Preclinical testing

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Gene transfer vectors targeted to human prostate cancer : do we need better preclinical testing systems?

Gene transfer vectors targeted to human prostate cancer : do we need better preclinical testing systems?

(www.giant.eu.com) to assess the validity of the preclinical testing procedures for near-to-patient testing. As mentioned previously, cell culture models of prostate epithelium often lack the luminal differentiation present in tumors, unless derived from a later stage metastatic tumor. As illustrated in Fig. 1A, a normal human prostate acinus consists of an upper luminal layer (60% of epithelial cells), in close contact with a basal cell layer (40% of epithelial cells). These proportions are grossly disrupted in higher Gleason grade prostate cancers. Most untreated hormone-naive prostate cancers have a lu- minal phenotype (express androgen receptor and luminal cytokeratin-18) and lack or contain < 1% basal cells (no p63=cytokeratin-5=14 expression). The LNCaP cell line (Horoszewicz et al., 1980) is frequently used to study hor- mone-sensitive (luminal) cancer, but LNCaP was isolated from a patient who had failed a primitive form of anti- hormone therapy (estramustine chemotherapy) and the cells express a mutant androgen receptor, which responds equally well to other steroid hormones (Veldscholte et al., 1990).
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In vitro primary cell culture as a physiologically relevant method for preclinical testing of human oncolytic adenovirus

In vitro primary cell culture as a physiologically relevant method for preclinical testing of human oncolytic adenovirus

As an alternative preclinical approach to animal testing, we have used human nonprostate primary cells in in vitro cell culture to test whether Ad[I/PPT-E1A] replication is limited only to the prostate target cells by assessing the specificity and sensitivity of Ad[I/PPT-E1A] replication and cytolytic killing in vitro. The primary cell types were chosen for study, because the parental organs are either close to the site of adenoviral administration or should be exposed to the highest percentage of cardiac output (blood flow) and would likely have in- creased contact with any circulating Ad[I/PPT-E1A] virus in vivo in the phase I GIANT human clinical trial. They in- cluded human vascular endothelial cells, bronchial epithelial cells, urothelial cells, and hepatocytes. In all cases, no repli- cation of the retargeted Ad[I/PPT-E1A] virus was seen, de- spite retention of the ability to attach to and penetrate the various cell types. We conclude that in vitro preclinical testing procedures using a relevant panel of human primary cells is a feasible approach for the preclinical analysis of the efficacy and specificity of oncolytic adenoviruses, and in this respect will have significant additional value next to animal models.
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Hip contact forces in asymptomatic total hip replacement patients differ from normal healthy individuals: Implications for preclinical testing

Hip contact forces in asymptomatic total hip replacement patients differ from normal healthy individuals: Implications for preclinical testing

Li, J, Redmond, AC, Jin, Z et al. (3 more authors) (2014) Hip contact forces in asymptomatic total hip replacement patients differ from normal healthy individuals: Implications for preclinical testing. Clinical Biomechanics, 29 (7). 747 - 751. ISSN 0268-0033

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Characteristics of a primate model of focal motor cortical seizures suitable for preclinical testing of therapies like DBS

Characteristics of a primate model of focal motor cortical seizures suitable for preclinical testing of therapies like DBS

Models of focal neocortical epilepsy secondary to topically applied penicillin have previously been de- scribed in large animals like cats [10], rabit [27], sheep [28] and monkey [29]. But there is a paucity of studies aimed at characterizing and quantifying semi-acute focal motor status epilepticus in primates. The development of such a model in primate is important because seizure progression might differ from species to species [30]. Critically, a primate model might be the most suited for preclinical testing of innovative therapies such as deep brain stimulation, local drug delivery, cooling of the epi- lepogenic zone or gene therapy, This was an important motivation in initiating this work. In fact subsequent to development of this model we have been successful in using it for testing Deep Brain Stimulation of basal gan- glia in focal motor seizures We could maintain the mod- eled primates for several months and perform number of
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VARIOUS ANIMAL MODELS FOR PRECLINICAL TESTING OF ANTI INFLAMMATORY AGENTS

