment recommendations are based on different combinations of DAAs. Current combination therapies rely on agents that target the different steps of viral replication by using different molecules from various DAAs families. Areas covered: In this review, the authors summarize data from of one of the recently developed NS5B polymerase inhibitors, dasabuvir, formerly known as ABT-333. Herein, the authors discuss the drug discovery data for dasabuvir including data from preclinical, toxicological resistance studies. The authors also review dasabuvir's clinical efficacy across various clinical challenges, in addition to its limitations in clinical practice. Expert opinion: Dasabuvir represents an important medical advance when used as a combination therapy for HCV. Unfortunately, it does present limitations like low genotypic coverage and further research is still required to address some of the lingering issues.

Rationale for nebivolol/valsartan combination for hypertension: review of preclinical and clinical data.

PubMed

Giles, Thomas D; Cockcroft, John R; Pitt, Bertram; Jakate, Abhijeet; Wright, Harold M

2017-09-01

: To treat hypertension, combining two or more antihypertensive drugs from different classes is often necessary. β-Blockers and renin-angiotensin-aldosterone system inhibitors, when combined, have been deemed 'less effective' based on partially overlapping mechanisms of action and limited evidence. Recently, the single-pill combination (SPC) of nebivolol (Neb) 5 mg - a vasodilatory β1-selective antagonist/β3 agonist - and valsartan 80 mg, an angiotensin II receptor blocker, was US Food and Drug Administration-approved for hypertension. Pharmacological profiles of Neb and valsartan, alone and combined, are well characterized. In addition, a large 8-week randomized trial in stages I-II hypertensive patients (N = 4161) demonstrated greater blood pressure-reducing efficacy for Neb/valsartan SPCs than component monotherapies with comparable tolerability. In a biomarkers substudy (N = 805), Neb/valsartan SPCs prevented valsartan-induced increases in plasma renin, and a greater reduction in plasma aldosterone was observed with the highest SPC dose vs. valsartan 320 mg/day. This review summarizes preclinical and clinical evidence supporting Neb/valsartan as an efficacious and well tolerated combination treatment for hypertension.

Preclinical Justification of pbi-shRNA EWS/FLI1 Lipoplex (LPX) Treatment for Ewing's Sarcoma.

PubMed

Rao, Donald D; Jay, Christopher; Wang, Zhaohui; Luo, Xiuquan; Kumar, Padmasini; Eysenbach, Hilary; Ghisoli, Maurizio; Senzer, Neil; Nemunaitis, John

2016-08-01

The EWS/FLI1 fusion gene is well characterized as a driver of Ewing's sarcoma. Bi-shRNA EWS/FLI1 is a functional plasmid DNA construct that transcribes both siRNA and miRNA-like effectors each of which targets the identical type 1 translocation junction region of the EWS/FLI1 transcribed mRNA sequence. Previous preclinical and clinical studies confirm the safety of this RNA interference platform technology and consistently demonstrate designated mRNA and protein target knockdown at greater than 90% efficiency. We initiated development of pbi-shRNA EWS/FLI1 lipoplex (LPX) for the treatment of type 1 Ewing's sarcoma. Clinical-grade plasmid was manufactured and both sequence and activity verified. Target protein and RNA knockdown of 85-92% was demonstrated in vitro in type 1 human Ewing's sarcoma tumor cell lines with the optimal bi-shRNA EWS/FLI1 plasmid. This functional plasmid was placed in a clinically tested, liposomal (LP) delivery vehicle followed by in vivo verification of activity. Type 1 Ewing's sarcoma xenograft modeling confirmed dose related safety and tumor response to pbi-shRNA EWS/FLI1 LPX. Toxicology studies in mini-pigs with doses comparable to the demonstrated in vivo efficacy dose resulted in transient fever, occasional limited hypertension at low- and high-dose assessment and transient liver enzyme elevation at high dose. These results provide the justification to initiate clinical testing.

Preclinical Justification of pbi-shRNA EWS/FLI1 Lipoplex (LPX) Treatment for Ewing's Sarcoma

PubMed Central

Rao, Donald D.; Jay, Christopher; Wang, Zhaohui; Luo, Xiuquan; Kumar, Padmasini; Eysenbach, Hilary; Ghisoli, Maurizio; Senzer, Neil; Nemunaitis, John

2016-01-01

The EWS/FLI1 fusion gene is well characterized as a driver of Ewing's sarcoma. Bi-shRNA EWS/FLI1 is a functional plasmid DNA construct that transcribes both siRNA and miRNA-like effectors each of which targets the identical type 1 translocation junction region of the EWS/FLI1 transcribed mRNA sequence. Previous preclinical and clinical studies confirm the safety of this RNA interference platform technology and consistently demonstrate designated mRNA and protein target knockdown at greater than 90% efficiency. We initiated development of pbi-shRNA EWS/FLI1 lipoplex (LPX) for the treatment of type 1 Ewing's sarcoma. Clinical-grade plasmid was manufactured and both sequence and activity verified. Target protein and RNA knockdown of 85–92% was demonstrated in vitro in type 1 human Ewing's sarcoma tumor cell lines with the optimal bi-shRNA EWS/FLI1 plasmid. This functional plasmid was placed in a clinically tested, liposomal (LP) delivery vehicle followed by in vivo verification of activity. Type 1 Ewing's sarcoma xenograft modeling confirmed dose related safety and tumor response to pbi-shRNA EWS/FLI1 LPX. Toxicology studies in mini-pigs with doses comparable to the demonstrated in vivo efficacy dose resulted in transient fever, occasional limited hypertension at low- and high-dose assessment and transient liver enzyme elevation at high dose. These results provide the justification to initiate clinical testing. PMID:27166877

A preclinical cognitive test battery to parallel the National Institute of Health Toolbox in humans: bridging the translational gap.

PubMed

Snigdha, Shikha; Milgram, Norton W; Willis, Sherry L; Albert, Marylin; Weintraub, S; Fortin, Norbert J; Cotman, Carl W

2013-07-01

A major goal of animal research is to identify interventions that can promote successful aging and delay or reverse age-related cognitive decline in humans. Recent advances in standardizing cognitive assessment tools for humans have the potential to bring preclinical work closer to human research in aging and Alzheimer's disease. The National Institute of Health (NIH) has led an initiative to develop a comprehensive Toolbox for Neurologic Behavioral Function (NIH Toolbox) to evaluate cognitive, motor, sensory and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age. This paper aims to analyze the strengths and limitations of animal behavioral tests that can be used to parallel those in the NIH Toolbox. We conclude that there are several paradigms available to define a preclinical battery that parallels the NIH Toolbox. We also suggest areas in which new tests may benefit the development of a comprehensive preclinical test battery for assessment of cognitive function in animal models of aging and Alzheimer's disease. Copyright © 2013 Elsevier Inc. All rights reserved.

A preclinical cognitive test battery to parallel the National Institute of Health Toolbox in humans: bridging the translational gap

PubMed Central

Snigdha, Shikha; Milgram, Norton W.; Willis, Sherry L.; Albert, Marylin; Weintraub, S.; Fortin, Norbert J.; Cotman, Carl W.

2013-01-01

A major goal of animal research is to identify interventions that can promote successful aging and delay or reverse age-related cognitive decline in humans. Recent advances in standardizing cognitive assessment tools for humans have the potential to bring preclinical work closer to human research in aging and Alzheimer’s disease. The National Institute of Health (NIH) has led an initiative to develop a comprehensive Toolbox for Neurologic Behavioral Function (NIH Toolbox) to evaluate cognitive, motor, sensory and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age. This paper aims to analyze the strengths and limitations of animal behavioral tests that can be used to parallel those in the NIH Toolbox. We conclude that there are several paradigms available to define a preclinical battery that parallels the NIH Toolbox. We also suggest areas in which new tests may benefit the development of a comprehensive preclinical test battery for assessment of cognitive function in animal models of aging and Alzheimer’s disease. PMID:23434040

Preclinical Testing of Antihuman CD28 Fab' Antibody in a Novel Nonhuman Primate Small Animal Rodent Model of Xenogenic Graft-Versus-Host Disease.

PubMed

Hippen, Keli L; Watkins, Benjamin; Tkachev, Victor; Lemire, Amanda M; Lehnen, Charles; Riddle, Megan J; Singh, Karnail; Panoskaltsis-Mortari, Angela; Vanhove, Bernard; Tolar, Jakub; Kean, Leslie S; Blazar, Bruce R

2016-12-01

Graft-versus-host disease (GVHD) is a severe complication of hematopoietic stem cell transplantation. Current therapies to prevent alloreactive T cell activation largely cause generalized immunosuppression and may result in adverse drug, antileukemia and antipathogen responses. Recently, several immunomodulatory therapeutics have been developed that show efficacy in maintaining antileukemia responses while inhibiting GVHD in murine models. To analyze efficacy and better understand immunological tolerance, escape mechanisms, and side effects of clinical reagents, testing of species cross-reactive human agents in large animal GVHD models is critical. We have previously developed and refined a nonhuman primate (NHP) large animal GVHD model. However, this model is not readily amenable to semi-high throughput screening of candidate clinical reagents. Here, we report a novel, optimized NHP xenogeneic GVHD (xeno-GVHD) small animal model that recapitulates many aspects of NHP and human GVHD. This model was validated using a clinically available blocking, monovalent anti-CD28 antibody (FR104) whose effects in a human xeno-GVHD rodent model are known. Because human-reactive reagents may not be fully cross-reactive or effective in vivo on NHP immune cells, this NHP xeno-GVHD model provides immunological insights and direct testing on NHP-induced GVHD before committing to the intensive NHP studies that are being increasingly used for detailed evaluation of new immune therapeutic strategies before human trials.

A multimodality imaging-compatible insertion robot with a respiratory motion calibration module designed for ablation of liver tumors: a preclinical study.

PubMed

Li, Dongrui; Cheng, Zhigang; Chen, Gang; Liu, Fangyi; Wu, Wenbo; Yu, Jie; Gu, Ying; Liu, Fengyong; Ren, Chao; Liang, Ping

2018-04-03

To test the accuracy and efficacy of the multimodality imaging-compatible insertion robot with a respiratory motion calibration module designed for ablation of liver tumors in phantom and animal models. To evaluate and compare the influences of intervention experience on robot-assisted and ultrasound-controlled ablation procedures. Accuracy tests on rigid body/phantom model with a respiratory movement simulation device and microwave ablation tests on porcine liver tumor/rabbit liver cancer were performed with the robot we designed or with the traditional ultrasound-guidance by physicians with or without intervention experience. In the accuracy tests performed by the physicians without intervention experience, the insertion accuracy and efficiency of robot-assisted group was higher than those of ultrasound-guided group with statistically significant differences. In the microwave ablation tests performed by the physicians without intervention experience, better complete ablation rate was achieved when applying the robot. In the microwave ablation tests performed by the physicians with intervention experience, there was no statistically significant difference of the insertion number and total ablation time between the robot-assisted group and the ultrasound-controlled group. The evaluation by the NASA-TLX suggested that the robot-assisted insertion and microwave ablation process performed by physicians with or without experience were more comfortable. The multimodality imaging-compatible insertion robot with a respiratory motion calibration module designed for ablation of liver tumors could increase the insertion accuracy and ablation efficacy, and minimize the influence of the physicians' experience. The ablation procedure could be more comfortable with less stress with the application of the robot.

Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fossa, Anthony A., E-mail: anthony.fossa@icardiac.com; Wisialowski, Todd A.; Cremers, Thomas

2012-11-01

Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood pressure (BP) and heart rate (HR) due to enhanced sympathetic neurotransmission, chronic treatment changes the responsiveness of the central noradrenergic system and suppresses these effects via autonomic regulation. To better understand the relationship between NE increases and cardiovascular safety, we investigated acute and chronic effects of the NRI reboxetine on central NE release and on BP and HR and electrical alternans, a measure ofmore » arrhythmia liability, in guinea pigs. NE release was assessed by microdialysis in medial prefrontal cortex (mPFC) and hypothalamic paraventricular nucleus (PVN); BP and HR were measured by telemetry. Animals were treated for 28 days with 15 mg/kg/day of reboxetine or vehicle via an osmotic minipump and then challenged with acute intravenous doses of reboxetine. Animals chronically treated with reboxetine had 2-fold higher extracellular basal NE levels in mPFC and PVN compared to basal levels after chronic vehicle treatment. BP was significantly increased after the first day of treatment, and gradually returned to vehicle levels by day 21. These data indicate that chronic NRI treatment may lead to an increase in central NE levels and a concomitant reduction in BP based on exposure–response curves compared to vehicle treatment, suggesting a larger separation between preclinical estimates of efficacy vs. safety compared to acute NRI treatment. -- Highlights: ► Acute RBX produces blood pressure increases acutely that decrease with chronic RBX ► Chronic RBX increases brain NE levels, a preclinical surrogate of improved efficacy ► Short-term screening of NRI often underestimates the chronic therapeutic index ► Chronic cardiovascular safety and efficacy more adequately address therapeutic index ► Similar paradigms may exist with other centrally and peripherally acting drugs.« less

BET Bromodomain Inhibitors Enhance Efficacy and Disrupt Resistance to AR Antagonists in the Treatment of Prostate Cancer.

PubMed

Asangani, Irfan A; Wilder-Romans, Kari; Dommeti, Vijaya L; Krishnamurthy, Pranathi M; Apel, Ingrid J; Escara-Wilke, June; Plymate, Stephen R; Navone, Nora M; Wang, Shaomeng; Feng, Felix Y; Chinnaiyan, Arul M

2016-04-01

Next-generation antiandrogen therapies, such as enzalutamide and abiraterone, have had a profound impact on the management of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC patients invariably develop resistance to these agents. Here, a series of clonal cell lines were developed from enzalutamide-resistant prostate tumor xenografts to study the molecular mechanism of resistance and test their oncogenic potential under various treatment conditions. Androgen receptor (AR) signaling was maintained in these cell lines, which acquired potential resistance mechanisms, including expression of AR-variant 7 (AR-v7) and glucocorticoid receptor. BET bromodomain inhibitors were shown previously to attenuate AR signaling in mCRPC; here, we demonstrate the efficacy of bromodomain and extraterminal (BET) inhibitors in enzalutamide-resistant prostate cancer models. AR antagonists, enzalutamide, and ARN509 exhibit enhanced prostate tumor growth inhibition when combined with BET inhibitors, JQ1 and OTX015, respectively. Taken together, these data provide a compelling preclinical rationale to combine BET inhibitors with AR antagonists to subvert resistance mechanisms. Therapeutic combinations of BET inhibitors and AR antagonists may enhance the clinical efficacy in the treatment of mCRPC. http://mcr.aacrjournals.org/content/molcanres/14/4/324/F1.large.jpg ©2016 American Association for Cancer Research.

Ensuring transparency and minimization of methodologic bias in preclinical pain research: PPRECISE considerations.

PubMed

Andrews, Nick A; Latrémolière, Alban; Basbaum, Allan I; Mogil, Jeffrey S; Porreca, Frank; Rice, Andrew S C; Woolf, Clifford J; Currie, Gillian L; Dworkin, Robert H; Eisenach, James C; Evans, Scott; Gewandter, Jennifer S; Gover, Tony D; Handwerker, Hermann; Huang, Wenlong; Iyengar, Smriti; Jensen, Mark P; Kennedy, Jeffrey D; Lee, Nancy; Levine, Jon; Lidster, Katie; Machin, Ian; McDermott, Michael P; McMahon, Stephen B; Price, Theodore J; Ross, Sarah E; Scherrer, Grégory; Seal, Rebecca P; Sena, Emily S; Silva, Elizabeth; Stone, Laura; Svensson, Camilla I; Turk, Dennis C; Whiteside, Garth

2016-04-01

There is growing concern about lack of scientific rigor and transparent reporting across many preclinical fields of biological research. Poor experimental design and lack of transparent reporting can result in conscious or unconscious experimental bias, producing results that are not replicable. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration sponsored a consensus meeting of the Preclinical Pain Research Consortium for Investigating Safety and Efficacy (PPRECISE) Working Group. International participants from universities, funding agencies, government agencies, industry, and a patient advocacy organization attended. Reduction of publication bias, increasing the ability of others to faithfully repeat experimental methods, and increased transparency of data reporting were specifically discussed. Parameters deemed essential to increase confidence in the published literature were clear, specific reporting of an a priori hypothesis and definition of primary outcome measure. Power calculations and whether measurement of minimal meaningful effect size to determine these should be a core component of the preclinical research effort provoked considerable discussion, with many but not all agreeing. Greater transparency of reporting should be driven by scientists, journal editors, reviewers, and grant funders. The conduct of high-quality science that is fully reported should not preclude novelty and innovation in preclinical pain research, and indeed, any efforts that curtail such innovation would be misguided. We believe that to achieve the goal of finding effective new treatments for patients with pain, the pain field needs to deal with these challenging issues.

Postretrieval Extinction Attenuates Alcohol Cue Reactivity in Rats.

PubMed

Cofresí, Roberto U; Lewis, Suzanne M; Chaudhri, Nadia; Lee, Hongjoo J; Monfils, Marie-H; Gonzales, Rueben A

2017-03-01

Conditioned responses to alcohol-associated cues can hinder recovery from alcohol use disorder (AUD). Cue exposure (extinction) therapy (CET) can reduce reactivity to alcohol cues, but its efficacy is limited by phenomena such as spontaneous recovery and reinstatement that can cause a return of conditioned responding after extinction. Using a preclinical model of alcohol cue reactivity in rats, we evaluated whether the efficacy of alcohol CET could be improved by conducting CET during the memory reconsolidation window after retrieval of cue-alcohol associations. Rats were provided with intermittent access to unsweetened alcohol. Rats were then trained to predict alcohol access based on a visual cue. Next, rats were treated with either standard extinction (n = 14) or postretrieval extinction (n = 13). Rats were then tested for long-term memory of extinction and susceptibility to spontaneous recovery and reinstatement. Despite equivalent extinction, rats treated with postretrieval extinction exhibited reduced spontaneous recovery and reinstatement relative to rats treated with standard extinction. Postretrieval CET shows promise for persistently attenuating the risk to relapse posed by alcohol cues in individuals with AUD. Copyright © 2017 by the Research Society on Alcoholism.

POST-RETRIEVAL EXTINCTION ATTENUATES ALCOHOL CUE REACTIVITY IN RATS

PubMed Central

Cofresí, Roberto U.; Lewis, Suzanne M.; Chaudhri, Nadia; Lee, Hongjoo J.; Monfils, Marie-H.; Gonzales, Rueben A.

2017-01-01

BACKGROUND Conditioned responses to alcohol-associated cues can hinder recovery from alcohol use disorder (AUD). Cue exposure (extinction) therapy (CET) can reduce reactivity to alcohol cues, but its efficacy is limited by phenomena such as spontaneous recovery and reinstatement that can cause a return of conditioned responding after extinction. Using a preclinical model of alcohol cue reactivity in rats, we evaluated whether the efficacy of alcohol CET could be improved by conducting CET during the memory reconsolidation window after retrieval of a cue-alcohol association. METHODS Rats were provided with intermittent access to unsweetened alcohol. Rats were then trained to predict alcohol access based on a visual cue. Next, rats were treated with either standard extinction (n=14) or post-retrieval extinction (n=13). Rats were then tested for long-term memory of extinction and susceptibility to spontaneous recovery and reinstatement. RESULTS Despite equivalent extinction, rats treated with post-retrieval extinction exhibited reduced spontaneous recovery and reinstatement relative to rats treated with standard extinction. CONCLUSIONS Post-retrieval CET shows promise for persistently attenuating the risk to relapse posed by alcohol cues in individuals with AUD. PMID:28169439

Oxytocin under opioid antagonism leads to supralinear enhancement of social attention

PubMed Central

Dal Monte, Olga; Anderson, Kevin M.; Tringides, Marios; Holmes, Avram J.

2017-01-01

To provide new preclinical evidence toward improving the efficacy of oxytocin (OT) in treating social dysfunction, we tested the benefit of administering OT under simultaneously induced opioid antagonism during dyadic gaze interactions in monkeys. OT coadministered with a μ-opioid receptor antagonist, naloxone, invoked a supralinear enhancement of prolonged and selective social attention, producing a stronger effect than the summed effects of each administered separately. These effects were consistently observed when averaging over entire sessions, as well as specifically following events of particular social importance, including mutual eye contact and mutual reward receipt. Furthermore, attention to various facial regions was differentially modulated depending on social context. Using the Allen Institute’s transcriptional atlas, we further established the colocalization of μ-opioid and κ-opioid receptor genes and OT genes at the OT-releasing sites in the human brain. These data across monkeys and humans support a regulatory relationship between the OT and opioid systems and suggest that administering OT under opioid antagonism may boost the therapeutic efficacy of OT for enhancing social cognition. PMID:28461466

Preclinical Evidence for the Efficacy of Ischemic Postconditioning against Renal Ischemia-Reperfusion Injury, a Systematic Review and Meta-Analysis

PubMed Central

Jonker, Simone J.; Menting, Theo P.; Warlé, Michiel C.; Ritskes-Hoitinga, Merel; Wever, Kimberley E.

2016-01-01

Background Renal ischemia-reperfusion injury (IRI) is a major cause of kidney damage after e.g. renal surgery and transplantation. Ischemic postconditioning (IPoC) is a promising treatment strategy for renal IRI, but early clinical trials have not yet replicated the promising results found in animal studies. Method We present a systematic review, quality assessment and meta-analysis of the preclinical evidence for renal IPoC, and identify factors which modify its efficacy. Results We identified 39 publications studying >250 control animals undergoing renal IRI only and >290 animals undergoing renal IRI and IPoC. Healthy, male rats undergoing warm ischemia were used in the vast majority of studies. Four studies applied remote IPoC, all others used local IPoC. Meta-analysis showed that both local and remote IPoC ameliorated renal damage after IRI for the outcome measures serum creatinine, blood urea nitrogen and renal histology. Subgroup analysis indicated that IPoC efficacy increased with the duration of index ischemia. Measures to reduce bias were insufficiently reported. Conclusion High efficacy of IPoC is observed in animal models, but factors pertaining to the internal and external validity of these studies may hamper the translation of IPoC to the clinical setting. The external validity of future animal studies should be increased by including females, comorbid animals, and transplantation models, in order to better inform clinical trial design. The severity of renal damage should be taken into account in the design and analysis of future clinical trials. PMID:26963819

Neuroprotective properties of curcumin in toxin-base animal models of Parkinson's disease: a systematic experiment literatures review.

PubMed

Wang, Xin-Shi; Zhang, Zeng-Rui; Zhang, Man-Man; Sun, Miao-Xuan; Wang, Wen-Wen; Xie, Cheng-Long

2017-08-17

Curcumin (diferuloylmethane), a polyphenol extracted from the plant Curcuma longa, is widely used in Southeast Asia, China and India in food preparation and for medicinal purposes. Meanwhile, the neuroprotective actions of curcumin have been documented for experimental therapy in Parkinson's disease (PD). In this study, we used a systematic review to comprehensively assess the efficacy of curcumin in experimental PD. Using electronic and manual search for the literatures, we identified studies describing the efficacy of curcumin in animal models of PD. We identified 13 studies with a total of 298 animals describing the efficacy of curcumin in animal models of PD. The methodological quality of all preclinical trials is ranged from 2 to 5. The majority of the experiment studies demonstrated that curcumin was more significantly neuroprotection effective than control groups for treating PD. Among them, five studies indicated that curcumin had an anti-inflammatory effect in the PD animal models (p < 0.05). Meanwhile, four studies showed the antioxidant capability of curcumin, by which it protected substantia nigra neurons and improved striatal dopamine levels. Furthermore, two studies in this review displayed that curcumin treatment was also effective in reducing neuronal apoptosis and improving functional outcome in animal models of PD. Most of the preclinical studies demonstrated the positive findings while one study reported that curcumin had no beneficial effects against Mn-induced disruption of hippocampal metal and neurotransmitter homeostasis. The results demonstrated a marked efficacy of curcumin in experimental model of PD, suggesting curcumin probably a candidate neuroprotective drug for human PD patients.

Long-acting rilpivirine for HIV prevention.

PubMed

Jackson, Akil; McGowan, Ian

2015-07-01

Long-acting injectable antiretroviral (ARV) formulations are being developed for the treatment and prevention of HIV infection. The purpose of this review is to summarize recent preclinical and clinical data on TMC278 (rilpivirine), a nonnucleoside reverse transcriptase inhibitor (NNRTI), that is being developed for both a treatment and prevention indication. Long-acting rilpivirine has demonstrated efficacy in preventing HIV acquisition in a humanized mouse model and has been found to be well tolerated and acceptable in several Phase I clinical trials. Pharmacokinetic data from Phase I studies suggest that 1200 mg of long-acting rilpivirine administered every 8 weeks would be associated with plasma and tissue levels of rilpivirine anticipated to be necessary for preventing HIV infection. This regimen is being evaluated in the HPTN-076 Phase II expanded safety study that will enroll women in South Africa, Zimbabwe, and the USA. The HPTN-076 study requires a 4-week run in with oral rilpivirine (25 mg capsules) before receiving 1200 mg of rilpivirine. It is not yet certain whether oral dosing will remain a prerequisite in future trials or post licensure. Long-acting rilpivirine shows promise as a candidate agent for HIV prevention. Preclinical efficacy has been demonstrated in a murine model. Phase I studies have shown good safety and efficacy, but breakthrough infection and resistance have been documented with lower doses of long-acting rilpivirine. Phase II development for a prevention indication is ongoing.

First-in-human Phase 1 CRISPR Gene Editing Cancer Trials: Are We Ready?

PubMed

Baylis, Francoise; McLeod, Marcus

2017-01-01

A prospective first-in-human Phase 1 CRISPR gene editing trial in the United States for patients with melanoma, synovial sarcoma, and multiple myeloma offers hope that gene editing tools may usefully treat human disease. An overarching ethical challenge with first-in-human Phase 1 clinical trials, however, is knowing when it is ethically acceptable to initiate such trials on the basis of safety and efficacy data obtained from pre-clinical studies. If the pre-clinical studies that inform trial design are themselves poorly designed - as a result of which the quality of pre-clinical evidence is deficient - then the ethical requirement of scientific validity for clinical research may not be satisfied. In turn, this could mean that the Phase 1 clinical trial will be unsafe and that trial participants will be exposed to risk for no potential benefit. To assist sponsors, researchers, clinical investigators and reviewers in deciding when it is ethically acceptable to initiate first-in-human Phase 1 CRISPR gene editing clinical trials, structured processes have been developed to assess and minimize translational distance between pre-clinical and clinical research. These processes draw attention to various features of internal validity, construct validity, and external validity. As well, the credibility of supporting evidence is to be critically assessed with particular attention to optimism bias, financial conflicts of interest and publication bias. We critically examine the pre-clinical evidence used to justify the first-inhuman Phase 1 CRISPR gene editing cancer trial in the United States using these tools. We conclude that the proposed trial cannot satisfy the ethical requirement of scientific validity because the supporting pre-clinical evidence used to inform trial design is deficient. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The Microphysiology Systems Database for Analyzing and Modeling Compound Interactions with Human and Animal Organ Models

PubMed Central

Vernetti, Lawrence; Bergenthal, Luke; Shun, Tong Ying; Taylor, D. Lansing

2016-01-01

Abstract Microfluidic human organ models, microphysiology systems (MPS), are currently being developed as predictive models of drug safety and efficacy in humans. To design and validate MPS as predictive of human safety liabilities requires safety data for a reference set of compounds, combined with in vitro data from the human organ models. To address this need, we have developed an internet database, the MPS database (MPS-Db), as a powerful platform for experimental design, data management, and analysis, and to combine experimental data with reference data, to enable computational modeling. The present study demonstrates the capability of the MPS-Db in early safety testing using a human liver MPS to relate the effects of tolcapone and entacapone in the in vitro model to human in vivo effects. These two compounds were chosen to be evaluated as a representative pair of marketed drugs because they are structurally similar, have the same target, and were found safe or had an acceptable risk in preclinical and clinical trials, yet tolcapone induced unacceptable levels of hepatotoxicity while entacapone was found to be safe. Results demonstrate the utility of the MPS-Db as an essential resource for relating in vitro organ model data to the multiple biochemical, preclinical, and clinical data sources on in vivo drug effects. PMID:28781990

Translating advances in the molecular basis of schizophrenia into novel cognitive treatment strategies.

PubMed

O'Tuathaigh, Colm M P; Moran, Paula M; Zhen, Xuechu C; Waddington, John L

2017-10-01

The presence and severity of cognitive symptoms, including working memory, executive dysfunction and attentional impairment, contributes materially to functional impairment in schizophrenia. Cognitive symptoms have proved to be resistant to both first- and second-generation antipsychotic drugs. Efforts to develop a consensus set of cognitive domains that are both disrupted in schizophrenia and are amenable to cross-species validation (e.g. the National Institute of Mental Health Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia and Research Domain Criteria initiatives) are an important step towards standardization of outcome measures that can be used in preclinical testing of new drugs. While causative genetic mutations have not been identified, new technologies have identified novel genes as well as hitherto candidate genes previously implicated in the pathophysiology of schizophrenia and/or mechanisms of antipsychotic efficacy. This review comprises a selective summary of these developments, particularly phenotypic data arising from preclinical genetic models for cognitive dysfunction in schizophrenia, with the aim of indicating potential new directions for pro-cognitive therapeutics. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc. © 2017 The British Pharmacological Society.

d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology.

PubMed

De Gregorio, Danilo; Comai, Stefano; Posa, Luca; Gobbi, Gabriella

2016-11-23

d-Lysergic Acid Diethylamide (LSD) is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles' reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD's mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT 2A receptor as a partial agonist and 5-HT 1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D₂, Trace Amine Associate receptor 1 (TAAR₁) and 5-HT 2A . More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD's effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA) mechanism or acting on TAAR₁ receptors.

d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology

PubMed Central

De Gregorio, Danilo; Comai, Stefano; Posa, Luca; Gobbi, Gabriella

2016-01-01

d-Lysergic Acid Diethylamide (LSD) is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles’ reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD’s mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT2A receptor as a partial agonist and 5-HT1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D2, Trace Amine Associate receptor 1 (TAAR1) and 5-HT2A. More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD’s effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA) mechanism or acting on TAAR1 receptors. PMID:27886063

Investigative safety science as a competitive advantage for Pharma.

PubMed

Moggs, Jonathan; Moulin, Pierre; Pognan, Francois; Brees, Dominique; Leonard, Michele; Busch, Steve; Cordier, Andre; Heard, David J; Kammüller, Michael; Merz, Michael; Bouchard, Page; Chibout, Salah-Dine

2012-09-01

Following a US National Academy of Sciences report in 2007 entitled "Toxicity Testing of the 21st Century: a Vision and a Strategy," significant advances within translational drug safety sciences promise to revolutionize drug discovery and development. The purpose of this review is to outline why investigative safety science is a competitive advantage for the pharmaceutical industry. The article discusses the essential goals for modern investigative toxicologists including: cross-species target biology; molecular pathways of toxicity; and development of predictive tools, models and biomarkers that allow discovery researchers and clinicians to anticipate safety problems and plan ways to address them, earlier than ever before. Furthermore, the article emphasizes the importance of investigating unanticipated clinical safety signals through a combination of mechanistic preclinical studies and/or molecular characterization of clinical samples from affected organs. The traditional boundaries between pharma industry teams focusing on safety/efficacy and preclinical/clinical development are rapidly disappearing in favor of translational safety science-centric organizations with a vision of bringing more effective medicines forward safely and quickly. Comparative biology and mechanistic toxicology approaches facilitate: i) identifying translational safety biomarkers; ii) identifying new drug targets/indications; and iii) mitigating off-target toxicities. These value-adding safety science contributions will change traditional toxicologists from side-effect identifiers to drug development enablers.

Nonsteroidal antagonists of the mineralocorticoid receptor.