VARIOUS ANIMAL MODELS FOR PRECLINICAL TESTING OF ANTI INFLAMMATORY AGENTS

vascular permeability, UV-erythema in guinea pigs, Croton-oil ear edema in rats and mice, Paw edema in rats, Collagen Induced Arthritis, Adjuvant Induced Arthritis, and Papaya Latex Indu[r]

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Preclinical Testing of a Novel Thin Film Nitinol Flow Diversion Stent in a Rabbit Elastase Aneurysm Model

Preclinical Testing of a Novel Thin Film Nitinol Flow Diversion Stent in a Rabbit Elastase Aneurysm Model

Disclosures: Yonghong Ding—RELATED: Grant: This work was partially supported by a National Institutes of Health Small Business Technology Transfer (STTR) grant (1R41NS074576). David F. Kallmes—RELATED: Grant: NeuroSigma,* Comments: Na- tional Institutes of Health Small Business Innovation Research (SBIR) grant subcon- tract; UNRELATED: Board Membership: GE Healthcare (cost-effectiveness board); Consultancy: ev3/Covidien/Medtronic, Comments: planning and implementing clinical trials; Grants/Grants Pending: MicroVention,* Sequent,* SurModics,* Cod- man,* ev3/Covidien/Medtronic,* Comments: preclinical and clinical research; Roy- alties: University of Virginia Patent Foundation (Spine Fusion); Travel/Accommoda- tions/Meeting Expenses Unrelated to Activities Listed: ev3/Covidien/Medtronic,* Comments: travel to the FDA panel meeting. Colin P. Kealey—RELATED: The work was partially funded by a STTR grant from the National Institutes of Health (1R41NS074576)*; UNRELATED: Employment: NeuroSigma (full-time employee); Pat- ents (planned, pending or issued): I am a coinventor on patents related to this technology that are owned and/or licensed by NeuroSigma*; Stock/Stock Options: I have stock options in NeuroSigma. Vikas Gupta—RELATED: Grant: National Insti- tutes of Health *; Consulting Fee or Honorarium: NeuroSigma, Comments: Work during May 2014 to March 2015 was performed as an independent consultant. Since April 2015, the work has been performed as full-time employee; Support for Travel to Meetings for the Study or Other Purposes: NeuroSigma; UNRELATED: Consul- tancy: NeuroSigma; Employment: NeuroSigma; Stock/Stock Options: NeuroSigma; Travel/Accommodations/Meeting Expenses Unrelated to Activities Listed: Neuro- Sigma. Alfred David Johnson—RELATED: Grant: National Institutes of Health (1R41NS074576)*; Support for Travel to Meetings for the Study or Other Purposes: Travel expenses were paid for experiments at the Mayo Clinic by NeuroSigma; UNRELATED: Other: salary from TiNi Alloy Company for work unrelated to the submitted work. Ramanathan Kadirvel—RELATED: Grant: National Institutes of Health (NS076491).* *Money paid to the institution.
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Canine cancer immunotherapy studies: linking mouse and human

Canine cancer immunotherapy studies: linking mouse and human

Despite recent major clinical breakthroughs in human cancer immunotherapy including the use of checkpoint inhibitors and engineered T cells, important challenges remain, including determining the sub-populations of patients who will respond and who will experience at times significant toxicities. Although advances in cancer immunotherapy depend on preclinical testing, the majority of in-vivo testing currently relies on genetically identical inbred mouse models which, while offering critical insights regarding efficacy and mechanism of action, also vastly underrepresent the heterogeneity and complex interplay of human immune cells and cancers. Additionally, laboratory mice uncommonly develop spontaneous tumors, are housed under specific-pathogen free conditions which markedly impacts immune development, and incompletely model key aspects of the tumor/immune microenvironment. The canine model represents a powerful tool in cancer immunotherapy research as an important link between murine models and human clinical studies. Dogs represent an attractive outbred combination of companion animals that experience spontaneous cancer development in the setting of an intact immune system. This allows for study of complex immune interactions during the course of treatment while also directly addressing long-term efficacy and toxicity of cancer immunotherapies. However, immune dissection requires access to robust and validated immune assays and reagents as well as appropriate numbers for statistical evaluation. Canine studies will need further optimization of these important mechanistic tools for this model to fulfill its promise as a model for immunotherapy. This review aims to discuss the canine model in the context of existing preclinical cancer immunotherapy models to evaluate both its advantages and limitations, as well as highlighting its growth as a powerful tool in the burgeoning field of both human and veterinary immunotherapy.
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Systems biology approaches for advancing the discovery of effective drug combinations