PubMed

Kolkhof, Peter; Nowack, Christina; Eitner, Frank

2015-09-01

The broad clinical use of steroidal mineralocorticoid receptor antagonists (MRAs) is limited by the potential risk of inducing hyperkalemia when given on top of renin-angiotensin system blockade. Drug discovery campaigns have been launched aiming for the identification of nonsteroidal MRAs with an improved safety profile. This review analyses the evidence for the potential of improved safety profiles of nonsteroidal MRAs and the current landscape of clinical trials with nonsteroidal MRAs. At least three novel nonsteroidal MRAs have reportedly demonstrated an improved therapeutic index (i.e. less risk for hyperkalemia) in comparison to steroidal antagonists in preclinical models. Five pharmaceutical companies have nonsteroidal MRAs in clinical development with a clear focus on the treatment of chronic kidney diseases. No clinical data have been published so far for MT-3995 (Mitsubishi), SC-3150 (Daiichi-Sankyo), LY2623091 (Eli Lilly) and PF-03882845 (Pfizer). In contrast, data from two clinical phase II trials are available for finerenone (Bayer) which demonstrated safety and efficacy in patients with heart failure and additional chronic kidney diseases, and significantly reduced albuminuria in patients with diabetic nephropathy. Neither hyperkalemia nor reductions in kidney function were limiting factors to its use. Novel, nonsteroidal MRAs are currently tested in clinical trials. Based on preclinical and first clinical data, these nonsteroidal MRAs might overcome the limitations of today's steroidal antagonists.

The importance of imaging strategies for pre-clinical and clinical in vivo distribution of oncolytic viruses

PubMed Central

Pelin, Adrian; Wang, Jiahu; Bell, John; Le Boeuf, Fabrice

2017-01-01

Oncolytic viruses (OVs) are an emergent and unique therapy for cancer patients. Similar to chemo- and radiation therapy, OV can lyse (kill) cancer cell directly. In general, the advantages of OVs over other treatments are primarily: a higher safety profile (as shown by less adverse effects), ability to replicate, transgene(s) delivery, and stimulation of a host’s immune system against cancer. The latter has prompted successful use of OVs with other immunotherapeutic strategies in a synergistic manner. In spite of extended testing in pre-clinical and clinical setting, using biologically derived therapeutics like virus always raises potential concerns about safety (replication at non-intended locations) and bio-availability of the product. Recent advent in in vivo imaging techniques dramatically improves the convenience of use, quality of pictures, and amount of information acquired. Easy assessing of safety/localization of the biotherapeutics like OVs became a new potential weapon in the physician’s arsenal to improve treatment outcome. Given that OVs are typically replicating, in vivo imaging can also track virus replication and persistence as well as precisely mapping tumor tissues presence. This review discusses the importance of imaging in vivo in evaluating OV efficacy, as well as currently available tools and techniques. PMID:29637059

Antivenom for Neuromuscular Paralysis Resulting From Snake Envenoming

PubMed Central

Silva, Anjana; Hodgson, Wayne C.; Isbister, Geoffrey K.

2017-01-01

Antivenom therapy is currently the standard practice for treating neuromuscular dysfunction in snake envenoming. We reviewed the clinical and experimental evidence-base for the efficacy and effectiveness of antivenom in snakebite neurotoxicity. The main site of snake neurotoxins is the neuromuscular junction, and the majority are either: (1) pre-synaptic neurotoxins irreversibly damaging the presynaptic terminal; or (2) post-synaptic neurotoxins that bind to the nicotinic acetylcholine receptor. Pre-clinical tests of antivenom efficacy for neurotoxicity include rodent lethality tests, which are problematic, and in vitro pharmacological tests such as nerve-muscle preparation studies, that appear to provide more clinically meaningful information. We searched MEDLINE (from 1946) and EMBASE (from 1947) until March 2017 for clinical studies. The search yielded no randomised placebo-controlled trials of antivenom for neuromuscular dysfunction. There were several randomised and non-randomised comparative trials that compared two or more doses of the same or different antivenom, and numerous cohort studies and case reports. The majority of studies available had deficiencies including poor case definition, poor study design, small sample size or no objective measures of paralysis. A number of studies demonstrated the efficacy of antivenom in human envenoming by clearing circulating venom. Studies of snakes with primarily pre-synaptic neurotoxins, such as kraits (Bungarus spp.) and taipans (Oxyuranus spp.) suggest that antivenom does not reverse established neurotoxicity, but early administration may be associated with decreased severity or prevent neurotoxicity. Small studies of snakes with mainly post-synaptic neurotoxins, including some cobra species (Naja spp.), provide preliminary evidence that neurotoxicity may be reversed with antivenom, but placebo controlled studies with objective outcome measures are required to confirm this. PMID:28422078

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules.

PubMed

Liu, Qian; Sun, Jessica D; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F; Cranmer, Lee D; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W Steve; Curd, John G; Matteucci, Mark D; Hart, Charles P

2012-06-01

Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2-8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302.

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules

PubMed Central

Liu, Qian; Sun, Jessica D.; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F.; Cranmer, Lee D.; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W. Steve; Curd, John G.; Matteucci, Mark D.

2014-01-01

Purpose Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Methods Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. Results The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2–8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. Conclusions TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302. PMID:22382881

Identification of new epilepsy treatments: issues in preclinical methodology.

PubMed

Galanopoulou, Aristea S; Buckmaster, Paul S; Staley, Kevin J; Moshé, Solomon L; Perucca, Emilio; Engel, Jerome; Löscher, Wolfgang; Noebels, Jeffrey L; Pitkänen, Asla; Stables, James; White, H Steve; O'Brien, Terence J; Simonato, Michele

2012-03-01

Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (1) new symptomatic antiseizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (2) disease-modifying treatments that prevent or ameliorate the process of epileptogenesis, and (3) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, that is, age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome, or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical antiepilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis, and comorbidities. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Identification of new treatments for epilepsy: issues in preclinical methodology

PubMed Central

Galanopoulou, Aristea S.; Buckmaster, Paul S.; Staley, Kevin J.; Moshé, Solomon L.; Perucca, Emilio; Engel, Jerome; Löscher, Wolfgang; Noebels, Jeffrey L.; Pitkänen, Asla; Stables, James; White, Steve H.; O’Brien, Terence J.; Simonato, Michele

2013-01-01

Summary Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (a) new symptomatic anti-seizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (b) disease modifying treatments that prevent or ameliorate the epileptogenic state, and (c) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, i.e. age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical anti-epilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis and comorbidities. PMID:22292566

Dietary phytochemicals and cancer chemoprevention: a review of the clinical evidence

PubMed Central

Kotecha, Ritesh; Takami, Akiyoshi; Espinoza, J. Luis

2016-01-01

Cancer chemoprevention involves the use of different natural or biologic agents to inhibit or reverse tumor growth. Epidemiological and pre-clinical data suggest that various natural phytochemicals and dietary compounds possess chemopreventive properties, and in-vitro and animal studies support that these compounds may modulate signaling pathways involved in cell proliferation and apoptosis in transformed cells, enhance the host immune system and sensitize malignant cells to cytotoxic agents. Despite promising results from experimental studies, only a limited number of these compounds have been tested in clinical trials and have shown variable results. In this review, we summarize the data regarding select phytochemicals including curcumin, resveratrol, lycopene, folates and tea polyphenols with emphasis on the clinical evidence supporting the efficacy of these compounds in high-risk populations. PMID:27232756

Neuropeptide Y, resilience, and PTSD therapeutics.

PubMed

Kautz, Marin; Charney, Dennis S; Murrough, James W

2017-05-10

Resilience to traumatic stress is a complex psychobiological process that protects individuals from developing posttraumatic stress disorder (PTSD) or other untoward consequences of exposure to extreme stress, including depression. Progress in translational research points toward the neuropeptide Y (NPY) system - among others - as a key mediator of stress response and as a potential therapeutic focus for PTSD. Substantial preclinical evidence supports the role of NPY in the modulation of stress response and in the regulation of anxiety in animal models. Clinical studies testing the safety and efficacy of modulating the NPY system in humans, however, have lagged behind. In the current article, we review the evidence base for targeting the NPY system as a therapeutic approach in PTSD, and consider impediments and potential solutions to therapeutic development. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Dietary phytochemicals and cancer chemoprevention: a review of the clinical evidence.

PubMed

Kotecha, Ritesh; Takami, Akiyoshi; Espinoza, J Luis

2016-08-09

Cancer chemoprevention involves the use of different natural or biologic agents to inhibit or reverse tumor growth. Epidemiological and pre-clinical data suggest that various natural phytochemicals and dietary compounds possess chemopreventive properties, and in-vitro and animal studies support that these compounds may modulate signaling pathways involved in cell proliferation and apoptosis in transformed cells, enhance the host immune system and sensitize malignant cells to cytotoxic agents. Despite promising results from experimental studies, only a limited number of these compounds have been tested in clinical trials and have shown variable results. In this review, we summarize the data regarding select phytochemicals including curcumin, resveratrol, lycopene, folates and tea polyphenols with emphasis on the clinical evidence supporting the efficacy of these compounds in high-risk populations.

Contrast-Enhanced Sonography Depicts Spontaneous Ovarian Cancer at Early Stages in a Preclinical Animal Model

PubMed Central

Barua, Animesh; Bitterman, Pincas; Bahr, Janice M.; Basu, Sanjib; Sheiner, Eyal; Bradaric, Michael J.; Hales, Dale B.; Luborsky, Judith L.; Abramowicz, Jacques S.

2011-01-01

Objective Our goal was to examine the feasibility of using laying hens, a preclinical model of human spontaneous ovarian cancer, in determining the kinetics of an ultrasound contrast agent indicative of ovarian tumor-associated neoangiogenesis in early-stage ovarian cancer. Methods Three-year-old White Leghorn laying hens with decreased ovarian function were scanned before and after intravenous injection of a human serum albumin–perflutren contrast agent at a dose of 5 µL/kg body weight. Gray scale morphologic characteristics, Doppler indices, the arrival time, peak intensity, and wash-out of the contrast agent were recorded and archived on still images and video clips. Hens were euthanized thereafter; sonographic predictions were compared at gross examination; and ovarian tissues were collected. Archived clips were analyzed to determine contrast parameters and Doppler intensities of vessels. A time-intensity curve per hen was drawn, and the area under the curve was derived. Tumor types and the density of ovarian microvessels were determined by histologic examination and immunohistochemistry and compared to sonographic predictions. Results The contrast agent significantly (P < .05) enhanced the visualization of microvessels, which was confirmed by immunohistochemistry. Contrast parameters, including the time of wash-out and area under the curve, were significantly different (P < .05) between ovaries of normal hens and hens with ovarian cancer and correctly detected cancer at earlier stages than the time of peak intensity. Conclusions The laying hen may be a useful animal model for determining ovarian tumor-associated vascular kinetics diagnostic of early-stage ovarian cancer using a contrast agent. This model may also be useful for testing the efficacy of different contrast agents in a preclinical setting. PMID:21357555

Pediatric cardiovascular safety: challenges in drug and device development and clinical application.

PubMed

Bates, Katherine E; Vetter, Victoria L; Li, Jennifer S; Cummins, Susan; Aguel, Fernando; Almond, Christopher; Dubin, Anne M; Elia, Josephine; Finkle, John; Hausner, Elizabeth A; Joseph, Francesca; Karkowsky, Abraham M; Killeen, Matthew; Lemacks, Jodi; Mathis, Lisa; McMahon, Ann W; Pinnow, Ellen; Rodriguez, Ignacio; Stockbridge, Norman L; Stockwell, Margaret; Tassinari, Melissa; Krucoff, Mitchell W

2012-10-01

Development of pediatric medications and devices is complicated by differences in pediatric physiology and pathophysiology (both compared with adults and within the pediatric age range), small patient populations, and practical and ethical challenges to designing clinical trials. This article summarizes the discussions that occurred at a Cardiac Safety Research Consortium-sponsored Think Tank convened on December 10, 2010, where members from academia, industry, and regulatory agencies discussed important issues regarding pediatric cardiovascular safety of medications and cardiovascular devices. Pediatric drug and device development may use adult data but often requires additional preclinical and clinical testing to characterize effects on cardiac function and development. Challenges in preclinical trials include identifying appropriate animal models, clinically relevant efficacy end points, and methods to monitor cardiovascular safety. Pediatric clinical trials have different ethical concerns from adult trials, including consideration of the subjects' families. Clinical trial design in pediatrics should assess risks and benefits as well as incorporate input from families. Postmarketing surveillance, mandated by federal law, plays an important role in both drug and device safety assessment and becomes crucial in the pediatric population because of the limitations of premarketing pediatric studies. Solutions for this wide array of issues will require collaboration between academia, industry, and government as well as creativity in pediatric study design. Formation of various epidemiologic tools including registries to describe outcomes of pediatric cardiac disease and its treatment as well as cardiac effects of noncardiovascular medications, should inform preclinical and clinical development and improve benefit-risk assessments for the patients. The discussions in this article summarize areas of emerging consensus and other areas in which consensus remains elusive and provide suggestions for additional research to further our knowledge and understanding of this topic. Copyright © 2012 Mosby, Inc. All rights reserved.

Genetically engineered Newcastle disease virus expressing interleukin-2 and TNF-related apoptosis-inducing ligand for cancer therapy

USDA-ARS?s Scientific Manuscript database

Recombinant Newcastle disease virus (rNDV) has shown oncolytic therapeutic efficacy in preclinical studies and are currently in clinical trials. In this study, we have evaluated the possibility to enhance the cancer therapeutic potential of NDV by means of inserting both interleukin-2 (IL-2) and tu...

Audio-Visual Aid in Teaching "Fatty Liver"

ERIC Educational Resources Information Center

Dash, Sambit; Kamath, Ullas; Rao, Guruprasad; Prakash, Jay; Mishra, Snigdha

2016-01-01

Use of audio visual tools to aid in medical education is ever on a rise. Our study intends to find the efficacy of a video prepared on "fatty liver," a topic that is often a challenge for pre-clinical teachers, in enhancing cognitive processing and ultimately learning. We prepared a video presentation of 11:36 min, incorporating various…

DNA vaccination for prostate cancer, from preclinical to clinical trials - where we stand?

PubMed Central

2012-01-01

Development of various vaccines for prostate cancer (PCa) is becoming an active research area. PCa vaccines are perceived to have less toxicity compared with the available cytotoxic agents. While various immune-based strategies can elicit anti-tumour responses, DNA vaccines present increased efficacy, inducing both humoural and cellular immunity. This immune activation has been proven effective in animal models and initial clinical trials are encouraging. However, to validate the role of DNA vaccination in currently available PCa management paradigms, strong clinical evidence is still lacking. This article provides an overview of the basic principles of DNA vaccines and aims to provide a summary of preclinical and clinical trials outlining the benefits of this immunotherapy in the management of PCa. PMID:23046944

Safety and efficacy evaluation of gelatin-based nanoparticles associated with UV filters.

PubMed

Oliveira, Camila Areias de; Dario, Michelli Ferrera; Sarruf, Fernanda Daud; Mariz, Inês Fátima Afonso; Velasco, Maria Valéria Robles; Rosado, Catarina; Baby, André Rolim

2016-04-01

The safety and efficacy assessment of nanomaterials is a major concern of industry and academia. These materials, due to their nanoscale size, can have chemical, physical, and biological properties that differ from those of their larger counterparts. The encapsulation of natural ingredients can provide marked improvements in sun protection efficacy. This strategy promotes solubility enhancement of flavonoids and yields an improved active ingredient with innovative physical, physicochemical and functional characteristics. Rutin, a flavonoid, has chemical and functional stability in topical vehicles exerting a synergistic effect in association with ultraviolet (UV) filters. However, the solubility of rutin is a limiting factor. Additionally, this bioactive compound does not have tendency to permeate across the stratum corneum. As an alternative to common synthetic based sunscreens, rutin-entrapped gelatin nanoparticles were designed. The present study investigated the pre-clinical safety of gelatin nanoparticles (GNPs) using an in vitro method and also assessed the clinical safety and efficacy of the association of GNPs with three commonly used chemical UV filters (ethylhexyl dimethyl PABA, ethylhexyl methoxycinnamate and methoxydibenzoylmethane). The non-irritant and adequate safety profile under sun-exposed skin conditions of the nanomaterials and the emulsions qualified the products for clinical efficacy assays. The in vivo results indicated that the GNPs increased the antioxidant protection of the emulsions developed. However, the presence of rutin in the nanosized material did not enhance performance on the SPF test. In conclusion, these findings characterized the nanomaterials as an innovative platform for multifunctional bioactive sunscreens. Copyright © 2015 Elsevier B.V. All rights reserved.

rAAV-compatible MiniPromoters for restricted expression in the brain and eye.

PubMed

de Leeuw, Charles N; Korecki, Andrea J; Berry, Garrett E; Hickmott, Jack W; Lam, Siu Ling; Lengyell, Tess C; Bonaguro, Russell J; Borretta, Lisa J; Chopra, Vikramjit; Chou, Alice Y; D'Souza, Cletus A; Kaspieva, Olga; Laprise, Stéphanie; McInerny, Simone C; Portales-Casamar, Elodie; Swanson-Newman, Magdalena I; Wong, Kaelan; Yang, George S; Zhou, Michelle; Jones, Steven J M; Holt, Robert A; Asokan, Aravind; Goldowitz, Daniel; Wasserman, Wyeth W; Simpson, Elizabeth M

2016-05-10

Small promoters that recapitulate endogenous gene expression patterns are important for basic, preclinical, and now clinical research. Recently, there has been a promising revival of gene therapy for diseases with unmet therapeutic needs. To date, most gene therapies have used viral-based ubiquitous promoters-however, promoters that restrict expression to target cells will minimize off-target side effects, broaden the palette of deliverable therapeutics, and thereby improve safety and efficacy. Here, we take steps towards filling the need for such promoters by developing a high-throughput pipeline that goes from genome-based bioinformatic design to rapid testing in vivo. For much of this work, therapeutically interesting Pleiades MiniPromoters (MiniPs; ~4 kb human DNA regulatory elements), previously tested in knock-in mice, were "cut down" to ~2.5 kb and tested in recombinant adeno-associated virus (rAAV), the virus of choice for gene therapy of the central nervous system. To evaluate our methods, we generated 29 experimental rAAV2/9 viruses carrying 19 different MiniPs, which were injected intravenously into neonatal mice to allow broad unbiased distribution, and characterized in neural tissues by X-gal immunohistochemistry for icre, or immunofluorescent detection of GFP. The data showed that 16 of the 19 (84 %) MiniPs recapitulated the expression pattern of their design source. This included expression of: Ple67 in brain raphe nuclei; Ple155 in Purkinje cells of the cerebellum, and retinal bipolar ON cells; Ple261 in endothelial cells of brain blood vessels; and Ple264 in retinal Müller glia. Overall, the methodology and MiniPs presented here represent important advances for basic and preclinical research, and may enable a paradigm shift in gene therapy.

Long term assessment of blood pressure transducer drift in rhesus monkeys chronically instrumented with telemetry implants.

PubMed

Regan, Hillary K; Lynch, Joseph J; Regan, Christopher P

2009-01-01

The accurate assessment of blood pressure is often a key component of preclinical cardiovascular disease/efficacy models and of screening models used to determine the effects of test agents on cardiovascular physiology. Of the many methods utilized in large animals, telemetry is becoming more widely used throughout preclinical testing, and non-human primates are playing an ever increasing role as a large animal model to evaluate the cardiovascular effect of novel test agents. Therefore, we sought to characterize pressure transducer drift of a telemetry implant in primates over an extended duration. We instrumented ten rhesus monkeys with a Konigsberg T27F implant and a chronic indwelling arterial catheter and cross calibrated the diastolic pressure recorded by the implant to the diastolic pressure that was simultaneously recorded through the arterial catheter using a calibrated external transducer/amplifier system. While all implanted pressure transducers experienced drift to some degree, magnitude of drift varied across animals (range of average drift 0.7-20.5 mmHg/month). Specifically, we found that all implants could be calibrated within the voltage range of the instrument up to 6 months after implantation despite the drift observed. Between 6 and 12 months, 3 of the 10 implants studied drifted outside the defined voltage range and were unusable, two more drifted off scale within 2 years, while the remainder remained within the operating voltage range. Given that pressure transducer drift was not consistent across implants or time, these data suggest careful assessment and quantitative correction for in vivo drift of telemetry blood pressure transducers implanted for extended duration should be considered.

Olodaterol Attenuates Citric Acid-Induced Cough in Naïve and Ovalbumin-Sensitized and Challenged Guinea Pigs

PubMed Central

Wex, Eva; Bouyssou, Thierry

2015-01-01

Excessive coughing is a common feature of airway diseases. Different G-protein coupled receptors, including β2-adrenergic receptors (β2-AR), have been implicated in the molecular mechanisms underlying the cough reflex. However, the potential antitussive property of β2-AR agonists in patients with respiratory disease is a matter of ongoing debate. The aim of our study was to test the efficacy of the long-acting β2-AR agonist olodaterol with regard to its antitussive property in a pre-clinical model of citric acid-induced cough in guinea pigs and to compare the results to different clinically relevant β2-AR agonists. In our study β2-AR agonists were intratracheally administered, as dry powder, into the lungs of naïve or ovalbumin-sensitized guinea pigs 15 minutes prior to induction of cough by exposure to citric acid. Cough events were counted over 15 minutes during the citric acid exposure. Olodaterol dose-dependently inhibited the number of cough events in naïve and even more potently and with a greater maximal efficacy in ovalbumin-sensitized guinea pigs (p < 0.01). Formoterol and salmeterol showed a trend towards reducing cough. On the contrary, indacaterol demonstrated pro-tussive properties as it significantly increased the number of coughs, both in naïve and ovalbumin-sensitized animals (p < 0.001). In conclusion, olodaterol, at doses eliciting bronchodilation, showed antitussive properties in a model of citric acid-induced cough in naïve and ovalbumin-sensitized guinea pigs. This is in agreement with pre-clinical and clinical studies showing antitussive efficacy of β2-AR agonists. Indacaterol increased the number of coughs in this model, which concurs with clinical data where a transient cough has been observed after indacaterol inhalation. While the antitussive properties of β2-AR agonists can be explained by their ability to lead to the cAMP-induced hyperpolarization of the neuron membrane thereby inhibiting sensory nerve activation and the cough reflex, the mechanism underlying the pro-tussive property of indacaterol is not known. PMID:25781609

International variation in the prevalence of preclinical colorectal cancer: Implications for predictive values of noninvasive screening tests and potential target populations for screening

PubMed Central

Stock, Christian; Brenner, Hermann

2017-01-01

Screening for colorectal cancer (CRC) is implemented in an increasing number of countries. We aimed to assess international variation in the prevalence of preclinical CRC and the resulting variation in positive and negative predictive values (PPVs, NPVs) of existing and potential CRC screening tests in various countries. Using age‐ and sex‐specific CRC incidence data and transition rates from preclinical to clinical CRC we estimated overall and age‐ and sex‐specific prevalence of preclinical CRC in the target population aged 50–74 years in different parts of the world. These prevalence estimates were used to derive PPVs and NPVs for existing and potential noninvasive screening tests with varying levels of sensitivity and specificity. Within all regions and countries, prevalence strongly increases with age and is higher in men than in women. In addition, major variation was seen between regions and countries, with overall prevalence varying between 1 and 0.1%. As a result, PPVs are expected to strongly vary between ∼10% for men in high incidence countries, such as Australia and Germany, and 1% for women in low incidence countries, whereas NPVs are expected to be consistently well above 99%. Variation in CRC prevalence profoundly affects expected PPVs of screening tests, and PPVs should be carefully considered when decisions on screening tests and strategies are made for specific populations and health care systems. Here, we provide estimates of preclinical CRC and expected PPVs and NPVs of noninvasive screening tests, which may enhance the empirical basis for planning of population‐based CRC screening strategies. PMID:28670788

Discovery and clinical introduction of first-in-class imipridone ONC201.

PubMed

Allen, Joshua E; Kline, C Leah B; Prabhu, Varun V; Wagner, Jessica; Ishizawa, Jo; Madhukar, Neel; Lev, Avital; Baumeister, Marie; Zhou, Lanlan; Lulla, Amriti; Stogniew, Martin; Schalop, Lee; Benes, Cyril; Kaufman, Howard L; Pottorf, Richard S; Nallaganchu, B Rao; Olson, Gary L; Al-Mulla, Fahd; Duvic, Madeleine; Wu, Gen Sheng; Dicker, David T; Talekar, Mala K; Lim, Bora; Elemento, Olivier; Oster, Wolfgang; Bertino, Joseph; Flaherty, Keith; Wang, Michael L; Borthakur, Gautam; Andreeff, Michael; Stein, Mark; El-Deiry, Wafik S

2016-11-08

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.

Discovery and clinical introduction of first-in-class imipridone ONC201

PubMed Central

Allen, Joshua E.; Kline, C. Leah B.; Prabhu, Varun V.; Wagner, Jessica; Ishizawa, Jo; Madhukar, Neel; Lev, Avital; Baumeister, Marie; Zhou, Lanlan; Lulla, Amriti; Stogniew, Martin; Schalop, Lee; Benes, Cyril; Kaufman, Howard L.; Pottorf, Richard S.; Nallaganchu, B. Rao; Olson, Gary L.; Al-Mulla, Fahd; Duvic, Madeleine; Wu, Gen Sheng; Dicker, David T.; Talekar, Mala K.; Lim, Bora; Elemento, Olivier; Oster, Wolfgang; Bertino, Joseph; Flaherty, Keith; Wang, Michael L.; Borthakur, Gautam; Andreeff, Michael; Stein, Mark; El-Deiry, Wafik S.

2016-01-01

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials. PMID:27602582

Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications

PubMed Central

Li, Junjie; Oyen, Raymond; Verbruggen, Alfons; Ni, Yicheng

2013-01-01

Hitting the evasive tumor cells proves challenging in targeted cancer therapies. A general and unconventional anticancer approach namely small molecule sequential dual-targeting theragnostic strategy (SMSDTTS) has recently been introduced with the aims to target and debulk the tumor mass, wipe out the residual tumor cells, and meanwhile enable cancer detectability. This dual targeting approach works in two steps for systemic delivery of two naturally derived drugs. First, an anti-tubulin vascular disrupting agent, e.g., combretastatin A4 phosphate (CA4P), is injected to selectively cut off tumor blood supply and to cause massive necrosis, which nevertheless always leaves peripheral tumor residues. Secondly, a necrosis-avid radiopharmaceutical, namely 131I-hypericin (131I-Hyp), is administered the next day, which accumulates in intratumoral necrosis and irradiates the residual cancer cells with beta particles. Theoretically, this complementary targeted approach may biologically and radioactively ablate solid tumors and reduce the risk of local recurrence, remote metastases, and thus cancer mortality. Meanwhile, the emitted gamma rays facilitate radio-scintigraphy to detect tumors and follow up the therapy, hence a simultaneous theragnostic approach. SMSDTTS has now shown promise from multicenter animal experiments and may demonstrate unique anticancer efficacy in upcoming preliminary clinical trials. In this short review article, information about the two involved agents, the rationale of SMSDTTS, its preclinical antitumor efficacy, multifocal targetability, simultaneous theragnostic property, and toxicities of the dose regimens are summarized. Meanwhile, possible drawbacks, practical challenges and future improvement with SMSDTTS are discussed, which hopefully may help to push forward this strategy from preclinical experiments towards possible clinical applications. PMID:23412554

Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications.

PubMed

Li, Junjie; Oyen, Raymond; Verbruggen, Alfons; Ni, Yicheng

2013-01-01

Hitting the evasive tumor cells proves challenging in targeted cancer therapies. A general and unconventional anticancer approach namely small molecule sequential dual-targeting theragnostic strategy (SMSDTTS) has recently been introduced with the aims to target and debulk the tumor mass, wipe out the residual tumor cells, and meanwhile enable cancer detectability. This dual targeting approach works in two steps for systemic delivery of two naturally derived drugs. First, an anti-tubulin vascular disrupting agent, e.g., combretastatin A4 phosphate (CA4P), is injected to selectively cut off tumor blood supply and to cause massive necrosis, which nevertheless always leaves peripheral tumor residues. Secondly, a necrosis-avid radiopharmaceutical, namely (131)I-hypericin ((131)I-Hyp), is administered the next day, which accumulates in intratumoral necrosis and irradiates the residual cancer cells with beta particles. Theoretically, this complementary targeted approach may biologically and radioactively ablate solid tumors and reduce the risk of local recurrence, remote metastases, and thus cancer mortality. Meanwhile, the emitted gamma rays facilitate radio-scintigraphy to detect tumors and follow up the therapy, hence a simultaneous theragnostic approach. SMSDTTS has now shown promise from multicenter animal experiments and may demonstrate unique anticancer efficacy in upcoming preliminary clinical trials. In this short review article, information about the two involved agents, the rationale of SMSDTTS, its preclinical antitumor efficacy, multifocal targetability, simultaneous theragnostic property, and toxicities of the dose regimens are summarized. Meanwhile, possible drawbacks, practical challenges and future improvement with SMSDTTS are discussed, which hopefully may help to push forward this strategy from preclinical experiments towards possible clinical applications.

Human tumor xenografts in mouse as a model for evaluating therapeutic efficacy of monoclonal antibodies or antibody-drug conjugate targeting receptor tyrosine kinases.

PubMed

Feng, Liang; Wang, Wei; Yao, Hang-Ping; Zhou, Jianwei; Zhang, Ruiwen; Wang, Ming-Hai

2015-01-01

Targeting receptor tyrosine kinases by therapeutic monoclonal antibodies and antibody-drug conjugates has met with tremendous success in clinical oncology. Currently, numerous therapeutic monoclonal antibodies are under preclinical development. The potential for moving candidate antibodies into clinical trials relies heavily on therapeutic efficacy validated by human tumor xenografts in mice. Here we describe methods used to determine therapeutic efficacy of monoclonal antibodies or antibody-drug conjugates specific to human receptor tyrosine kinase using human tumor xenografts in mice as the model. The end point of the study is to determine whether treatment of tumor-bearing mice with a monoclonal antibody or antibody-drug conjugates results in significant delay of tumor growth.

Development of a Hampton University Program for Novel Breast Cancer Imaging and Therapy Research

DTIC Science & Technology

2013-04-01

intracavitary brachytherapy procedures during laboratory pre-clinical imaging and dosimetry equipment testing, calibration and data processing, in collaboration... electronics and detector instrumentation development; 4) breast phantom construction and implantation; 5) laboratory pre-clinical device testing...such as the ionization chamber, diode, radiographic verification 6 films and thermoluminescent dosimeters ( TLD ) but the scintillator fiber detectors

Preclinical safety testing for cell-based products using animals.

PubMed

McBlane, James W

2015-09-01

The objectives of preclinical testing include to show why there might be therapeutic benefit in patients and to provide information on the product's toxicity. For cell-based products, given even once, there may be long term exposure and this could imply, unlike for conventional drugs, that all preclinical studies may be needed prior to first human use. The duration of exposure to cells should be studied in animals to guide toxicity assessments. Distribution of cells after administration by a route resembling that intended in humans should be studied to understand potential risks. Risk of tumour formation with the product may also need to be characterised. To the extent that this information can be generated by in vitro testing, studies in animals may not be needed and limitations on the capability of preclinical data to predict human toxicity are recognised: species-specificity make some cell products act only in humans and a human cell-product might be expected to be rejected by immunocompetent animals. Does this suggest testing in immunosuppressed animals or of development of an animal-cell product supposedly similar to the human cell product? No single answer seems to fit every situation. Copyright © 2015.

New viruses for cancer therapy: meeting clinical needs

PubMed Central

Miest, Tanner S.; Cattaneo, Roberto

2014-01-01

Early-stage clinical trials of oncolytic virotherapy have reported the safety of several virus platforms, and viruses from three families have progressed to advanced efficacy trials. In addition, preclinical studies have established proof-of-principle for many new genetic engineering strategies. Thus, the virotherapy field now has available a diverse collection of viruses that are equipped to address unmet clinical needs owing to improved systemic administration, greater tumour specificity and enhanced oncolytic efficacy. The current key challenge for the field is to develop viruses that replicate with greater efficiency within tumours while achieving therapeutic synergy with currently available treatments. PMID:24292552

Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling

PubMed Central

Le Bihan, Amélie; Angulo-Barturen, Iñigo; Binkert, Christoph; Boss, Christoph; Brun, Reto; Brunner, Ralf; Buchmann, Stephan; Dechering, Koen J.; Delves, Michael; Ewerling, Sonja; Ferrer, Santiago; Fischli, Christoph; Gamo–Benito, Francisco Javier; Heidmann, Bibia; Jiménez-Díaz, María Belén; Leroy, Didier; Martínez, Maria Santos; Meyer, Solange; Moehrle, Joerg J.; Noviyanti, Rintis; Sanz, Laura María; Sauerwein, Robert W.; Scheurer, Christian; Schleiferboeck, Sarah; Sinden, Robert; Snyder, Christopher; Straimer, Judith; Wirjanata, Grennady; Marfurt, Jutta; Weller, Thomas; Clozel, Martine; Wittlin, Sergio

2016-01-01

Background Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. Method and Findings The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3–4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11–16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23–39). The compound’s preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose–efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. Conclusion The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study. PMID:27701420

Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

PubMed

Le Bihan, Amélie; de Kanter, Ruben; Angulo-Barturen, Iñigo; Binkert, Christoph; Boss, Christoph; Brun, Reto; Brunner, Ralf; Buchmann, Stephan; Burrows, Jeremy; Dechering, Koen J; Delves, Michael; Ewerling, Sonja; Ferrer, Santiago; Fischli, Christoph; Gamo-Benito, Francisco Javier; Gnädig, Nina F; Heidmann, Bibia; Jiménez-Díaz, María Belén; Leroy, Didier; Martínez, Maria Santos; Meyer, Solange; Moehrle, Joerg J; Ng, Caroline L; Noviyanti, Rintis; Ruecker, Andrea; Sanz, Laura María; Sauerwein, Robert W; Scheurer, Christian; Schleiferboeck, Sarah; Sinden, Robert; Snyder, Christopher; Straimer, Judith; Wirjanata, Grennady; Marfurt, Jutta; Price, Ric N; Weller, Thomas; Fischli, Walter; Fidock, David A; Clozel, Martine; Wittlin, Sergio

2016-10-01

Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study.

Proteomic Data Resources for EDRN Ovary Cancer Researchers within the EDRN — EDRN Public Portal

Cancer.gov

This project will generate a highly valuable data resource and make it available to all EDRN ovarian cancer researchers. The resource will include comprehensive proteomic (tandem mass spectrometry, MS/MS) data generated from plasma samples that have been collected between four months and four years prior to clinical detection of ovarian cancer. These pre-clinical samples, provided from the Beta Carotene and Retinol Efficacy Trial (CARET) prospective study, will be interrogated using IPAS, the proteomic profiling method developed by the Hanash Laboratory and with the quantitative methods developed by the McIntosh laboratory. In addition, we will combine these pre-clinical data with already completed IPAS interrogations of plasma collected at the time of ovarian cancer diagnosis. Thus together we will provide information on both pre-clinical and clinical behavior of a large number of proteins. Based on our preliminary work we are able to quantify over 500 plasma proteins in each of these experiments, many of which are putative ovarian cancer biomarkers, showing the platform is capable of providing useful information regarding biomarker candidates.

ESC Working Group Cellular Biology of the Heart: Position Paper: improving the preclinical assessment of novel cardioprotective therapies

PubMed Central

Lecour, Sandrine; Bøtker, Hans E.; Condorelli, Gianluigi; Davidson, Sean M.; Garcia-Dorado, David; Engel, Felix B.; Ferdinandy, Peter; Heusch, Gerd; Madonna, Rosalinda; Ovize, Michel; Ruiz-Meana, Marisol; Schulz, Rainer; Sluijter, Joost P.G.; Van Laake, Linda W.; Yellon, Derek M.; Hausenloy, Derek J.

2014-01-01

Ischaemic heart disease (IHD) remains the leading cause of death and disability worldwide. As a result, novel therapies are still needed to protect the heart from the detrimental effects of acute ischaemia–reperfusion injury, in order to improve clinical outcomes in IHD patients. In this regard, although a large number of novel cardioprotective therapies discovered in the research laboratory have been investigated in the clinical setting, only a few of these have been demonstrated to improve clinical outcomes. One potential reason for this lack of success may have been the failure to thoroughly assess the cardioprotective efficacy of these novel therapies in suitably designed preclinical experimental animal models. Therefore, the aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to provide recommendations for improving the preclinical assessment of novel cardioprotective therapies discovered in the research laboratory, with the aim of increasing the likelihood of success in translating these new treatments into improved clinical outcomes. PMID:25344369

Physiological remodeling of bifurcation aneurysms: preclinical results of the eCLIPs device.

PubMed

Marotta, Thomas R; Riina, Howard A; McDougall, Ian; Ricci, Donald R; Killer-Oberpfalzer, Monika

2018-02-01

OBJECTIVE Intracranial bifurcation aneurysms are complex lesions for which current therapy, including simple coiling, balloon- or stent-assisted coiling, coil retention, or intrasaccular devices, is inadequate. Thromboembolic complications due to a large burden of intraluminal metal, impedance of access to side branches, and a high recurrence rate, due largely to the unmitigated high-pressure flow into the aneurysm (water hammer effect), are among the limitations imposed by current therapy. The authors describe herein a novel device, eCLIPs, and its use in a preclinical laboratory study that suggests the device's design and functional features may overcome many of these limitations. METHODS A preclinical model of wide-necked bifurcation aneurysms in rabbits was used to assess functional features and efficacy of aneurysm occlusion by the eCLIPs device. RESULTS The eCLIPs device, in bridging the aneurysm neck, allows coil retention, disrupts flow away from the aneurysm, leaves the main vessel and side branches unencumbered by intraluminal metal, and serves as a platform for endothelial growth across the neck, excluding the aneurysm from the circulation. CONCLUSIONS The eCLIPs device permits physiological remodeling of the bifurcation.

Partnering with Big Pharma-What Academics Need to Know.

PubMed

Lipton, Stuart A; Nordstedt, Christer

2016-04-21

Knowledge of the parameters of drug development can greatly aid academic scientists hoping to partner with pharmaceutical companies. Here, we discuss the three major pillars of drug development-pharmacodynamics, pharmacokinetics, and toxicity studies-which, in addition to pre-clinical efficacy, are critical for partnering with Big Pharma to produce novel therapeutics. Copyright © 2016 Elsevier Inc. All rights reserved.

The long road of biopharmaceutical drug development: from inception to marketing.

PubMed

Mundae, M K; Ostör, A J K

2010-01-01

The development of therapeutics is costly, time-consuming and has high attrition rates. Biopharmaceutical medications differ from traditional agents in their discovery, design, structure and formulation. Prior to marketing a drug must show efficacy and acceptable toxicity in both preclinical and clinical trials. Regulatory bodies have a pivotal role in the licensing, naming and marketing of an agent.

PREVENT Cancer Preclinical Drug Development Program (PREVENT) | Division of Cancer Prevention

Cancer.gov

The PREVENT program provides a structure for the introduction of new agents, drugs and vaccines to inhibit, retard or reverse the cancer process. The program was designed to optimize translational opportunities from discovery to the clinic, and provide a mechanism to identify and study efficacy and pharmacodynamics biomarkers that will help in phase II trials to evaluate drug

Efficacy of Pimobendan in the Prevention of Congestive Heart Failure or Sudden Death in Doberman Pinschers with Preclinical Dilated Cardiomyopathy (The PROTECT Study)

PubMed Central

Summerfield, NJ; Boswood, A; O'Grady, MR; Gordon, SG; Dukes-McEwan, J; Oyama, MA; Smith, S; Patteson, M; French, AT; Culshaw, GJ; Braz-Ruivo, L; Estrada, A; O'Sullivan, ML; Loureiro, J; Willis, R; Watson, P

2012-01-01

Background The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported. Hypothesis That chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival. Animals Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America. Methods The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin capsules) or visually identical placebo. The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint. Results The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = .1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441–1152 days) versus the placebo group (441 days, IQR 151–641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491–1531 days) versus the placebo group (466 days, IQR 236–710 days) (log-rank P = .034). Conclusion and Clinical Importance The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome. PMID:23078651

Ensuring transparency and minimization of methodologic bias in preclinical pain research: PPRECISE considerations

PubMed Central

Andrews, Nick A.; Latrémolière, Alban; Basbaum, Allan I.; Mogil, Jeffrey S.; Porreca, Frank; Rice, Andrew S.C.; Woolf, Clifford J.; Currie, Gillian L.; Dworkin, Robert H.; Eisenach, James C.; Evans, Scott; Gewandter, Jennifer S.; Gover, Tony D.; Handwerker, Hermann; Huang, Wenlong; Iyengar, Smriti; Jensen, Mark P.; Kennedy, Jeffrey D.; Lee, Nancy; Levine, Jon; Lidster, Katie; Machin, Ian; McDermott, Michael P.; McMahon, Stephen B.; Price, Theodore J.; Ross, Sarah E.; Scherrer, Grégory; Seal, Rebecca P.; Sena, Emily S.; Silva, Elizabeth; Stone, Laura; Svensson, Camilla I.; Turk, Dennis C.; Whiteside, Garth

2015-01-01

Abstract There is growing concern about lack of scientific rigor and transparent reporting across many preclinical fields of biological research. Poor experimental design and lack of transparent reporting can result in conscious or unconscious experimental bias, producing results that are not replicable. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public–private partnership with the U.S. Food and Drug Administration sponsored a consensus meeting of the Preclinical Pain Research Consortium for Investigating Safety and Efficacy (PPRECISE) Working Group. International participants from universities, funding agencies, government agencies, industry, and a patient advocacy organization attended. Reduction of publication bias, increasing the ability of others to faithfully repeat experimental methods, and increased transparency of data reporting were specifically discussed. Parameters deemed essential to increase confidence in the published literature were clear, specific reporting of an a priori hypothesis and definition of primary outcome measure. Power calculations and whether measurement of minimal meaningful effect size to determine these should be a core component of the preclinical research effort provoked considerable discussion, with many but not all agreeing. Greater transparency of reporting should be driven by scientists, journal editors, reviewers, and grant funders. The conduct of high-quality science that is fully reported should not preclude novelty and innovation in preclinical pain research, and indeed, any efforts that curtail such innovation would be misguided. We believe that to achieve the goal of finding effective new treatments for patients with pain, the pain field needs to deal with these challenging issues. PMID:26683237

Frugal Chemoprevention: Targeting Nrf2 with Foods Rich in Sulforaphane

PubMed Central

Yang, Li; Palliyaguru, Dushani L.; Kensler, Thomas W.

2015-01-01

With the properties of efficacy, safety, tolerability, practicability and low cost, foods containing bioactive phytochemicals are gaining significant attention as elements of chemoprevention strategies against cancer. Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane], a naturally occurring isothiocyanate produced by cruciferous vegetables such as broccoli, is found to be a highly promising chemoprevention agent against not only variety of cancers such as breast, prostate, colon, skin, lung, stomach or bladder carcinogenesis, but also cardiovascular disease, neurodegenerative diseases, and diabetes. For reasons of experimental exigency, pre-clinical studies have focused principally on sulforaphane itself, while clinical studies have relied on broccoli sprout preparations rich in either sulforaphane or its biogenic precursor, glucoraphanin. Substantive subsequent evaluation of sulforaphane pharmacokinetics and pharmacodynamics has been undertaken using either pure compound or food matrices. Sulforaphane affects multiple targets in cells. One key molecular mechanism of action for sulforaphane entails activation of the Nrf2- Keap1 signaling pathway although other actions contribute to the broad spectrum of efficacy in different animal models. This review summarizes the current status of pre-clinical chemoprevention studies with sulforaphane and highlights the progress and challenges for the application of foods rich in sulforaphane and/or glucoraphanin in the arena of clinical chemoprevention. PMID:26970133

Drug screening in 3D in vitro tumor models: overcoming current pitfalls of efficacy read-outs.

PubMed

Santo, Vítor E; Rebelo, Sofia P; Estrada, Marta F; Alves, Paula M; Boghaert, Erwin; Brito, Catarina

2017-01-01

There is cumulating evidence that in vitro 3D tumor models with increased physiological relevance can improve the predictive value of pre-clinical research and ultimately contribute to achieve decisions earlier during the development of cancer-targeted therapies. Due to the role of tumor microenvironment in the response of tumor cells to therapeutics, the incorporation of different elements of the tumor niche on cell model design is expected to contribute to the establishment of more predictive in vitro tumor models. This review is focused on the several challenges and adjustments that the field of oncology research is facing to translate these advanced tumor cells models to drug discovery, taking advantage of the progress on culture technologies, imaging platforms, high throughput and automated systems. The choice of 3D cell model, the experimental design, choice of read-outs and interpretation of data obtained from 3D cell models are critical aspects when considering their implementation in drug discovery. In this review, we foresee some of these aspects and depict the potential directions of pre-clinical oncology drug discovery towards improved prediction of drug efficacy. Copyright © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Allogeneic mesenchymal precursor cells (MPCs): an innovative approach to treating advanced heart failure.

PubMed

Westerdahl, Daniel E; Chang, David H; Hamilton, Michele A; Nakamura, Mamoo; Henry, Timothy D

2016-09-01

Over 37 million people worldwide are living with Heart Failure (HF). Advancements in medical therapy have improved mortality primarily by slowing the progression of left ventricular dysfunction and debilitating symptoms. Ultimately, heart transplantation, durable mechanical circulatory support (MCS), or palliative care are the only options for patients with end-stage HF. Regenerative therapies offer an innovative approach, focused on reversing myocardial dysfunction and restoring healthy myocardial tissue. Initial clinical trials using autologous (self-donated) bone marrow mononuclear cells (BMMCs) demonstrated excellent safety, but only modest efficacy. Challenges with autologous stem cells include reduced quality and efficacy with increased patient age. The use of allogeneic mesenchymal precursor cells (MPCs) offers an "off the shelf" therapy, with consistent potency and less variability than autologous cells. Preclinical and initial clinical trials with allogeneic MPCs have been encouraging, providing the support for a large ongoing Phase III trial-DREAM-HF. We provide a comprehensive review of preclinical and clinical data supporting MPCs as a therapeutic option for HF patients. The current data suggest allogeneic MPCs are a promising therapy for HF patients. The results of DREAM-HF will determine whether allogeneic MPCs can decrease major adverse clinical events (MACE) in advanced HF patients.

Therapeutic potential of TDT 067 (terbinafine in Transfersome): a carrier-based dosage form of terbinafine for onychomycosis.

PubMed

Sigurgeirsson, Bárdur; Ghannoum, Mahmoud

2012-10-01

Current topical treatments for onychomycosis are unsatisfactory. New topical agents that offer efficacy without the potential adverse effects of oral antifungal therapy would benefit patients with this condition and encourage a greater treatment rate. Currently available topical therapies are reviewed, and new approaches for enhancing delivery of the established antifungal terbinafine through the nail are summarized. We focus on the use of ultra-deformable lipid vesicles to facilitate delivery of terbinafine to the nail and surrounding tissue. TDT 067 (terbinafine in Transfersome) is the only such therapy in development for onychomycosis, and we review published preclinical and clinical studies on this formulation. TDT 067 offers the use of new technology to deliver an established antifungal, terbinafine. Preclinical data suggest that the Transfersome accelerates entry of terbinafine released from TDT 067 into fungi and potentiates its antifungal effects, resulting in enhanced activity, compared with conventional terbinafine. This translated into high rates of mycological cure and evidence of clinical effect in a study of TDT 067 administered twice daily for 12 weeks in patients with onychomycosis. An ongoing Phase-III trial involving more than 700 patients treated for 48 weeks is investigating the efficacy and safety of TDT 067.

Update on the use of defibrotide.

PubMed

Guglielmelli, Tommasina; Bringhen, Sara; Palumbo, Antonio

2012-03-01

Defibrotide is a polydisperse oligonucleotide obtained from porcine intestinal mucosa and prepared by controlled depolymerization of DNA. It is a nucleic acid polymer, predominantly single-stranded, which has anti-ischemic and anti-thrombotic properties. The efficacy and safety of defibrotide in the treatment of veno-occlusive disease (VOD) occurring after high-dose chemotherapy and hematopoietic stem-cell transplantation is now well established in Phase II - III trials. A recent randomized, Phase III trial in pediatric patients has also demonstrated its role in the prevention of VOD. Preclinical studies reported the inhibitory effects of defibrotide on myeloma cells' growth through an antiangiogenic action and a regulation of the tumor-microenvironment interactions. A recent Phase II trial underlines the efficacy and safety of defibrotide-thalidomide-melphalan combination in the treatment of relapsed/refractory multiple myeloma. Defibrotide may be effective in the prophylaxis and the treatment of veno-occlusive disease. Recent experimental results suggest that defibrotide may belong to the new generation of anti-cancer drugs that can prevent tumor angiogenesis. In multiple myeloma, defibrotide may overcome the prothrombotic effect of thalidomide on endothelial cells. Further preclinical and clinical investigations are needed to assess the precise role of defibrotide in the treatment of patients with multiple myeloma.

Rationale for nebivolol/valsartan combination for hypertension: review of preclinical and clinical data

PubMed Central

Giles, Thomas D.; Cockcroft, John R.; Pitt, Bertram; Jakate, Abhijeet; Wright, Harold M.

2017-01-01

To treat hypertension, combining two or more antihypertensive drugs from different classes is often necessary. β-Blockers and renin–angiotensin–aldosterone system inhibitors, when combined, have been deemed ‘less effective’ based on partially overlapping mechanisms of action and limited evidence. Recently, the single-pill combination (SPC) of nebivolol (Neb) 5 mg – a vasodilatory β1-selective antagonist/β3 agonist – and valsartan 80 mg, an angiotensin II receptor blocker, was US Food and Drug Administration-approved for hypertension. Pharmacological profiles of Neb and valsartan, alone and combined, are well characterized. In addition, a large 8-week randomized trial in stages I–II hypertensive patients (N = 4161) demonstrated greater blood pressure-reducing efficacy for Neb/valsartan SPCs than component monotherapies with comparable tolerability. In a biomarkers substudy (N = 805), Neb/valsartan SPCs prevented valsartan-induced increases in plasma renin, and a greater reduction in plasma aldosterone was observed with the highest SPC dose vs. valsartan 320 mg/day. This review summarizes preclinical and clinical evidence supporting Neb/valsartan as an efficacious and well tolerated combination treatment for hypertension. PMID:28509722

Enhancement of the efficacy of therapeutic proteins by formulation with PEGylated liposomes; a case of FVIII, FVIIa and G-CSF.

PubMed

Yatuv, Rivka; Robinson, Micah; Dayan, Inbal; Baru, Moshe

2010-02-01

Improving the pharmacodynamics of protein drugs has the potential to improve the care and the quality of life of patients suffering from a variety of diseases. Four approaches to improve protein drugs are described: PEGylation, amino acid substitution, fusion to carrier proteins and encapsulation. A new platform technology based on the binding of proteins/peptides to the outer surface of PEGylated liposomes (PEGLip) is then presented. Binding of proteins to PEGLip is non-covalent, highly specific and dependent on an amino acid consensus sequence within the proteins. Association of proteins with PEGLip results in substantial enhancement of the pharmacodynamic properties of proteins following administration. This has been demonstrated in preclinical studies and clinical trials with coagulation factors VIII and VIIa. It has also been demonstrated in preclinical studies with granulocyte colony-stimulating factor. A mechanism is presented that explains the improvements in hemostatic efficacy of PEGLip-formulated coagulation factors VIII and VIIa. The reader will gain an understanding of the advantages and disadvantages of each of the approaches discussed. PEGLip formulation is an important new approach to improve the pharmacodynamics of protein drugs. This approach may be applied to further therapeutic proteins in the future.

Neuromotor tolerability and behavioural characterisation of cannabidiolic acid, a phytocannabinoid with therapeutic potential for anticipatory nausea.

PubMed

Brierley, Daniel I; Samuels, James; Duncan, Marnie; Whalley, Benjamin J; Williams, Claire M

2016-01-01

Anticipatory nausea (AN) is a poorly controlled side effect experienced by chemotherapy patients. Currently, pharmacotherapy is restricted to benzodiazepine anxiolytics, which have limited efficacy, have significant sedative effects and induce dependency. The non-psychoactive phytocannabinoid, cannabidiolic acid (CBDA), has shown considerable efficacy in pre-clinical AN models, however determination of its neuromotor tolerability profile is crucial to justify clinical investigation. Provisional evidence for appetite-stimulating properties also requires detailed investigation. This study aims to assess the tolerability of CBDA in locomotor activity, motor coordination and muscular strength tests, and additionally for ability to modulate feeding behaviours. Male Lister Hooded rats administered CBDA (0.05-5 mg/kg; p.o.) were assessed in habituated open field (for locomotor activity), static beam and grip strength tests. A further study investigated whether these CBDA doses modulated normal feeding behaviour. Finally, evidence of anxiolytic-like effects in the habituated open field prompted testing of 5 mg/kg CBDA for anxiolytic-like activity in unhabituated open field, light/dark box and novelty-suppressed feeding (NSF) tests. CBDA had no adverse effects upon performance in any neuromotor tolerability test, however anxiolytic-like behaviour was observed in the habituated open field. Normal feeding behaviours were unaffected by any dose. CBDA (5 mg/kg) abolished the increased feeding latency in the NSF test induced by the 5-HT1AR antagonist, WAY-100,635, indicative of anxiolytic-like effects, but had no effect on anxiety-like behaviour in the novel open field or light/dark box. CBDA is very well tolerated and devoid of the sedative side effect profile of benzodiazepines, justifying its clinical investigation as a novel AN treatment.

A reproducible method for the isolation and expansion of ovine mesenchymal stromal cells from bone marrow for use in regenerative medicine preclinical studies.

PubMed

Caminal, Marta; Vélez, Roberto; Rabanal, Rosa Maria; Vivas, Daniel; Batlle-Morera, Laura; Aguirre, Màrius; Barquinero, Jordi; García, Joan; Vives, Joaquim

2017-12-01

The use of multipotent mesenchymal stromal cells (MSCs) as candidate medicines for treating a variety of pathologies is based on their qualities as either progenitors for the regeneration of damaged tissue or producers of a number of molecules with pharmacological properties. Preclinical product development programmes include the use of well characterized cell populations for proof of efficacy and safety studies before testing in humans. In the field of orthopaedics, an increasing number of translational studies use sheep as an in vivo test system because of the similarities with humans in size and musculoskeletal architecture. However, robust and reproducible methods for the isolation, expansion, manipulation and characterization of ovine MSCs have not yet been standardised. The present study describes a method for isolation and expansion of fibroblastic-like, adherent ovine MSCs that express CD44, CD90, CD140a, CD105 and CD166, and display trilineage differentiation potential. The 3-week bioprocess proposed here typically yielded cell densities of 1.4 × 10 4 MSCs/cm 2 at passage 2, with an expansion factor of 37.8 and approximately eight cumulative population doublings. The osteogenic potential of MSCs derived following this methodology was further evaluated in vivo in a translational model of osteonecrosis of the femoral head, in which the persistence of grafted cells in the host tissue and their lineage commitment into osteoblasts and osteocytes was demonstrated by tracking enhanced green fluorescent protein-labelled cells. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Factors influencing preclinical in vivo evaluation of mumps vaccine strain immunogenicity

PubMed Central

Halassy, B; Kurtović, T; Brgles, M; Lang Balija, M; Forčić, D

2015-01-01

Immunogenicity testing in animals is a necessary preclinical assay for demonstration of vaccine efficacy the results of which are often the basis for the decision whether to proceed or withdraw the further development of the novel vaccine candidate. However, in vivo assays are rarely, if at all, optimized and validated. Here we clearly demonstrate the importance of in vivo assay (mumps virus immunogenicity testing in guinea pigs) optimization for gaining reliable results and the suitability of Fractional factorial design of experiments (DoE) for such a purpose. By the use of DoE with resolution IV (2IV(4-1)) we clearly revealed that the parameters significantly increasing assay sensitivity were interval between animal immunizations followed by the body weight of experimental animals. The quantity (0 versus 2%) of the stabilizer (fetal bovine serum, FBS) in the sample was shown as non-influencing parameter in DoE setup. However, the separate experiment investigating only the FBS influence, and performed under other parameters optimally set, showed that FBS also influences the results of immunogenicity assay. Such finding indicated that (a) factors with strong influence on the measured outcome can hide the effects of parameters with modest/low influence and (b) the matrix of mumps virus samples to be compared for immunogenicity must be identical for reliable virus immunogenicity comparison. Finally the 3 mumps vaccine strains widely used for decades in the licensed vaccines were for the first time compared in an animal model, and results obtained were in line with their reported immunogenicity in human population supporting the predictive power of the optimized in vivo assay. PMID:26376015

Factors influencing preclinical in vivo evaluation of mumps vaccine strain immunogenicity.

PubMed

Halassy, B; Kurtović, T; Brgles, M; Lang Balija, M; Forčić, D

2015-01-01

Immunogenicity testing in animals is a necessary preclinical assay for demonstration of vaccine efficacy the results of which are often the basis for the decision whether to proceed or withdraw the further development of the novel vaccine candidate. However, in vivo assays are rarely, if at all, optimized and validated. Here we clearly demonstrate the importance of in vivo assay (mumps virus immunogenicity testing in guinea pigs) optimization for gaining reliable results and the suitability of Fractional factorial design of experiments (DoE) for such a purpose. By the use of DoE with resolution IV (2IV((4-1))) we clearly revealed that the parameters significantly increasing assay sensitivity were interval between animal immunizations followed by the body weight of experimental animals. The quantity (0 versus 2%) of the stabilizer (fetal bovine serum, FBS) in the sample was shown as non-influencing parameter in DoE setup. However, the separate experiment investigating only the FBS influence, and performed under other parameters optimally set, showed that FBS also influences the results of immunogenicity assay. Such finding indicated that (a) factors with strong influence on the measured outcome can hide the effects of parameters with modest/low influence and (b) the matrix of mumps virus samples to be compared for immunogenicity must be identical for reliable virus immunogenicity comparison. Finally the 3 mumps vaccine strains widely used for decades in the licensed vaccines were for the first time compared in an animal model, and results obtained were in line with their reported immunogenicity in human population supporting the predictive power of the optimized in vivo assay.

Extraluminal biodegradable splint to treat upper airway anterior malacia: A preclinical proof of principle.

PubMed

Gorostidi, François; Courbon, Cécile; Burki, Marco; Reinhard, Antoine; Sandu, Kishore

2018-02-01

Upper airway malacia highly complicates the treatment of benign laryngotracheal stenosis, and no ideal option is available to date. We here explore the use of extraluminal biodegradable splints in an animal model of long-segment anterior tracheomalacia (TM). We show the efficacy, as well as the tissue tolerance, of a custom-made biodegradable extraluminal device surgically inserted around the trachea. Preclinical animal study. Anterior TM was induced in rabbits through an anterior neck approach by removing eight consecutive anterior tracheal rings without damaging the underlying mucosa. Malacia was corrected during the same surgery by pexy sutures, suspending the tracheal mucosa to an experimental biodegradable device. Symptoms, survival, and tissue reaction were compared to healthy and sham surgery controls. The model induced death by respiratory failure within minutes. Ten animals received the experimental treatment, and those who survived the perioperative period remained asymptomatic with a maximum follow-up of 221 days. Histological studies at programmed euthanasia showed complete degradation of the prosthesis, with significant remnant fibrosis around the trachea. However, the tracheal stiffness of test segments was comparatively less than that of control segments. Extraluminal biodegradable splints rescued animals with a condition otherwise incompatible with life. It was well tolerated, leaving peritracheal fibrosis that was not as stiff as normal trachea. The external tracheal stiffening was sufficient for the test animals to live through the phase of severe acute hypercollapsibility. This represents a valid option to help pediatric patients with laryngotracheal stenosis and associated cartilaginous airway malacia. NA. Laryngoscope, 128:E53-E58, 2018. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

Therapeutic Applications of PARP Inhibitors: Anticancer Therapy and Beyond

PubMed Central

Curtin, Nicola; Szabo, Csaba

2013-01-01

The aim of this article is to describe the current and potential clinical translation of pharmacological inhibitors of poly(ADP-ribose) polymerase (PARP) for the therapy of various diseases. The first section of the present review summarizes the available preclinical and clinical data with PARP inhibitors in various forms of cancer. In this context, the role of PARP in single-strand DNA break repair is relevant, leading to replication-associated lesions that cannot be repaired if homologous recombination (HRR) repair is defective, and the synthetic lethality of PARP inhibitors in HRR-defective cancer. HRR defects are classically associated with BRCA1 and 2 mutations associated with familial breast and ovarian cancer, but there may be many other causes of HRR defects. Thus, PARP inhibitors may be the drugs of choice for BRCA mutant breast and ovarian cancers, and extend beyond these tumors if appropriate biomarkers can be developed to identify HRR defects. Multiple lines of preclinical data demonstrate that PARP inhibition increases cytotoxicity and tumor growth delay in combination with temozolomide, topoisomerase inhibitors and ionizing radiation. Both single agent and combination clinical trials are underway. The final part of the first section of the present review summarizes the current status of the various PARP inhibitors that are in various stages of clinical development. The second section of the present review summarizes the role of PARP in selected non-oncologic indications. In a number of severe, acute diseases (such as stroke, neurotrauma, circulatory shock and acute myocardial infarction) the clinical translatability of PARP inhibition is supported by multiple lines of preclinical data, as well as observational data demonstrating PARP activation in human tissue samples. In these disease indications, PARP overactivation due to oxidative and nitrative stress drives cell necrosis and pro-inflammatory gene expression, which contributes to disease pathology. Accordingly, multiple lines of preclinical data indicate the efficacy of PARP inhibitors to preserve viable tissue and to down-regulate inflammatory responses. As the clinical trials with PARP inhibitors in various forms of cancer progress, it is hoped that a second line of clinical investigations, aimed at testing of PARP inhibitors for various non-oncologic indications, will be initiated, as well. PMID:23370117

Preclinical characterization of three transient receptor potential vanilloid receptor 1 antagonists for early use in human intradermal microdose analgesic studies.

PubMed

Sjögren, E; Halldin, M M; Stålberg, O; Sundgren-Andersson, A K

2018-05-01

The transient receptor potential vanilloid receptor 1 (TRPV1) is a nonselective cation channel involved in the mediation of peripheral pain to the central nervous system. As such, the TRPV1 is an accessible molecular target that lends itself well to the understanding of nociceptive signalling. This study encompasses preclinical investigations of three molecules with the prospect to establish them as suitable analgesic model compounds in human intradermal pain relief studies. The inhibitory effectiveness was evaluated by means of in vitro assays, TRPV1 expressing Chinese hamster ovary cells (CHO-K1) and rat dorsal root ganglion cultures in fluorescent imaging plate reader and whole cell patch clamp systems, as well as in vivo by capsaicin-evoked pain-related behavioural response studies in rat. Secondary pharmacology, pharmacokinetics and preclinical safety were also assessed. In vitro, all three compounds were effective at inhibiting capsaicin-activated TRPV1. The concentration producing 50% inhibition (IC 50 ) determined was in the range of 3-32 nmol/L and 10-501 nmol/L using CHO-K1 and dorsal root ganglion cultures, respectively. In vivo, all compounds showed dose-dependent reduction in capsaicin-evoked pain-related behavioural responses in rat. None of the three compounds displayed any significant activity on any of the secondary targets tested. The compounds were also shown to be safe from a toxicological, drug metabolism and pharmacokinetic perspective, for usage in microgram doses in the human skin. The investigated model compounds displayed ideal compound characteristics as pharmacological and translational tools to address efficacy on the human native TRPV1 target in human skin in situ. This work details the pharmaceutical work-up of three TRPV1-active investigational compounds, to obtain regulatory approval, for subsequent use in humans. This fast and cost-effective preclinical development path may impact research beyond the pain management area, as it allows human target engagement information gathering early in drug development. © 2018 European Pain Federation - EFIC®.

The Hamburg Selection Procedure for Dental Students – Introduction of the HAM-Nat as subject-specific test for study aptitude

PubMed Central

Kothe, Christian; Hissbach, Johanna; Hampe, Wolfgang

2013-01-01

Introduction: The present study examines the question whether the selection of dental students should be based solely on average school-leaving grades (GPA) or whether it could be improved by using a subject-specific aptitude test. Methods: The HAM-Nat Natural Sciences Test was piloted with freshmen during their first study week in 2006 and 2007. In 2009 and 2010 it was used in the dental student selection process. The sample size in the regression models varies between 32 and 55 students. Results: Used as a supplement to the German GPA, the HAM-Nat test explained up to 12% of the variance in preclinical examination performance. We confirmed the prognostic validity of GPA reported in earlier studies in some, but not all of the individual preclinical examination results. Conclusion: The HAM-Nat test is a reliable selection tool for dental students. Use of the HAM-Nat yielded a significant improvement in prediction of preclinical academic success in dentistry. PMID:24282449

Targeting MYCN-Driven Transcription By BET-Bromodomain Inhibition.