Systems biology approaches for advancing the discovery of effective drug combinations

Figure 3 Future strategy for drug combination predictions with parallel integration of computational modeling, preclinical testing, and clinical trials. A) Future combinatorial drug disc[r]

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Developing preclinical models of neuroblastoma: driving therapeutic testing

Developing preclinical models of neuroblastoma: driving therapeutic testing

the long development time (an average of 65 days), mak- ing it difficult for rapid, high-throughput testing [52, 53]. To address some of the limitations of the TH-MYCN model, a mouse with Cre inducible MYCN expression (LSL-MYCN;Dbh-iCre) was created [53]. This model has a better-defined transgene insertion site allowing tumors to develop at multiple locations in the neural crest, such as the adrenals, the celiac ganglia, and the superior cer- vical ganglia. Additionally, this model allows for tumor development in multiple mouse strain backgrounds, which is important when combining the TH-MYCN mouse with other cancer relevant alleles [53]. LSL- MYCN;Dbh-iCre mice recapitulates NB histology and molecular expression patterns [53]. These mice are ad- vantageous compared to TH-MYCN mice as the trans- gene insertion is localized to the commonly used ROSA26 locus, which, when discontinued, causes no phenotypic change in mice. Alternatively, the TH- MYCN mouse primarily inserts into the distal region of chromosome 18, the effects of which have not fully been characterized. While the insertion site has been changed, MYCN expression increased to comparable levels as the TH-MYCN model. Cell lines derived from the LSL-MYCN;Dbh-iCre mouse also respond to the MYCN targeting drugs MLN8327 and JQ1 [53]. This model presents a more defined MYCN-amplified tumor model for preclinical testing, and could prove useful for future testing of therapies aimed at treating high risk MYCN-amplified NB.
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Regulation of immunotherapeutic products for cancer and FDA’s role in product development and clinical evaluation

Regulation of immunotherapeutic products for cancer and FDA’s role in product development and clinical evaluation

An adjuvant is an agent that augments or directs the specific immune response to an antigen (in this case, the immunotherapeutic product). It is often co-mixed or co- administered with the antigen to induce a more robust immune response. Adjuvants act through diverse mecha- nisms, such as creating an antigen repository effect, interacting with specific innate immune pathways, and serving as ligands for different pattern recognition recep- tors. There are many different forms of adjuvants, includ- ing traditional aluminum salts (e.g., aluminum hydroxide, aluminum phosphate), lipopolysaccharides and their deriv- atives, cytokines, CpG oligodeoxynucleotide, and others. The adjuvant used determines, to some degree, the general type of immune response that will be generated by the immunotherapeutic product. Therefore, data to sup- port the rationale for the adjuvant selected is important. Potential toxicities may be caused by the administration of the adjuvant alone (e.g., induction of hypersensitivity and autoimmunity; induction of proinflammatory effects), or by possible additive or synergistic effects when given in combination with the immunotherapeutic product. There- fore, preclinical testing should include the assessment of the safety and activity of the immunotherapeutic product alone, the adjuvant alone, and the immunotherapeutic product in combination with the adjuvant, administered according to the planned clinical immunization regimen and route of administration. For general principles regard- ing preclinical considerations for adjuvants in therapeutic vaccines, refer to the European Medicines Agency document ‘Guideline on Adjuvants in Vaccines for Human Use; January 2005 [38] .
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Randomized, placebo-controlled trial evaluating the safety of one-year administration of green tea catechins

Randomized, placebo-controlled trial evaluating the safety of one-year administration of green tea catechins