PubMed

Henssen, Anton; Althoff, Kristina; Odersky, Andrea; Beckers, Anneleen; Koche, Richard; Speleman, Frank; Schäfers, Simon; Bell, Emma; Nortmeyer, Maike; Westermann, Frank; De Preter, Katleen; Florin, Alexandra; Heukamp, Lukas; Spruessel, Annika; Astrahanseff, Kathy; Lindner, Sven; Sadowski, Natalie; Schramm, Alexander; Astorgues-Xerri, Lucile; Riveiro, Maria E; Eggert, Angelika; Cvitkovic, Esteban; Schulte, Johannes H

2016-05-15

Targeting BET proteins was previously shown to have specific antitumoral efficacy against MYCN-amplified neuroblastoma. We here assess the therapeutic efficacy of the BET inhibitor, OTX015, in preclinical neuroblastoma models and extend the knowledge on the role of BRD4 in MYCN-driven neuroblastoma. The efficacy of OTX015 was assessed in in vitro and in vivo models of human and murine MYCN-driven neuroblastoma. To study the effects of BET inhibition in the context of high MYCN levels, MYCN was ectopically expressed in human and murine cells. The effect of OTX015 on BRD4-regulated transcriptional pause release was analyzed using BRD4 and H3K27Ac chromatin immunoprecipitation coupled with DNA sequencing (ChIP-Seq) and gene expression analysis in neuroblastoma cells treated with OTX015 compared with vehicle control. OTX015 showed therapeutic efficacy against preclinical MYCN-driven neuroblastoma models. Similar to previously described BET inhibitors, concurrent MYCN repression was observed in OTX015-treated samples. Ectopic MYCN expression, however, did not abrogate effects of OTX015, indicating that MYCN repression is not the only target of BET proteins in neuroblastoma. When MYCN was ectopically expressed, BET inhibition still disrupted MYCN target gene transcription without affecting MYCN expression. We found that BRD4 binds to super-enhancers and MYCN target genes, and that OTX015 specifically disrupts BRD4 binding and transcription of these genes. We show that OTX015 is effective against mouse and human MYCN-driven tumor models and that BRD4 not only targets MYCN, but specifically occupies MYCN target gene enhancers as well as other genes associated with super-enhancers. Clin Cancer Res; 22(10); 2470-81. ©2015 AACR. ©2015 American Association for Cancer Research.

Consideration of species differences in developing novel molecules as cognition enhancers.

PubMed

Young, Jared W; Jentsch, J David; Bussey, Timothy J; Wallace, Tanya L; Hutcheson, Daniel M

2013-11-01

The NIH-funded CNTRICS initiative has coordinated efforts to promote the vertical translation of novel procognitive molecules from testing in mice, rats and non-human primates, to clinical efficacy in patients with schizophrenia. CNTRICS highlighted improving construct validation of tasks across species to increase the likelihood that the translation of a candidate molecule to humans will be successful. Other aspects of cross-species behaviors remain important however. This review describes cognitive tasks utilized across species, providing examples of differences and similarities of innate behavior between species, as well as convergent construct and predictive validity. Tests of attention, olfactory discrimination, reversal learning, and paired associate learning are discussed. Moreover, information on the practical implication of species differences in drug development research is also provided. The issues covered here will aid in task development and utilization across species as well as reinforcing the positive role preclinical research can have in developing procognitive treatments for psychiatric disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

Medicinal plants and natural products in amelioration of arsenic toxicity: a short review.

PubMed

Bhattacharya, Sanjib

2017-12-01

Chronic arsenic toxicity (arsenicosis) is considered a serious public health menace worldwide, as there is no specific, safe, and efficacious therapeutic management of arsenicosis. To collate the studies on medicinal plants and natural products with arsenic toxicity ameliorative effect, active pre-clinically and/or clinically. Literature survey was carried out by using Google, Scholar Google and Pub-Med. Only the scientific journal articles found on the internet for last two decades were considered. Minerals and semi-synthetic or synthetic analogs of natural products were excluded. Literature study revealed that 34 medicinal plants and 14 natural products exhibited significant protection from arsenic toxicity, mostly in preclinical trials and a few in clinical studies. This research could lead to development of a potentially useful agent in clinical management of arsenicosis in humans.

Trial watch: Naked and vectored DNA-based anticancer vaccines

PubMed Central

Bloy, Norma; Buqué, Aitziber; Aranda, Fernando; Castoldi, Francesca; Eggermont, Alexander; Cremer, Isabelle; Sautès-Fridman, Catherine; Fucikova, Jitka; Galon, Jérôme; Spisek, Radek; Tartour, Eric; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

2015-01-01

One type of anticancer vaccine relies on the administration of DNA constructs encoding one or multiple tumor-associated antigens (TAAs). The ultimate objective of these preparations, which can be naked or vectored by non-pathogenic viruses, bacteria or yeast cells, is to drive the synthesis of TAAs in the context of an immunostimulatory milieu, resulting in the (re-)elicitation of a tumor-targeting immune response. In spite of encouraging preclinical results, the clinical efficacy of DNA-based vaccines employed as standalone immunotherapeutic interventions in cancer patients appears to be limited. Thus, efforts are currently being devoted to the development of combinatorial regimens that allow DNA-based anticancer vaccines to elicit clinically relevant immune responses. Here, we discuss recent advances in the preclinical and clinical development of this therapeutic paradigm. PMID:26155408

Photobiomodulation (PBM) with 20 W at 640 nm: pre-clinical results and propagation model

NASA Astrophysics Data System (ADS)

Gendron, Denis J.; Ménage, Alexander R.

2017-02-01

A novel treatment modality for photobiomodulation (PBM) is introduced called High Intensity Physio Light (HIPL) Therapy with a light source at 640 nm wavelength, 20 nm bandwidth, and up to 20 W in large 10 cm flat beam. This report exemplifies the efficacy performance of this method with three pre-clinical cases: (i) ankle: sport injury, (ii) foot: bone fractures, and (iii) shoulder: musculoskeletal disorder (MSD). In all cases, the patients systematically experienced a significant pain reduction (by 2 / 10 - 4 / 10) on a visual pain scale. In case (ii) and (iii), a steady improvement and complete recovery of the patient was respectfully obtained. This report describes the experimental treatment condition for each case, and introduces an intensity-dependant propagation model to explain our observation.

Trial watch: Naked and vectored DNA-based anticancer vaccines.

PubMed

Bloy, Norma; Buqué, Aitziber; Aranda, Fernando; Castoldi, Francesca; Eggermont, Alexander; Cremer, Isabelle; Sautès-Fridman, Catherine; Fucikova, Jitka; Galon, Jérôme; Spisek, Radek; Tartour, Eric; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

2015-05-01

One type of anticancer vaccine relies on the administration of DNA constructs encoding one or multiple tumor-associated antigens (TAAs). The ultimate objective of these preparations, which can be naked or vectored by non-pathogenic viruses, bacteria or yeast cells, is to drive the synthesis of TAAs in the context of an immunostimulatory milieu, resulting in the (re-)elicitation of a tumor-targeting immune response. In spite of encouraging preclinical results, the clinical efficacy of DNA-based vaccines employed as standalone immunotherapeutic interventions in cancer patients appears to be limited. Thus, efforts are currently being devoted to the development of combinatorial regimens that allow DNA-based anticancer vaccines to elicit clinically relevant immune responses. Here, we discuss recent advances in the preclinical and clinical development of this therapeutic paradigm.

How Can Gastric Cancer Molecular Profiling Guide Future Therapies?

PubMed

Corso, Simona; Giordano, Silvia

2016-07-01

Gastric cancer is the third greatest global cause of cancer-related deaths. Despite its high prevalence, only recently have comprehensive genomic surveys shed light on its molecular alterations. As surgery is the only curative treatment strategy and chemotherapy has shown limited efficacy, new treatments are urgently needed. Many molecular therapies for gastric cancer have entered clinical trials but-apart from Trastuzumab and Ramucirumab-all have failed. We analyze the current knowledge of the genetic 'landscape' of gastric cancers, elaborating on novel, preclinical approaches. We posit that this knowledge lays the basis for identifying bona fide molecular targets and developing solid therapeutic approaches, requiring accurate patient selection and taking advantage of preclinical models to assist clinical development of novel combination strategies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Treatment of TBI with Hormonal and Pharmacological Support, Preclinical Validation Using Diffuse and Mechanical TBI Animal Models

DTIC Science & Technology

2016-05-01

Award Number: PT075653 (grant) W81XWH-08-2-0153 (contract) TITLE: Treatment of TBI with Hormonal and Pharmacological Support, Preclinical...TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-08-2-0153 Treatment of TBI with Hormonal and Pharmacological Support, Preclinical Validation Using...rats. Our in vivo tests also included MRI imaging, focusing on edema resolution and reduction of diffuse axonal damage (fractional anisotropy

Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition.

PubMed

Hoeflich, Klaus P; Merchant, Mark; Orr, Christine; Chan, Jocelyn; Den Otter, Doug; Berry, Leanne; Kasman, Ian; Koeppen, Hartmut; Rice, Ken; Yang, Nai-Ying; Engst, Stefan; Johnston, Stuart; Friedman, Lori S; Belvin, Marcia

2012-01-01

Combinations of MAP/ERK kinase (MEK) and phosphoinositide 3-kinase (PI3K) inhibitors have shown promise in preclinical cancer models, leading to the initiation of clinical trials cotargeting these two key cancer signaling pathways. GDC-0973, a novel selective MEK inhibitor, and GDC-0941, a class I PI3K inhibitor, are in early stage clinical trials as both single agents and in combination. The discovery of these selective inhibitors has allowed investigation into the precise effects of combining inhibitors of two major signaling branches downstream of RAS. Here, we investigated multiple biomarkers in the mitogen-activated protein kinase (MAPK) and PI3K pathway to search for points of convergence that explain the increased apoptosis seen in combination. Using washout studies in vitro and alternate dosing schedules in mice, we showed that intermittent inhibition of the PI3K and MAPK pathway is sufficient for efficacy in BRAF and KRAS mutant cancer cells. The combination of GDC-0973 with the PI3K inhibitor GDC-0941 resulted in combination efficacy in vitro and in vivo via induction of biomarkers associated with apoptosis, including Bcl-2 family proapoptotic regulators. Therefore, these data suggest that continuous exposure of MEK and PI3K inhibitors in combination is not required for efficacy in preclinical cancer models and that sustained effects on downstream apoptosis biomarkers can be observed in response to intermittent dosing. ©2011 AACR.

Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment.

PubMed

Wagner, Jessica; Kline, C Leah; Zhou, Lanlan; Campbell, Kerry S; MacFarlane, Alexander W; Olszanski, Anthony J; Cai, Kathy Q; Hensley, Harvey H; Ross, Eric A; Ralff, Marie D; Zloza, Andrew; Chesson, Charles B; Newman, Jenna H; Kaufman, Howard; Bertino, Joseph; Stein, Mark; El-Deiry, Wafik S

2018-06-01

ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in a first-in-human trial in which patients were dosed every 3 weeks. We hypothesized that dose intensification of ONC201 may impact antitumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observed accumulation of activated NK+ and CD3+ cells within ONC201-treated tumors and that NK cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant Bax-/- tumors. Immunocompetent NCR1-GFP mice, in which NK cells express GFP, demonstrated GFP+ NK cell infiltration of syngeneic MC38 colorectal tumors. Activation of primary human NK cells and increased degranulation occurred in response to ONC201. Coculture experiments identified a role for TRAIL in human NK-mediated antitumor cytotoxicity. Preclinical results indicate the potential utility for ONC201 plus anti-PD-1 therapy. We observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients after ONC201 treatment. The results offer what we believe to be a unique pathway of immune stimulation for cancer therapy.

The role of the time-kill kinetics assay as part of a preclinical modeling framework for assessing the activity of anti-tuberculosis drugs.

PubMed

Bax, Hannelore I; Bakker-Woudenberg, Irma A J M; de Vogel, Corné P; van der Meijden, Aart; Verbon, Annelies; de Steenwinkel, Jurriaan E M

2017-07-01

Novel treatment strategies for tuberculosis are urgently needed. Many different preclinical models assessing anti-tuberculosis drug activity are available, but it is yet unclear which combination of models is most predictive of clinical treatment efficacy. The aim of this study was to determine the role of our in vitro time kill-kinetics assay as an asset to a predictive preclinical modeling framework assessing anti-tuberculosis drug activity. The concentration- and time-dependent mycobacterial killing capacities of six anti-tuberculosis drugs were determined during exposure as single drugs or in dual, triple and quadruple combinations towards a Mycobacterium tuberculosis Beijing genotype strain and drug resistance was assessed. Streptomycin, rifampicin and isoniazid were most active against fast-growing M. tuberculosis. Isoniazid with rifampicin or high dose ethambutol were the only synergistic drug combinations. The addition of rifampicin or streptomycin to isoniazid prevented isoniazid resistance. In vitro ranking showed agreement with early bactericidal activity in tuberculosis patients for some but not all anti-tuberculosis drugs. The time-kill kinetics assay provides important information on the mycobacterial killing dynamics of anti-tuberculosis drugs during the early phase of drug exposure. As such, this assay is a valuable component of the preclinical modeling framework. Copyright © 2017 Elsevier Ltd. All rights reserved.

Discovery of dual orexin receptor antagonists with rat sleep efficacy enabled by expansion of the acetonitrile-assisted/diphosgene-mediated 2,4-dichloropyrimidine synthesis.

PubMed

Roecker, Anthony J; Mercer, Swati P; Harrell, C Meacham; Garson, Susan L; Fox, Steven V; Gotter, Anthony L; Prueksaritanont, Thomayant; Cabalu, Tamara D; Cui, Donghui; Lemaire, Wei; Winrow, Christopher J; Renger, John J; Coleman, Paul J

2014-05-01

Recent clinical studies have demonstrated that dual orexin receptor antagonists (OX1R and OX2R antagonists or DORAs) represent a novel treatment option for insomnia patients. Previously we have disclosed several compounds in the diazepane amide DORA series with excellent potency and both preclinical and clinical sleep efficacy. Additional SAR studies in this series were enabled by the expansion of the acetonitrile-assisted, diphosgene-mediated 2,4-dichloropyrimidine synthesis to novel substrates providing an array of Western heterocycles. These heterocycles were utilized to synthesize analogs in short order with high levels of potency on orexin 1 and orexin 2 receptors as well as in vivo sleep efficacy in the rat. Copyright © 2014 Elsevier Ltd. All rights reserved.

Treating Leick with like: response to criticisms of the use of entanglement to illustrate homeopathy.

PubMed

Milgrom, Lionel R

2008-04-01

In criticising papers which recently appeared in Homeopathy, Leick claims that no double blind randomised clinical trials (DBRCTs) show that homeopathy is efficacious, and that specific effects of substances diluted beyond Avogadro's limit are implausible. He states that generalised entanglement models should be able to improve the design of experiments to test ultra-high dilutions, and disparages the authors' understandings of quantum physics. The paper responds to those criticisms. Several DBRCTs have shown that homeopathy has effects which are not due to placebo and these are now supported by preclinical work. This area of theory is in its infancy and it is unreasonable to expect it to have generated experiments at this stage. The authors have used accepted interpretations of quantum theory: Leick's view is coloured by skepticism concerning homeopathy.

The relation between burnout and sleep disorders in medical students.

PubMed

Pagnin, Daniel; de Queiroz, Valéria; Carvalho, Yeska Talita Maia Santos; Dutra, Augusto Sergio Soares; Amaral, Monique Bastos; Queiroz, Thiago Thomasin

2014-08-01

The aim of this study is to assess the mutual relationships between burnout and sleep disorders in students in the preclinical phase of medical school. This study collected data on 127 medical students who filled in the Maslach Burnout Inventory-Student Survey, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Beck Depression Inventory, and Beck Anxiety Inventory. Hierarchical logistic regressions tested the reciprocal influence between sleep disorders and burnout, controlling for depression and anxiety. Regular occurrence of emotional exhaustion, poor sleep quality, and excessive daytime sleepiness affected 60, 65, and 63% of medical students, respectively. Emotional exhaustion and daytime sleepiness influenced each other. Daytime sleep dysfunctions affected unidirectionally the occurrence of cynicism and academic efficacy. The odds of emotional exhaustion (odds ratio (OR)=1.21, 95% confidence interval (CI)=1.08 to 1.35) and cynicism (OR=2.47, 95% CI=1.25 to 4.90) increased when daytime sleepiness increased. Reciprocally, the odds of excessive daytime sleepiness (OR=2.13, 95% CI=1.22 to 3.73) increased when emotional exhaustion worsened. Finally, the odds of academic efficacy decreased (OR=0.86, 95% CI=0.75 to 0.98) when daytime sleepiness increased. Burnout and sleep disorders have relevant bidirectional effects in medical students in the early phase of medical school. Emotional exhaustion and daytime sleepiness showed an important mutual influence. Daytime sleepiness linked unidirectionally with cynicism and academic efficacy.

Nab-Paclitaxel Plus S-1 Shows Increased Antitumor Activity in Patient-Derived Pancreatic Cancer Xenograft Mouse Models.

PubMed

Li, Jian-Ang; Xu, Xue-Feng; Han, Xu; Fang, Yuan; Shi, Chen-Ye; Jin, Da-Yong; Lou, Wen-Hui

2016-03-01

To investigate the antitumor activity of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus S-1 in patient-derived pancreatic cancer xenograft mouse models and to explore biomarkers that could predict drug efficacy. Ten patient-derived xenograft models were established. The third-generation tumor-bearing mice were randomized into 4 treatment groups: (1) control; (2) S-1; (3) nab-paclitaxel; (4) S-1 plus nab-paclitaxel. Resected tumors were tested by immunohistochemistry for the expression of thymidylate synthase, orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase (DPD), secreted protein that is acidic and rich in cysteine, human epidermal growth factor receptor 2 (HER2), collagen-1, and CD31. Tumor growth inhibition of the S-1 group, nab-paclitaxel group, and combination group was 69.52%, 86.63%, 103.56%, respectively (P < 0.05). The efficacy of S-1 is better in thymidylate synthase-negative, OPRT-positive, and DPD-negative tumors. The efficacy of nab-paclitaxel is better in HER2-positive tumors. Collagen-1 was decreased and CD31 was increased in tumors treated with nab-paclitaxel and S-1 plus nab-paclitaxel compared with control or S-1. This preclinical study showed that S-1 plus nab-paclitaxel exerted significantly better antitumor activity than S-1 or nab-paclitaxel alone. Thymidylate synthase, OPRT, and DPD were possibly biomarkers of S-1 and HER2 of nab-paclitaxel.

Investigation of New Morpholino Oligomers to Increase Survival Motor Neuron Protein Levels in Spinal Muscular Atrophy

PubMed Central

Ramirez, Agnese; Crisafulli, Sebastiano G.; Rizzuti, Mafalda; Bresolin, Nereo; Comi, Giacomo P.; Corti, Stefania

2018-01-01

Spinal muscular atrophy (SMA) is an autosomal-recessive childhood motor neuron disease and the main genetic cause of infant mortality. SMA is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene, which results in SMN protein deficiency. Only one approved drug has recently become available and allows for the correction of aberrant splicing of the paralogous SMN2 gene by antisense oligonucleotides (ASOs), leading to production of full-length SMN protein. We have already demonstrated that a sequence of an ASO variant, Morpholino (MO), is particularly suitable because of its safety and efficacy profile and is both able to increase SMN levels and rescue the murine SMA phenotype. Here, we optimized this strategy by testing the efficacy of four new MO sequences targeting SMN2. Two out of the four new MO sequences showed better efficacy in terms of SMN protein production both in SMA induced pluripotent stem cells (iPSCs) and SMAΔ7 mice. Further, the effect was enhanced when different MO sequences were administered in combination. Our data provide an important insight for MO-based treatment for SMA. Optimization of the target sequence and validation of a treatment based on a combination of different MO sequences could support further pre-clinical studies and the progression toward future clinical trials. PMID:29316633

Investigation of New Morpholino Oligomers to Increase Survival Motor Neuron Protein Levels in Spinal Muscular Atrophy.

PubMed

Ramirez, Agnese; Crisafulli, Sebastiano G; Rizzuti, Mafalda; Bresolin, Nereo; Comi, Giacomo P; Corti, Stefania; Nizzardo, Monica

2018-01-06

Spinal muscular atrophy (SMA) is an autosomal-recessive childhood motor neuron disease and the main genetic cause of infant mortality. SMA is caused by deletions or mutations in the survival motor neuron 1 ( SMN1 ) gene, which results in SMN protein deficiency. Only one approved drug has recently become available and allows for the correction of aberrant splicing of the paralogous SMN2 gene by antisense oligonucleotides (ASOs), leading to production of full-length SMN protein. We have already demonstrated that a sequence of an ASO variant, Morpholino (MO), is particularly suitable because of its safety and efficacy profile and is both able to increase SMN levels and rescue the murine SMA phenotype. Here, we optimized this strategy by testing the efficacy of four new MO sequences targeting SMN2 . Two out of the four new MO sequences showed better efficacy in terms of SMN protein production both in SMA induced pluripotent stem cells (iPSCs) and SMAΔ7 mice. Further, the effect was enhanced when different MO sequences were administered in combination. Our data provide an important insight for MO-based treatment for SMA. Optimization of the target sequence and validation of a treatment based on a combination of different MO sequences could support further pre-clinical studies and the progression toward future clinical trials.

Emerging Applications of Stem Cell and Regenerative Medicine to Sports Injuries

PubMed Central

Ajibade, David A.; Vance, Danica D.; Hare, Joshua M.; Kaplan, Lee D.; Lesniak, Bryson P.

2014-01-01

Background: The treatment of sports-related musculoskeletal injuries with stem cells has become more publicized because of recent reports of high-profile athletes undergoing stem cell procedures. There has been increased interest in defining the parameters of safety and efficacy and the indications for potential use of stem cells in clinical practice. Purpose: To review the role of regenerative medicine in the treatment of sports-related injuries. Study Design: Review. Method: Relevant studies were identified through a PubMed search combining the terms stem cells and cartilage, ligament, tendon, muscle, and bone from January 2000 to August 2013. Studies and works cited in these studies were also reviewed. Results: Treatment of sports-related injuries with stem cells shows potential for clinical efficacy from the data available from basic science and animal studies. Conclusion: Cell-based therapies and regenerative medicine offer safe and potentially efficacious treatment for sports-related musculoskeletal injuries. Basic science and preclinical studies that support the possibility of enhanced recovery from sports injuries using cell-based therapies are accumulating; however, more clinical evidence is necessary to define the indications and parameters for their use. Accordingly, exposing patients to cell-based therapies could confer an unacceptable risk profile with minimal or no benefit. Continued clinical testing with animal models and clinical trials is necessary to determine the relative risks and benefits as well as the indications and methodology of treatment. PMID:26535296

The predictive validity of the BioMedical Admissions Test for pre-clinical examination performance.

PubMed

Emery, Joanne L; Bell, John F

2009-06-01

Some medical courses in the UK have many more applicants than places and almost all applicants have the highest possible previous and predicted examination grades. The BioMedical Admissions Test (BMAT) was designed to assist in the student selection process specifically for a number of 'traditional' medical courses with clear pre-clinical and clinical phases and a strong focus on science teaching in the early years. It is intended to supplement the information provided by examination results, interviews and personal statements. This paper reports on the predictive validity of the BMAT and its predecessor, the Medical and Veterinary Admissions Test. Results from the earliest 4 years of the test (2000-2003) were matched to the pre-clinical examination results of those accepted onto the medical course at the University of Cambridge. Correlation and logistic regression analyses were performed for each cohort. Section 2 of the test ('Scientific Knowledge') correlated more strongly with examination marks than did Section 1 ('Aptitude and Skills'). It also had a stronger relationship with the probability of achieving the highest examination class. The BMAT and its predecessor demonstrate predictive validity for the pre-clinical years of the medical course at the University of Cambridge. The test identifies important differences in skills and knowledge between candidates, not shown by their previous attainment, which predict their examination performance. It is thus a valid source of additional admissions information for medical courses with a strong scientific emphasis when previous attainment is very high.

Survival benefit with proapoptotic molecular and pathologic responses from dual targeting of mammalian target of rapamycin and epidermal growth factor receptor in a preclinical model of pancreatic neuroendocrine carcinogenesis.

PubMed

Chiu, Christopher W; Nozawa, Hiroaki; Hanahan, Douglas

2010-10-10

Pancreatic neuroendocrine tumors (PNETs), although rare, often metastasize, such that surgery, the only potentially curative therapy, is not possible. There is no effective systemic therapy for patients with advanced PNETs. Therefore, new strategies are needed. Toward that end, we investigated the potential benefit of dual therapeutic targeting of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) kinases, using a preclinical mouse model of PNET. Rapamycin and erlotinib, inhibitors of mTOR and EGFR, respectively, were used to treat RIP-Tag2 transgenic mice bearing advanced multifocal PNET. Tumor growth and survival were monitored, and tumors were surveyed for potential biomarkers of response to the therapeutics. Rapamycin monotherapy was notably efficacious, prolonging survival concomitant with tumor stasis (stable disease). However, the tumors developed resistance, as evidenced by eventual relapse to progressive tumor growth. Erlotinib monotherapy slowed tumor growth and elicited a marginal survival benefit. In combination, there was an unprecedented survival benefit in the face of this aggressive multifocal cancer and, in contrast to either monotherapy, the development of adaptive resistance was not apparent. Additionally, the antiapoptotic protein survivin was implicated as a biomarker of sensitivity and beneficial responses to the dual targeted therapy. Preclinical trials in a mouse model of endogenous PNET suggest that combined targeting of the mTOR and EGFR signaling pathways could have potential clinical benefit in treating PNET. These results have encouraged development of an ongoing phase II clinical trial aimed to evaluate the efficacy of this treatment regimen in human neuroendocrine tumors.

ASK1 Inhibition Halts Disease Progression in Preclinical Models of Pulmonary Arterial Hypertension.

PubMed

Budas, Grant R; Boehm, Mario; Kojonazarov, Baktybek; Viswanathan, Gayathri; Tian, Xia; Veeroju, Swathi; Novoyatleva, Tatyana; Grimminger, Friedrich; Hinojosa-Kirschenbaum, Ford; Ghofrani, Hossein A; Weissmann, Norbert; Seeger, Werner; Liles, John T; Schermuly, Ralph T

2018-02-01

Progression of pulmonary arterial hypertension (PAH) is associated with pathological remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of MAPKs (mitogen-activated protein kinases), which stimulate apoptosis, inflammation, and fibrosis. We investigated whether pharmacological inhibition of the redox-sensitive apical MAPK, ASK1 (apoptosis signal-regulating kinase 1), can halt the progression of pulmonary vascular and RV remodeling. A selective, orally available ASK1 inhibitor, GS-444217, was administered to two preclinical rat models of PAH (monocrotaline and Sugen/hypoxia), a murine model of RV pressure overload induced by pulmonary artery banding, and cellular models. Oral administration of GS-444217 dose dependently reduced pulmonary arterial pressure and reduced RV hypertrophy in PAH models. The therapeutic efficacy of GS-444217 was associated with reduced ASK1 phosphorylation, reduced muscularization of the pulmonary arteries, and reduced fibrotic gene expression in the RV. Importantly, efficacy was observed when GS-444217 was administered to animals with established disease and also directly reduced cardiac fibrosis and improved cardiac function in a model of isolated RV pressure overload. In cellular models, GS-444217 reduced phosphorylation of p38 and JNK (c-Jun N-terminal kinase) induced by adenoviral overexpression of ASK1 in rat cardiomyocytes and reduced activation/migration of primary mouse cardiac fibroblasts and human pulmonary adventitial fibroblasts derived from patients with PAH. ASK1 inhibition reduced pathological remodeling of the pulmonary vasculature and the right ventricle and halted progression of pulmonary hypertension in rodent models. These preclinical data inform the first description of a causal role of ASK1 in PAH disease pathogenesis.

Recombinant polymorphic membrane protein D in combination with a novel, second-generation lipid adjuvant protects against intra-vaginal Chlamydia trachomatis infection in mice.

PubMed

Paes, Wayne; Brown, Naj; Brzozowski, Andrzej M; Coler, Rhea; Reed, Steve; Carter, Darrick; Bland, Martin; Kaye, Paul M; Lacey, Charles J N

2016-07-29

The development of a chlamydial vaccine that elicits protective mucosal immunity is of paramount importance in combatting the global spread of sexually transmitted Chlamydia trachomatis (Ct) infections. While the identification and prioritization of chlamydial antigens is a crucial prerequisite for efficacious vaccine design, it is likely that novel adjuvant development and selection will also play a pivotal role in the translational potential of preclinical Ct vaccines. Although the molecular nature of the immuno-modulatory component is of primary importance, adjuvant formulation and delivery systems may also govern vaccine efficacy and potency. Our study provides the first preclinical evaluation of recombinant Ct polymorphic membrane protein D (rPmpD) in combination with three different formulations of a novel second-generation lipid adjuvant (SLA). SLA was rationally designed in silico by modification of glucopyranosyl lipid adjuvant (GLA), a TLR4 agonistic precursor molecule currently in Phase II clinical development. We demonstrate robust protection against intra-vaginal Ct challenge in mice, evidenced by significantly enhanced resistance to infection and reduction in mean bacterial load. Strikingly, protection was found to correlate with the presence of robust anti-rPmpD serum and cervico-vaginal IgG titres, even in the absence of adjuvant-induced Th1-type cellular immune responses elicited by each SLA formulation, and we further show that anti-rPmpD antibodies recognize Ct EBs. These findings highlight the utility of SLA and rational molecular design of adjuvants in preclinical Ct vaccine development, but also suggest an important role for anti-rPmpD antibodies in protection against urogenital Ct infection. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

The Preclinical and Clinical Effects of Vilazodone for the Treatment of Major Depressive Disorder

PubMed Central

Sahli, Zeyad T.; Banerjee, Pradeep; Tarazi, Frank I.

2016-01-01

ABSTRACT Introduction: Major depressive disorder (MDD) is the leading cause of disability worldwide, and according to the STAR*D trial, only 33% of patients with MDD responded to initial drug therapy. Augmentation of the leading class of antidepressant treatment, selective serotonin reuptake inhibitors (SSRIs), with the 5-HT1A receptor agonist buspirone has been shown to be effective in treating patients that do not respond to initial SSRI therapy. This suggests that newer treatments may improve the clinical picture of MDD. The US Food and Drug Administration (FDA) approved the antidepressant drug vilazodone (EMD 68843), a novel SSRI and 5-HT1A receptor partial agonist. Vilazodone has a half-life between 20–24 hours, reaches peak plasma concentrations at 3.7–5.3 hours, and is primarily metabolized by the hepatic CYP450 3A4 enzyme system. Areas covered: The authors review the preclinical and clinical profile of vilazodone. The roles of serotonin, the 5-HT1A receptor, and current pharmacotherapy approaches for MDD are briefly reviewed. Next, the preclinical pharmacological, behavioral, and physiological effects of vilazodone are presented, followed by the pharmacokinetic properties and metabolism of vilazodone in humans. Last, a brief summary of the main efficacy, safety, and tolerability outcomes of clinical trials of vilazodone is provided. Expert opinion: Vilazodone has shown efficacy versus placebo in improving depression symptoms in several double-blind, placebo-controlled trials. The long-term safety and tolerability of vilazodone treatment has also been established. Further studies are needed that directly compare patients treated with an SSRI (both with and without an adjunctive 5-HT1A partial agonist) versus patients treated with vilaozodone. PMID:26971593

Experimental design and reporting standards for improving the internal validity of pre-clinical studies in the field of pain: Consensus of the IMI-Europain consortium.

PubMed

Knopp, K L; Stenfors, C; Baastrup, C; Bannon, A W; Calvo, M; Caspani, O; Currie, G; Finnerup, N B; Huang, W; Kennedy, J D; Lefevre, I; Machin, I; Macleod, M; Rees, H; Rice, A S C; Rutten, K; Segerdahl, M; Serra, J; Wodarski, R; Berge, O-G; Treedef, R-D

2017-12-29

Background and aims Pain is a subjective experience, and as such, pre-clinical models of human pain are highly simplified representations of clinical features. These models are nevertheless critical for the delivery of novel analgesics for human pain, providing pharmacodynamic measurements of activity and, where possible, on-target confirmation of that activity. It has, however, been suggested that at least 50% of all pre-clinical data, independent of discipline, cannot be replicated. Additionally, the paucity of "negative" data in the public domain indicates a publication bias, and significantly impacts the interpretation of failed attempts to replicate published findings. Evidence suggests that systematic biases in experimental design and conduct and insufficiencies in reporting play significant roles in poor reproducibility across pre-clinical studies. It then follows that recommendations on how to improve these factors are warranted. Methods Members of Europain, a pain research consortium funded by the European Innovative Medicines Initiative (IMI), developed internal recommendations on how to improve the reliability of pre-clinical studies between laboratories. This guidance is focused on two aspects: experimental design and conduct, and study reporting. Results Minimum requirements for experimental design and conduct were agreed upon across the dimensions of animal characteristics, sample size calculations, inclusion and exclusion criteria, random allocation to groups, allocation concealment, and blinded assessment of outcome. Building upon the Animals in Research: Reportingin vivo Experiments (ARRIVE) guidelines, reporting standards were developed for pre-clinical studies of pain. These include specific recommendations for reporting on ethical issues, experimental design and conduct, and data analysis and interpretation. Key principles such as sample size calculation, a priori definition of a primary efficacy measure, randomization, allocation concealments, and blinding are discussed. In addition, considerations of how stress and normal rodent physiology impact outcome of analgesic drug studies are considered. Flow diagrams are standard requirements in all clinical trials, and flow diagrams for preclinical trials, which describe number of animals included/excluded, and reasons for exclusion are proposed. Creation of a trial registry for pre-clinical studies focused on drug development in order to estimate possible publication bias is discussed. Conclusions More systematic research is needed to analyze how inadequate internal validity and/or experimental bias may impact reproducibility across pre-clinical pain studies. Addressing the potential threats to internal validity and the sources of experimental biases, as well as increasing the transparency in reporting, are likely to improve preclinical research broadly by ensuring relevant progress is made in advancing the knowledge of chronic pain pathophysiology and identifying novel analgesics. Implications We are now disseminating these Europain processes for discussion in the wider pain research community. Any benefit from these guidelines will be dependent on acceptance and disciplined implementation across pre-clinical laboratories, funding agencies and journal editors, but it is anticipated that these guidelines will be a first step towards improving scientific rigor across the field of pre-clinical pain research.

Behavioural pharmacology of the α5-GABAA receptor antagonist S44819: Enhancement and remediation of cognitive performance in preclinical models.

PubMed

Gacsályi, István; Móricz, Krisztina; Gigler, Gábor; Wellmann, János; Nagy, Katalin; Ling, István; Barkóczy, József; Haller, József; Lambert, Jeremy J; Szénási, Gábor; Spedding, Michael; Antoni, Ferenc A

2017-10-01

Previous work has shown that S44819 is a novel GABAA receptor (GABA A R) antagonist, which is selective for extrasynaptic GABA A Rs incorporating the α5 subunit (α5-GABA A Rs). The present study reports on the preclinical neuropsychopharmacological profile of S44819. Significantly, no sedative or pro-convulsive side effects of S44819 were found at doses up to 30 mg/kg i.p. Object recognition (OR) memory in intact mice was enhanced by S44819 (0.3 mg/kg p.o.) given before the acquisition trial. Mice treated with phencyclidine for two weeks and tested six days after the cessation of treatment failed to show OR memory. This deficit was corrected by a single administration of S44819 (0.1, 0.3 or 1 mg/kg p.o.) prior to the acquisition trial. The amnestic effect of ketamine in rats tested in the eight-arm radial maze (reference and working memory versions) was blocked by S44819 (3 mg/kg p.o.). Extinction of cued fear was preserved during treatment with S44819 (3 mg/kg/diem i.p.). Administration of S44819 had no significant effect in the Vogel-conflict test, the elevated plus maze, the forced swim, the marble-burying and the tail-suspension tests. In contrast, anxiolytic/antidepressant-like effects of the compound were found in paradigms that have mnemonic components, such as social interaction, fear-potentiated startle and social avoidance induced by negative life experience. In summary, S44819 enhanced intact recognition memory and ameliorated memory deficits induced by inhibition of NMDA receptors. Anxiolytic/antidepressant efficacy was limited to paradigms involving cognitive function. In conclusion, S44819 is a novel psychoactive pro-cognitive compound with potential as a therapeutic agent in dementia. Copyright © 2017 Elsevier Ltd. All rights reserved.

Formulation, stability study, and pre-clinical evaluation of a vaginal cream containing curcumin in a rat model of vulvovaginal candidiasis.

PubMed

de Souza Fernandes, Lígia; Amorim, Yuri Martins; Silva, Elton Libério da; Silva, Samuel Calixto; Santos, Alécia Junia Aparecida; Peixoto, Franciele Natália; Pires, Luara Moniele Neves; Sakamoto, Raquel Yumi; Pinto, Flávia do Carmo Horta; Scarpa, Maria Virgínia Costa; Gonzaga de Freitas Araújo, Marcelo

2018-03-08

Owing to the growing resistance among isolates of Candida species to usual antifungal agents and the well-known therapeutic potential of curcumin, the purpose of this study was to develop and validate a vaginal formulation containing this substance and to evaluating its effectiveness in the treatment of experimental vulvovaginal candidiasis METHODS: Curcumin was incorporated in a vaginal cream in three concentrations (0.01, 0.1 and 1.0%). The different concentrations of the cream and its controls were intravaginally administered in an immunosuppressed rat model to evaluate the efficacy in the treatment of experimental vulvovaginal candidiasis. Samples of the cream were also subjected to centrifugation and physical stability tests and an analytical method for quantification of curcumin was validated based on HPLC RESULTS: The formulation was stable and the HPLC method could be considered suitable for the quantitative determination of curcumin in the cream. After six days of pre-clinical study, the number of infected animals was 1/6 in all groups treated with curcumin vaginal cream and the fungal burden showed a progressive reduction. Reduction of the inflammatory infiltrate was observed in the group treated with 1.0% cream CONCLUSION: Vaginal cream containing curcumin could be considered a promising effective antifungal medicine in the treatment of vulvovaginal candidiasis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Methods for Tumor Targeting with Salmonella typhimurium A1-R.

PubMed

Hoffman, Robert M; Zhao, Ming

2016-01-01

Salmonella typhimurium A1-R (S. typhimurium A1-R) has shown great preclinical promise as a broad-based anti-cancer therapeutic (please see Chapter 1 ). The present chapter describes materials and methods for the preclinical study of S. typhimurium A1-R in clinically-relevant mouse models. Establishment of orthotopic metastatic mouse models of the major cancer types is described, as well as other useful models, for efficacy studies of S. typhimurium A1-R or other tumor-targeting bacteria, as well. Imaging methods are described to visualize GFP-labeled S. typhimurium A1-R, as well as GFP- and/or RFP-labeled cancer cells in vitro and in vivo, which S. typhimurium A1-R targets. The mouse models include metastasis to major organs that are life-threatening to cancer patients including the liver, lung, bone, and brain and how to target these metastases with S. typhimurium A1-R. Various routes of administration of S. typhimurium A1-R are described with the advantages and disadvantages of each. Basic experiments to determine toxic effects of S. typhimurium A1-R are also described. Also described are methodologies for combining S. typhimurium A1-R and chemotherapy. The testing of S. typhimurium A1-R on patient tumors in patient-derived orthotopic xenograft (PDOX) mouse models is also described. The major methodologies described in this chapter should be translatable for clinical studies.

A big data approach to the concordance of the toxicity of pharmaceuticals in animals and humans.

PubMed

Clark, Matthew; Steger-Hartmann, Thomas

2018-07-01

Although lack of efficacy is an important cause of late stage attrition in drug development the shortcomings in the translation of toxicities observed during the preclinical development to observations in clinical trials or post-approval is an ongoing topic of research. The concordance between preclinical and clinical safety observations has been analyzed only on relatively small data sets, mostly over short time periods of drug approvals. We therefore explored the feasibility of a big-data analysis on a set of 3,290 approved drugs and formulations for which 1,637,449 adverse events were reported for both humans animal species in regulatory submissions over a period of more than 70 years. The events reported in five species - rat, dog, mouse, rabbit, and cynomolgus monkey - were treated as diagnostic tests for human events and the diagnostic power was computed for each event/species pair using likelihood ratios. The animal-human translation of many key observations is confirmed as being predictive, such as QT prolongation and arrhythmias in dog. Our study confirmed the general predictivity of animal safety observations for humans, but also identified issues of such automated analyses which are on the one hand related to data curation and controlled vocabularies, on the other hand to methodological changes over the course of time. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

A Low Power Micro Deep Brain Stimulation Device for Murine Preclinical Research.

PubMed

Kouzani, Abbas Z; Abulseoud, Osama A; Tye, Susannah J; Hosain, M D Kamal; Berk, Michael

2013-01-01

Deep brain stimulation has emerged as an effective medical procedure that has therapeutic efficacy in a number of neuropsychiatric disorders. Preclinical research involving laboratory animals is being conducted to study the principles, mechanisms, and therapeutic effects of deep brain stimulation. A bottleneck is, however, the lack of deep brain stimulation devices that enable long term brain stimulation in freely moving laboratory animals. Most of the existing devices employ complex circuitry, and are thus bulky. These devices are usually connected to the electrode that is implanted into the animal brain using long fixed wires. In long term behavioral trials, however, laboratory animals often need to continuously receive brain stimulation for days without interruption, which is difficult with existing technology. This paper presents a low power and lightweight portable microdeep brain stimulation device for laboratory animals. Three different configurations of the device are presented as follows: 1) single piece head mountable; 2) single piece back mountable; and 3) two piece back mountable. The device can be easily carried by the animal during the course of a clinical trial, and that it can produce non-stop stimulation current pulses of desired characteristics for over 12 days on a single battery. It employs passive charge balancing to minimize undesirable effects on the target tissue. The results of bench, in-vitro, and in-vivo tests to evaluate the performance of the device are presented.

Several down, a few to go: histamine H3 receptor ligands making the final push towards the market?

PubMed

Kuhne, Sebastiaan; Wijtmans, Maikel; Lim, Herman D; Leurs, Rob; de Esch, Iwan J P

2011-12-01

The histamine H(3) receptor (H(3)R) plays a pivotal role in a plethora of therapeutic areas. Blocking the H(3)R with antagonists/inverse agonists has been postulated to be of broad therapeutic use. Indeed, H(3)R antagonists/inverse agonists have been extensively evaluated in the clinic. Here, we address new developments, insights obtained and challenges encountered in the clinical evaluations. For recent H(3)R clinical candidates, the status and results of the corresponding clinical trial(s) will be discussed along with preclinical data. In all, it becomes evident that clinical evaluation of H(3)R antagonists/inverse agonists is characterized by mixed results. On one hand, Pitolisant has successfully passed several Phase II trials and seems to be the most advanced compound in the clinic now, being in Phase III. On the other hand, some compounds (e.g., PF-03654647 and MK-0249) failed at Phase II clinical level for several indications. A challenging feature in H(3)R research is the multifaceted role of the receptor at a molecular/biochemical level, which can complicate targeting by small molecules at several (pre)clinical levels. Accordingly, H(3)R antagonists/inverse agonists require further testing to pinpoint the determinants for clinical efficacy and to aid in the final push towards the market.

Preclinical and clinical development of YFV 17D-based chimeric vaccines against dengue, West Nile and Japanese encephalitis viruses.

PubMed

Guy, Bruno; Guirakhoo, Farshad; Barban, Veronique; Higgs, Stephen; Monath, Thomas P; Lang, Jean

2010-01-08

Dengue viruses (DENV), West Nile virus (WNV) and Japanese encephalitis virus (JEV) are major global health and growing medical problems. While a live-attenuated vaccine exists since decades against the prototype flavivirus, yellow fever virus (YFV), there is an urgent need for vaccines against dengue or West Nile diseases, and for improved vaccines against Japanese encephalitis. Live-attenuated chimeric viruses were constructed by replacing the genes coding for Premembrane (prM) and Envelope (E) proteins from YFV 17D vaccine strain with those of heterologous flaviviruses (ChimeriVax technology). This technology has been used to produce vaccine candidates for humans, for construction of a horse vaccine for West Nile fever, and as diagnostic reagents for dengue, Japanese encephalitis, West Nile and St. Louis encephalitis infections. This review focuses on human vaccines and their characterization from the early stages of research through to clinical development. Phenotypic and genetic properties and stability were examined, preclinical evaluation through in vitro or animal models, and clinical testing were carried out. Theoretical environmental concerns linked to the live and genetically modified nature of these vaccines have been carefully addressed. Results of the extensive characterizations are in accordance with the immunogenicity and excellent safety profile of the ChimeriVax-based vaccine candidates, and support their development towards large-scale efficacy trials and registration.

Low dose native type II collagen prevents pain in a rat osteoarthritis model

PubMed Central

2013-01-01

Background Osteoarthritis is the most widespread joint-affecting disease. Patients with osteoarthritis experience pain and impaired mobility resulting in marked reduction of quality of life. A progressive cartilage loss is responsible of an evolving disease difficult to treat. The characteristic of chronicity determines the need of new active disease modifying drugs. Aim of the present research is to evaluate the role of low doses of native type II collagen in the rat model of osteoarthritis induced by sodium monoiodoacetate (MIA). Methods 1, 3 and 10 mg kg-1 porcine native type II collagen were daily per os administered for 13 days starting from the day of MIA intra-articular injection. Results On day 14, collagen-treated rats showed a significant prevention of pain threshold alterations induced by MIA. Evaluation were performed on paws using mechanical noxious (Paw pressure test) or non-noxious (Electronic Von Frey test) stimuli, and a decrease of articular pain was directly measured on the damaged joint (PAM test). The efficacy of collagen in reducing pain was as higher as the dose was lowered. Moreover, a reduced postural unbalance, measured as hind limb weight bearing alterations (Incapacitance test), and a general improvement of motor activity (Animex test) were observed. Finally, the decrease of plasma and urine levels of CTX-II (Cross Linked C-Telopeptide of Type II Collagen), a biomarker of cartilage degradation, suggests a collagen-dependent decrease of structural joint damage. Conclusions These results describe the preclinical efficacy of low dosages of native type II collagen as pain reliever by a mechanism that involves a protective effect on cartilage. PMID:23915264

Tau and Amyloid Positron Emission Tomography Imaging Predict Driving Performance Among Older Adults with and without Preclinical Alzheimer's Disease.

PubMed

Roe, Catherine M; Babulal, Ganesh M; Mishra, Shruti; Gordon, Brian A; Stout, Sarah H; Ott, Brian R; Carr, David B; Ances, Beau M; Morris, John C; Benzinger, Tammie L S

2018-01-01

Abnormal levels of Alzheimer's disease (AD) biomarkers, measured by positron emission tomography imaging using amyloid-based radiotracers and cerebrospinal fluid, are associated with impaired driving performance in older adults. We examined whether preclinical AD staging, defined using amyloid imaging and tau imaging using the radiotracer T807 (AKA flortaucipir or AV-1451), was associated with receiving a marginal/fail rating on a standardized road test (n = 42). Participants at Stage 2 (positive amyloid and tau scans) of preclinical AD were more likely to receive a marginal/fail rating compared to participants at Stage 0 or 1. Stage 2 preclinical AD may manifest in worse driving performance.

Pre-admission criteria and pre-clinical achievement: Can they predict medical students performance in the clinical phase?

PubMed

Salem, Raneem O; Al-Mously, Najwa; AlFadil, Sara; Baalash, Amal

2016-01-01

Various factors affect medical students' performance during clinical phase. Identifying these factors would help in mentoring weak students and help in selection process for residency programmes. Our study objective is to evaluate the impact of pre-admission criteria, and pre-clinical grade point average (GPA) on undergraduate medical students' performance during clinical phase. This study has a cross-sectional design that includes fifth- and sixth-year female medical students (71). Data of clinical and pre-clinical GPA in medical school and pre-admission to medical school tests scores were collected. A significant correlation between clinical GPA with the pre-clinical GPA was observed (p < 0.05). Such significant correlation was not seen with other variables under study. A regression analysis was performed, and the only significant predictor of students clinical performance was the pre-clinical GPA (p < 0.001). However, no significant difference between students' clinical and pre-clinical GPA for both cohorts was observed (p > 0.05). Pre-clinical GPA is strongly correlated with and can predict medical students' performance during clinical years. Our study highlighted the importance of evaluating the academic performances of students in pre-clinical years before they move into clinical years in order to identify weak students to mentor them and monitor their progress.

Preclinical QT safety assessment: cross-species comparisons and human translation from an industry consortium.

PubMed

Holzgrefe, Henry; Ferber, Georg; Champeroux, Pascal; Gill, Michael; Honda, Masaki; Greiter-Wilke, Andrea; Baird, Theodore; Meyer, Olivier; Saulnier, Muriel

2014-01-01

In vivo models have been required to demonstrate relative cardiac safety, but model sensitivity has not been systematically investigated. Cross-species and human translation of repolarization delay, assessed as QT/QTc prolongation, has not been compared employing common methodologies across multiple species and sites. Therefore, the accurate translation of repolarization results within and between preclinical species, and to man, remains problematic. Six pharmaceutical companies entered into an informal consortium designed to collect high-resolution telemetered data in multiple species (dog; n=34, cynomolgus; n=37, minipig; n=12, marmoset; n=14, guinea pig; n=5, and man; n=57). All animals received vehicle and varying doses of moxifloxacin (3-100 mg/kg, p.o.) with telemetered ECGs (≥500 Hz) obtained for 20-24h post-dose. Individual probabilistic QT-RR relationships were derived for each subject. The rate-correction efficacies of the individual (QTca) and generic correction formulae (Bazett, Fridericia, and Van de Water) were objectively assessed as the mean squared slopes of the QTc-RR relationships. Normalized moxifloxacin QTca responses (Veh Δ%/μM) were derived for 1h centered on the moxifloxacin Tmax. All QT-RR ranges demonstrated probabilistic uncertainty; slopes varied distinctly by species where dog and human exhibited the lowest QT rate-dependence, which was much steeper in the cynomolgus and guinea pig. Incorporating probabilistic uncertainty, the normalized QTca-moxifloxacin responses were similarly conserved across all species, including man. The current results provide the first unambiguous evidence that all preclinical in vivo repolarization assays, when accurately modeled and evaluated, yield results that are consistent with the conservation of moxifloxacin-induced QT prolongation across all common preclinical species. Furthermore, these outcomes are directly transferable across all species including man. The consortium results indicate that the implementation of standardized QTc data presentation, QTc reference cycle lengths, and rate-correction coefficients can markedly improve the concordance of preclinical and clinical outcomes in most preclinical species. Copyright © 2013 Elsevier Inc. All rights reserved.

A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease.

PubMed

Vichinsky, Elliott; Onyekwere, Onyinye; Porter, John; Swerdlow, Paul; Eckman, James; Lane, Peter; Files, Beatrice; Hassell, Kathryn; Kelly, Patrick; Wilson, Felicia; Bernaudin, Françoise; Forni, Gian Luca; Okpala, Iheanyi; Ressayre-Djaffer, Catherine; Alberti, Daniele; Holland, Jaymes; Marks, Peter; Fung, Ellen; Fischer, Roland; Mueller, Brigitta U; Coates, Thomas

2007-02-01

Deferasirox is a once-daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open-label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change in liver iron concentration (LIC) using biosusceptometry, was a secondary objective. A total of 195 adult and paediatric patients received deferasirox (n = 132) or deferoxamine (n = 63). Adverse events most commonly associated with deferasirox were mild, including transient nausea, vomiting, diarrhoea, abdominal pain and skin rash. Abnormal laboratory studies with deferasirox were occasionally associated with mild non-progressive increases in serum creatinine and reversible elevations in liver function tests. Discontinuation rates from deferasirox (11.4%) and deferoxamine (11.1%) were similar. Over 1 year, similar dose-dependent LIC reductions were observed with deferasirox and deferoxamine. Once-daily oral deferasirox has acceptable tolerability and appears to have similar efficacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease.

Rational Combinations of Targeted Agents in AML

PubMed Central

Bose, Prithviraj; Grant, Steven

2015-01-01

Despite modest improvements in survival over the last several decades, the treatment of AML continues to present a formidable challenge. Most patients are elderly, and these individuals, as well as those with secondary, therapy-related, or relapsed/refractory AML, are particularly difficult to treat, owing to both aggressive disease biology and the high toxicity of current chemotherapeutic regimens. It has become increasingly apparent in recent years that coordinated interruption of cooperative survival signaling pathways in malignant cells is necessary for optimal therapeutic results. The modest efficacy of monotherapy with both cytotoxic and targeted agents in AML testifies to this. As the complex biology of AML continues to be elucidated, many “synthetic lethal” strategies involving rational combinations of targeted agents have been developed. Unfortunately, relatively few of these have been tested clinically, although there is growing interest in this area. In this article, the preclinical and, where available, clinical data on some of the most promising rational combinations of targeted agents in AML are summarized. While new molecules should continue to be combined with conventional genotoxic drugs of proven efficacy, there is perhaps a need to rethink traditional philosophies of clinical trial development and regulatory approval with a focus on mechanism-based, synergistic strategies. PMID:26113989

Combination of palbociclib and radiotherapy for glioblastoma

PubMed Central

Whittaker, Shane; Madani, Daniel; Joshi, Swapna; Chung, Sylvia A; Johns, Terrance; Day, Bryan; Khasraw, Mustafa; McDonald, Kerrie L

2017-01-01

The cyclin-dependent kinase inhibitor, palbociclib has shown compelling efficacy in breast cancer patients. Several pre-clinical studies of glioblastoma (GBM) have also shown palbociclib to be efficacious. In this study, we investigated palbociclib in combination with radiation therapy (RT) for treating GBM. We tested palbociclib (with and without RT) on four patient-derived cell lines (PDCLs; RB1 retained; CDKN2A loss). We investigated the impact of therapy on the cell cycle and apoptosis using flow cytometry, in vitro. Balb/c nude mice were intracranially injected with the PDCL, GBM-L1 and treated orally with palbociclib (with and without RT). Overall survival was measured. Palbociclib treatment resulted in a significant increase in the percentage of cells in the G1 cell cycle phase. Apoptotic cell death, measured by Annexin V was induced. Palbociclib combined with RT acted synergistically with the significant impediment of colony formation. The oral treatment of mice with palbociclib did not show any significant survival advantage when compared to control mice, however when combined with RT, a survival advantage of 8 days was observed. Our results support the use of palbociclib as an adjuvant treatment to RT and warrant translation to the clinic. PMID:28690875

Route of Delivery Modulates the Efficacy of Mesenchymal Stem Cell Therapy for Myocardial Infarction: A Meta-Analysis of Preclinical Studies and Clinical Trials.

PubMed

Kanelidis, Anthony J; Premer, Courtney; Lopez, Juan; Balkan, Wayne; Hare, Joshua M

2017-03-31

Accumulating data support a therapeutic role for mesenchymal stem cell (MSC) therapy; however, there is no consensus on the optimal route of delivery. We tested the hypothesis that the route of MSC delivery influences the reduction in infarct size and improvement in left ventricular ejection fraction (LVEF). We performed a meta-analysis investigating the effect of MSC therapy in acute myocardial infarction (AMI) and chronic ischemic cardiomyopathy preclinical studies (58 studies; n=1165 mouse, rat, swine) which revealed a reduction in infarct size and improvement of LVEF in all animal models. Route of delivery was analyzed in AMI swine studies and clinical trials (6 clinical trials; n=334 patients). In AMI swine studies, transendocardial stem cell injection reduced infarct size (n=49, 9.4% reduction; 95% confidence interval, -15.9 to -3.0), whereas direct intramyocardial injection, intravenous infusion, and intracoronary infusion indicated no improvement. Similarly, transendocardial stem cell injection improved LVEF (n=65, 9.1% increase; 95% confidence interval, 3.7 to 14.5), as did direct intramyocardial injection and intravenous infusion, whereas intracoronary infusion demonstrated no improvement. In humans, changes of LVEF paralleled these results, with transendocardial stem cell injection improving LVEF (n=46, 7.0% increase; 95% confidence interval, 2.7 to 11.3), as did intravenous infusion, but again intracoronary infusion demonstrating no improvement. MSC therapy improves cardiac function in animal models of both AMI and chronic ischemic cardiomyopathy. The route of delivery seems to play a role in modulating the efficacy of MSC therapy in AMI swine studies and clinical trials, suggesting the superiority of transendocardial stem cell injection because of its reduction in infarct size and improvement of LVEF, which has important implications for the design of future studies. © 2016 American Heart Association, Inc.

Peer-assisted learning: filling the gaps in basic science education for preclinical medical students.

PubMed

Sammaraiee, Yezen; Mistry, Ravi D; Lim, Julian; Wittner, Liora; Deepak, Shantal; Lim, Gareth

2016-09-01

In contrast to peer-assisted learning (PAL) in clinical training, there is scant literature on the efficacy of PAL during basic medical sciences teaching for preclinical students. A group of senior medical students aimed to design and deliver clinically oriented small-group tutorials after every module in the preclinical curriculum at a United Kingdom medical school. Twenty tutorials were delivered by senior students throughout the year to first- and second-year students. A baseline questionnaire was delivered to inform the development of the program followed by an end-point questionnaire the next year (n = 122). Quizzes were administered before and after five separate tutorials to assess changes in mean student scores. Additionally, each tutorial was evaluated via a questionnaire for participants (n = 949). All five posttutorial quizzes showed a significant improvement in mean student score (P < 0.05). Questionnaires showed students found the program to be relevant and useful for revision purposes and appreciated how tutorials contextualized basic science to clinical medicine. Students appreciated the interactive nature of the sessions and found receiving personalized feedback about their learning and consolidating information with someone familiar with the material to be useful. With the inclusion of the program, students felt there were now an adequate number of tutorials during the year. In conclusion, this study shows that senior medical students can design and deliver a program that adds value to the mostly lecture-based formal preclinical curriculum. We hope that our study can prompt further work to explore the effect of PAL on the teaching of basic sciences during preclinical studies. Copyright © 2016 The American Physiological Society.

Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis.

PubMed

Nielsen, Suzanne; Sabioni, Pamela; Trigo, Jose M; Ware, Mark A; Betz-Stablein, Brigid D; Murnion, Bridin; Lintzeris, Nicholas; Khor, Kok Eng; Farrell, Michael; Smith, Andrew; Le Foll, Bernard

2017-08-01

Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED 50 ) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the ED 50 of morphine alone. In addition, the ED 50 for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n=2) than the ED 50 of codeine alone. One case series (n=3) provided very-low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration. Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia. In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, whereas one of the nine clinical studies identified provided very-low-quality evidence of such an effect. Prospective high-quality-controlled clinical trials are required to determine the opioid-sparing effect of cannabinoids.

Neuraxial Analgesia In Neonates And Infants: Review of Clinical and Preclinical Strategies for the Development of Safety and Efficacy Data

PubMed Central

Walker, Suellen M.; Yaksh, Tony L.

2015-01-01

Neuraxial agents provide robust pain control, have the potential to improve outcomes, and are an important component of the perioperative care of children. Opioids or clonidine improve analgesia when added to perioperative epidural infusions; analgesia is significantly prolonged by addition of clonidine, ketamine, neostigmine or tramadol to single shot caudal injections of local anesthetic; and neonatal intrathecal anesthesia/analgesia is increasing in some centers. However, it is difficult to determine the relative risk-benefit of different techniques and drugs without detailed and sensitive data related to analgesia requirements, side-effects, and follow-up. Current data related to benefits and complications in neonates and infants are summarized, but variability in current neuraxial drug use reflects the relative lack of high quality evidence. Recent preclinical reports of adverse effects of general anesthetics on the developing brain have increased awareness of the potential benefit of neuraxial anesthesia/analgesia to avoid or reduce general anesthetic dose requirements. However, the developing spinal cord is also vulnerable to drug-related toxicity, and although there are well-established preclinical models and criteria for assessing spinal cord toxicity in adult animals, until recently there had been no systematic evaluation during early life. Therefore, the second half of this review presents preclinical data evaluating age-dependent changes in the pharmacodynamic response to different spinal analgesics, and recent studies evaluating spinal toxicity in specific developmental models. Finally, we advocate use of neuraxial agents with the widest demonstrable safety margin and suggest minimum standards for preclinical evaluation prior to adoption of new analgesics or preparations into routine clinical practice. PMID:22798528

Rapid, non-invasive imaging of alphaviral brain infection: reducing animal numbers and morbidity to identify efficacy of potential vaccines and antivirals.

PubMed

Patterson, Michael; Poussard, Allison; Taylor, Katherine; Seregin, Alexey; Smith, Jeanon; Peng, Bi-Hung; Walker, Aida; Linde, Jenna; Smith, Jennifer; Salazar, Milagros; Paessler, Slobodan

2011-11-21

Rapid and accurate identification of disease progression are key factors in testing novel vaccines and antivirals against encephalitic alphaviruses. Typical efficacy studies utilize a large number of animals and severe morbidity or mortality as an endpoint. New technologies provide a means to reduce and refine the animal use as proposed in Hume's 3Rs (replacement, reduction, refinement) described by Russel and Burch. In vivo imaging systems (IVIS) and bioluminescent enzyme technologies accomplish the reduction of animal requirements while shortening the experimental time and improving the accuracy in localizing active virus replication. In the case of murine models of viral encephalitis in which central nervous system (CNS) viral invasion occurs rapidly but the disease development is relatively slow, we visualized the initial brain infection and enhance the data collection process required for efficacy studies on antivirals or vaccines that are aimed at preventing brain infection. Accordingly, we infected mice through intranasal inoculation with the genetically modified pathogen, Venezuelan equine encephalitis, which expresses a luciferase gene. In this study, we were able to identify the invasion of the CNS at least 3 days before any clinical signs of disease, allowing for reduction of animal morbidity providing a humane means of disease and vaccine research while obtaining scientific data accurately and more rapidly. Based on our data from the imaging model, we confirmed the usefulness of this technology in preclinical research by demonstrating the efficacy of Ampligen, a TLR-3 agonist, in preventing CNS invasion. Copyright © 2011 Elsevier Ltd. All rights reserved.

Pre-clinical cognitive phenotypes for Alzheimer disease: a latent profile approach.

PubMed

Hayden, Kathleen M; Kuchibhatla, Maragatha; Romero, Heather R; Plassman, Brenda L; Burke, James R; Browndyke, Jeffrey N; Welsh-Bohmer, Kathleen A

2014-11-01

Cognitive profiles for pre-clinical Alzheimer disease (AD) can be used to identify groups of individuals at risk for disease and better characterize pre-clinical disease. Profiles or patterns of performance as pre-clinical phenotypes may be more useful than individual test scores or measures of global decline. To evaluate patterns of cognitive performance in cognitively normal individuals to derive latent profiles associated with later onset of disease using a combination of factor analysis and latent profile analysis. The National Alzheimer Coordinating Centers collect data, including a battery of neuropsychological tests, from participants at 29 National Institute on Aging-funded Alzheimer Disease Centers across the United States. Prior factor analyses of this battery demonstrated a four-factor structure comprising memory, attention, language, and executive function. Factor scores from these analyses were used in a latent profile approach to characterize cognition among a group of cognitively normal participants (N = 3,911). Associations between latent profiles and disease outcomes an average of 3 years later were evaluated with multinomial regression models. Similar analyses were used to determine predictors of profile membership. Four groups were identified; each with distinct characteristics and significantly associated with later disease outcomes. Two groups were significantly associated with development of cognitive impairment. In post hoc analyses, both the Trail Making Test Part B, and a contrast score (Delayed Recall - Trails B), significantly predicted group membership and later cognitive impairment. Latent profile analysis is a useful method to evaluate patterns of cognition in large samples for the identification of preclinical AD phenotypes; comparable results, however, can be achieved with very sensitive tests and contrast scores. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

New Breed of Mice May Improve Accuracy for Preclinical Testing of Cancer Drugs | FNLCR Staging

Cancer.gov

A new breed of lab animals, dubbed “glowing head mice,” may do a better job than conventional mice in predicting the success of experimental cancer drugs—while also helping to meet an urgent need for more realistic preclinical animal models. Th

Biological mechanisms of immune escape and implications for immunotherapy in head and neck squamous cell carcinoma

PubMed Central

Moy, Jennifer D.; Moskovitz, Jessica M.; Ferris, Robert L.