In preclinical chronic toxicity studies performed in dogs administered during a fasting state have revealed some distinctive limiting toxicities, including gastrointestinal, hepatic and renal toxicities [21]. The GTC mixture used in these studies were formulated primarily with EGCG [≥55%] in addition to 10% each of epigallocatechin, epicatechin, and epigallocatechin gallate [21]. Using the same dose levels, when these studies were conducted in non-fasted dogs, toxicities were unremarkable, suggesting that the fasting condition may have contributed to the increased vulnerability of the target organs to toxicity with GTC. In a preclinical study [17] targeting TRAMP mice with several doses of a standardized GTC-PolyE, we failed to observe liver or other toxicities. Similarly, in animal studies with EGCG, Isbrucker et al. [37] did not observe toxicities, including liver toxicities. In the past few years, several case reports of liver toxicity including liver failure have been reported with oral green tea extracts when used for weight loss or for other indications [20–25]. The dose of GTC used in these case reports ranged from 375 mgs [22–24] for 4 months to 1.8 grams GTC per day [25], predominantly used as weight loss supplements along with other ingredients. However, the liver toxicities reported have included non-standardized formulations with varying doses, compositions and duration of use of GTC. Additionally, the intake was predominantly self- reported cases with poor documentation of other potential contaminants as well as concomitant medications that may have been consumed with the green tea. The results of our
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Prostate cancer and the unfolded protein response

Prostate cancer and the unfolded protein response

UPR activation as a cytoprotective response is supported by the fact that XBP1 overexpression in cancer cells directly promotes tumorigenesis, such as in chronic lymphocytic leukemia [49]. In multiple myeloma (MM), targeting the activated IRE1α and subsequent XBP1 splicing by a number of compounds has been tested with promising results in preclinical models. Furthermore, there were synergistic effects in combination with bortezomib, the FDA approved proteasome inhibitor for MM [50]. Another study demonstrated that XBP1s loss may confer MM cells resistance to bortezomib [51]. XBP1 interacts with hypoxia-inducible factor 1-alpha (HIF1α) in triple negative breast cancer and drives tumor progression by inducing hypoxia signature gene expression [52]. Interestingly, a recent study also showed that XBP1 can blunt the antitumor activity by interfering with the function of tumor-associated dendritic cells [53]. The XBP1s and ATF6α target, P58IPK, has been linked to survival of malignant cells facing ER stress, mediating an adaptive response to chronic UPR signaling [54].
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Medicinal properties of some Indian spices Rakesh Kumar Singh*, Kanti Bhooshan Pandey** and Syed Ibrahim Rizvi**

Medicinal properties of some Indian spices Rakesh Kumar Singh*, Kanti Bhooshan Pandey** and Syed Ibrahim Rizvi**

Cumin, in India popularly called as Jeera is the dried fruit of small herbaceous plants belongs to the Apiaceae family.. It was popular even during the Biblical times as an efficient dig[r]

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A proposal for a new PhD level curriculum on quantitative methods for drug development

A proposal for a new PhD level curriculum on quantitative methods for drug development

Statistical Methods for Research and Preclinical Development Relevance: Understanding of challenges and statistical solutions in the area of research and preclinical development Duration[r]

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Original Article Toxicity testing of epidermal growth factor receptor-targeted hybrid peptide for preclinical study

Original Article Toxicity testing of epidermal growth factor receptor-targeted hybrid peptide for preclinical study

Abstract: Background: We previously reported that EGFR2R-lytic hybrid peptide was generated from the chemical conjugation of an epidermal growth factor receptor (EGFR)-targeted peptide and a cell-killing lytic peptide. This pep- tide had effective cytotoxic and anti-tumor activities in vitro and in vivo against EGFR-expressing cancers, suggesting it may be a novel candidate for a molecular-targeted anti-cancer drug. Methods: In this preclinical study, the toxicity of this hybrid peptide was examined in mice by monitoring body weight, performing clinical and biochemical exami- nations of blood samples, and observing histological changes. Results: No remarkable toxicity after intravenous injection of the hybrid peptide was observed up to a dose of 15 mg/kg, although a decrease in the alveolar space of the lung was identified from histological observations. Toxicity of the EGFR2R-lytic hybrid peptide in mice was also tested after oral administration. A significant change in body weight was not observed until a single dose of 300 mg/kg, but a decrease in body weight was observed at repeated doses of 75 or 150 mg/kg. However, the tendency for body weight increase was similar between the saline (control) and hybrid peptide groups after the completion of the administration period. In the case of oral administration, the dosage of the hybrid peptide could be increased to a significantly higher range compared with intravenous administration without serious toxicity. Conclusion: The results of this study should facilitate further preclinical studies on the EGFR2R-lytic hybrid peptide and its applica- tion in future cancer therapies.
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Effect of natural polymer on conventional and sustained release properties of indomethacin tablets K. Vijaya Sri, D. Srinivas, Ch. Ajay Kumar and D. Ravishanker