2017-01-01

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with high morbidity and mortality. Despite advances in cytotoxic therapies and surgical techniques, overall survival (OS) has not improved over the past few decades. This emphasises the need for intense investigation into novel therapies with good tumour control and minimal toxicity. Cancer immunotherapy has led this endeavour, attempting to improve tumour recognition and expand immune responses against tumour cells. While various forms of HNSCC immunotherapy are in preclinical trials, the most promising direction thus far has been with monoclonal antibodies (mAbs), targeting growth factor and immune checkpoint receptors. Preclinical and early phase trials have shown unprecedented efficacy with minimal adverse effects. This article will review biological mechanisms of immune escape and implications for immunotherapy in HNSCC. PMID:28324750

Characterization of a sensitive mouse Aβ40 PD biomarker assay for Alzheimer's disease drug development in wild-type mice.

PubMed

Lu, Yanmei; Hoyte, Kwame; Montgomery, William H; Luk, Wilman; He, Dongping; Meilandt, William J; Zuchero, Y Joy Yu; Atwal, Jasvinder K; Scearce-Levie, Kimberly; Watts, Ryan J; DeForge, Laura E

2016-05-01

Transgenic mice that overexpress human amyloid precursor protein with Swedish or London (APPswe or APPlon) mutations have been widely used for preclinical Alzheimer's disease (AD) drug development. AD patients, however, rarely possess these mutations or overexpress APP. We developed a sensitive ELISA that specifically and accurately measures low levels of endogenous Aβ40 in mouse plasma, brain and CSF. In wild-type mice treated with a bispecific anti-TfR/BACE1 antibody, significant Aβ reductions were observed in the periphery and the brain. APPlon transgenic mice showed a slightly less reduction, whereas APPswe mice did not have any decrease. This sensitive and well-characterized mouse Aβ40 assay enables the use of wild-type mice for preclinical PK/PD and efficacy studies of potential AD therapeutics.

A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents

PubMed Central

Gray, Kevin M.; Carpenter, Matthew J.; Baker, Nathaniel L.; DeSantis, Stacia M.; Kryway, Elisabeth; Hartwell, Karen J.; McRae-Clark, Aimee L.; Brady, Kathleen T.

2012-01-01

Objective Preclinical findings suggest that the over-the-counter supplement N-acetylcysteine, via glutamate modulation in the nucleus accumbens, holds promise as a pharmacotherapy targeting substance dependence. We sought to investigate N-acetylcysteine as a novel cannabis cessation treatment in adolescents, a vulnerable group for whom existing treatments have limited efficacy. Method In this 8-week double-blind randomized placebo-controlled trial, treatment-seeking cannabis-dependent adolescents (age 15-21, N = 116) received N-acetylcysteine (1200 mg) or placebo twice daily, each added to a contingency management intervention and brief (≤10 minute) weekly cessation counseling. The primary efficacy measure was the odds of negative weekly urine cannabinoid tests during treatment among participants receiving N-acetylcysteine versus placebo, via intent-to-treat analysis. The primary tolerability measure was frequency of adverse events, compared by treatment group. Results N-acetylcysteine was well tolerated with minimal adverse events. N-acetylcysteine participants had more than twice the odds, compared to placebo participants, of submitting negative urine cannabinoid tests during treatment (odds ratio = 2.4, [95% CI: 1.1-5.2], p = 0.029). Exploratory secondary abstinence outcomes numerically favored N-acetylcysteine, but were not statistically significant. Conclusions This is the first randomized trial of pharmacotherapy for cannabis dependence in any age group yielding a positive primary cessation outcome via intent-to-treat analysis. Findings support N-acetylcysteine as a pharmacotherapy to complement psychosocial treatment for cannabis dependence in adolescents. Further research is needed to replicate these findings and explore the efficacy of N-acetylcysteine across a variety of treatment contexts and outcomes. Trial Registration clinicaltrials.gov identifier: NCT 01005810 PMID:22706327

The Recombinant Bacille Calmette-Guérin Vaccine VPM1002: Ready for Clinical Efficacy Testing.

PubMed

Nieuwenhuizen, Natalie E; Kulkarni, Prasad S; Shaligram, Umesh; Cotton, Mark F; Rentsch, Cyrill A; Eisele, Bernd; Grode, Leander; Kaufmann, Stefan H E

2017-01-01

The only licensed vaccine against tuberculosis (TB), bacille Calmette-Guérin (BCG), protects against severe extrapulmonary forms of TB but is virtually ineffective against the most prevalent form of the disease, pulmonary TB. BCG was genetically modified at the Max Planck Institute for Infection Biology to improve its immunogenicity by replacing the urease C encoding gene with the listeriolysin encoding gene from Listeria monocytogenes . Listeriolysin perturbates the phagosomal membrane at acidic pH. Urease C is involved in neutralization of the phagosome harboring BCG. Its depletion allows for rapid phagosome acidification and promotes phagolysosome fusion. As a result, BCGΔ ureC :: hly (VPM1002) promotes apoptosis and autophagy and facilitates release of mycobacterial antigens into the cytosol. In preclinical studies, VPM1002 has been far more efficacious and safer than BCG. The vaccine was licensed to Vakzine Projekt Management and later sublicensed to the Serum Institute of India Pvt. Ltd., the largest vaccine producer in the world. The vaccine has passed phase I clinical trials in Germany and South Africa, demonstrating its safety and immunogenicity in young adults. It was also successfully tested in a phase IIa randomized clinical trial in healthy South African newborns and is currently undergoing a phase IIb study in HIV exposed and unexposed newborns. A phase II/III clinical trial will commence in India in 2017 to assess efficacy against recurrence of TB. The target indications for VPM1002 are newborn immunization to prevent TB as well as post-exposure immunization in adults to prevent TB recurrence. In addition, a Phase I trial in non-muscle invasive bladder cancer patients has been completed, and phase II trials are ongoing. This review describes the development of VPM1002 from the drawing board to its clinical assessment.

Selective Cathepsin S Inhibition with MIV-247 Attenuates Mechanical Allodynia and Enhances the Antiallodynic Effects of Gabapentin and Pregabalin in a Mouse Model of Neuropathic Pain.

PubMed

Hewitt, Ellen; Pitcher, Thomas; Rizoska, Biljana; Tunblad, Karin; Henderson, Ian; Sahlberg, Britt-Louise; Grabowska, Urszula; Classon, Björn; Edenius, Charlotte; Malcangio, Marzia; Lindström, Erik

2016-09-01

Cathepsin S inhibitors attenuate mechanical allodynia in preclinical neuropathic pain models. The current study evaluated the effects when combining the selective cathepsin S inhibitor MIV-247 with gabapentin or pregabalin in a mouse model of neuropathic pain. Mice were rendered neuropathic by partial sciatic nerve ligation. MIV-247, gabapentin, or pregabalin were administered alone or in combination via oral gavage. Mechanical allodynia was assessed using von Frey hairs. Neurobehavioral side effects were evaluated by assessing beam walking. MIV-247, gabapentin, and pregabalin concentrations in various tissues were measured. Oral administration of MIV-247 (100-200 µmol/kg) dose-dependently attenuated mechanical allodynia by up to approximately 50% reversal when given as a single dose or when given twice daily for 5 days. No behavioral deficits were observed at any dose of MIV-247 tested. Gabapentin (58-350 µmol/kg) and pregabalin (63-377 µmol/kg) also inhibited mechanical allodynia with virtually complete reversal at the highest doses tested. The minimum effective dose of MIV-247 (100 µmol/kg) in combination with the minimum effective dose of pregabalin (75 µmol/kg) or gabapentin (146 µmol/kg) resulted in enhanced antiallodynic efficacy without augmenting side effects. A subeffective dose of MIV-247 (50 µmol/kg) in combination with a subeffective dose of pregabalin (38 µmol/kg) or gabapentin (73 µmol/kg) also resulted in substantial efficacy. Plasma levels of MIV-247, gabapentin, and pregabalin were similar when given in combination as to when given alone. Cathepsin S inhibition with MIV-247 exerts significant antiallodynic efficacy alone, and also enhances the effect of gabapentin and pregabalin without increasing side effects or inducing pharmacokinetic interactions. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Drug development: from concept to marketing!

PubMed

Tamimi, Nihad A M; Ellis, Peter

2009-01-01

Drug development is an expensive, long and high-risk business taking 10-15 years and is associated with a high attrition rate. It is driven by medical need, disease prevalence and the likelihood of success. Drug candidate selection is an iterative process between chemistry and biology, refining the molecular properties until a compound suitable for advancing to man is found. Typically, about one in a thousand synthesised compounds is ever selected for progression to the clinic. Prior to administration to humans, the pharmacology and biochemistry of the drug is established using an extensive range of in vitro and in vivo test procedures. It is also a regulatory requirement that the drug is administered to animals to assess its safety. Later-stage animal testing is also required to assess carcinogenicity and effects on the reproductive system. Clinical phases of drug development include phase I in healthy volunteers to assess primarily pharmacokinetics, safety and toleration, phase II in a cohort of patients with the target disease to establish efficacy and dose-response relationship and large-scale phase III studies to confirm safety and efficacy. Experience tells us that approximately only 1 in 10 drugs that start the clinical phase will make it to the market. Each drug must demonstrate safety and efficacy in the intended patient population and its benefits must outweigh its risks before it will be approved by the regulatory agencies. Strict regulatory standards govern the conduct of pre-clinical and clinical trials as well as the manufacturing of pharmaceutical products. The assessment of the new medicinal product's safety continues beyond the initial drug approval through post-marketing monitoring of adverse events. Copyright 2009 S. Karger AG, Basel.

Preclinical Colorectal Cancer Chemopreventive Efficacy and p53-Modulating Activity of 3′,4′,5′-Trimethoxyflavonol, a Quercetin Analog

PubMed Central

Howells, Lynne M; Britton, Robert G; Mazzoletti, Marco; Greaves, Peter; Broggini, Massimo; Brown, Karen; Steward, William P; Gescher, Andreas J; Sale, Stewart

2010-01-01

Some naturally occurring flavonols, exemplified by quercetin, appear to possess experimental cancer chemopreventive efficacy. Modulation of p53 is a mechanism thought to contribute to their activity. The hypothesis was tested that a synthetic flavonol, 3′,4′,5′-trimethoxyflavonol (TMFol), can interfere with tumor development and p53 expression in two models of colorectal carcinogenesis, ApcMin mice and human-derived HCT116 adenocarcinoma-bearing nude mice. Mice received TMFol with their diet (0.2%) from weaning to week 16 in the case of ApcMin, or from either day 7 prior to (“TMFol early”) or day 7 after (“TMFol late”) tumor inoculation in HCT116 mice. The ability of TMFol to affect tumor proliferation or apoptosis, as reflected by staining for Ki-67 or cleaved caspase 3, respectively, was studied in HCT116 tumors. TMFol tumor levels were measured by HPLC. Consumption of TMFol reduced small intestinal adenoma burden in ApcMin mice by 47%, compared to control mice (P<0.002). The TMFol early regimen approximately halved HCT116 tumor size (P<0.05), decreased tumor proliferation and increased apoptosis, whilst the TMFol late regimen had no significant effect, when compared to controls. In tumor tissues from mice, in which TMFol reduced tumor development, p53 expression was increased, 3-fold in ApcMin and 1.5-fold in HCT116 tumor-bearing mice (P=0.02). TMFol increased p53 also in cells derived from these tumors. TMFol was detected in HCT116 tumors, but levels did not correlate to tumor burden. TMFol was not mutagenic in the Ames test. The results suggest that chemical modification of the flavonol structure may generate safe and efficacious cancer chemopreventive agents. PMID:20628003

Lack of efficacy of L-759274, a novel neurokinin 1 (substance P) receptor antagonist, for the treatment of generalized anxiety disorder.

PubMed

Michelson, David; Hargreaves, Richard; Alexander, Robert; Ceesay, Paulette; Hietala, Jarmo; Lines, Christopher; Reines, Scott

2013-02-01

Preclinical studies suggest that substance P acting at neurokinin 1 (NK1) receptors may be involved in stress responses and NK1 receptor antagonists show activity in tests of anxiety. These data raise the possibility that NK1 receptor antagonists could be potential anxiolytic treatments in humans. We evaluated this hypothesis clinically using the NK1 antagonist L-759274. This is a randomized, double-blind, placebo- and active-controlled, multicentre, proof-of-concept trial. Patients with generalized anxiety disorder were randomized 1:1:1 to 6 wk of treatment with 40 mg L-759274 (n = 73), 1-6 mg lorazepam (n = 69) or placebo (n = 71). Efficacy was assessed using the Hamilton Anxiety Scale (HAMA). A positron emission tomography (PET) study was also performed in 16 healthy subjects to determine the relationship between NK1 receptor occupancy and plasma levels of L-759274 to verify adequate target engagement by the doses tested during the clinical trial. No statistically significant difference in mean change from baseline HAMA score at 6 wk was seen for L-759274 vs. placebo [difference = 1.0 (95% confidence intervals (CI) -1.2 to 3.2), p = 0.359] whereas the lorazepam group did show a significant improvement vs. placebo (difference = -2.7, 95% CI -5.0 to -0.4, p = 0.020) and L-759274 (difference = 3.7, 95% CI 1.5-6.0, p = 0.001]. Results from the PET study indicated that the L-759274 dosing regimen used in the clinical trial likely provided high levels of NK1 receptor occupancy (>90%), supporting the view that it was an adequate proof-of-concept trial. The NK1 receptor antagonist L-759274 does not appear to be efficacious for the treatment of generalized anxiety disorder.

Immunogenicity of HPV prophylactic vaccines: Serology assays and their use in HPV vaccine evaluation and development.

PubMed

Pinto, Ligia A; Dillner, Joakim; Beddows, Simon; Unger, Elizabeth R

2018-01-17

When administered as standard three-dose schedules, the licensed HPV prophylactic vaccines have demonstrated extraordinary immunogenicity and efficacy. We summarize the immunogenicity of these licensed vaccines and the most commonly used serology assays, with a focus on key considerations for one-dose vaccine schedules. Although immune correlates of protection against infection are not entirely clear, both preclinical and clinical evidence point to neutralizing antibodies as the principal mechanism of protection. Thus, immunogenicity assessments in vaccine trials have focused on measurements of antibody responses to the vaccine. Non-inferiority of antibody responses after two doses of HPV vaccines separated by 6 months has been demonstrated and this evidence supported the recent WHO recommendations for two-dose vaccination schedules in both boys and girls 9-14 years of age. There is also some evidence suggesting that one dose of HPV vaccines may provide protection similar to the currently recommended two-dose regimens but robust data on efficacy and immunogenicity of one-dose vaccine schedules are lacking. In addition, immunogenicity has been assessed and reported using different methods, precluding direct comparison of results between different studies and vaccines. New head-to-head vaccine trials evaluating one-dose immunogenicity and efficacy have been initiated and an increase in the number of trials relying on immunobridging is anticipated. Therefore, standardized measurement and reporting of immunogenicity for the up to nine HPV types targeted by the current vaccines is now critical. Building on previous HPV serology assay standardization and harmonization efforts initiated by the WHO HPV LabNet in 2006, new secondary standards, critical reference reagents and testing guidelines will be generated as part of a new partnership to facilitate harmonization of the immunogenicity testing in new HPV vaccine trials. Copyright © 2018 Elsevier Ltd. All rights reserved.

Global measurement of coagulation in plasma from normal and haemophilia dogs using a novel modified thrombin generation test – Demonstrated in vitro and ex vivo

PubMed Central

Madsen, Daniel Elenius; Nichols, Timothy C.; Merricks, Elizabeth P.; Waters, Emily K.; Wiinberg, Bo

2017-01-01

Introduction Canine models of severe haemophilia resemble their human equivalents both regarding clinical bleeding phenotype and response to treatment. Therefore pre-clinical studies in haemophilia dogs have allowed researchers to make valuable translational predictions regarding the potency and efficacy of new anti-haemophilia drugs (AHDs) in humans. To refine in vivo experiments and reduce number of animals, such translational studies are ideally preceded by in vitro prediction of compound efficacy using a plasma based global coagulation method. One such widely used method is the thrombin generation test (TGT). Unfortunately, commercially available TGTs are incapable of distinguishing between normal and haemophilia canine plasma, and therefore in vitro prediction using TGT has so far not been possible in canine plasma material. Aim Establish a modified TGT capable of: 1) distinguishing between normal and haemophilia canine plasma, 2) monitoring correlation between canine plasma levels of coagulation factor VIII (FVIII) and IX (FIX) and thrombin generation, 3) assessing for agreement between compound activity and thrombin generation in ex vivo samples. Methods A modified TGT assay was established where coagulation was triggered using a commercially available activated partial thromboplastin time reagent. Results With the modified TGT a significant difference was observed in thrombin generation between normal and haemophilia canine plasma. A dose dependent thrombin generation was observed when assessing haemophilia A and B plasma spiked with dilution series of FVIII and FIX, respectively. Correlation between FVIII activity and thrombin generation was observed when analyzing samples from haemophilia A dogs dosed with canine FVIII. Limit of detection was 0.1% (v/v) FVIII or FIX. Conclusion A novel modified TGT suitable for monitoring and prediction of replacement therapy efficacy in plasma from haemophilia A and B dogs was established. PMID:28384182

Acquisition of dental skills in preclinical technique courses: influence of spatial and manual abilities.

PubMed

Schwibbe, Anja; Kothe, Christian; Hampe, Wolfgang; Konradt, Udo

2016-10-01

Sixty years of research have not added up to a concordant evaluation of the influence of spatial and manual abilities on dental skill acquisition. We used Ackerman's theory of ability determinants of skill acquisition to explain the influence of spatial visualization and manual dexterity on the task performance of dental students in two consecutive preclinical technique courses. We measured spatial and manual abilities of applicants to Hamburg Dental School by means of a multiple choice test on Technical Aptitude and a wire-bending test, respectively. Preclinical dental technique tasks were categorized as consistent-simple and inconsistent-complex based on their contents. For analysis, we used robust regression to circumvent typical limitations in dental studies like small sample size and non-normal residual distributions. We found that manual, but not spatial ability exhibited a moderate influence on the performance in consistent-simple tasks during dental skill acquisition in preclinical dentistry. Both abilities revealed a moderate relation with the performance in inconsistent-complex tasks. These findings support the hypotheses which we had postulated on the basis of Ackerman's work. Therefore, spatial as well as manual ability are required for the acquisition of dental skills in preclinical technique courses. These results support the view that both abilities should be addressed in dental admission procedures in addition to cognitive measures.

A proposed integrated approach for the preclinical evaluation of phage therapy in Pseudomonas infections

NASA Astrophysics Data System (ADS)

Danis-Wlodarczyk, Katarzyna; Vandenheuvel, Dieter; Jang, Ho Bin; Briers, Yves; Olszak, Tomasz; Arabski, Michal; Wasik, Slawomir; Drabik, Marcin; Higgins, Gerard; Tyrrell, Jean; Harvey, Brian J.; Noben, Jean-Paul; Lavigne, Rob; Drulis-Kawa, Zuzanna

2016-06-01

Bacteriophage therapy is currently resurging as a potential complement/alternative to antibiotic treatment. However, preclinical evaluation lacks streamlined approaches. We here focus on preclinical approaches which have been implemented to assess bacteriophage efficacy against Pseudomonas biofilms and infections. Laser interferometry and profilometry were applied to measure biofilm matrix permeability and surface geometry changes, respectively. These biophysical approaches were combined with an advanced Airway Surface Liquid infection model, which mimics in vitro the normal and CF lung environments, and an in vivo Galleria larvae model. These assays have been implemented to analyze KTN4 (279,593 bp dsDNA genome), a type-IV pili dependent, giant phage resembling phiKZ. Upon contact, KTN4 immediately disrupts the P. aeruginosa PAO1 biofilm and reduces pyocyanin and siderophore production. The gentamicin exclusion assay on NuLi-1 and CuFi-1 cell lines revealed the decrease of extracellular bacterial load between 4 and 7 logs and successfully prevents wild-type Pseudomonas internalization into CF epithelial cells. These properties and the significant rescue of Galleria larvae indicate that giant KTN4 phage is a suitable candidate for in vivo phage therapy evaluation for lung infection applications.

Preclinical Models in Chimeric Antigen Receptor-Engineered T-Cell Therapy.

PubMed

Siegler, Elizabeth Louise; Wang, Pin

2018-05-01

Cancer immunotherapy has enormous potential in inducing long-term remission in cancer patients, and chimeric antigen receptor (CAR)-engineered T cells have been largely successful in treating hematological malignancies in the clinic. CAR-T therapy has not been as effective in treating solid tumors, in part due to the immunosuppressive tumor microenvironment. Additionally, CAR-T therapy can cause dangerous side effects, including off-tumor toxicity, cytokine release syndrome, and neurotoxicity. Animal models of CAR-T therapy often fail to predict such adverse events and frequently overestimate the efficacy of the treatment. Nearly all preclinical CAR-T studies have been performed in mice, including syngeneic, xenograft, transgenic, and humanized mouse models. Recently, a few studies have used primate models to mimic clinical side effects better. To date, no single model perfectly recapitulates the human immune system and tumor microenvironment, and some models have revealed CAR-T limitations that were contradicted or missed entirely in other models. Careful model selection based on the primary goals of the study is a crucial step in evaluating CAR-T treatment. Advancements are being made in preclinical models, with the ultimate objective of providing safer, more effective CAR-T therapy to patients.

The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity

PubMed Central

Barretina, Jordi; Caponigro, Giordano; Stransky, Nicolas; Venkatesan, Kavitha; Margolin, Adam A.; Kim, Sungjoon; Wilson, Christopher J.; Lehár, Joseph; Kryukov, Gregory V.; Sonkin, Dmitriy; Reddy, Anupama; Liu, Manway; Murray, Lauren; Berger, Michael F.; Monahan, John E.; Morais, Paula; Meltzer, Jodi; Korejwa, Adam; Jané-Valbuena, Judit; Mapa, Felipa A.; Thibault, Joseph; Bric-Furlong, Eva; Raman, Pichai; Shipway, Aaron; Engels, Ingo H.; Cheng, Jill; Yu, Guoying K.; Yu, Jianjun; Aspesi, Peter; de Silva, Melanie; Jagtap, Kalpana; Jones, Michael D.; Wang, Li; Hatton, Charles; Palescandolo, Emanuele; Gupta, Supriya; Mahan, Scott; Sougnez, Carrie; Onofrio, Robert C.; Liefeld, Ted; MacConaill, Laura; Winckler, Wendy; Reich, Michael; Li, Nanxin; Mesirov, Jill P.; Gabriel, Stacey B.; Getz, Gad; Ardlie, Kristin; Chan, Vivien; Myer, Vic E.; Weber, Barbara L.; Porter, Jeff; Warmuth, Markus; Finan, Peter; Harris, Jennifer L.; Meyerson, Matthew; Golub, Todd R.; Morrissey, Michael P.; Sellers, William R.; Schlegel, Robert; Garraway, Levi A.

2012-01-01

The systematic translation of cancer genomic data into knowledge of tumor biology and therapeutic avenues remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacologic annotation is available1. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number, and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacologic profiles for 24 anticancer drugs across 479 of the lines, this collection allowed identification of genetic, lineage, and gene expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Altogether, our results suggest that large, annotated cell line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of “personalized” therapeutic regimens2. PMID:22460905

Preclinical Development of Cell-Based Products: a European Regulatory Science Perspective.

PubMed

McBlane, James W; Phul, Parvinder; Sharpe, Michaela

2018-06-25

This article describes preclinical development of cell-based medicinal products for European markets and discusses European regulatory mechanisms open to developers to aid successful product development. Cell-based medicinal products are diverse, including cells that are autologous or allogeneic, have been genetically modified, or not, or expanded ex vivo, and applied systemically or to an anatomical site different to that of their origin; comments applicable to one product may not be applicable to others, so bespoke development is needed, for all elements - quality, preclinical and clinical. After establishing how the product is produced, proof of potential for therapeutic efficacy, and then safety, of the product need to be determined. This includes understanding biodistribution, persistence and toxicity, including potential for malignant transformation. These elements need to be considered in the context of the intended clinical development. This article describes regulatory mechanisms available to developers to support product development that aim to resolve scientific issues prior to marketing authorization application, to enable patients to have faster access to the product than would otherwise be the case. Developers are encouraged to be aware of both the scientific issues and regulatory mechanisms to ensure patients can be supplied with these products.

Benefit of combination therapy in epilepsy: a review of the preclinical evidence with levetiracetam.

PubMed

Kaminski, Rafal M; Matagne, Alain; Patsalos, Philip N; Klitgaard, Henrik

2009-03-01

Levetiracetam (Keppra) is an antiepileptic drug (AED) characterized by a novel mechanism of action, unique profile of activity in seizure models, and broad-spectrum clinical efficacy. The present report critically reviews several preclinical studies focused on combination therapy with levetiracetam and other anticonvulsants in various seizure and epilepsy models. Administration of levetiracetam together with many different clinically used AEDs or other anticonvulsants generally enhances their protective activity and, among existing AEDs, this was particularly prevalent with valproate. The protective activity of other AEDs was also enhanced by levetiracetam, which seems to be a universal finding that is independent of seizure model or drug combination studied. However, particularly strong enhancement was observed when levetiracetam was combined with agents either enhancing GABAergic or reducing glutamatergic neurotransmission. Importantly, these combinations were not associated with exacerbation of side effects or pharmacokinetic interactions. Based on the available preclinical data, it appears that combination treatment with levetiracetam and other anticonvulsants provides additional therapeutic benefit that may be attributed to its novel and distinct mechanism of action. Moreover, combinations of levetiracetam with clinically used AEDs that enhance GABAergic inhibition may be considered for rational polytherapy, which is often necessary in drug-resistant patients.

The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity.

PubMed

Barretina, Jordi; Caponigro, Giordano; Stransky, Nicolas; Venkatesan, Kavitha; Margolin, Adam A; Kim, Sungjoon; Wilson, Christopher J; Lehár, Joseph; Kryukov, Gregory V; Sonkin, Dmitriy; Reddy, Anupama; Liu, Manway; Murray, Lauren; Berger, Michael F; Monahan, John E; Morais, Paula; Meltzer, Jodi; Korejwa, Adam; Jané-Valbuena, Judit; Mapa, Felipa A; Thibault, Joseph; Bric-Furlong, Eva; Raman, Pichai; Shipway, Aaron; Engels, Ingo H; Cheng, Jill; Yu, Guoying K; Yu, Jianjun; Aspesi, Peter; de Silva, Melanie; Jagtap, Kalpana; Jones, Michael D; Wang, Li; Hatton, Charles; Palescandolo, Emanuele; Gupta, Supriya; Mahan, Scott; Sougnez, Carrie; Onofrio, Robert C; Liefeld, Ted; MacConaill, Laura; Winckler, Wendy; Reich, Michael; Li, Nanxin; Mesirov, Jill P; Gabriel, Stacey B; Getz, Gad; Ardlie, Kristin; Chan, Vivien; Myer, Vic E; Weber, Barbara L; Porter, Jeff; Warmuth, Markus; Finan, Peter; Harris, Jennifer L; Meyerson, Matthew; Golub, Todd R; Morrissey, Michael P; Sellers, William R; Schlegel, Robert; Garraway, Levi A

2012-03-28

The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.

Feasibility of spatial frequency domain imaging (SFDI) for optically characterizing a preclinical oncology model.

PubMed

Tabassum, Syeda; Zhao, Yanyu; Istfan, Raeef; Wu, Junjie; Waxman, David J; Roblyer, Darren

2016-10-01

Determination of chemotherapy efficacy early during treatment would provide more opportunities for physicians to alter and adapt treatment plans. Diffuse optical technologies may be ideally suited to track early biological events following chemotherapy administration due to low cost and high information content. We evaluated the use of spatial frequency domain imaging (SFDI) to characterize a small animal tumor model in order to move towards the goal of endogenous optical monitoring of cancer therapy in a controlled preclinical setting. The effects of key measurement parameters including the choice of imaging spatial frequency and the repeatability of measurements were evaluated. The precision of SFDI optical property extractions over repeat mouse measurements was determined to be within 3.52% for move and replace experiments. Baseline optical properties and chromophore values as well as intratumor heterogeneity were evaluated over 25 tumors. Additionally, tumor growth and chemotherapy response were monitored over a 45 day longitudinal study in a small number of mice to demonstrate the ability of SFDI to track treatment effects. Optical scattering and oxygen saturation increased as much as 70% and 25% respectively in treated tumors, suggesting SFDI may be useful for preclinical tracking of cancer therapies.

The Alzheimer’s Prevention Initiative composite cognitive test score: Sample size estimates for the evaluation of preclinical Alzheimer’s disease treatments in presenilin 1 E280A mutation carriers

PubMed Central

Ayutyanont, Napatkamon; Langbaum, Jessica B.; Hendrix, Suzanne B.; Chen, Kewei; Fleisher, Adam S.; Friesenhahn, Michel; Ward, Michael; Aguirre, Camilo; Acosta-Baena, Natalia; Madrigal, Lucìa; Muñoz, Claudia; Tirado, Victoria; Moreno, Sonia; Tariot, Pierre N.; Lopera, Francisco; Reiman, Eric M.

2014-01-01

Objective There is a need to identify a cognitive composite that is sensitive to tracking preclinical AD decline to be used as a primary endpoint in treatment trials. Method We capitalized on longitudinal data, collected from 1995 to 2010, from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the world’s largest known early-onset autosomal dominant AD (ADAD) kindred to identify a composite cognitive test with the greatest statistical power to track preclinical AD decline and estimate the number of carriers age 30 and older needed to detect a treatment effect in the Alzheimer’s Prevention Initiative’s (API) preclinical AD treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of one to seven cognitive tests/sub-tests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a two and five year follow-up period, using data from non-carriers during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top performing combinations and representation of relevant cognitive domains. Results This optimal test combination included CERAD Word List Recall, CERAD Boston Naming Test (high frequency items), MMSE Orientation to Time, CERAD Constructional Praxis and Ravens Progressive Matrices (Set A) with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR=0.38) or the entire CERAD-Col battery (MSDR=0.76). A sample size of 75 cognitively normal PSEN1-E280A mutation carriers age 30 and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, p=0.05). Conclusions We have identified a composite cognitive test score representing multiple cognitive domains that has improved power compared to the most sensitive single test item to track preclinical AD decline in ADAD mutation carriers and evaluate preclinical AD treatments. This API composite cognitive test score will be used as the primary endpoint in the first API trial in cognitively unimpaired ADAD carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset AD, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytical approaches. PMID:24816373

Experimental Lung Cancer Drug Shows Early Promise | Poster

Cancer.gov

By Frank Blanchard, Staff Writer A first-of-its-kind drug is showing early promise in attacking certain lung cancers that are hard to treat because they build up resistance to conventional chemotherapy. The drug, CO-1686, performed well in a preclinical study involving xenograft and transgenic mice, as reported in the journal Cancer Discovery. It is now being evaluated for safety and efficacy in Phase I and II clinical trials.

Lead optimization of antimalarial propafenone analogues.

PubMed

Lowes, David; Pradhan, Anupam; Iyer, Lalitha V; Parman, Toufan; Gow, Jason; Zhu, Fangyi; Furimsky, Anna; Lemoff, Andrew; Guiguemde, W Armand; Sigal, Martina; Clark, Julie A; Wilson, Emily; Tang, Liang; Connelly, Michele C; Derisi, Joseph L; Kyle, Dennis E; Mirsalis, Jon; Guy, R Kiplin

2012-07-12

Previously reported studies identified analogues of propafenone that had potent antimalarial activity, reduced cardiac ion channel activity, and properties that suggested the potential for clinical development for malaria. Careful examination of the bioavailability, pharmacokinetics, toxicology, and efficacy of this series of compounds using rodent models revealed orally bioavailable compounds that are nontoxic and suppress parasitemia in vivo. Although these compounds possess potential for further preclinical development, they also carry some significant challenges.

Epicutaneous immunotherapy for food allergy as a novel pathway for oral tolerance induction.

PubMed

Mondoulet, Lucie; Dioszeghy, Vincent; Thébault, Claude; Benhamou, Pierre-Henri; Dupont, Christophe

2015-01-01

Epicutaneous immunotherapy is a developing technique, aiming at desensitizing patients with food allergy with less risks that oral ingestion or injection could generate. Several clinical trials have been performed and are currently running, in milk and peanut allergy, assessing the safety of the technique and its efficacy. Preclinical models indicate a major role in the mechanisms of desensitization, for example, Tregs and epigenetic modifications.

Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies

DOE PAGES

Kariolis, Mihalis S.; Miao, Yu Rebecca; Diep, Anh; ...

2016-11-28

The AXL receptor and its activating ligand, growth arrest–specific 6 (GAS6), are important drivers of metastasis and therapeutic resistance in human cancers. Given the critical roles that GAS6 and AXL play in refractory disease, this signaling axis represents an attractive target for therapeutic intervention. But, the strong picomolar binding affinity between GAS6 and AXL and the promiscuity of small molecule inhibitors represent important challenges faced by current anti-AXL therapeutics. We have addressed these obstacles by engineering a second-generation, high-affinity AXL decoy receptor with an apparent affinity of 93 femtomolar to GAS6. Our decoy receptor, MYD1-72, profoundly inhibited disease progression inmore » aggressive preclinical models of human cancers and induced cell killing in leukemia cells. When directly compared with the most advanced anti-AXL small molecules in the clinic, MYD1-72 achieved superior antitumor efficacy while displaying no toxicity. Furthermore, we uncovered a relationship between AXL and the cellular response to DNA damage whereby abrogation of AXL signaling leads to accumulation of the DNA-damage markers γH2AX, 53BP1, and RAD51. MYD1-72 exploited this relationship, leading to improvements upon the therapeutic index of current standard-of-care chemotherapies in preclinical models of advanced pancreatic and ovarian cancer.« less

Frugal chemoprevention: targeting Nrf2 with foods rich in sulforaphane.

PubMed

Yang, Li; Palliyaguru, Dushani L; Kensler, Thomas W

2016-02-01

With the properties of efficacy, safety, tolerability, practicability and low cost, foods containing bioactive phytochemicals are gaining significant attention as elements of chemoprevention strategies against cancer. Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane], a naturally occurring isothiocyanate produced by cruciferous vegetables such as broccoli, is found to be a highly promising chemoprevention agent against not only a variety of cancers such as breast, prostate, colon, skin, lung, stomach or bladder, but also cardiovascular disease, neurodegenerative diseases, and diabetes. For reasons of experimental exigency, preclinical studies have focused principally on sulforaphane itself, while clinical studies have relied on broccoli sprout preparations rich in either sulforaphane or its biogenic precursor, glucoraphanin. Substantive subsequent evaluation of sulforaphane pharmacokinetics and pharmacodynamics has been undertaken using either pure compound or food matrices. Sulforaphane affects multiple targets in cells. One key molecular mechanism of action for sulforaphane entails activation of the Nrf2-Keap1 signaling pathway although other actions contribute to the broad spectrum of efficacy in different animal models. This review summarizes the current status of pre-clinical chemoprevention studies with sulforaphane and highlights the progress and challenges for the application of foods rich in sulforaphane and/or glucoraphanin in the arena of clinical chemoprevention. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of a powered air-purifying respirator intervention on indium exposure reduction and indium related biomarkers among ITO sputter target manufacturing workers.

PubMed

Liu, Hung-Hsin; Chen, Chang-Yuh; Lan, Cheng-Hang; Chang, Cheng-Ping; Peng, Chiung-Yu

2016-01-01

This study aimed to evaluate the efficacy of powered air-purifying respirators (PAPRs) worn by the workers, and to investigate the effect of this application on exposure and preclinical effects in terms of workplace measuring and biomarker monitoring in ITO sputter target manufacturing plants and workers, respectively. Fifty-four workers were recruited and investigated from 2010-2012, during which PAPRs were provided to on-site workers in September 2011. Each worker completed questionnaires and provided blood and urine samples for analysis of biomarkers of indium exposure and preclinical effects. Area and personal indium air samples were randomly collected from selected worksites and from participants. The penetration percentage of the respirator (concentration inside respirator divided by concentration outside respirator) was 6.6%. Some biomarkers, such as S-In, SOD, GPx, GST, MDA, and TMOM, reflected the decrease in exposure and showed lower levels, after implementation of PAPRs. This study is the first to investigate the efficacy of PAPRs for reducing indium exposure. The measurement results clearly showed that the implementation of PAPRs reduces levels of indium-related biomarkers. These findings have practical applications for minimizing occupational exposure to indium and for managing the health of workers exposed to indium.

Preclinical efficacy and safety of an anti-IL-1β vaccine for the treatment of type 2 diabetes

PubMed Central

Spohn, Gunther; Schori, Christian; Keller, Iris; Sladko, Katja; Sina, Christina; Guler, Reto; Schwarz, Katrin; Johansen, Pål; Jennings, Gary T; Bachmann, Martin F

2014-01-01

Neutralization of the inflammatory cytokine interleukin-1β (IL-1β) is a promising new strategy to prevent the β-cell destruction, which leads to type 2 diabetes. Here, we describe the preclinical development of a therapeutic vaccine against IL-1β consisting of a detoxified version of IL-1β chemically cross-linked to virus-like particles of the bacteriophage Qβ. The vaccine was well tolerated and induced robust antibody responses in mice, which neutralized the biological activity of IL-1β, as shown both in cellular assays and in challenge experiments in vivo. Antibody titers were long lasting but reversible over time and not associated with the development of potentially harmful T cell responses against IL-1β. Neutralization of IL-1β by vaccine-induced antibodies had no influence on the immune responses of mice to Listeria monocytogenes and Mycobacterium tuberculosis. In a diet-induced model of type 2 diabetes, immunized mice showed improved glucose tolerance, which was mediated by improved insulin secretion by pancreatic β-cells. Hence, immunization with IL-1β conjugated to virus-like particles has the potential to become a safe, efficacious, and cost-effective therapy for the prevention and long-term treatment of type 2 diabetes. PMID:26015986

Effect of Probiotics on Central Nervous System Functions in Animals and Humans: A Systematic Review

PubMed Central

Wang, Huiying; Lee, In-Seon; Braun, Christoph; Enck, Paul

2016-01-01

To systematically review the effects of probiotics on central nervous system function in animals and humans, to summarize effective interventions (species of probiotic, dose, duration), and to analyze the possibility of translating preclinical studies. Literature searches were conducted in Pubmed, Medline, Embase, and the Cochrane Library. Only randomized controlled trials were included. In total, 38 studies were included: 25 in animals and 15 in humans (2 studies were conducted in both). Most studies used Bifidobacterium (eg, B. longum, B. breve, and B. infantis) and Lactobacillus (eg, L. helveticus, and L. rhamnosus), with doses between 109 and 1010 colony-forming units for 2 weeks in animals and 4 weeks in humans. These probiotics showed efficacy in improving psychiatric disorder-related behaviors including anxiety, depression, autism spectrum disorder (ASD), obsessive-compulsive disorder, and memory abilities, including spatial and non-spatial memory. Because many of the basic science studies showed some efficacy of probiotics on central nervous system function, this background may guide and promote further preclinical and clinical studies. Translating animal studies to human studies has obvious limitations but also suggests possibilities. Here, we provide several suggestions for the translation of animal studies. More experimental designs with both behavioral and neuroimaging measures in healthy volunteers and patients are needed in the future. PMID:27413138

Effect of Probiotics on Central Nervous System Functions in Animals and Humans: A Systematic Review.

PubMed

Wang, Huiying; Lee, In-Seon; Braun, Christoph; Enck, Paul

2016-10-30

To systematically review the effects of probiotics on central nervous system function in animals and humans, to summarize effective interventions (species of probiotic, dose, duration), and to analyze the possibility of translating preclinical studies. Literature searches were conducted in Pubmed, Medline, Embase, and the Cochrane Library. Only randomized controlled trials were included. In total, 38 studies were included: 25 in animals and 15 in humans (2 studies were conducted in both). Most studies used Bifidobacterium (eg, B. longum , B. breve , and B. infantis ) and Lactobacillus (eg, L. helveticus , and L. rhamnosus ), with doses between 10⁸ and 10¹⁰ colony-forming units for 2 weeks in animals and 4 weeks in humans. These probiotics showed efficacy in improving psychiatric disorder-related behaviors including anxiety, depression, autism spectrum disorder (ASD), obsessive-compulsive disorder, and memory abilities, including spatial and non-spatial memory. Because many of the basic science studies showed some efficacy of probiotics on central nervous system function, this background may guide and promote further preclinical and clinical studies. Translating animal studies to human studies has obvious limitations but also suggests possibilities. Here, we provide several suggestions for the translation of animal studies. More experimental designs with both behavioral and neuroimaging measures in healthy volunteers and patients are needed in the future.

Exposure-response relationships in patients with metastatic renal cell carcinoma receiving sunitinib: maintaining optimum efficacy in clinical practice.

PubMed

Ravaud, Alain; Bello, Carlo L

2011-06-01

Targeted agents such as sunitinib, an oral, multitargeted receptor tyrosine kinase inhibitor, have greatly improved the prognosis for patients with metastatic renal cell carcinoma (mRCC). In this review we analyse data from sunitinib preclinical and clinical studies in detail and consider the key implications for the effective use of sunitinib in clinical practice. Sunitinib has shown efficacy and acceptable tolerability in patients with mRCC in phase II and III clinical studies. In a pivotal phase III study in treatment-naïve patients with mRCC, median progression-free survival for sunitinib-treated patients was double of that with interferon-α (P < 0.001). Median overall survival was 26.4 versus 21.8 months, respectively (P = 0.0510). In preclinical and phase I/II studies, sunitinib inhibits tyrosine kinase inhibitors in a dose-dependent manner, suggesting a correlation between increasing exposure and greater response. A pharmacokinetics/pharmacodynamics meta-analysis investigating the relationship between clinical end points and sunitinib exposure showed that increased sunitinib exposure was associated with a greater probability of objective response, longer time to tumour progression and overall survival, as well as some increased risk of specific adverse events. It is important to consider the relationship between exposure and response to maximize clinical benefit from sunitinib treatment.

Paramagnetic and fluorescent liposomes for target-specific imaging and therapy of tumor angiogenesis

PubMed Central

Kluza, Ewelina; Van Tilborg, Geralda A. F.; van der Schaft, Daisy W. J.; Griffioen, Arjan W.; Mulder, Willem J. M.; Nicolay, Klaas

2010-01-01

Angiogenesis is essential for tumor growth and metastatic potential and for that reason considered an important target for tumor treatment. Noninvasive imaging technologies, capable of visualizing tumor angiogenesis and evaluating the efficacy of angiostatic therapies, are therefore becoming increasingly important. Among the various imaging modalities, magnetic resonance imaging (MRI) is characterized by a superb spatial resolution and anatomical soft-tissue contrast. Revolutionary advances in contrast agent chemistry have delivered versatile angiogenesis-specific molecular MRI contrast agents. In this paper, we review recent advances in the preclinical application of paramagnetic and fluorescent liposomes for noninvasive visualization of the molecular processes involved in tumor angiogenesis. This liposomal contrast agent platform can be prepared with a high payload of contrast generating material, thereby facilitating its detection, and is equipped with one or more types of targeting ligands for binding to specific molecules expressed at the angiogenic site. Multimodal liposomes endowed with contrast material for complementary imaging technologies, e.g., MRI and optical, can be exploited to gain important preclinical insights into the mechanisms of binding and accumulation at angiogenic vascular endothelium and to corroborate the in vivo findings. Interestingly, liposomes can be designed to contain angiostatic therapeutics, allowing for image-supervised drug delivery and subsequent monitoring of therapeutic efficacy. PMID:20390447

Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kariolis, Mihalis S.; Miao, Yu Rebecca; Diep, Anh

The AXL receptor and its activating ligand, growth arrest–specific 6 (GAS6), are important drivers of metastasis and therapeutic resistance in human cancers. Given the critical roles that GAS6 and AXL play in refractory disease, this signaling axis represents an attractive target for therapeutic intervention. But, the strong picomolar binding affinity between GAS6 and AXL and the promiscuity of small molecule inhibitors represent important challenges faced by current anti-AXL therapeutics. We have addressed these obstacles by engineering a second-generation, high-affinity AXL decoy receptor with an apparent affinity of 93 femtomolar to GAS6. Our decoy receptor, MYD1-72, profoundly inhibited disease progression inmore » aggressive preclinical models of human cancers and induced cell killing in leukemia cells. When directly compared with the most advanced anti-AXL small molecules in the clinic, MYD1-72 achieved superior antitumor efficacy while displaying no toxicity. Furthermore, we uncovered a relationship between AXL and the cellular response to DNA damage whereby abrogation of AXL signaling leads to accumulation of the DNA-damage markers γH2AX, 53BP1, and RAD51. MYD1-72 exploited this relationship, leading to improvements upon the therapeutic index of current standard-of-care chemotherapies in preclinical models of advanced pancreatic and ovarian cancer.« less

Azilsartan as a Potent Antihypertensive Drug with Possible Pleiotropic Cardiometabolic Effects: A Review Study

PubMed Central

Georgiopoulos, Georgios; Katsi, Vasiliki; Oikonomou, Dimitrios; Vamvakou, Georgia; Koutli, Evangelia; Laina, Aggeliki; Tsioufis, Constantinos; Nihoyannopoulos, Petros; Tousoulis, Dimitrios

2016-01-01

Background: Hypertension related cardiovascular (CV) complications could be amplified by the presence of metabolic co-morbidities. Azilsartan medoxomil (AZL-M) is the eighth approved member of angiotensin II receptor blockers (ARBs), a drug class of high priority in the management of hypertensive subjects with diabetes mellitus type II (DMII). Methods: Under this prism, we performed a systematic review of the literature for all relevant articles in order to evaluate the efficacy, safety, and possible clinical role of AZL-M in hypertensive diabetic patients. Results: AZL-M was found to be more effective in terms of reducing indices of blood pressure over alternative ARBs or angiotensin-converting enzyme (ACE) inhibitors with minimal side effects. Preclinical studies have established pleiotropic effects for AZL-M beyond its primary antihypertensive role through differential gene expression, up-regulation of membrane receptors and favorable effect on selective intracellular biochemical and pro-atherosclerotic pathways. Conclusion: Indirect but accumulating evidence from recent literature supports the efficacy and safety of AZL-M among diabetic patients. However, no clinical data exist to date that evince a beneficial role of AZL-M in patients with metabolic disorders on top of its antihypertensive effect. Further clinical studies are warranted to assess the pleiotropic cardiometabolic benefits of AZL-M that are derived from preclinical research. PMID:27536242

Azilsartan as a Potent Antihypertensive Drug with Possible Pleiotropic Cardiometabolic Effects: A Review Study.

PubMed

Georgiopoulos, Georgios; Katsi, Vasiliki; Oikonomou, Dimitrios; Vamvakou, Georgia; Koutli, Evangelia; Laina, Aggeliki; Tsioufis, Constantinos; Nihoyannopoulos, Petros; Tousoulis, Dimitrios

2016-01-01

Hypertension related cardiovascular (CV) complications could be amplified by the presence of metabolic co-morbidities. Azilsartan medoxomil (AZL-M) is the eighth approved member of angiotensin II receptor blockers (ARBs), a drug class of high priority in the management of hypertensive subjects with diabetes mellitus type II (DMII). Under this prism, we performed a systematic review of the literature for all relevant articles in order to evaluate the efficacy, safety, and possible clinical role of AZL-M in hypertensive diabetic patients. AZL-M was found to be more effective in terms of reducing indices of blood pressure over alternative ARBs or angiotensin-converting enzyme (ACE) inhibitors with minimal side effects. Preclinical studies have established pleiotropic effects for AZL-M beyond its primary antihypertensive role through differential gene expression, up-regulation of membrane receptors and favorable effect on selective intracellular biochemical and pro-atherosclerotic pathways. Indirect but accumulating evidence from recent literature supports the efficacy and safety of AZL-M among diabetic patients. However, no clinical data exist to date that evince a beneficial role of AZL-M in patients with metabolic disorders on top of its antihypertensive effect. Further clinical studies are warranted to assess the pleiotropic cardiometabolic benefits of AZL-M that are derived from preclinical research.

Issues related to development of antiepileptogenic therapies.

PubMed

Pitkänen, Asla; Nehlig, Astrid; Brooks-Kayal, Amy R; Dudek, F Edward; Friedman, Daniel; Galanopoulou, Aristea S; Jensen, Frances E; Kaminski, Rafal M; Kapur, Jaideep; Klitgaard, Henrik; Löscher, Wolfgang; Mody, Istvan; Schmidt, Dieter

2013-08-01

Several preclinical proof-of-concept studies have provided evidence for positive treatment effects on epileptogenesis. However, none of these hypothetical treatments has advanced to the clinic. The experience in other fields of neurology such as stroke, Alzheimer's disease, or amyotrophic lateral sclerosis has indicated several problems in the design of preclinical studies, which likely contribute to failures in translating the positive preclinical data to the clinic. The Working Group on "Issues related to development of antiepileptogenic therapies" of the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) has considered the possible problems that arise when moving from proof-of-concept antiepileptogenesis (AEG) studies to preclinical AEG trials, and eventually to clinical AEG trials. This article summarizes the discussions and provides recommendations on how to design a preclinical AEG monotherapy trial in adult animals. We specifically address study design, animal and model selection, number of studies needed, issues related to administration of the treatment, outcome measures, statistics, and reporting. In addition, we give recommendations for future actions to advance the preclinical AEG testing. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Pharmacotherapy of amphetamine-type stimulant dependence: an update.

PubMed

Brensilver, Matthew; Heinzerling, Keith G; Shoptaw, Steven

2013-09-01

Methamphetamine- or amphetamine-type stimulants are the second most frequently used illicit drug worldwide, second only to cannabis. Behavioural treatments are efficacious, but their impact is limited underscoring the need for other treatment options, notably, pharmacotherapy. A review of randomised controlled trials of pharmacotherapies for methamphetamine- or amphetamine-type stimulants was performed using PubMed and Google Scholar databases. Evidence for efficacy of medications is reported. Clinical trials have yielded no broadly effective pharmacotherapy. Promising signals have been observed for methylphenidate, naltrexone, bupropion and mirtazapine in subgroups of patients in reducing stimulant use (e.g. patients with less severe dependence at baseline and men who have sex with men), though none has produced an unambiguous, replicable signal of efficacy. Problems in Phase II trials, including high dropout rates, missing data and a lack of agreement on outcomes, complicate efforts to find a broadly effective pharmacotherapy for amphetamine-type stimulant disorders. Efforts to address these problems include calls for better validation of pharmacological target exposure, receptor binding and functional modulation. As well, there is a need for agreement in using findings from preclinical and early phases of the medication development process for selecting better pharmacotherapy candidates. After over 20 years of efforts worldwide to develop a broadly effective medication for dependence on methamphetamine- or amphetamine-type stimulants, no candidate has emerged. This highlights the need for new compounds, consistent and stringent research methods, better integration between preclinical and clinical stages of medication development, and improved collaboration between government, industry and researchers. © 2013 Australasian Professional Society on Alcohol and other Drugs.

Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases.

PubMed

Sini, Patrizia; Gürtler, Ulrich; Zahn, Stephan K; Baumann, Christoph; Rudolph, Dorothea; Baumgartinger, Rosa; Strauss, Eva; Haslinger, Christian; Tontsch-Grunt, Ulrike; Waizenegger, Irene C; Solca, Flavio; Bader, Gerd; Zoephel, Andreas; Treu, Matthias; Reiser, Ulrich; Garin-Chesa, Pilar; Boehmelt, Guido; Kraut, Norbert; Quant, Jens; Adolf, Günther R

2016-10-01

Although the MAPK pathway is frequently deregulated in cancer, inhibitors targeting RAF or MEK have so far shown clinical activity only in BRAF- and NRAS-mutant melanoma. Improvements in efficacy may be possible by combining inhibition of mitogenic signal transduction with inhibition of cell-cycle progression. We have studied the preclinical pharmacology of BI 847325, an ATP-competitive dual inhibitor of MEK and Aurora kinases. Potent inhibition of MEK1/2 and Aurora A/B kinases by BI 847325 was demonstrated in enzymatic and cellular assays. Equipotent effects were observed in BRAF-mutant cells, whereas in KRAS-mutant cells, MEK inhibition required higher concentrations than Aurora kinase inhibition. Daily oral administration of BI 847325 at 10 mg/kg showed efficacy in both BRAF- and KRAS-mutant xenograft models. Biomarker analysis suggested that this effect was primarily due to inhibition of MEK in BRAF-mutant models but of Aurora kinase in KRAS-mutant models. Inhibition of both MEK and Aurora kinase in KRAS-mutant tumors was observed when BI 847325 was administered once weekly at 70 mg/kg. Our studies indicate that BI 847325 is effective in in vitro and in vivo models of cancers with BRAF and KRAS mutation. These preclinical data are discussed in the light of the results of a recently completed clinical phase I trial assessing safety, tolerability, pharmacokinetics, and efficacy of BI 847325 in patients with cancer. Mol Cancer Ther; 15(10); 2388-98. ©2016 AACR. ©2016 American Association for Cancer Research.

Titanium-nitride-oxide-coated coronary stents: insights from the available evidence.

PubMed

Karjalainen, Pasi P; Nammas, Wail

2017-06-01

Coating of stent surface with a biocompatible material is suggested to improve stent safety profile. A proprietary process was developed to coat titanium-nitride-oxide on the stent surface, based on plasma technology that uses the nano-synthesis of gas and metal. Preclinical in vitro and in vivo investigation confirmed blood compatibility of titanium (nitride-) oxide films. Titanium-nitride-oxide-coated stents demonstrated a better angiographic outcome, compared with bare-metal stents at mid-term follow-up; however, they failed to achieve non-inferiority for angiographic outcome versus second-generation drug-eluting stents. Observational studies showed adequate clinical outcome at mid-term follow-up. Non-randomized studies showed an outcome of titanium-nitride-oxide-coated stents comparable to - or better than - first-generation drug-eluting stents at long-term follow-up. Two randomized controlled trials demonstrated comparable efficacy outcome, and a better safety outcome of titanium-nitride-oxide-coated stents versus drug-eluting stents at long-term follow-up. Evaluation by optical coherence tomography at mid-term follow-up revealed better neointimal strut coverage associated with titanium-nitride-oxide-coated stents versus drug-eluting stents; yet, neointimal hyperplasia thickness was greater. Key messages Stents coated with titanium-nitride-oxide demonstrated biocompatibility in preclinical studies: they inhibit platelet and fibrin deposition, and reduce neointimal growth. In observational and non-randomized studies, titanium-nitride-oxide-coated stents were associated with adequate safety and efficacy outcome. In randomized trials of patients with acute coronary syndrome, titanium-nitride-oxide-coated stents were associated with a better safety outcome, compared with drug-eluting stents; efficacy outcome was comparable.

A Systematic Review and Meta-Analysis of Bone Marrow Derived Mononuclear Cells in Animal Models of Ischemic Stroke

PubMed Central

Vahidy, Farhaan S.; Rahbar, Mohammad H.; Zhu, Hongjian; Rowan, Paul J.; Bambhroliya, Arvind B.; Savitz, Sean I.

2016-01-01

Background and Purpose Bone marrow derived mononuclear cells (BMMNCs) offer the promise of augmenting post-stroke recovery. There is mounting evidence of safety and efficacy of BMMNCs from pre-clinical studies of ischemic stroke (IS), however their pooled effects have not been described. Methods Using PRIMSA guidelines, we conducted a systematic review of pre-clinical literature for intravenous use of BMMNCs followed by meta-analyses of histological and behavioral outcomes. Studies were selected based on pre-defined criteria. Data were abstracted by two independent investigators. Following quality assessment, the pooled effects were generated using mixed effect models. Impact of possible biases on estimated effect size was evaluated. Results Standardized mean difference (SMD), 95% confidence interval (CI) for reduction in lesion volume was significantly beneficial for BMMNC treatment (SMD −3.3, 95% CI: −4.3, −2.3), n = 113 each for BMMNC and controls. BMMNC treated animals (n = 161) also had improved function measured by cylinder test (SMD −2.4, 95% CI: −3.1, −1.6), as compared to controls (n = 205). A trend for benefit was observed for adhesive removal test and neurological deficit score. Study quality score (median: 6, Q1-Q3: 5-7) was correlated with year of publication. There was funnel plot asymmetry, however the pooled effects were robust to the correction of this bias and remained significant in favor of BMMNC treatment. Conclusions BMMNCs demonstrate beneficial effects across histological and behavioral outcomes in animal IS models. Though study quality has improved over time, considerable degree of heterogeneity calls for standardization in the conduct and reporting of experimentation. PMID:27165959

Human IgG subclass cross-species reactivity to mouse and cynomolgus monkey Fcγ receptors.

PubMed

Derebe, Mehabaw G; Nanjunda, Rupesh K; Gilliland, Gary L; Lacy, Eilyn R; Chiu, Mark L

2018-05-01

In therapeutic antibody discovery and early development, mice and cynomolgus monkey are used as animal models to assess toxicity, efficacy and other properties of candidate molecules. As more candidate antibodies are based on human immunoglobulin (IgG) subclasses, many strategies are pursued to simulate the human system in the test animal. However, translation rate from a successful preclinical trial to an approved drug is extremely low. This may partly be due to differences in interaction of human IgG based candidate molecules to endogenous Fcγ receptors of model animals in comparison to those of human Fcγ receptors. In this study, we compare binding characteristics of human IgG subclasses commonly used in drug development (IgG1, IgG2, IgG4) and their respective Fc silent versions (IgG1σ, IgG2σ, IgG4 PAA) to human, mouse, and cynomolgus monkey Fcγ receptors. To control interactions between Fab and Fc domains, the test IgGs all have the same variable region sequences. We found distinct variations of interaction of human IgG subclasses to model animal Fcγ receptors in comparison to their human counterparts. Particularly, cynomolgus monkey Fcγ receptors showed consistently tighter binding to human IgGs than human Fcγ receptors. Moreover, the presumably Fc silent human IgG4 PAA framework bound to cynomolgus monkey FcγRI with nanomolar affinity while only very weak binding was observed for the human FcγRI. Our results highlighted the need for a thorough in vitro affinity characterization of candidate IgGs against model animal Fcγ receptors and careful design of preclinical studies. Copyright © 2018. Published by Elsevier B.V.

Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study.

PubMed

Bekker, Pirow; Dairaghi, Daniel; Seitz, Lisa; Leleti, Manmohan; Wang, Yu; Ertl, Linda; Baumgart, Trageen; Shugarts, Sarah; Lohr, Lisa; Dang, Ton; Miao, Shichang; Zeng, Yibin; Fan, Pingchen; Zhang, Penglie; Johnson, Daniel; Powers, Jay; Jaen, Juan; Charo, Israel; Schall, Thomas J

2016-01-01

The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg) and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773.

Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study

PubMed Central

Bekker, Pirow; Dairaghi, Daniel; Seitz, Lisa; Leleti, Manmohan; Wang, Yu; Ertl, Linda; Baumgart, Trageen; Shugarts, Sarah; Lohr, Lisa; Dang, Ton; Miao, Shichang; Zeng, Yibin; Fan, Pingchen; Zhang, Penglie; Johnson, Daniel; Powers, Jay; Jaen, Juan; Charo, Israel; Schall, Thomas J.

2016-01-01

The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg) and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773. PMID:27768695

Of Mice and not Humans: How Reliable are Animal Models for Evaluation of Herpes CD8+-T cell-Epitopes-Based Immunotherapeutic Vaccine Candidates?

PubMed Central

Dasgupta, Gargi; BenMohamed, Lbachir

2011-01-01

Herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) -specific CD8+ T cells that reside in sensory ganglia, appears to control recurrent herpetic disease by aborting or reducing spontaneous and sporadic reactivations of latent virus. A reliable animal model is the ultimate key factor to test the efficacy of therapeutic vaccines that boost the level and the quality of sensory ganglia-resident CD8+ T cells against spontaneous herpes reactivation from sensory neurons, yet its relevance has been often overlooked. Herpes vaccinologists are hesitant about using mouse as a model in pre-clinical development of therapeutic vaccines because they do not adequately mimic spontaneous viral shedding or recurrent symptomatic diseases, as occurs in human. Alternatives to mouse models are rabbits and guinea pigs in which reactivation arise spontaneously with clinical features relevant to human disease. However, while rabbits and guinea pigs develop spontaneous HSV reactivation and recurrent ocular and genital disease none of them can mount CD8+ T cell responses specific to Human Leukocyte Antigen- (HLA-) restricted epitopes. In this review, we discuss the advantages and limitations of these animal models and describe a novel “humanized” HLA transgenic rabbit, which shows spontaneous HSV-1 reactivation, recurrent ocular disease and mounts CD8+ T cell responses to HLA-restricted epitopes. Adequate investments are needed to develop reliable preclinical animal models, such as HLA class I and class II double transgenic rabbits and guinea pigs to balance the ethical and financial concerns associated with the rising number of unsuccessful clinical trials for therapeutic vaccine formulations tested in unreliable mouse models. PMID:21718746

The preclinical testing strategy for the development of novel chemical entities for the treatment of asthma.

PubMed

Hahn, Christian; Erb, Klaus Joseph

2008-06-01

Identifying and developing novel chemical entities (NCE) for the treatment of asthma is a time-consuming process and liabilities that endanger the successful progression of a compound from research into the patient are found throughout all phases of drug discovery. In particular the failure of advanced compounds in clinical studies due to lack of efficacy and/or safety concerns is tremendously costly. Therefore, in order to try and reduce the failure rate in clinical trials various in vitro and in vivo tests are performed during preclinical development, to rapidly identify liabilities, eliminate high risk compounds and promote promising potential drug candidates. To achieve this objective, numerous prerequisites have to be met regarding the physico-chemical properties of the compound, and bioactivity or model systems are needed to rate the therapeutic potential of new compounds. Drug liabilities such as target and species specificity, formulation issues, pharmacokinetics as well as pharmacodynamics and the toxic potential of the compound have to be analyzed in great detail before a compound can enter a clinical trial. A particularly challenging aspect of developing novel NCEs for the treatment of asthma is choosing and setting up in vivo models believed to be predictive for human disease. Numerous companies have in the past and are currently developing NCEs targeting many different pathways and cells with the aim to treat asthma. However, currently the only NCE having a significant market share are long-acting beta-agonists (LABA), inhaled and orally active steroids and leukotriene receptor antagonists. In the past many novel NCE for the treatment of asthma were effective in animal models but failed in the clinic. In this review we outline the prerequisites of novel NCE needed for clinical development.

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

PubMed Central

Shavit, Yehuda; Grace, Peter M.; Rice, Kenner C.; Maier, Steven F.; Watkins, Linda R.

2011-01-01

Vastly stimulated by the discovery of opioid receptors in the early 1970s, preclinical and clinical research was directed at the study of stereoselective neuronal actions of opioids, especially those played in their crucial analgesic role. However, during the past decade, a new appreciation of the non-neuronal actions of opioids has emerged from preclinical research, with specific appreciation for the nonclassic and nonstereoselective sites of action. Opioid activity at Toll-like receptors, newly recognized innate immune pattern recognition receptors, adds substantially to this unfolding story. It is now apparent from molecular and rodent data that these newly identified signaling events significantly modify the pharmacodynamics of opioids by eliciting proinflammatory reactivity from glia, the immunocompetent cells of the central nervous system. These central immune signaling events, including the release of cytokines and chemokines and the associated disruption of glutamate homeostasis, cause elevated neuronal excitability, which subsequently decreases opioid analgesic efficacy and leads to heightened pain states. This review will examine the current preclinical literature of opioid-induced central immune signaling mediated by classic and nonclassic opioid receptors. A unification of the preclinical pharmacology, neuroscience, and immunology of opioids now provides new insights into common mechanisms of chronic pain, naive tolerance, analgesic tolerance, opioid-induced hyperalgesia, and allodynia. Novel pharmacological targets for future drug development are discussed in the hope that disease-modifying chronic pain treatments arising from the appreciation of opioid-induced central immune signaling may become practical. PMID:21752874

A Laminated Microfluidic Device for Comprehensive Preclinical Testing in the Drug ADME Process

PubMed Central

An, Fan; Qu, Yueyang; Luo, Yong; Fang, Ning; Liu, Yang; Gao, Zhigang; Zhao, Weijie; Lin, Bingcheng

2016-01-01

New techniques are urgently needed to replace conventional long and costly pre-clinical testing in the new drug administration process. In this study, a laminated microfluidic device was fabricated to mimic the drug ADME response test in vivo. This proposed device was loaded and cultured with functional cells for drug response investigation and organ tissues that are involved in ADME testing. The drug was introduced from the top of the device and first absorbed by the Caco-2 cell layer, and then metabolized by the primary hepatocyte layer. It subsequently interacted with the MCF-7 cell layer, distributed in the lung, heart and fat tissues, and was finally eliminated through the dialysis membrane. Throughout this on-chip ADME process, the proposed device can be used as a reliable tool to simultaneously evaluate the drug anti-tumor activity, hepatotoxicity and pharmacokinetics. Furthermore, this device was proven to be able to reflect the hepatic metabolism of a drug, drug distribution in the target tissues, and the administration method of a drug. Furthermore, this microdevice is expected to reduce the number of drug candidates and accelerate the pre-clinical testing process subject to animal testing upon adaptation in new drug discovery. PMID:27122192

A Laminated Microfluidic Device for Comprehensive Preclinical Testing in the Drug ADME Process.