Effect of natural polymer on conventional and sustained release properties of indomethacin tablets K. Vijaya Sri, D. Srinivas, Ch. Ajay Kumar and D. Ravishanker

Key words: Vigna mungo , phyto-physicochemical, indomethacin, conventional /sustained release matrix tablets, evaluation, anti-inflammatory activity and stability.. Author for correspon[r]

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Screening of dietary nucleotides from natural sources for therapeutic uses S. D. Sonkawade and G. R. Naik

Screening of dietary nucleotides from natural sources for therapeutic uses S. D. Sonkawade and G. R. Naik

Key words: Dietary nucleotides, mitochondrial dysfunction, natural sources, nucleomax, sugarcane and uridine rich compounds.. Author for correspondence: Dr.[r]

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Chemical marker compounds and their essential role in quality control of herbal medicines N.M.A. Rasheed, K. Nagaiah, P.R. Goud and V.U.M. Sharma

Chemical marker compounds and their essential role in quality control of herbal medicines N.M.A. Rasheed, K. Nagaiah, P.R. Goud and V.U.M. Sharma

of study and information on matching placebo, if applicable; availability of retention samples for future testing, if desired. Standardization of herbal drugs for Global competitiveness such as raw materials needs to be authentic, physico-chemical standards, storage conditions, size and shape. Processing of raw material include material, energy inputs, operational uniformity, safety and occupational health, intermediate quality whereas finished product include physicochemical properties, biological assay, storage stability, user safety etc.

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Return on Investment and Effort Expenditure in the Software Development Environment

Return on Investment and Effort Expenditure in the Software Development Environment

Figure 3 shows how security testing can be distributed among in-house and outsource and manual versus automated axes. Penetration testing is generally preferred done in-house and manually, but vulnerability scanning; including perimeter scanning can be automated and outsourced. Co-sourcing can be applied to either case because, unlike pure outsourcing, internal resources are available.

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Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine

Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine

A retrospective epidemiologic analysis showed that a detergent-extracted menin- gococcal outer membrane vesicle (dOMV) vaccine called MeNZB designed and imple- mented in a widespread vaccination program to control an epidemic of group B meningococcal disease in New Zealand, showed diminished coverage in populations subsequently infected with N. gonorrhoeae— calculated as 31% effectiveness of MenZB in decreasing gonococcal infection—reduced to 14% in populations coinfected with N. gonorrhoeae and chlamydia, a frequent clinical occurrence (37–39). Meningococci and gonococci share several similarities, and it is possible that one or more proteins in MeNZB that cross-react with N. gonorrhoeae may elicit protective immune responses. Individuals administered a licensed group B meningococcal vaccine, Bexsero, which contains 5 recombinant meningococcal protein antigens in addition to the same dOMV that constitutes MeNZB (40), elicit antibodies, immunochemically, that cross-react with N. gonorrhoeae (41). Antibodies elicited by immunizing mice with Bexsero or MeNZB were reported to support bactericidal activity against N. gonorrhoeae (42). However, a separate study did not reveal bactericidal antibody activity against N. gonorrhoeae FA1090 in immune sera from individuals vaccinated with Bexsero (20). How MeNZB provides protection against gonorrhea remains unclear; possible additional mecha- nisms may include reduction of adhesion of N. gonorrhoeae to human cervical cells (42). Currently, several gonococcal vaccine candidates are undergoing preclinical evaluation (reviewed in reference 5), some of which elicit bactericidal activity (43–45).
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