PubMed

An, Fan; Qu, Yueyang; Luo, Yong; Fang, Ning; Liu, Yang; Gao, Zhigang; Zhao, Weijie; Lin, Bingcheng

2016-04-28

New techniques are urgently needed to replace conventional long and costly pre-clinical testing in the new drug administration process. In this study, a laminated microfluidic device was fabricated to mimic the drug ADME response test in vivo. This proposed device was loaded and cultured with functional cells for drug response investigation and organ tissues that are involved in ADME testing. The drug was introduced from the top of the device and first absorbed by the Caco-2 cell layer, and then metabolized by the primary hepatocyte layer. It subsequently interacted with the MCF-7 cell layer, distributed in the lung, heart and fat tissues, and was finally eliminated through the dialysis membrane. Throughout this on-chip ADME process, the proposed device can be used as a reliable tool to simultaneously evaluate the drug anti-tumor activity, hepatotoxicity and pharmacokinetics. Furthermore, this device was proven to be able to reflect the hepatic metabolism of a drug, drug distribution in the target tissues, and the administration method of a drug. Furthermore, this microdevice is expected to reduce the number of drug candidates and accelerate the pre-clinical testing process subject to animal testing upon adaptation in new drug discovery.

Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder.

PubMed

Postuma, Ronald B; Gagnon, Jean-François; Vendette, Mélanie; Desjardins, Catherine; Montplaisir, Jacques Y

2011-05-01

For development of neuroprotective therapy, neurodegenerative disease must be identified as early as possible. However, current means of identifying "preclinical" neurodegeneration are limited. Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) are at >50% risk of synuclein-mediated neurodegenerative disease--this provides a unique opportunity to directly observe preclinical synucleinopathy and to test potential markers of preclinical disease. Patients with RBD without neurodegenerative disease were enrolled in a prospective cohort starting in 2004. Olfaction and color vision were tested at baseline, then annually for 5 years. Test results were compared between patients who developed neurodegenerative disease and those who remained disease-free. Out of 64 patients, 62 (97%) participated in annual follow-up. During follow-up, 21 developed disease, and 41 remained disease-free. Out of 21, 16 developed a combination of parkinsonism and dementia, 4 developed isolated parkinsonism (all with tremor), and 1 developed isolated dementia. Compared to those remaining disease-free, patients destined to develop disease had worse baseline olfaction (University of Pennsylvania Smell Identification Test [UPSIT] = 58.3 ± 27.0% age/sex-adjusted normal vs 80.2 ± 26.3%; p = 0.003) and color vision (Farnsworth-Munsell 100-Hue color test [FM-100] errors 153.0 ± 82.2% normal vs 120.2 ± 26.5%; p = 0.022). Kaplan-Meier 5-year-disease-free survival in those with normal olfaction was 86.0%, vs 35.4% with impaired olfaction (p = 0.029). Disease-free survival with normal color vision was 70.3%, vs 26.0% with impaired vision (p = 0.009). Both olfaction and color vision were reduced as much as 5 years before disease diagnosis, with only slight decline in preclinical stages. Olfaction and color vision identify early-stage synuclein-mediated neurodegenerative diseases. In most cases, abnormalities are measurable at least 5 years before disease onset, and progress slowly in the preclinical stages. Copyright © 2011 American Neurological Association.

How modeling and simulation have enhanced decision making in new drug development.

PubMed

Miller, Raymond; Ewy, Wayne; Corrigan, Brian W; Ouellet, Daniele; Hermann, David; Kowalski, Kenneth G; Lockwood, Peter; Koup, Jeffrey R; Donevan, Sean; El-Kattan, Ayman; Li, Cheryl S W; Werth, John L; Feltner, Douglas E; Lalonde, Richard L

2005-04-01

The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer's disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the "Learn-Confirm" paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug Application was applied to confirm the evidence of efficacy across these dose levels. Modeling and simulation analyses showed that the two studies corroborate each other with respect to the pain relief profiles. The use of PK/PD information confirmed evidence of efficacy across the three studied doses, eliminating the need for additional clinical trials and thus supporting the approval of the product. It can be speculated that the work by Lewis Sheiner reflected in the FDA document titled "Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products" made this scientific approach to the drug approval process possible.

Analytical Chemistry in the Regulatory Science of Medical Devices.

PubMed

Wang, Yi; Guan, Allan; Wickramasekara, Samanthi; Phillips, K Scott

2018-06-12

In the United States, regulatory science is the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of all Food and Drug Administration-regulated products. Good regulatory science facilitates consumer access to innovative medical devices that are safe and effective throughout the Total Product Life Cycle (TPLC). Because the need to measure things is fundamental to the regulatory science of medical devices, analytical chemistry plays an important role, contributing to medical device technology in two ways: It can be an integral part of an innovative medical device (e.g., diagnostic devices), and it can be used to support medical device development throughout the TPLC. In this review, we focus on analytical chemistry as a tool for the regulatory science of medical devices. We highlight recent progress in companion diagnostics, medical devices on chips for preclinical testing, mass spectrometry for postmarket monitoring, and detection/characterization of bacterial biofilm to prevent infections.

Animal Models of Hemophilia and Related Bleeding Disorders

PubMed Central

Lozier, Jay N.; Nichols, Timothy C.

2013-01-01

Animal models of hemophilia and related diseases are important for development of novel treatments and to understand the pathophysiology of bleeding disorders in humans. Testing in animals with the equivalent human disorder provides informed estimates of doses and measures of efficacy, which aids in design of human trials. Many models of hemophilia A, hemophilia B, and von Willebrand disease have been developed from animals with spontaneous mutations (hemophilia A dogs, rats, sheep; hemophilia B dogs; and von Willebrand disease pigs and dogs), or by targeted gene disruption in mice to create hemophilia A, B, or VWD models. Animal models have been used to generate new insights into the pathophysiology of each bleeding disorder and also to perform pre-clinical assessments of standard protein replacement therapies as well as novel gene transfer technology. Both the differences between species and differences in underlying causative mutations must be considered in choosing the best animal for a specific scientific study PMID:23956467

Preclinical and clinical aspects on the use of amifostine as chemoprotector in neuroblastoma patients.

PubMed

Fulda, S; Fichtner, I; Hero, B; Berthold, F

2001-01-01

In several studies in adults, amifostine (WR-2721) and its active metabolite WR-1065 have shown protection against myelo- and nephrotoxicity of chemotherapeutic agents without compromising cytotoxic efficacy to the tumor. In the present study, the effect of amifostine and WR-1065 on neuroblastoma tumor growth and its protective potential for hematotoxicity were investigated. Neither amifostine nor WR-1065 reduced the cytotoxic effect of six drugs commonly used for this tumor when tested on neuroblastoma cells in vitro. In mice carrying human xeno-transplanted neuroblastoma, tumor growth and antitumor activity of chemotherapy were unaffected by amifostine. In addition, hematotoxicity of alkylators was relieved in some cases. In patients with neuroblastoma, amifostine only slightly reduced bone marrow toxicity and was highly emetogenic. Therefore, amifostine warrants further investigation before its widespread clinical use in the treatment of children with neuroblastoma.

Nanomedicines for chronic non-infectious arthritis: the clinician's perspective.

PubMed

Rubinstein, Israel; Weinberg, Guy L

2012-09-01

Rheumatoid arthritis (RA) and osteoarthritis (OA) are prevalent chronic health conditions. However, despite recent advances in medical therapeutics, their treatment still represents an unmet medical need because of safety and efficacy concerns with currently prescribed drugs. Accordingly, there is an urgent need to develop and test new drugs for RA and OA that selectively target inflamed joints thereby mitigating damage to healthy tissues. Conceivably, biocompatible, biodegradable, disease-modifying antirheumatic nanomedicines (DMARNs) could represent a promising therapeutic approach for RA and OA. To this end, the unique physicochemical properties of drug-loaded nanocarriers coupled with pathophysiological characteristics of inflamed joints amplify bioavailability and bioactivity of DMARNs and promote their selective targeting to inflamed joints. This, in turn, minimizes the amount of drug required to control articular inflammation and circumvents collateral damage to healthy tissues. Thus, nanomedicine could provide selective control both in space and time of the inflammatory process in affected joints. However, bringing safe and efficacious DMARNs for RA and OA to the marketplace is challenging because regulatory agencies have no official definition of nanotechnology, and rules and definitions for nanomedicines are still being developed. Although existing toxicology tests may be adequate for most DMARNs, as new toxicity risks and adverse health effects derived from novel nanomaterials with intended use in humans are identified, additional toxicology tests would be required. Hence, we propose that detailed pre-clinical in vivo safety assessment of promising DMARNs leads for RA and OA, including risks to the general population, must be conducted before clinical trials begin. Published by Elsevier Ireland Ltd.

Nanomedicines for chronic non-infectious arthritis: the clinician's perspective.

PubMed

Rubinstein, Israel; Weinberg, Guy L

2012-09-01

Rheumatoid arthritis (RA) and osteoarthritis (OA) are prevalent chronic health conditions. However, despite recent advances in medical therapeutics, their treatment still represents an unmet medical need because of safety and efficacy concerns with currently prescribed drugs. Accordingly, there is an urgent need to develop and test new drugs for RA and OA that selectively target inflamed joints thereby mitigating damage to healthy tissues. Conceivably, biocompatible, biodegradable, disease-modifying antirheumatic nanomedicines (DMARNs) could represent a promising therapeutic approach for RA and OA. To this end, the unique physicochemical properties of drug-loaded nanocarriers coupled with pathophysiological characteristics of inflamed joints amplify bioavailability and bioactivity of DMARNs and promote their selective targeting to inflamed joints. This, in turn, minimizes the amount of drug required to control articular inflammation and circumvents collateral damage to healthy tissues. Thus, nanomedicine could provide selective control both in space and time of the inflammatory process in affected joints. However, bringing safe and efficacious DMARNs for RA and OA to the marketplace is challenging because regulatory agencies have no official definition of nanotechnology, and rules and definitions for nanomedicines are still being developed. Although existing toxicology tests may be adequate for most DMARNs, as new toxicity risks and adverse health effects derived from novel nanomaterials with intended use in humans are identified, additional toxicology tests would be required. Hence, we propose that detailed pre-clinical in vivo safety assessment of promising DMARNs leads for RA and OA, including risks to the general population, must be conducted before clinical trials begin. Published by Elsevier Inc.

Premise for Standardized Sepsis Models.

PubMed

Remick, Daniel G; Ayala, Alfred; Chaudry, Irshad; Coopersmith, Craig M; Deutschman, Clifford; Hellman, Judith; Moldawer, Lyle; Osuchowski, Marcin

2018-06-05

Sepsis morbidity and mortality exacts a toll on patients and contributes significantly to healthcare costs. Preclinical models of sepsis have been used to study disease pathogenesis and test new therapies, but divergent outcomes have been observed with the same treatment even when using the same sepsis model. Other disorders such as diabetes, cancer, malaria, obesity and cardiovascular diseases have used standardized, preclinical models that allow laboratories to compare results. Standardized models accelerate the pace of research and such models have been used to test new therapies or changes in treatment guidelines. The National Institutes of Health (NIH) mandated that investigators increase data reproducibility and the rigor of scientific experiments and has also issued research funding announcements about the development and refinement of standardized models. Our premise is that refinement and standardization of preclinical sepsis models may accelerate the development and testing of potential therapeutics for human sepsis, as has been the case with preclinical models for other disorders. As a first step towards creating standardized models, we suggest 1) standardizing the technical standards of the widely used cecal ligation and puncture model and 2) creating a list of appropriate organ injury and immune dysfunction parameters. Standardized sepsis models could enhance reproducibility and allow comparison of results between laboratories and may accelerate our understanding of the pathogenesis of sepsis.

Development of the Sanofi Pasteur tetravalent dengue vaccine: One more step forward.

PubMed

Guy, Bruno; Briand, Olivier; Lang, Jean; Saville, Melanie; Jackson, Nicholas

2015-12-10

Sanofi Pasteur has developed a recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) that is in late-stage development. The present review summarizes the different steps in the development of this dengue vaccine, with a particular focus on the clinical data from three efficacy trials, which includes one proof-of-concept phase IIb (NCT00842530) and two pivotal phase III efficacy trials (NCT01373281 and NCT01374516). Earlier studies showed that the CYD-TDV candidate had a satisfactory safety profile and was immunogenic across the four vaccine serotypes in both in vitro and in vivo preclinical tests, as well as in initial phase I to phase II clinical trials in both flavivirus-naïve and seropositive individuals. Data from the 25 months (after the first injection) active phase of the two pivotal phase III efficacy studies shows that CYD-TDV (administered at 0, 6, and 12 months) is efficacious against virologically-confirmed disease (primary endpoint) and has a good safety profile. Secondary analyses also showed efficacy against all four dengue serotypes and protection against severe disease and hospitalization. The end of the active phases in these studies completes more than a decade of development of CYD-TDV, but considerable activities and efforts remain to address outstanding scientific, clinical, and immunological questions, while preparing for the introduction and use of CYD-TDV. Additional safety observations were recently reported from the first complete year of hospital phase longer term surveillance for two phase 3 studies and the first and second completed years for one phase 2b study, demonstrating the optimal age for intervention from 9 years. Dengue is a complex disease, and both short-term and long-term safety and efficacy will continue to be addressed by ongoing long-term follow-up and future post-licensure studies. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Progress in Developing Virus-like Particle Influenza Vaccines

PubMed Central

Quan, Fu-Shi; Lee, Young-Tae; Kim, Ki-Hye; Kim, Min-Chul; Kang, Sang-Moo

2016-01-01

Summary Recombinant vaccines based on virus-like particles (VLPs) or nanoparticles have been successful in their safety and efficacy in preclinical and clinical studies. The technology of expressing enveloped VLP vaccines has combined with molecular engineering of proteins in membrane-anchor and immunogenic forms mimicking the native conformation of surface proteins on the enveloped viruses. This review summarizes recent developments in influenza VLP vaccines against seasonal, pandemic, and avian influenza viruses from the perspective of use in humans. The immunogenicity and efficacies of influenza VLP vaccine in the homologous and cross-protection were reviewed. Discussions include limitations of current influenza vaccination strategies and future directions to confer broadly cross protective new influenza vaccines as well as vaccination. PMID:27058302

Pre-hospital haemostatic dressings: a systematic review.

PubMed

Granville-Chapman, J; Jacobs, N; Midwinter, M J

2011-05-01

Uncontrolled haemorrhage is a leading cause of prehospital death after military and civilian trauma. Exsanguination from extremity wounds causes over half of preven military combat deaths and wounds to the anatomical junctional zones provide a particular challenge for first responders. Commercial products have been developed, which claim to outperform standard gauze bandages in establishing and maintaining non-surgical haemostasis. Since 2004, two advanced haemostatic dressing products, HemCon and QuikClot have been widely deployed in military operations. Newer products have since become available which aim to provide more efficient haemostasis than and thus supersede HemCon and QuikClot. To conduct a systematic review of clinical and preclinical evidence to compare the relative efficacy and safety of available haemostatic products, which are of relevance to pre-hospital military and civilian emergency medical providers. An English language literature search was performed, using PubMed and Web of Knowledge Databases, with cross-referencing, focussed product searches and communication with product manufacturers. For studies employing animal models, the injury model was required to produce fatal haemorrhage. Products were categorised by primary mode of action as either factor concentrators,mucoadhesive agents or procoagulant supplementors. From 60 articles collated, 6 clinical papers and 37 preclinical animal trials were eligible for inclusion in this review. Products have been tested in three different types of haemorrhage model: low pressure, high volume venous bleeding, high pressure arterial bleeding and mixed arterial-venous bleeding. The efficacy of products varies with the model adopted. Criteria for the 'ideal battle field haemostatic dressing' have previously been defined by Pusateri, but no product has yet attained suchstatus. Since 2004, HemCon (a mucoadhesive agent) and QuikClot (a factor concentrator) have been widely deployed by United States and United Kingdom Armed Forces; retrospective clinical data supports their efficacy. However, in some recent animal models of lethal haemorrhage, WoundStat(mucoadhesive), Celox (mucoadhesive) and CombatGauze (procoagulant supplementor) have all outperformed both HemCon and QuikClot products. HemCon and QuikClot have augmented the haemostatic capabilities of the military first aid responder, but newer products demonstrate potential to be more effective and should be considered as replacements for current in service systems. These products could have utility for civilian pre-hospital care. 2010 Elsevier Ltd. All rights reserved.

MIDG-Emerging grid technologies for multi-site preclinical molecular imaging research communities.

PubMed

Lee, Jasper; Documet, Jorge; Liu, Brent; Park, Ryan; Tank, Archana; Huang, H K

2011-03-01

Molecular imaging is the visualization and identification of specific molecules in anatomy for insight into metabolic pathways, tissue consistency, and tracing of solute transport mechanisms. This paper presents the Molecular Imaging Data Grid (MIDG) which utilizes emerging grid technologies in preclinical molecular imaging to facilitate data sharing and discovery between preclinical molecular imaging facilities and their collaborating investigator institutions to expedite translational sciences research. Grid-enabled archiving, management, and distribution of animal-model imaging datasets help preclinical investigators to monitor, access and share their imaging data remotely, and promote preclinical imaging facilities to share published imaging datasets as resources for new investigators. The system architecture of the Molecular Imaging Data Grid is described in a four layer diagram. A data model for preclinical molecular imaging datasets is also presented based on imaging modalities currently used in a molecular imaging center. The MIDG system components and connectivity are presented. And finally, the workflow steps for grid-based archiving, management, and retrieval of preclincial molecular imaging data are described. Initial performance tests of the Molecular Imaging Data Grid system have been conducted at the USC IPILab using dedicated VMware servers. System connectivity, evaluated datasets, and preliminary results are presented. The results show the system's feasibility, limitations, direction of future research. Translational and interdisciplinary research in medicine is increasingly interested in cellular and molecular biology activity at the preclinical levels, utilizing molecular imaging methods on animal models. The task of integrated archiving, management, and distribution of these preclinical molecular imaging datasets at preclinical molecular imaging facilities is challenging due to disparate imaging systems and multiple off-site investigators. A Molecular Imaging Data Grid design, implementation, and initial evaluation is presented to demonstrate the secure and novel data grid solution for sharing preclinical molecular imaging data across the wide-area-network (WAN).

Imaging-guided preclinical trials of vascular targeting in prostate cancer

NASA Astrophysics Data System (ADS)

Kalmuk, James

Purpose: Prostate cancer is the most common non-cutaneous malignancy in American men and is characterized by dependence on androgens (Testosterone/Dihydrotestosterone) for growth and survival. Although reduction of serum testosterone levels by surgical or chemical castration transiently inhibits neoplastic growth, tumor adaptation to castrate levels of androgens results in the generation of castration-resistant prostate cancer (CRPC). Progression to CRPC following androgen deprivation therapy (ADT) has been associated with changes in vascular morphology and increased angiogenesis. Based on this knowledge, we hypothesized that targeting tumor vasculature in combination with ADT would result in enhanced therapeutic efficacy against prostate cancer. Methods: To test this hypothesis, we examined the therapeutic activity of a tumor-vascular disrupting agent (tumor-VDA), EPC2407 (Crolibulin(TM)), alone and in combination with ADT in a murine model of prostate cancer (Myc-CaP). A non-invasive multimodality imaging approach based on magnetic resonance imaging (MRI), bioluminescence imaging (BLI), and ultrasound (US) was utilized to characterize tumor response to therapy and to guide preclinical trial design. Imaging results were correlated with histopathologic (H&E) and immunohistochemical (CD31) assessment as well as tumor growth inhibition and survival analyses. Results: Our imaging techniques were able to capture an acute reduction (within 24 hours) in tumor perfusion following castration and VDA monotherapy. BLI revealed onset of recurrent disease 5-7 days post castration prior to visible tumor regrowth suggestive of vascular recovery. Administration of VDA beginning 1 week post castration for 3 weeks resulted in sustained vascular suppression, inhibition of tumor regrowth, and conferred a more pronounced survival benefit compared to either monotherapy. Conclusion: The high mortality rate associated with CRPC underscores the need for investigating novel treatment strategies for this patient population. The results of our preclinical studies demonstrated the therapeutic potential of vascular targeting in combination with ADT against prostate cancer as well as highlight the capability of imaging to guide study design. Further investigation into the utility of VDAs in combination with ADT in prostate cancer is warranted.

Characterization of Dysferlin Deficient SJL/J Mice to Assess Preclinical Drug Efficacy: Fasudil Exacerbates Muscle Disease Phenotype

PubMed Central

Rayavarapu, Sree; Van der meulen, Jack H.; Gordish-Dressman, Heather; Hoffman, Eric P.; Nagaraju, Kanneboyina; Knoblach, Susan M.

2010-01-01

The dysferlin deficient SJL/J mouse strain is commonly used to study dysferlin deficient myopathies. Therefore, we systematically evaluated behavior in relatively young (9–25 weeks) SJL/J mice and compared them to C57BL6 mice to determine which functional end points may be the most effective to use for preclinical studies in the SJL/J strain. SJL/J mice had reduced body weight, lower open field scores, higher creatine kinase levels, and less muscle force than did C57BL6 mice. Power calculations for expected effect sizes indicated that grip strength normalized to body weight and open field activity were the most sensitive indicators of functional status in SJL/J mice. Weight and open field scores of SJL/J mice deteriorated over the course of the study, indicating that progressive myopathy was ongoing even in relatively young (<6 months old) SJL/J mice. To further characterize SJL/J mice within the context of treatment, we assessed the effect of fasudil, a rho-kinase inhibitor, on disease phenotype. Fasudil was evaluated based on previous observations that Rho signaling may be overly activated as part of the inflammatory cascade in SJL/J mice. Fasudil treated SJL/J mice showed increased body weight, but decreased grip strength, horizontal activity, and soleus muscle force, compared to untreated SJL/J controls. Fasudil either improved or had no effect on these outcomes in C57BL6 mice. Fasudil also reduced the number of infiltrating macrophages/monocytes in SJL/J muscle tissue, but had no effect on muscle fiber degeneration/regeneration. These studies provide a basis for standardization of preclinical drug testing trials in the dysferlin deficient SJL/J mice, and identify measures of functional status that are potentially translatable to clinical trial outcomes. In addition, the data provide pharmacological evidence suggesting that activation of rho-kinase, at least in part, may represent a beneficial compensatory response in dysferlin deficient myopathies. PMID:20886045

A translational approach to evaluate the efficacy and safety of the novel AMPA receptor positive allosteric modulator org 26576 in adult attention-deficit/hyperactivity disorder.

PubMed

Adler, Lenard A; Kroon, René A; Stein, Mark; Shahid, Mohammed; Tarazi, Frank I; Szegedi, Armin; Schipper, Jacques; Cazorla, Pilar

2012-12-01

It has been posited that glutamate dysregulation contributes to the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). Modulation of glutamate neurotransmission may provide alternative therapeutic options. The novel 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor positive allosteric modulator Org 26576 was investigated with a translational approach including preclinical and clinical testing. Neonatal rat 6-hydroxydopamine lesion-induced hyperactivity was used as preclinical model. Seventy-eight ADHD adults entered a multicenter, double-blind, placebo-controlled, two-period crossover trial. After 1 week placebo lead-in, 67 subjects were randomized into one of four treatment sequences: sequence A (n = 15) Org 26576 (100 mg b.i.d.) for 3 weeks, followed by a 2-week placebo crossover and 3 weeks placebo; sequence B (n = 16) 5 weeks placebo followed by 3 weeks Org 26576 (100 mg b.i.d.); sequence C (n = 18) Org 26576 flexible dose (100-300 mg b.i.d.) for 3 weeks, then 5 weeks placebo; sequence D (n = 18) 5 weeks placebo followed by 3 weeks Org 26576 (100-300 mg b.i.d.). The Adult ADHD Investigator Symptom Rating Scale was used to assess changes in ADHD symptomatology. Org 26576 (1, 3, 10 mg/kg intraperitoneal) produced dose-dependent inhibition of locomotor hyperactivity in 6-hydroxydopamine-lesioned rats. Org 26576 (100 mg b.i.d.) was superior to placebo in treating symptoms of adult ADHD subjects. The primary Adult ADHD Investigator Symptom Rating Scale results were supported by some secondary analyses. However, Org 26576 (100-300 mg b.i.d.) did not confirm these results. Most frequently reported adverse events were nausea, dizziness, and headache. These preclinical and clinical findings suggest that Org 25676 may have utility in the treatment of ADHD. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Image-guided thoracic surgery in the hybrid operation room.

PubMed

Ujiie, Hideki; Effat, Andrew; Yasufuku, Kazuhiro

2017-01-01

There has been an increase in the use of image-guided technology to facilitate minimally invasive therapy. The next generation of minimally invasive therapy is focused on advancement and translation of novel image-guided technologies in therapeutic interventions, including surgery, interventional pulmonology, radiation therapy, and interventional laser therapy. To establish the efficacy of different minimally invasive therapies, we have developed a hybrid operating room, known as the guided therapeutics operating room (GTx OR) at the Toronto General Hospital. The GTx OR is equipped with multi-modality image-guidance systems, which features a dual source-dual energy computed tomography (CT) scanner, a robotic cone-beam CT (CBCT)/fluoroscopy, high-performance endobronchial ultrasound system, endoscopic surgery system, near-infrared (NIR) fluorescence imaging system, and navigation tracking systems. The novel multimodality image-guidance systems allow physicians to quickly, and accurately image patients while they are on the operating table. This yield improved outcomes since physicians are able to use image guidance during their procedures, and carry out innovative multi-modality therapeutics. Multiple preclinical translational studies pertaining to innovative minimally invasive technology is being developed in our guided therapeutics laboratory (GTx Lab). The GTx Lab is equipped with similar technology, and multimodality image-guidance systems as the GTx OR, and acts as an appropriate platform for translation of research into human clinical trials. Through the GTx Lab, we are able to perform basic research, such as the development of image-guided technologies, preclinical model testing, as well as preclinical imaging, and then translate that research into the GTx OR. This OR allows for the utilization of new technologies in cancer therapy, including molecular imaging, and other innovative imaging modalities, and therefore enables a better quality of life for patients, both during and after the procedure. In this article, we describe capabilities of the GTx systems, and discuss the first-in-human technologies used, and evaluated in GTx OR.

Utilization of diagnostic ultrasound and intravenous lipid-encapsulated perfluorocarbons in non-invasive targeted cardiovascular therapeutics.

PubMed

Porter, Thomas R; Choudhury, Songita A; Xie, Feng

2016-01-01

Diagnostic ultrasound (DUS) pressures have the ability to induce inertial cavitation (IC) of systemically administered microbubbles; this bioeffect has many diagnostic and therapeutic implications in cardiovascular care. Diagnostically, commercially available lipid-encapsulated perfluorocarbons (LEP) can be utilized to improve endocardial and vascular border delineation as well as assess myocardial perfusion. Therapeutically, the liquid jets induced by IC can alter endothelial function and dissolve thrombi within the immediate vicinity of the cavitating microbubbles. The cavitating LEP can also result in the localized release of any bound therapeutic substance at the site of insonation. DUS-induced IC has been tested in pre-clinical studies to determine what effect it has on acute vascular and microvascular thrombosis as well as nitric oxide (NO) release. These pre-clinical studies have consistently shown that DUS-induced IC of LEP is effective in restoring coronary vascular and microvascular flow in acute ST segment elevation myocardial infarction (STEMI), with microvascular flow improving even if upstream large vessel flow has not been achieved. The initial clinical trials examining the efficacy of short pulse duration DUS high mechanical index impulses in patients with STEMI are underway, and preliminary studies have suggested that earlier epicardial vessel recanalization can be achieved prior to arriving in the cardiac catheterization laboratory. DUS high mechanical index impulses have also been effective in pre-clinical studies for targeting DNA delivery that has restored islet cell function in type I diabetes and restored vascular flow in the extremities downstream from a peripheral vascular occlusion. Improvements in this technique will come from three dimensional arrays for therapeutic applications, more automated delivery techniques that can be applied in the field, and use of submicron-sized acoustically activated LEP droplets that may better permeate the clot prior to DUS activation and cavitation. This article will focus on these newer developments for DUS therapeutic applications.

Preclinical Alzheimer's disease and longitudinal driving decline.

PubMed

Roe, Catherine M; Babulal, Ganesh M; Head, Denise M; Stout, Sarah H; Vernon, Elizabeth K; Ghoshal, Nupur; Garland, Brad; Barco, Peggy P; Williams, Monique M; Johnson, Ann; Fierberg, Rebecca; Fague, M Scot; Xiong, Chengjie; Mormino, Elizabeth; Grant, Elizabeth A; Holtzman, David M; Benzinger, Tammie L S; Fagan, Anne M; Ott, Brian R; Carr, David B; Morris, John C

2017-01-01

Links between preclinical AD and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs. 104 OAs (65+ years) with normal cognition took part in biomarker measurements, a road test, clinical and psychometric batteries and self-reported their driving habits. Higher values of CSF tau/Aβ 42 and ptau 181 /Aβ 42 ratios, but not uptake on PIB amyloid imaging (p=.12), predicted time to a rating of Marginal or Fail on the driving test using Cox proportional hazards models. Hazards ratios (95% confidence interval) were 5.75 (1.70-19.53), p=.005 for CSF tau/Aβ 42 ; 6.19 (1.75-21.88) and p=.005 for CSF ptau 181 /Aβ 42 . Preclinical AD predicted time to receiving a Marginal or Fail rating on an on-road driving test. Driving performance shows promise as a functional outcome in AD prevention trials.

The Use of Minipigs for Preclinical Safety Assessment by the Pharmaceutical Industry: Results of an IQ DruSafe Minipig Survey.

PubMed

Colleton, Curtis; Brewster, David; Chester, Anne; Clarke, David O; Heining, Peter; Olaharski, Andrew; Graziano, Michael

2016-04-01

The use of minipigs in preclinical safety testing of pharmaceuticals is considered an alternative to the more traditional dog and nonhuman primate (NHP) nonrodent species. Substantial evidence exists to suggest that the anatomy, physiology, and biochemistry of minipigs are similar enough to humans to consider them as valid nonrodent models for pharmaceutical safety testing. Since the utilization of minipigs was last assessed over 5 years ago, the Preclinical Safety Leadership Group (DruSafe) of the International Consortium for Innovation and Quality in Pharmaceutical Development conducted this survey to provide an updated assessment of the utility, perceived value, and impediments to the use of minipigs in preclinical safety testing. Of the 32 participating members of DruSafe, 15 responded to the survey representing both large and small companies. Respondents indicated that the minipig has been utilized mostly for short-term safety assessment studies with dermal, oral, and parenteral routes of administration. Minipigs are widely accepted as appropriate models for cardiovascular assessments and have been used to a limited extent for reproductive toxicology testing. Overall responses indicated that safety testing for large molecules using this species is relatively low due to a lack of background data, reagents or biomarkers, concerns regarding immune system characterization and poor suitability for developmental toxicity assessments. Most companies utilized contract research organizations for definitive safety toxicity assessment studies. Conclusions of this survey indicate that minipig is an acceptable nonrodent species largely limited to studies using small molecules, primarily dermal products, and results are comparable to those reported 5 years ago. © The Author(s) 2016.

Spatial reversal learning in preclinical scrapie-inoculated mice.

PubMed

Lysons, A M; Woollard, S J

1996-04-10

Acquisition and reversal of a two-choice spatial discrimination were tested in scrapie-inoculated mice. Both acquisition and reversal were normal in mice tested 138 and 103 days prior to the onset of clinical symptoms. At 65 days before onset of clinical symptoms, scrapie-inoculated mice required more trails to criterion in reversal learning, but this effect was not significant in a second experiment (68 days preclinical) and was transient: no effect was seen 33 days before symptoms. However, the course of reversal learning was abnormal in all three late preclinical groups (68, 65 and 33 days before symptoms). Reversal learning in these three groups was characterized by a rapid extinction of the original discrimination, followed by a period, absent in controls, during which performance showed no further improvement. This effect corresponds in time of onset to the appearance of characteristic neuropathological features.